1

PHCL 412/512: introduction to

pharmacology -Midterm Study Guide



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Lecture I
Introduction and History of Pharmacology
Lecturer: Dr. Qin Chen, Ph. D.

List of Terms:
Term Definition
Pharmacology Science of drugs, from the Greek: Pharmakos = medicine or drug and
Logos = Study
Pharmacy Uses of Drugs
Pharmaceutics The process of turning a new chemical entity into a medication.
Pharmaceutical
Drug
Chemical substance for medical diagnosis, treatment, or prevention of
disease.
Pharmacopoeia A book containing directions for identification of samples and
preparation of compound medicines, published by the authority. =
Textbook or Computer Database
Pharmacognosy Study of drugs from natural sources.

A Brief History of Pharmacology:
Pharmacology has studied and developed all over the
word, particularly in China, the Islamic World, Egypt, and
Greece, and utilized various natural sources, such as
animal parts, plants, minerals. More recently, more
synthetic compounds have be used in pharmacology.

Shen Nong (or Divine Farmer) was one of the first predecessors of
pharmacology, originating in 2000 B.C. He mainly specialized in Chinese
herbal medicine, and wrote the Herb-Root Classic (Bencoao Jing,
compilated by 300 B.C. 200 A.D.). He discovered the effects of certain
herbs by testing them on himself. However, according to
legend, he also passed away pursuing such research.

Thoth was considered the Egyptian goddess of knowledge,
and the Medical Book of Thoth (1550-1292 B.C.E.), the
religious scroll, contain cures for diseases from plant and
animal mixtures. The Ebers Papyrus (dating from 1552
B.C.E.) contained 700 drugs, such as beer, turpentine,
beries, poppy, lead, salt, minerals). This is the worlds oldest
preserved medical and pharmacological record. It had 700
recipes for treatment of different medical conditions.

Hippocrates (460-377 B.C.) was an Ancient Greek Physician
from the Greek Island of Kos. He is considered the Father of
Western Medicine, and separated medicine from religion and
superstition. He discovered the pharmacological properties
of the bark and leaves of the willow tree. The legend is that if an individual
had a fever or was in pain, they could chew or consume the bark and leaves
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of the willow tree and such illness would subside. He attributed illness and
sickness to an imbalance of certain entities in your body known as humors.

Diocles of Carystus was another Greek physician who was considered a
Younger Hippocrates. He studied a wide range of medicine, particularly
anatomy, and wrote on pharmacotherapeutic treatises in 400 B.C.E. He
emphasized also the use of diet, nutrition, and medicinal uses of plants.

Pedanius Dioscorides (40-90 A.D.) was a third Greek
physician who wrote the De Materia Medica, which was a
5-volume book containing Medical materials, and is still
widely used for more than 1500 years.

Aulus Cornelius Celsus was a Roman encyclopedist who
wrote De Medicine, which was a compendium of eight
books, in which books 5 and 6 consisted of pharmacology,
which later contributed to diet and pharmacy.

Galen (129-200 A.D.) was a Roman physician, surgeon,
and philosopher who promoted Hippocratic teaching. He
wrote 600 treatises totaling 10 million words. He
researched on anatomy, physiology, pathology,
pharmacology, and neurology based on dissections of
monkeys and pigs. He discovered that the larynx is the main generator of
voice. He also discussed the use of stimulants (agonists) and inhibitors
(antagonists) in the circulatory system, nervous system, and respiratory
system.

The Islamic Golden Age (750-1257) was a series of efforts in the Islamic
World to discuss pharmacology. Al-Kindi (801-873) was an Arab
physician who wrote De Gradibus, a book on the mathematical calculations
quantifying drug strength. Muhammad Ibn Zakariya Razi (865-915)
promoted medical uses of chemical compounds. Sabur bin Sahl was an
Arabic physician who developed the first pharmacopoedia as well as
formulas preparation (869 A.D.) in the form of powsders, tablets,
ointments, and syrups. Abu al-Qasim Al-Zahrawi (936-1013) was involved
in liber servitoris as well as preparation of medicine by sublimation and
distillation. Al-Biruni wrote the Kitab al-Saydalah (The Book of Drugs,
973-1050) which described the properties of drugs as well as the role of
the pharmacy and pharmacist. Ibn Sinna (Avicenna) wrote the Canon of
Medicine (the Law of Medicine, 1025) which described over 700
preparations, their properties, mode of action, as well as their indication.
Al-Muwaffaq developed the foundations of the true properties of remedies,
such as arsenious oxide, silicic acid, sodium carbonate vs. potassium
carbonate, and discussed the poisonous nature of copper and lead
compounds and the distillation of seawater for drinking.

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Phillippus Aureolus Theophrastus Bombastus von
Hohenheim (1493-1541) took on the name Paracelsus
(equal or greater than Celsus) and was a German-
Swiss Renaissance physician, botanist, alchemist, and
astrologer. He was involved in the use of chemical and
minerals (zinc) in medicine. He is deemed by some as
the father of toxicology, with his statement, All things
are poison, and nothing is without poison; only the
dose permits something not to be poisonous.

William Withering (1741-1799) was an English botanist,
geologist, chemist, and physician. He was able to utilize an
extract of the foxglove plant to treat dropsy (congestive heart
failure), which allowed him to discover digitalis.

Meriwether Lewis and William Clark led the Lewis and Clark
Expedition based with the Corps of Discovery (1804-1806) which was
commissioned by President Thomas Jefferson. They studied plants,
animal life, and geography in the Ohio Valley, and further supported the
use of willow bark tea to treat fever and pains.

Friedrich Serturner (1783-1841) was a German who
isolated alkaloid from opium. He later overdosed himself
and three friends from this alkaloid. This alkaloid was
named Morphine, after the Greek god of dreams,
Morpheus. He overdosed himself and his three friends on
this same substance.

Modern pharmacology arose from Friedrich Wohler (1800-
1882), a German chemist who synthesized organic
compounds, such as urea. He was also the co-discoverer of
beryllium, silicon, aluminum, and isolated yttrium,
beryllium, and titanium.

Rudolph Buchheim (1820-1879) was a German pharmacologist who
engaged in experimental science and modern pharmacology (since 1847).
He was a professor at the University of Dorpat in Estonia,
and established the first pharmacological institute. He
developed his first pharmacology laboratory in the
basement of his home, and developed the bioassay. He
was also professor of pharmacology and toxicology at the
University of Giessen.

Oswald Schmiedeberg (1838-1921) was a medical doctor
from the University of Dorpat, an 1866 recipient. He was
the Professor of Pharmacology at the University of
Strasbourg (since 1872) and developed the Outline of Pharmacology in
1878. He discovered the use of glucuronic acid as a conjugate in xenobiotic
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metabolism, an its relation in cartilage, collagen, and amyloid. He also
discovered the muscarine effect on the heart, and is considered the
founder of modern pharmacology. He trained most of the men who
became professors at German universities and elsewhere.

John Jacob Abel (1857-1938) received his M.D. in 1888 at the University
of Strsbourg. He was the First chain in pharmacology at
the University of Michigan (1891) and chaired the
pharmacology department at Johns Hopkins University
from 1893). He studied the isolation of epinephrine from
adrenal gland extracts (1897-1898), as well as isolated
amino acids from the blood (1914) and isolated histamine
from pituitary extract (1919). He was able to prepare
pure crystalline insulin (1926) and co-founded the
Journal of Biological Chemistry in 1905 and the Journal
of Pharmacology and Experimental Therapeutics (1909).

Claude Bernard (1813-1878) was a French physiologist
who experimented in medicine. He discovered the
mechanism of curare (which was used as arrow poison) as
it acts at the neuromuscular junction to interrupt the
stimulation of muscle by nerve impulses (1842). He
discovered the uses of pancreatic secretions in the
digestion of fats (1848), and the secretions of glucose into the blood by the
liver (1848), and discovered that the liver was the major producer of
sugar (1855). He isolated glycogen (1857), and discovered the concept of
homeostasis.

Pharmacologists who have won the Nobel Prize (per ASPET)
Recipient Year Research
Paul Greengard 2000 Signal Transduction in Nervous System
Robert F. Furchgott, Ferid Murad 1998 Nitric Oxide
Alfred G. Gilman 1994 G-Protein
Edwin G. Krebs 1992 Protein phosphorylation as a regulatory mechanism
Sir James W. Black, Gertrude B.
Elion
1988 Chemotherapy
Earl W. Sutherland, Jr. 1971 Action of Hormones
Julius Axelrod 1970 Humoral transmitters in nerve terminals
Linus Carl Pauling 1954 Chemical bonds in structure of complex substances
Herbert Spencer Gasser 1944 Action potential of nerve fibers
Corneille J.F. Heymans 1938 Brain control of blood pressure and oxygen content
Sir Henry Hallett Dale 1936 Acetylcholine as neurotransmitter
Frederick Grant Banting 1923 Discovery of Insulin

Nobel Prizes Closely Related to Pharmacology
Recipient Year Research
Emil Adolf Von Behring 1901 Serum therapy against diphtheria
Frederick Grant Banting and John
James Rickard Macleod
1923 Discovery of Insulin
Sir Henry Hallett Dale and Otto
Loewi
1936 Acetylcholine as a neurotransmitter
Gerhard Domagk 1939 Sulfonamidochrysoidine (Prontosil) as antibiotics
Sir Alexander Fleming, Ernst Boris
Chain, Sir Howard Walter Florey
1945 Discovery of Penicillin
Edward Calvin Kendall, Tadeus
Reichstein, Philip Showalter Hench
1950 Adrenal Cortex Hormones
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Selman Abraham Waksman 1952 Discovery of streptomycin
Daniel Bovet 1957 Drugs block neurotransmitters, antihistamines
Konrad Bock, Feodor Lynen 1964 Cholesterol and fatty acid metabolism
Sir Bernard Katz, Ulf von Euler,
Julius Axelrod
1970 Synaptic neurotransmitters (catecholamines)
Earl W. Sutherland 1971 cAMP as second messengers for epinephrine
Roger Guillernin, Andrew V.
Schally, Rosalyn Yalow
1977 Peptide hormones (TRH, GnRH)
Sun K. Bergstrom, Bengt I,
Samuelsson, John R. Vane
1982 Discovery of prostaglandins
Michael S. Brown and Joseph L.
Goldstein
1985 Regulation of cholesterol metabolism
Stanley Cohen, Rita Levi-
Montalcini
1986 Discovery of growth factors
Sir James w. Black, Gertrude B.
Elion, George H. Hitchings
1988 Antimetabolites for chemotherapy
Edmond H. Fischer, Edwin G. Krebs 1992 Reversible protein phosphorylation
Alfred G. Gilman, Martin Rodbell 1994 G-proteins
Robert F. Furchgott, Louis J.
Ignarro, Ferid Murad
1998 Nitric Oxide
Arvid Carlsson, Paul Greengard,
Eric R. Kandel
2000 Signal transduction of nervous system

Major Pharmaceutical Companies
Rank Country Company
1 U.S.A. Pfizer
2 Switzerland Novartis
3 U.S.A. Merck and Company
4 Germany Bayer
5 United
Kingdom
GlaxoSmithKline
6 U.S.A. Johnson and Johnson
7 France Sanofi
8 Switzerland Hoffman-La Roche
9 United
Kingdom
AstraZeneca
10 U.S.A. Abbott Laboratories
11 U.S.A. Bristol-Myers Squib
12 U.S.A. Eli Lilly and Company
13 U.S.A. Amgen
14 Germany Boehringer Ingelheim
15 U.S.A. Schering-Plough
16 U.S.A. Baxter International
17 Japan Takedo Pharmaceutical Company
18 U.S.A. Genentech
19 U.S.A. Procter and Gamble

7
Lecture II
Pharmacodynamics and Pharmacokinetics
Lecturer: Dr. Patrick Ronaldson, Ph. D.

Pharmacokinetics is defined as how the body deals with drugs, from the
Greek word pharmakon (meaning drug) and the word kinetic (meaning
movement). It studies the quantitative analysis of the relationship
between the dose of a drug and the ensuing changes in drug concentration
in the blood and other tissues. There are many pharmacological and
chemical events involved when an individual takes a pill, including
absorption, metabolism, and clearance.

Pharmacokinetics, or how the drugs are
handled by the body, is organized into
four distinct phases, giving the acronym
ADME:
1. Absorption
2. Distribution
3. Metabolism
4. Elimination

The illustration provides an extremely
detailed overview of ADME. As the drug
is broken down, facilitating the
chemicals liberation from the tablet
form. It must then be absorbed into the
bloodstream, and possibly bound to
plasma proteins, namely albumin.

Drugs are not always administered orally. This complex system can
involve enteral methods of drug delivery (sublingual, oral, rectal),
parenteral (subcutaneous, intramuscular, intravenous, spinal, and
intraosseal), or even topical (skin and inhalation). Pharmacokinetics is an
attempt to explain with physiologically, anatomically, and chemically the
drug and its action. However, it is important to understand drug
movement across the membrane.

How does a drug move across these
cellular barriers? Drugs do need to be
absorbed and also need to cross a barrier.
There are really only four discussed forms
of movement across cellular barriers:
1. Paracellular Transport: Movement
of hydrophilic compounds across
with the assistance of channels.
2. Diffusion: Movement of compounds
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across the membrane with
3. Facilitated Diffusion: Use of membrane carriers to move
hydrophilic compounds.
4. Drug Transporters: Transmembrane proteins that utilize the
energy of ATP hydrolysis to carry biological processes.

However, there are many considerations in the part of the drug as well as
on the part of the tissue that can affect the drugs absorption. On the part
of the drug, absorption can be affected by the following:
1. Lipid Solubility: More hydrophobic compounds may move more
readily than more hydrophilic compounds. However, it is important
for the compound to not have 100% lipophilicity because it can
impede the passage of drugs.
2. Molecular Size and Weight: Large bulky drugs cannot cross well.
For example, proteins cannot cross the membrane of the gut for this
reason.
3. pKa-value: This value can help up determine the ratio of unionized
and ionized forms of the compound, and can affect the ability to
cross the gastrointestinal (GI) tract.

Absorption can be affected by membrane permeability by the following:
1. Membrane Permeability: The lipid composition plays a role.
2. pH: pH of the tissue can affect the absorption rate.
3. Local Blood Flow: Well-perfused organs can allow higher rates of
drug absorption in comparison to poorly-
perfused organs.
4. Local Anatomy: The small intestine tends to
provide a better absorptive environment in
comparison to the stomach because of the
intestinal villi.
5. Transport Mechanisms: Different
mechanisms have different rates.

We can examine the movement of drugs in the body through permeation
and Ficks law. Movement is affected by three things: (1) Permeation, (2)
Ficks Law of Diffusion, and (3) Water and Lipid Solubility. The following
is a table summary of the membrane permeation.

Mechanism Active/Passive? Governed by Ficks Law?
Aqueous Diffusion Passive Yes
Lipid Diffusion Passive Yes
Transport by Special Carriers Active (but is capacity limted) No
Endocytosis, Pinocytosis Active No

But what is Ficks law of diffusion? Ficks Law of Diffusion predicts the
rate of movement of molecules across a barrier, and states that most drugs
move down their concentration gradient in passive diffusion. It is
calculated as the following:
9
!"#$ !" !"# !"#$ ! !
!"#$%#&'(&)"# !"#$%&'( !!"#$"%&'(')* !"#$$%&%#'( ! !"#$
!"#$%&'" !!!"#$%&&
or

! !
!!!!!!
!!
.

Water and lipid solubility is the third factor in
the movement of drugs in the body. Aqueous
diffusion depends on the degree of ionization, as
water likes charges. Lipid Diffusion is pH
dependent, as many drugs are weak acids or
weak bases. Thus, the ionization of weak acids and bases can be
determined by the Henderson-Hasselbach equation which is simply
described as the following equation: !" ! !"
!
!!"#
!!"#$%&%"'&()!
!!"#$#%&$'(!
! For weak
acids, it can be calculated as: !" ! !"
!
!!"#
!
!
!"
. For weak bases, it can be
calculated as: !" ! !"
!
!!"#
!!!
!!"
!
!
. Most drugs are either weak acids, weak
bases or amphoteric. A drugs pKa value represents the pH at which 50%
of the molecules in solution are ionized, where there is an equal ratio of
ionized and non-ionized compounds. Acids are increasingly ionized in a
basic environment. Bases are increasingly ionized in an acid environment.
For example, aspirin is a weak acid, and is readily absorbed across the
stomach lining. Differences in the pH of body fluids
can lead to drug trapping in certain compartments,
which can lead to changes in absorption and/or
elimination.
Body Fluid Range of pH
Stomach 1.9-2.6
Intestine 6.4-7.6
Urine 5.0-8.0
Breast Milk 6.4-7.6
It is important to remember
that drugs will not diffusion
in its ionized form, but only
in its non-ionized form. Such
elements of the Bronsted-
Lowry acids and bases can
facilitate ion trapping by
the kidney. Pyrimethamine
is a weak base of pKa = 7.0.
The urine pH can be adjusted
from 5.5 to 8.0. To acidify urine, one can utilize NH4Cl, while making urine
more alkaline requires the addition of NaHCO3. This is because the ionized
for is not reabsorbed, and can be rapidly excreted. In an overdose of a
weak base, you can acidify urine with NH4Cl, while overdose of a weak acid
typically requires alkalinzing urine with NaHCO3. Essentially, we can
manipulate the urine to allow non-ionized compounds to be excreted out of
the body. Drug formulations are important because they can help
determine the rate of absorption. They can be given as liquids, tablets,
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enteric-coated tablets, etc. The rate of absorption for various preparations
is as follows (from fastest to slowest):
1. Liquids
2. Suspension Solutions
3. Powders
4. Capsules
5. Tablets
6. Coated Tablets
7. Enteric-Coated Tablets

A secondary part of drug absorption is complexation.
The drug can be liberated or inhibited in the presence
of other compounds in the stomach. As seen with
tetracycline, an empty stomach optimizes tetracycline
absorption over time. However, the presence of
divalent and trivalent cations can promote chelation
with tetracycline. A third part of drug absorption
is the alteration in GI motility. It can determine
whether a compound sits in the GI tract longer or
shorter and can consequently affect absorption.
Propantheline decreases the GI transit, causing
more absorption of digoxin. Metoclopramide
increases GI transit, and spur less absorption of
digoxin. The point is that you can speed up or slow down transit, and can
possibly affect absorption. The final consideration is interference with
drug absorption. Charcoaid interferes with drug absorption because it is a
terrific binding agent. Essentially, it binds with the drug in question and
then allows the drug to be passed through the stool.

Now, we are in the D in ADME, or Distribution. The distribution of drugs
can be affected by four factors:
1. Size of Organ: The skeletal muscle is a large organ that is difficult to
fill, while the brain is a smaller organ that fills quickly. Larger
organs are much more harder to fill, while smaller organs can fill up
quickly.
2. Blood Flow: Well-perfused organis will achieve high tissue
concentrations. Poor organs will yield low tissue concentrations.
3. Solubility: Highly lipid soluble drugs like organs and tissue with
high lipid content, such as in the brain.
4. Binding: Particularly plasma protein
binding. When drugs are bound to plasma
proteins, you can increase the free
concentration of a drug by introduction
with another drug.

In protein binding, the major plasma protein is
albumin. If you have a drug, such as D1, that
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has is bound at a certain percentage. With the introduction of another
drug that has higher binding (D2), you can increase the concentration of
free D1 in the system.

Placental transfer is another mechanism in
the alteration of drug distribution.
Pregnancy is a very big thing because the
placental membrane is not only a membrane
but has a lot of efflux transporters. Drugs
that are introduced to the mother can cross
to the fetus. However, there are some drugs
that are charged, and consequently cannot
cross the placenta, while other drugs are
noncharged and can cross the placenta, as seen in the
comparison between thiopental and tubocurarine.

The blood-brain barrier is a series of tight-junctions
consisting of astrocytes and capillaries. Tight-
junctions are ideal because they limit paracellular
diffusion and provide high trans-endothelial
resistance (approximately 6,000 Ohms per square
centimeter). It is extremely tight. Tight junctions are
dynamic protein complexes. The brain acts to maintain homeostasis.
There are a variety of transporters at the luminal (blood) and abluminal
(brain) side of the endothelial cell:
1. ATP-Binding Cassette (ABC)
a. P-Glycoprotein: They are considered the gorillas of the
transpoters. They limit drug absorption at the brain. They
protein tissues from toxins and exogenous chemicals. The
better question to ask is what drugs are NOT substrates for the
transport.
b. Multidrug Resistance Proteins
c. Breast Cancer
Resistance Protein
2. Solute Carriers (SLC)
a. Organic Anion
Transporting
Polypeptides

The blood-brain barrier helps
maintain homeostasis and
restricts access to toxic
xenobiotics/metabolites.

Orally observed drugs undergo a first-pass effect, which is
a phenomenon of drug metabolism whereby the
concentration of a drug is greatly reduced before it
reaches systemic circulation. Basically, a fraction of drug
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is lost during the process of absorption. It is generally related to the liver
and gut wall. The drug is swallowed and it is absorbed by the digestive
system and consequently enters the hepatic portal system. It is carried
through the portal vein into the liver before reaching the body,
metabolizing many drugs to the point of metabolizing little that enters into
the circulatory system. This creates a reduction
in the bioavailability of the drug. The primary
systems affected are (1) the gastrointestinal
lumen, (2) gut wall enzymes, (3) bacterial
enzymes, and (4) hepatic enzymes. There are
significant differences between oral and
intravenous administration. The onset involves the
drug reaching the liver and getting metabolized. In
intravenous administration, the duration of a drug is
shorter in comparison to the same drug administered
orally.

Bioavailbility (F) is the fraction of drug absorbed into
the systemic circulation. Bioavailibility is
calculated as:
!"#$ !"#$% !!! !"#$% !!"#$%!
!"#$ !"#$% !!! !"#$% !!"#$!"#$%&'!
!!"" . The
bioavailability (F) can change with
different modes, and with such changes in
bioavailability, there are changes in half-lives. What happened to the
drug? It got metabolized. We can discuss another factor, namely the
apparent volume of distribution (Vd). It is pharmacological/theoretical
volume that a drug would have to occupy if it were uniformly distributed to
provide the same concentration in blood plasma. Drugs move between
compartments. When the drug is absorbed in blood, it can move to the site
of action and to peripheral tissues. The Volume of distribution is the
volume that relates the amount of drug given to the body to the plasma
concentration. It is calculated as: !
!
!
!"#$%& !" !"#$ !" !!! !"#! !!"!
!"#$%# !"#$ !"#!$#%&'%("# !
!"
!
!
. If the
therapeutic serum concentration of a drug is known, you can calculate the
dose to give based on the apparent volume of distribution. The dose is
calculated as: !"#$ ! !
!
!!
!
, where Cp is the plasma concentration in
milligrams per Liter.

Remember that the apparent volume of distribution is the volume of fluid
which the drug would occupy if it were evenly distributed through that
volume at the concentration measured in the plasma (central
compartment). It is largely an abstract or theoretical concept since it does
not represent an actual physical volume inside the animal. The Vd relates
the dose of drug administered to the resulting concentration in the plasma.
It is utilized because of convenience and because the ratio of the dose
administered to the plasma concentration has units of volume. The
volume of distribution rarely corresponds to an actual physical volume.
The ranges of volumes of distribution are as follows:

13

However, we can notice several trends. A lipophilic drug will tend to have
a larger volume of distribution. However, a drug with a high affinity for
plasma proteins will have a small
volume of distribution. The key
points are that (1) drugs with a
large Vd mean that a typically
larger dose of drug will be needed to
achieve a target drug concentration
in the plasma and ultimately the
desired response and (2) lipid-
soluble drugs have a larger Vd than
water-soluble drugs. Drugs are
distributed in multiple phases.
First phase drugs are distributed to high flow
areas such as the heart, liver, kidneys, and
brain). Later phases drugs are distributed to
low flow areas such as bones, fat, and skin.

Metabolism and Excretion are the M and E of
ADME. Metabolism will be covered in the next
lectures. However, the movement of drugs are
between compartments, and there are alteration of
drug excretion, such as (1) GI & Biliary (minor),
(2) Kidneys (major), Lungs (minor), and Skin
(minor). Kidneys are the major route of excretion.
The enterohepatic circulation is the major
circulation involved in biliary excretion and GI
elimination. The kidneys are the more major
contributor to excretion. The kidneys contain a
multitude of transporters, which allow the kidneys
to handle a multitude of drugs. What is the major
determinant of kidney function is renal clearance.
When blood goes to the kidney, the drugs get
filtered out, and is consequently processed and eliminated. In renal
epithelial, there is a diversity of transporters.

We can know how fast a drug is metabolized or eliminated from the body by
biological half-life, and we also need to understand the concept of
clearance. Clearance relates the rate of elimination to the plasma
14
concentration. It is essentially the amount removed per unit time.
Clearance is calculated by the following: !" !
!"#$ !" !"#$#%&'#(% !" !"#$ !
!"
!!
!
!"#$!" !"#$ !"#!$#%&'%("# !
!"
!
!
.
Most drugs are cleared by the kidneys and relate to renal clearance, which
is defined as the volume of plasma that is totally cleared of a drug in one
minute during passage through the kidneys.

In order to understand clearance, we need to understand kinetics. There
are two types of kinetics discussed in pharmacology:
1. Zero-Order Kinetics: The rate of elimination is constant regardless
of concentration. There is a fixed amount of drug that can be
handled at any time.
2. First-Order Kinetics: The rate of elimination is proportionate to the
concentration, where the higher the concentration, the greater the
amount of the drug eliminated per unit time. A constant fraction of
the drug is metabolized per unit time. Note that for many drugs that
are cleared by the kidneys, the clearance rate is dependent on the
blood flow through that organ.

It can be summarized in the following table
Rate Order Description Visual
Zero-Order Constant rate of elimination

First-Order Rate of elimination if proportional to concentration


This introduces the concept of half-life. The
half-life (t1/2) is the derived parameter,
completely determined by volume of
distribution (Vd) and clearance (CL). It is
calculated by: !
!!!
!
!!!"#!!
!
!!
. There is also a
concept of multicompartment distribution,
where after absorption, many drugs
undergo an early distribution phase
followed by a slower elimination phase.
There is a back and forth between blood
and tissues. Half-life determines the rate
at which blood concentration rises during
constant infusion.

15
As a physician or practitioner, it is important to
achieve the desired drug levels. The amount of
drug delivered is equal to the amount metabolized
and eliminated (steady state, Cpss). Steady state is
attained after approximately four half times. The time
to steady state is independent of dosage. Steady-state
concentrations are proportional to dose/dosage
interval and are proportional to the ratio of
bioavailability to clearance. The fluctuations are
proportional to dose
interval/half-time. It is blunted
by slow absorption. The
multiple dosing regimen is given
at each half-life. It takes 5 half-
lives to reach steady state. The
half-life is important because it
determines the rate at which
blood concentration rises during constant infusion. What will increase the
plasma half-life? It can be increased by (1) an increased volume of
distribution and (2) decreased clearance. However, the dosage often needs
to be adjusted when elimination is altered by disease. In renal disease or
reduced cardiac output, there is a reduction in the clearance of drugs. We
can correct the dose by the following calculation: !"##$%&$' !"#$ !

!"#$%&# !"#$ !!"#$%&!
!
! !"#$%!"!"# !"#$%$&'#
!"" !"!!"#
. Normal creatinine clearance is around
100 mL/min or 6 L/hr. In males it is between 97-137 mL/min. In females,
it is 88-128 mL/min. Males tend to have a higher creatinine clearance
because they have a higher degree of skeletal mass. However, creatinine
clearance is affected by age. Each decade corresponds to a decrease of
about 6.5 mL/min. Now another question arises. How do I maintain a
constant blood level of a drug? This can be done with dose regimens, and
even giving a loading dose. Dose Regimens is a plan for drug
administration over a period of time. It is important to achieve therapeutic
levels of the drug in the blood, without exceeding the minimum toxic
concentration. If the therapeutic dose must be achieved rapidly and the Vd
is large, then a large loading dose may be needed to onset the therapy. The
loading dose is calculated as the following equation: !"#$%&' !"#$ !

!"#$%& !" !"#$%"&'$"() !!"#$%"& !"#!"# !"#$%#&'(&)"#
!"#$%$"&$'"&"()
. This is roughly translated as
!" !
!
!
!!!!!
!""
!
!"
!
!
!
. Dose regimens are a plan for drug administration over a
period of time. It is necessary to achieve therapeutic levels of the drug in
the blood, without exceeding the minimum toxic concentration. The
maintenance rate (maintenance dose) of drug administration is equal to
the rate of elimination at steady state. The maintenance dose is a function
of clearance. It can be calculated as:
!"#$%&$"$'& !"#$ !
!"#$%$&'# !!"#$%"& !"#$%# !"#$%#&'(&)"#
!"#$%$"&$'"&"()
or !" !
!"!
!
!!
!!!
!""
!
!"
!
!
!
.
16
Lecture III
Drug Metabolism and Pharmacodynamics
Lecturer: Dr. Patrick Ronaldson, Ph. D.

Metabolism is the M in the ADME, and alteration of drug metabolism is
impotant when it comes to drugs and drug products. It consists of three
major concepts:
1. Lipophilic to Hydrophilic: If we are to ultimately eliminate drugs
via the kidneys, we need to make from a lipophilic compound to a
hydrophilic compound.
2. First Pass Effect (in oral administration): It can affect a lot of
things.
3. Cytochrome P450

However, in order to understand metabolism, we need to understand
biotransformation. Biotransformation is the process in which drugs are
modified by the organism. Usually, any sort of biotransformation process
involves enzymes. It happens with respect to drug metabolism. Enzymes
are there to metabolize endogenous substrates, vitamins, steroids,
hormones, etc. The biotransformation of metabolism focuses on decreasing
the lipid solubility, eventually making the drug more water-soluble. Drug
metabolism decreases lipophilicity, and makes it water soluble for
elimination through the kidneys. Once again, the purpose of
biotransformation is to allow a chemical transition from lipophilic to
hydrophilic. It involves taking the active drug and converting it to a
metabolite. Metabolites can act as an active drug, active toxicant, or
become inactive. There are even compounds known as pro-drugs that
readily convert to the active compounds.

How do we relate the concentrations to the effect?
If we look at the curve, as the drug concentration
increases in serum, we have a delay in effect.
When the drug reaches its peak, the effect is
delayed, but the drugs concentration begins to fall.
Therefore, drug concentration is proportional to drug effect. Where can we
see biotransformation? We can see it in many chemicals, such as ethanol
and thiopental. Ethanol, without the aid of biotransformation, can remain
in the body for approximately four weeks. With the effects of
biotransformation, it can last in a much shorter period (approximately 20
mg/dL/h). Thiopental would remain in the body for years without
biotransformation, but fortunately it can be cleared from the body in 3-8
hours with such chemical processes.

With oral administration, we do need to take into account the First Pass
Effect. When you take a drug that is absorbed across the wall, the drug can
hit many things in the liver. The liver then can metabolize out the drug.
17
The concentration gets thinner. The liver is not the only tissue that can
metabolize the drug. There can be metabolism in other tissues as well. The
drug is taken into the GI tract and is absorbed into the GI wall. Then the
drug is placed into the hepatic vein and pumped into the aorta. Some of
the drugs can get back into the hepatic artery and go into the liver and be
cycled to clearance. The drugs travel through the celiac artery and
superior and inferior mesenteric arteries and go back into the GI tract.
This provides an efficient means of filtering a drug out through
recirculation. The concentration of drug in plasma can drop quickly after
administration.

Biotransformation can be dictated
by two types of reactions: (1) Phase I and (2) Phase II. Phase I reactions
include (1) oxidation (with Cytochrome P450), (2) reduction, (3)
deamination, and (4) hydrolysis. Phase II reactions involve addition (i.e.,
conjugation) of subgroups to OH, NH2, and SH function groups on a drug
molecule. This is not saying that theyre sequential. Some compounds
may only need to be metabolized by Phase I reactions while other
compounds may go directly to Phase II reactions. But the
biotransformation can give a lot more pharmacological knowledge. It
determines the therapeutic half-life. It may produce the active metabolite,
and also allows a site of drug-drug interaction. The results of
biotransformation can be the halting of the pharmacological effect, with an
exception, where there is production of an active metabolite. It restricts
distribution, and facilitates excretion, making the drug much more
hydrophilic. The major organs involved in biotransformation include:
1. The Liver (High Capacity)
2. Intestines, Lung, Kidney (Medium Capacity)
3. Skin, Testis, Placenta, Adrenals (Low Capacity)
4. Brain? ! It is starting to be more appreciated as an organ that
metabolizes drugs, mainly because the substrate specificity is
greatly restricted in brain.

So, we see biotransformation with a simple
chemical, such as benzene. Benzene is a notably
hydrophobic compound, with an aromatic ring
and no function groups. It has an extremely low
solubility (1/1,430). When benzene undergoes
the Phase I reaction, it is converted to phenol (a
hydroxyl group replaces one of the protons), bringing
its solubility to 1/15. However, with a pKa in
physiological conditions at 10, it is much difficult to
deprotonate the hydroxyl group in phenol. When phenol undergoes a
Phase II reaction, then it is converted to glucuronide, bringing its solubility
to 1/3 and the pKa to 3.4, allowing deprotonation and secretion out into the
urine.

18
We can also see a Phase I
biotransformation, occurring with a
variety of substrates, a variety of
reactions (especially those with
oxidation or hydroxylation). It can
allow reactive oxidation, or even add
or expose a functional group. One key
part of the Phase I biotransformation
involves the Cytochrome P450 Family.

The Cytochrome P450 Family consists of eighteen
groups of enzymes, with 54 subfamilies that are
classified according to biochemical characteristics.
The predominant one in humans is the CYP3A4/5,
which performs approximately 36% of Phase I
metabolism. It can also be noted that 50% of all
drugs utilize CYP 3A4/5.

One kind of Phase I reaction is hydrolysis. It
involves esterases and amidases. It essentially
adds water across a covalent bond, and exposes
the function group(s). This occurs in most
tissues and in plasma. Other reactions can
include aromatic hydroxylation and hydrolysis
with amidase, with the example in Mepivicaine.
Phase II Biotransformation may involve
coupling of a new function group to a drug or
metabolite (through conjugation). The purpose
is to increase water solubility and ionization.
The result is to enhance renal or biliary
excretion. Phase II biotransformations help
yield pharmacologically inactive compounds. Particular molecules can
undergo several Phase II reactions. Major Conjugation Reactions are
listed:
Conjugation Conjugate Chemical
Group
Reactions
Glucuroni-
dation
Acidic sugar -OH, -COOH, -
NH2, -SH

Sulfation Sulfate -OH, -NH2
Methylation CH3
+
-OH, -NH2
Acetylation CH3COO
-
-NH2
Amino Acid Amino Acid -COOH
Glutathione GSH Electrophiles


19
One example of a glutathione conjugation is the conjugation of Tylenol to
mercapturic acid, a cysteine conjugate. Mercapturic acids are extremely
hydrophilic and can consequently be eliminated easily.

There are two types of
agents that can affect
the rate of
biotransformation:
inductors and
inhibitors. Inductors
increase the rate of
biotransformation, and
can spur increased
expression of
biotransformation
enzymes. Inductors
can ultimately
decrease the plasma
concentration of a
drug due to metabolism of the drug. Ultimately, this results in a decreased
half-life. Some of the major players Inhibition leads to a decreased rate of
biotransformation. It is involved in drug-drug interactions, and results in
an increased half-life. For instance, grapefruit juice inhibits CYP3A4.
Another example is that cimetidine inhibits many cytochrome p450s. The
following is a list of inducers and inhibitors:
Inducers Inhibitors
St. Johns Wort Grape Fruit Juice
Phenobarbital Cimetidine
Pentobarbital Valproic Acid
Carbamezapine Verapamil
Phenytoin Ketoconazole
Rifampin Haloperidol
Modafinil

Now it is important to discuss
pharmacogenetics, mainly to introduce the
human variation in biotransformation.
Humans are physiologically and physically
different. Different races utilize different
CYP450 enzymes. There are two types
of outliers, namely rapid metabolizers
and poor metabolizers. Rapid
metabolizers have lower than normal
serum concentrations, while poor
metabolizers have higher than normal
serum concentrations. Some drugs
can affect poor metabolizers and drug-
drug interactions at some CYP450 enzymes, such as Serzone (Nefazodone
HCL) with CYP3A4. Other variables affecting drug metabolism include:
20
" Enzyme Induction
" Enzyme Inhibition
" Diet
" GI Flora
" Age
" Disease
" Genes
" Sex

The following table describes the statistical
differences in the various demographics and
metabolic pathways:
Metabolic System CYP 2C19 CYP 2D6 CYP 1A2
Drugs Metabolized via
Pathway
S-mephenytoin,
Omeprazole, Others
Codeine, Dextromethorphan,
Tricyclic Antidepressants,
Captopril, Flecainide, Many Others
Caffeine, Theophylline,
Acetaminophen,
Propranolol, Others
% of Caucasians
(decreased or low
activity)
3-5 3-10 12-13
% of Blacks (decreased
or low activity)
3-5 0-2 12-13
% of Asians
(decreased or low
activity)
18-23 0-2 12-13

Men and women have different drug metabolism.
For instance, men metabolize drugs such as
chlordiazepoxide and diazepam faster than women.
This is because such drugs can distribute into fat,
increase the half-life and decrease clearance rates
of the drug. Aging can also increase the half-life of
drugs. Diseases can affect biotransformation also,
mainly because CYP450 enzymes are also affect and
the liver is the site of biotransformation.

Bioactivation is actually where the metabolite can lead
to a reactive intermediate. Some reactive
intermediates are toxic and can bind to nucleic acids
or proteins. For instance, acetaminophen
transformation and bioactivation can produce
reactive intermediates that can cause necrosis, brain
edema, and death. However, it is easily cleared out of
the system. However, with use of alcohol, the reactive
intermediate of acetaminophen is often not cleared as fast, and can dwell
in the liver and bloodstream.

Pharmacodynamics is the study of the biochemical and physiological
effects of drugs on the body or on microorgnisms or parasites within or on
the body and the mechanisms of drug action and the relationship between
concentration and effect. Essentially, it studies the mechanism of drug
action. Receptors are specific molecules in a biological system that drugs
21
interact with. The interaction between a drug and a receptor produces a
change in the function of the system. Most receptors are proteins, having
high affinity but low capacity. Effectors are molecules that translate the
drug-receptor interaction into a change in cellular activity. When we get
drug receptor-effector response, the drug
binds, something happens in the cell, and
an effect occurs.

In order for drugs to interact to receptors, they should have (1) shape, (2)
size, (3) charge, and (4) atomic composition. This ultimately leads to the
lock and key theory of drug-receptor interaction. The drug acts like a
key and the receptor acts like a lock. When it interacts correctly, it can
create a drug-receptor complex. The binding of a drug to its particular
receptor can be dynamic. How well a drug binds to a receptor is dictated by
the affinity of the drug for the receptor. This can be shown by the following
reaction:

Essentially, this illustrates that if the rate of the reverse reaction is much
more favorable than the rate of the forward reaction, then the scenario
would provide a low dissociation constant (Kd). A low dissociation
constant allows for high affinity. When concentration of a drug is equal to
Kd, then the drug will occupy 50% of its receptors. This formula
demonstrates that as affinity decreases, the receptor occupancy will also
decrease: ! !
!"#$!!"#"$%&! !"#$%&'&(
!"!#$ !"#"$%&!'
!
!"
! ! !"
!
!
! !!
!
!

The majority of all receptors are proteins, and
receptors bind with drugs and bring about a change in
cell function. The evidence is in (1) the extreme
potency/efficacy of drugs, (2) chemical
selectivity (i.e., similar molecules producing
similar effects), and (3) molecular cloning
and reconstitution. Sometimes a change in
one carbon will still allow some difference in shape, while enantiomers may
yield one desired effect in one enantiomer over another. From a structural
point of view, one enantiomer may fully occupy the receptor binding
pocket, while the other enantiomer only provides a partial match. This
shows the stereo-selectivity of the receptors. Drug receptors consist of
three interrelated components, with (1) recognition, (2) transduction, and
(3) amplification. Recognition is mainly the interaction between the drug
and receptor. Transduction is the recognition of the signal to cause
activation or inhibition, and amplification is mainly the exponential
expression for a desired effect. There are several types of receptors and
their effectors, as shown:
22


Dose-response curves are considered the cornerstone of pharmacology.
The EC50 is the effective concentration for 50% response.
Another curve is the log-dose response curve. You can
tell two things from dose-response curves:
1. Potency: amount of drug required to produce a
response. It can cause a left/right shift of the dose-
response curve.
2. Efficacy: Ability of a drug to induce a
maximal response. This can be determined
by the height of the dose-response curve.
There are two types of drugs: agonists and
antagonists. Agonists bind to a receptor and elicit a
pharmacological effect. Antagonists bind to a
receptor but do not elicit a pharmacological effect.
Antagonists can prevent/inhibit the ability of an
agonist to bind and elicit an effect. There are
several types of agonist:
1. Full Agonists: They bind and activate a
receptor, displaying the full efficacy of the
receptor.
2. Partial Agonist: Receptor elicits a biological
effect or a balance of activated and
inactivated receptors affinity for active
form. There is no full biological effect.
3. Inactive Compound (Antagonist): Have
equal preference for the activated and
inactivated receptors.
4. Inverse Agonist: Opposite effect of what the
agonist would do due to affinity for the
inactivated receptor.

There are also three types of antagonists:
1. Competitive Antagonist: Competition for the same binding site
2. Noncompetitive Antagonism: Binds but the affinity is so much
greater to allow competition by the drug.
23
3. Allosteric Inhibition: Binding to a site away from the binding site to
block the action of the binding site.

We can see the effects of a competitive antagonist in a
dose-response curve, particularly in acetylcholine to
induce smooth muscle contraction. A partial agonist
produces an effect if no full agonist is present, but acts
as an antagonist in the presence of a full agonist.
Drugs can also produce more than one effect as the
dose increases. One example is morphine. As the
dosage increases, the effects can range from
constipation and antitussive effects to respiratory
depression and death.

Now it often goes into the question the therapeutic index. It is a
comparison of the amount of the therapeutic agent that causes the
therapeutic effect to the amount that causes death
or toxicity. Succinctly, it is how selective is a drug
in producing its desired effects versus its adverse
effects. It can be calculated by the following
formula: !" !
!"
!"
!"
!"
, where LD50 is the lethal dose
while the ED50 is the effective dose.

With drug safety, there must be understanding of the
therapeutic window. The therapeutic window of a drug is
the range of drug dosages, which can treat disease
effectively while staying within the safety range. It is,
succinctly, the range of steady-state concentrations that provides
therapeutic efficacy with minimal toxicity. It is calculated by: !" !
!"#$%&$ !""#$%
!!!"#$!%&'( !""#$%
!
!"#"$%& !"#$% !""#$%
!!!"#$!%&'( !""#$%
. However, there are several factors
influencing dose-response relationships:

In review, agonists retain affinity, selectivity, potency, and efficacy.
Antagonists retain affinity, selectivity, and potency. Competitive
antagonists decrease potency, and non-competitive antagonists decrease
both potency and efficacy. The drugs often produce more than one effect.
Drug response depends on the tissue it acts on.
24
Lecture IV
Drug Receptor and Targets
Lecturer: Dr. Qin Chen, Ph. D.

In previous lectures, pharmacology was
discussed in terms of drug action in two
fronts, the molecular level and the systemic
(whole organism) level. At the molecular
level, we can observe that the drugs
mechanism can yield a biological effect. For
example, aspirin will bind to cyclooxygenase.
At the whole organism level, we can see the
therapeutic effect of a drug and its unwanted, adverse, or side effect.
Drugs can affect a patient therapeutically or adversely. They result from
drug interaction with specific molecules in our body. It is important to
understand what drugs interact with which receptor.

All drugs have a biological effect. It not only has the desired effect, but also
has undesirable effects. There are many biological effects of drugs:
" Killing harmful invading organisms, such as bacteria and viruses (as
in antibiotics and antiviral drugs).
" Killing cancer cells (chemotherapeutic agents)
" Neutralizing acid (antacids).
" Modifying underactive physiological process (e.g. insulin)
" Modifying overactive physiological processes (e.g. enzyme
inhibitors)

The mechanism of the biological effects of drugs is in the interaction
between an exogenous chemical (drug) and the endogenous biochemical
target (receptor). The drug is essentially interacting with the target
molecule. Knowing which receptor is involved in which disease is
important in the development of drugs. Drug-receptor interaction is
important for therapeutic decisions in clinical practice.

Why should we understand the drug receptor concept? It is important for
three reasons:
1. Receptors largely determine the quantitative relations between dose
or concentration of a drug and its pharmacological effects.
2. Receptors are responsible for the selectivity of drug action.
3. Receptors mediate the actions of pharmacologic agonists and
antagonists. Ultimately the receptors are the agents that give off the
response.

The drug receptor is a drug target. The receptors consist mostly of protein.
However, there are some drugs that do not target a protein, such as
25
antacids (Calcium carbonate or magnesium hydroxide) and charcoal.
Some drug receptor proteins can include (but are not limited to):
" Enzymes
" Endocrine factor receptors, such as G-protein coupled receptors,
tyrosine kinase receptors, and nuclear hormone receptors.
" Signaling molecules
" Ion channels
" Cell structure proteins

There are two locations of receptor:
1. Cell surface, such as those receptors for growth factor, endocrine
factor, G-protein coupled receptors, and ion channels. Classic
receptor proteins are plasma membrane proteins to pharmacologists
and microbiologists.
2. Intracellular Receptors, such as those for enzymes and nuclear
receptors.

However, another question arises. Does one ligand code for only one
receptor? The answer is no. A single ligand can code for multiple
receptors, depending on:
" Pharmacologically distinct types that are coded by different
genes. The amino acid sequences can be very different.
" Subtypes, which allows relation in terms of amino acid sequences.
" Structure of the receptor: One receptor can be made of different
subunits.
" Post translational modifications
" Downstream signaling pathways
" Tissue distributions: Can be dependent on the receptor as well as
the associated vasculature.
" Abundance and Ratio
" Factors affecting receptor expression

There are several examples of such drugs. One of them is the Dopamine
Receptor. There are several different subtypes of dopamine, and are
different in terms of distribution, amino acid sequence and/or post-
translational modifications, and in downstream signaling. The table
describes these dopamine receptor subtypes:
Dopamine Receptor
Subtype
Organs Expressed Downstream Signaling Molecules
D1 Widely expressed throughout the brain,
pulmonary artery
G!s and activation of adenylate
cyclase
D2 Pulmonary Artery G!i and inhibit adenylate cyclase
D3 Brain (Islands of Calleja and Nucleus
Accumbens)
G!i and inhibit adenylate cyclase
D4 Pulmonary Artery, Atria, Polymorphisms
associated with ADD
G!i and inhibit adenylate cyclase
D5 Pulmonary Artery G!s and activation of adenylate
cyclase

Another example involves the catecholamine receptor (adrenoceptor)
subtypes. There are pharmacologically distinct types, ! and ". They are
26
different in amino acid sequences due to different genes, and are different
in downstream signaling molecules. A table describes the following:
Type Subtype Downstream Signaling Molecule
! 1 Gq coupled receptor
2 Gi coupled receptor
" 1 Gs coupled receptor
2 Gs coupled receptor, Gi coupled receptor
3 Gs coupled receptor

A common feature of ligand binding to membrane receptor is signal
transduction. When a extracellular ligand binds to a receptor at the
membrane, it spurs signal transduction to yield a biological effect. What
the binding essentially does is spur an intracellular effect to produce that
biological effect. What triggers signal transduction is another field of
study. There are several types of receptors, which can be described in the
following table:
Receptor Diagram Description Examples
G-Protein
Coupled
Receptor

Large protein family of
transmembrane receptors
that sense molecules
outside the cell and
activate inside signal
transduction pathways,
and ultimately cellular
responses.
Dopamine,
Muscarinic
Acetylcholin,
Opioid,
Angiotensin,
Oxytocin,
Rhodopsin,
Prostanoids,
Melatonin
Receptor
Tyrosine
Kinase

High-affinity cell surface
receptors for many
polypeptide growth factors,
cytokines, and hormones.
They are not only key
regulators of normal
cellular processes but also
have a critical role in the
development and
progression of many types
of cancer.
EGF, Insulin,
IGF, PDGF,
FGF, VEGF
Cytokine
Receptor

Receptors that bind
cytokines. They play a role
in the inflammatory
response.
Interferon,
Interleukins
Nuclear
Receptor

Class of proteins found
within cells that are
responsible for sensing
steroid and thyroid
hormones and certain
other molecules. They
work with other proteins to
regulate the expression of
specific genes, controlling
the development,
homeostasis, and
metabolism of the
organism.
Gluco-
corticoids,
Estrogen,
Progesterone,
Testosterone,
Thyroid
Hormone,
Retinoids,
Vitamin D
!"#$%&'() +%,#-'. /'0'#&%$1
2(3 4"45
Examples: Dopamine, Muscarinic Acetylcholine, Opioid, Angiotensin, Oxytocin,
Rhodopsin, Prostanoids, Melantonin
How many GPCRs? >662, 950
Database: www.gpcr.org

7 transmembrane domains
Receptor Tyrosine Kinase
Examples: EGF, Insulin, IGF, PDGF, FGF, VEGF
Cytokine Receptor
Examples: interferon, interleukins,
Nuclear Receptor
!"# %&%'
Examples: glucocorticoids, estrogen, progesterone, testosterone,
thyroid hormone, retinoids, vitamin D,
27
Ion
Channels

Pore-forming proteins that
help establish and control
the voltage gradient across
the plasma membrane of
cells by alloing a flow of
ions down their
electrochemical gradient.
Digitalis,
Verapamil

The following are the most studied signaling pathways:
" G-proteins
" Phosphoinositide 3-Kinase
" Protein Kinase A
" Mitogen Activated Protein Kinases (MAPKs)
" Protein Kinase C
" Calcium Calmodulin-dependent protein kinase (CaM kinase)

One example of cytokine receptors is tumor necrosis factor-!. TNF-! is a
cytokine involved in systemic inflammation and is a member of a group of
cytokines that stimulate the
acute phase reaction. When
extrinsic activating ligands
bind to TNF, the death
domain and TRADD/FADD
adaptors catalyze the
activation of Caspase 8,
which further
catalyzes/activates Caspase
3 and further catalyzes
activation of Caspases 6 and
7. They ultimately will
permit apoptosis, with DNA
fragmentation, membrane
blebbing, protein
degradation, and cell shrinkage. This is apoptosis via the external
pathway.

The G-protein is a guanine nucleotide-binding protein. It hydrolyzes GTP
to GDP. There are two classes of G-proteins, the (1) monomeric small
GTPase such as those in the Ras family of small GTPase, and the (2)
heterotrimeric G-protein complex, consisting of G
!
, G
"
, and G
#
subunits.
There are also several subclasses per function:
" Gs!
stimulatory of cAMP production
" Gi! inhibitory of cAMP production
" Go!
G other
" G
!q Activates phospholipase C
Ion Channel
!"# %&%'
a lipid kinase adds phosphate to the 3-position of inositol ring of
phosphatidylinositol (PtdIns) and phosphoinositides
Phosphoinositide 3-Kinase (PI3K):
28
" G
!t transducin
regulation

There are also different
downstream signals:
" Adenylyl cyclase
" Phospholipase C
" Phospholipase A2
" Phosphodiesterase

The main kinase is phosphoinositide 3-kinase
(PI3K). They are a family of enzymes involved
in cellular functions such as cell growth,
proliferation, differentiation, motility, survival,
and intracellular trafficking, which in turn are
often involved in cancer. A lipid kinase adds
phosphate to the 3-position of the inositol ring of
phosphatidylinositol (PtdIns) and
phosphoinositides. What is interesting is that it
is phosphorylating lipids. This is one of the
main kinases to tyrosine kinase and GPCRs.

Protein Kinase A is another family of enzymes
whose activity is dependent on cellular levels of
cyclic AMP (cAMP). It is involved in regulation
of glycogen, sugar, and lipid
metabolism. Anchoring proteins have
designated specificity of substrate
phosphorylation.

The MAPK pathway is a chain of
proteins in the cell that communicates
a signal from a receptor on the surface
of the cell to the DNA in the nucleus of
the cell. It consists of an activator
protein binding, membrane
translocation, oligomerization, and phosphorylation activating MAP3K,
which then activates MEK, which consequently activates MAPK. The
biological response can be proliferation, apoptosis, developmental
morphogenesis, cell cycle arrest, innate and acquired immunity, cell
repair, etc.

Protein Kinase C is a family of protein kinase
enzymes that are involved in controlling the
function of other proteins through the
phosphorylation of hydroxyl groups of serine
and threonine amino acid residues on these
proteins. PKC enzymes in urn are activated by
Anchoring proteins: designated specificity of substrate phosphorylation
Protein Kinase A
MAPK pathway
Protein Kinase C
Autophosphorylate
Subcellular distribution of PKCs and their substrates
Binding of a ligand or substrate activates PKCs
Translocate to membrane fraction
Substrates: Ser or Thr in a variety of Arg-rich sequences
29
signals such as increases in the concentration of diacylglycerol or calcium
ions. They autophoshorylate and have maintain a subcellular distribution
of PKCs and their substrates. The binding of a ligand or substrate activates
PKCs. They translocate to the membrane fraction. The substrates are
serine or threonine in a variety of arginine-rich sequences.

As you can tell on the chart from the Human Genome Project, there are
1,543 genes (5% of the total) coding for receptors. There are 376 genes
coding for signaling molecules (approximately 1.2% of the total), and 500
coding for signaling kinases. Together they interact to yield the biological
effect. We can provide a summary with the following diagram.

With drug research and development, there are also
regulatory, bureaucratic factors involved in producing
a single drug. There is the basic research, which
involves synthesis, examination, and screening. Next,
there are preclinical tests on animals, than clinical
trials (Phase I, Phase II, and Phase III), and then Phase IV (post-marketing
surveillance) with introduction and registration into the market. The
success of drug development is dependent on:
" Most desirable effect (e.g. specific receptor targeting)
" Least undesirable effect
" Well-absorption
" Distribution to target tissues
" Metabolism does not generate toxic products
" Metabolites are eliminated in reasonable time frames.
Review of Pharmacokinetics
Pharmacodynamics is the mechanisms of drug
action, including molecular, biochemical, and physiological effects of drugs.
Pharmacokinetics is the process of drug molecules moves from one
physiological compartment to another, therefore the effect of such on the
usefulness of drugs. This includes drug absorption, distribution,
metabolism, and elimination (ADME).

It is important to remember that there are many drug and protein
interactions from a structural point of view. One enantiomer may fully
occupy the receptor-binding pocket, while the other enantiomer is only a
partial match. Consequently, these partial mismatches can contribute to
side as well as adverse effects. We can measure the drug activity with the
dose-response curve. The dose-response curve describes the change in
effect on an organism caused by differing levels of exposure to a stressor
after a certain exposure time.

It is also important to remember that there are several types of inhibitors,
which are described in the following table:
Drugs and Protein Interaction: Structural Point of View
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Type of
Inhibitor
Description Diagram
Competitive Binding of the inhibitor to the active site on the enzyme prevents binding of
the substrate, and vice versa.

Pseudo-
Irreversible
Slowly dissociate from their receptor, and does not completely halt binding.

Allosteric Regulation of enzyme or other protein by binding an effector molecule at the
allosteric site, or the site other than the proteins active site.


Drugs can also fall into two categories, described in this table:
Type of
Drug
Description Diagram
Agonist Chemical that binds to a receptor of
a cell and triggers a response by that
cell.

Antagonist Receptor ligand or drug that does
not provoke a biological response
itself upon binding to a receptor, but
blocks or dampens agonist- mediated
responses.


Agonists
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Antagonists
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31
We can measure the drugs effectiveness in terms of potency and efficacy,
which will be elaborated in this table:
Term Description Diagram
Potency Amount of drug required producing a
response.

Efficacy Ability of a drug to induce a maximal
response.


It is also important to remember that the complexity of most diseases can
be due to:
" Single Genes
" Multiple Genes
" Interaciton between Genes
" Epigenetic Regulation
" Overlapping Signaling Pathways of Normal vs. Disease States
Case Study
A 51-year old man presents to his medical clinic due to difficulty breathing.
The patient is afebrile and normotensive, but tachypneic. Auscultation of
the chest reveals diffuse wheeze. The physician provisionally makes the
diagnosis of bronchial asthma and administers epinephrine by
intramuscular injection, improving the patients breathing over several
minutes. A normal chest X-ray is subsequently obtained, and the medical
history is remarkable only for mild hypertension that was recentlytreated
with propranolol. The physician instructs the patient to discontinue use of
propranolol, and changes the patients anti-hypertensive medication to
verapamil. Why is the physician correct to discontinue propranolol? Why
is verapamil a better choice for managing hypertension in this patient?
Answer
Propranolol, a non-selective beta-adrenoceptor block, is a useful
antihypertensive agent because it reduces cardiac output and probably
vascular resistance as well. However, it also prevents beta-2-receptor-
induced bronchodilation and may participate bronchoconstriction in
susceptible individuals. Calcium channel blockers such as verapamil also
reduce blood pressure but do not cause bronchoconstriction or prevent
bronchodilation. Selection of the most appropriate drug or drug group for
one condition requires awareness of the other conditions of a patient may
have and receptor selectivity of the drug groups available.

Potency: amount of drug required to produce a response
Efficacy: ability of a drug to induce a maximal response
Potency: amount of drug required to produce a response
Efficacy: ability of a drug to induce a maximal response
32
Lecture V
Autonomic Drugs: Autonomic
Physiology Review
Lecturer: Dr. Meredith Hay, Ph.D.
Learning Objectives
Anatomy
1. Explain how various regions of the central nervous system regulate
autonomic nervous system function.
2. Describe how the neuroeffector junction in the autonomic nervous
system differs from that of a neuron-to-neuron and the somatic
system synapses.
3. Compare and contrast the anatomical features of the sympathetic
and parasympathetic systems.
Neurochemistry
1. For each neurotransmitter in the autonomic nervous system, list the
neurons that release them and the type and location of receptors
that bind with them.
2. Describe the mechanism by which neurotransmitters are removed.
3. Distinguish between cholinergic and adrenergic receptors.
Physiology
1. Explain how autonomic reflexes contribute to homeostasis.
2. Describe the overall and specific functions of the sympathetic
system.
3. Describe the overall and specific functions of the parasympathetic
system.
4. Describe and understand the role and function of the arterial
baroreflex.

Because so many drugs exert the therapeutic
and side effects by altering the function of
the autonomic nervous system, a thorough
understanding of autonomic anatomy and
physiology is a critical prerequisite for
understanding cardiovascular
pharmacology. The pharmacological
response to a class of autonomic drugs can be
predicted if the organ innervation and receptor classification are known.

Most of the time, the sympathetic and parasympathetic nervous systems
act in concert with each other, but usually as opposites. We can think
about the sympathetic nervous system as a fight or flight response and
the parasympathetic nervous system as a rest and digest. There is
33
competition between these two systems. One will have dominance in either
the sympathetic or the parasympathetic nervous systems. The
sympathetic nervous system is very diffuse in its anatomy. You want all
its organ activated at once to ensure survival. The parasympathetic
nervous system is extremely discrete, specific to different organs. With
the parasympathetic, you can activate one organ. The sympathetic
preganglionic cell bodies are in the spinal cord, while the sympathetic
postganglionic neurons are in the sympathetic chain. The parasympathetic
preganglionic neurons are in the brain stem, while the parasympathetic
postganglionic neurons are in the organs themselves. It allows the
parasympathetic nervous system to activate a specific organ, giving its
ability to be discrete. (LO Anatomy, Question 1)

We know about the somatic nervous system (brain and spinal cord), which
controls different functions. They get afferent and efferent information.
The somatic nervous system is involved in conscious function. The
postganglionic neurons are in the sympathetic chain. The sympathetic
nervous system is illustrated in green. Almost every organ is dually
innervated. The pink is in the
parasympathetic nervous system and
the postganglionic neurons are in the
organs themselves. (LO Anatomy,
Question 2)

One of the fundamental differences
between the somatic nervous system
and the autonomic nervous system is
that in the somatic, there is one
neuron that goes out and innervates a muscle. Whereas in the autonomic
nervous system, either parasympathetic or sympathetic, there is almost
always two neurons involved (with the exception of the adrenal gland).
Individuals dont think about breathing or pumping their heart. Once
again, the somatic nervous system only contains one neuron, while the
autonomic nervous system motor pathway is a two-neuron pathway. (LO
Anatomy, Question 3)

The autonomic nervous system is a part of the peripheral nervous system
that acts as a control system functioning largely below the level of
consciousness, controlling visceral functions. The autonomic nervous
system is involved in the regulation of heart rate, digestion, respiratory
ate, salivation, perspiration, pupillary dilation, micturition, and sexual
arousal. The responses to sympathetic and parasympathetic nerve
stimulation are frequently antagonistic, as exemplified by their opposing
effects on heart rate and gut motility. It is important to remember that the
autonomic nervous systems purpose is to maintain homeostasis. The
second most important function is to get the body for fighting, reaction, or
survival. If its normally performing homeostasis, it is getting ready to
react. It is important to note the dual innervation by the autonomic
34
system (essentially by both divisions of the autonomic nervous system).
Most organs are dually innervated by both the sympathetic and
parasympathetic nervous system. Usually, one system predominates in
controlling the activity of a given organ. For example, in the heart, the
vagus (Cranial Nerve X) is the predominant controlling factor for rate.
The pharmacological response to a class of autonomic drugs can be
predicted if the organ innervation and receptor classification are known.
If a drug inhibits the activity of one limb of the autonomic nervous system,
it may activate the other limb of the autonomic nervous system. In a
dually innervated organ, the side effects associated with that drug will be
caused by the unopposed activity of the other limb of the autonomic
nervous system in that organ. (LO Physiology, Question 1) The
following diagram can illustrate this:

One particular organ that is known for its innervation
is the heart. The heart is well innervated by both
branches of the autonomic nervous system. For the
most part, when the heart rate is under discussion, the
vagus controls most of the heart rate. When people get
scared, their sympathetic activity not only increases,
but the parasympathetic nervous activity goes down.
The SA node is innervated by the parasympathetic
nervous system to place the brakes on the heart rate.
The sympathetic nerves control the heart rate as well
as the strength of the contraction. Remember that it is a fight or flight,
and involves a series of noticeable and hidden effects:
Noticeable Effects Hidden Effects
" Pupil dilation
" Mouth goes dry
" Tension of neck and shoulder muscles
" Heart pumps faster
" Chest pains
" Brain gets body ready for action.
" Adrenaline released for fight/flight. (Surge of
norepinephrine and epinephrine).
" Rise in blood pressure
" Liver releases glucose to provide energy for
35
" Palpitations
" Sweating
" Muscle tension for action
" Breathing fast and shallow
Hyperventilation (Bronchodilation)
" Oxygen needed for muscles
muscles.
" Digestion slows or ceases.
" Sphincters close, then relax
" Cortisol released (depression of the immune
system)

There are many diagram of the sympathetic nervous system. This is for
the pre-ganglionic body in the thoracolumbar spinal cord. Spinal injury
can have changes in organ function depending on the level of the injury. If
you have higher injury, you can have decreased organ function or death.
This is why to think about the anatomy and the sympathetic nervous
system.

This is with the anteromedial lateral horn of the spinal cord, where the
preganglionic cell body is. They actually have more than one choice.
There is redundancy in the anatomy. It is not just one neuron comes out,
visits the ganglia, goes into the heart. There is actually the neuron is at
this level. Sometimes theyll come into this chain, but not synapse, but
might move one or two nodes up, and then go to the
organ. Or it will synapse to the horn and then move
down. There is redundancy in the organ. It also
facilitates rapid response to the organs.

The adrenal gland is one of the exceptions.
Innervation to the adrenal gland itself goes all the
way though the sympathetic chain until it reaches the
adrenal medulla. This means that the synapse is in
the gland. It can cause body-wide release of
epinephrine (a.k.a. adrenaline and norepinephrine)
in an extreme emergency, known as an adrenalin rush or surge.

When we talk about sympathetic drugs, we need to know what happens to
each of these drugs when you give an agonist or an antagonist. The
sympathetic division discharges as a unit in emergency situations. The
effects of this discharge are of considerable value in preparing to cope with
the emergency. For example, sympathetic activity accelerates the heart
rate and raises blood pressure (providing better perfusion of the vital
organs and muscles) and constricts the blood vessels of the skin (which
limits bleeding from wounds).

Increasing sympathetic activity causes:
16
Adrenal gland is exception
Synapse in gland
Can cause body-wide release oI
epinephrine aka adrenaline and
norepinephrine in an extreme
emergency
(adrenaline rush or surge)
36
1. Increases in heart rate and contractility: Rate and force of
contraction go up.
2. Increase in Blood Pressure, due to vasoconstriction of the blood
vessels.
3. Renal and cutaneous blood flows are decreased, to reduce
necessity or urination and having to vasodilate.
4. Splanchnic blood flow is decreased, as blood does not ned to go to
the spleen.
5. Blood flow to the liver and muscles is increased due to the
increase in synthesis and use of energy and increase transport of
energy sources.
6. Increased blood glucose due to glycogenolysis and gluconeogenesis,
due to sympathetic innervation to the beta cells of the pancreas.
7. Visceral activity is decreased.
8. Bronchioles are dilated to facilitate ventilation.
9. Pupils are dilated.
(LO Physiology, Question 2)
The preganglionic cell body for the
parasympathetic nervous system is particularly
in the midbrain and pons or in the sacral region.
The neuron leaves the midbrain and travels all
the way down to its organs and consequently
innervates the organ, whether it is in the gut or
the heart, and in that organ is where you find that
postganglionic neuron.

With the parasympathetic nervous system comes a
parasympathetic discharge. In a general way, the
functions promoted by activity in the
parasympathetic division of the autonomic nervous
system are those concerned with the less physical
aspects of day-to-day living. For example,
parasympathetic activity favors digestion and
absorption of food by increasing the activity of the intestinal musculature,
increasing gastric secretion, and relaxing of the pyloric sphincter.

Increasing parasympathetic activity involves thinking about rest and
digest:
1. Heart rate decreases, due to activation of the parasympathetic
nervous system and the heart rate going down.
2. Gastrointestinal secretions are increased to essentially promote
digestion.
3. Contraction of the gall bladder.
4. Increased glucose storage in the liver.
5. Retina is protected from light.
6. Urinary bladder and rectum are emptied.
(LO Physiology, Question 3)
20
Central control oI the
Autonomic NS
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Reticular formation-Brain Stem:
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37
The best way to remember this is with the acronym SLUDD:
" S Salivation
" L Lacrimation
" U Urination
" D Digestion
" D Defecation

On top of the autonomic nervous system, there is an overlay of the rest of
the brain on the autonomic nervous system. And that is obvious because
you have an autonomic response. The amygdala is the main limbic region
for emotions. It stimulates sympathetic activity, and can be voluntary
when individuals decide to recall a frightful experience. This is because
the cerebral cortex acts through the amygdala. The hypothalamus is the
main integration center, utilizing peptide action and the paraventricular
nuclei. The reticular formation, a part of the brain stem, has the most
direct influence over autonomic function RVLM, NTS. Essentially, higher
order functions do impact the nervous system. What is included here is a
summary thus far:

When we start discussing drugs, we start talking about modulation of
neurotransmitter receptors. Drugs that block that process will affect
something to do with neurotransmission. Remember that the somatic
nervous system is needed to move
your foot, brain, etc., and the
autonomic is involved in unconscious
movements. Preganglionic neurons
both release acetylcholine. It is
important to remember. Post-
ganglionic neurons are where things
get a little different. The
postganglionic neurons in sympathetic
components release catecholamines,
norepinephrine and epinephrine. The
parasympathetic components secrete
Summary thus far.
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acetylcholine.

It can be also noted in the
following diagram also. The top
nervous system, the somatic
nervous system, releases
acetylcholine, acts on nicotinic
Type II receptors. In the middle,
the sympathetic preganglionic
fiber releases acetylcholine to
Nicotinic Type I receptors and
activates the chain. It releases
norepinephrine and activates either alpha-receptors or beta-receptors.
Now what happens with sympathetic activation to the heart is a
consequent increase in heart rate. The parasympathetic preganglionic
fiber goes to the end organ, activates the neuron, and releases
acetylcholine in the gut, but acts on the muscarinic receptor. (LO
Neurochemistry, Question 1)

With different receptors there are different classifications. Lets talk about
cholinergic receptors. Nicotinic receptors are ligand-gated ion channels.
They let sodium cations pass to produce action potentials. Nicotinic Type I
receptors are in the sympathetic and parasympathetic ganglia. They are
also in the adrenal medulla and almost every receptor will be in the central
nervous system. Type II receptors are involved in the somatic nervous
system. They are in skeletal muscle, and also in the brain.

There is also another way to think about it. The illustration above is a
parasympathetic ganglionic synapse. The action potential fires, and goes
through the ganglia. Calcium enters the presynaptic end. The transmitter
(acetylcholine) is released, and acetylcholine binds to the nicotinic
receptor to allow sodium cations to move and excite the postganglionic
neuron. There are three ways by which neurotransmitters are removed
from the synaptic cleft: (1) enzymatic degradation, (2) re-uptake, and (3)
diffusion. There are drugs that will inhibit or act on acetylcholinesterase.
ACh
N2
Nicotinic 2
receptors
Smooth muscle
Cardiac muscle
gland
ganglion
Postganglionic
fiber
Preganglionic
fiber
Sympathetic
Adrenal
Medulla
Epi
NE
ACh ACh
Parasympathetic
Somatic
Nervous system
Central
Nervous System
Peripheral
Nervous System
Effector
Organ
Autonomic
Nervous system

muscarinic
receptors
N1
Nicotinic 1
receptors


Alpha/beta
receptors
N1
39
There is overstimulation of the receptors because of blockers. (LO
Neurochemistry, Question 2) There are cholinergic (acetylcholine
receptors) and the muscarinic receptors (IP3 and decrease cAMP,
activation of potassium channel). There are three types:
Receptor Type Action Location
M1 IP3 CNS, Autonomic Ganglia
M2 Increase IK, decrease
cAMP via Gi
Heart, Sinoatrial Node, Atrioventricular Nodes Atria
Muscle, Ventricles
M3 IP3, Ca
2+
via Gq Exocrine Glands, Smooth Muscle, Endothelial Cells

Often G-protein coupled receptors make heavy use of second messenger
systems. The action potential goes down, releasing acetylcholine, binds to
the receptor, and has its effect on the receptor organ. This can be shown in
another parasympathetic organ synapse. There are specific drugs that
block adenylyl cyclase and the side effects will be dependent upon using
which receptors.

Where these receptors are expressed can allow information as to what
they do. We have two major categories of transmitter systems. The
postganglionic nervous system releases epinephrine and norepinephrine.
The response you get from the organ will depend on whether it affects
alpha-receptors or beta-receptors. There are different types of alpha and
beta-receptors, which is shown in the table. (LO Neurochemistry,
Question 3)
Type Subtype Action Location Description
Alpha Alpha-1 IP3 Postjunctional sites on
effector organs
innervated by the
sympathetic nerves and
the Central Nervous
System.
If you activate the alpha-1-receptor
with a drug, the effects can include
vasoconstriction and spur increases in
blood pressure.
Alpha-2 Decrease
cAMP
Prejunctional sites on
sympathetic neurons,
prejunctional sites on
cardiac parasympathetic
neurons, and some
postjunctional sites on
effector organs.
The alpha-2-receptors inhibit
norepinephrine release. It is
predominantly presynaptic inhibitor of
norepinephrine release.
Beta Beta-1 Adenylyl
Cyclase
Cardiac muscle and
conduction tissue,
adipocytes, and granular
juxtaglomerular cells of
kidney, and central
nervous system.
Activation of the beta-1 causes
increased blood pressure and increased
sympathetic innervation (increased
heart rate and force of contraction)
Beta-2 Adenylyl
Cyclase
Postjunctional on
arterioles and venules,
Activation of the beta-2 receptors
causes bronchodilation.
40
bronchioles, uterus, GI,
liver, and Central Nervous
System

You can remember with the mnemonic: KISS and KICK til youre SICK of
SEX (QISS and QIQ til youre SIQ of SQS): This gives the G-protein type
(Gq, Gi, or Gs) for all the receptors. Receptors are in alphabetical order:
" Alpha-1: Q
" Alpha-2: I
" Beta-1: S
" Beta-3: S
" M1: Q
" M2: I
" M3: Q
" D1: S
" D2: I
" H1: Q
" H2: S
" V1: Q
" V2: S

A sympathetic ganglionic synapse involves the nerve coming out of the
spinal cord, performing action potentials, and entering the sympathetic
chain. The nerves release acetylcholine and stimulate nicotinic receptors,
shown in the following diagram (LO Physiology, Question 2):

It gets even interesting at the organ site. As you stimulate norepinephrine,
and depending on the end organ, the response will depend on the receptors
expressed.

41
The arterial baroreflex is essential the
bodys effort to bring it back to
homeostasis. The arterial baroreflex arch
involves passage of information along an
afferent pathway, reaction of CNS sites to
the received impulse, and resulting change
in efferent discharge. For example,
increases in arterial pressure, detected as
stretching at the aortic and carotid sinus
baroreceptors, leads to vagal activation and
inhibition of sympathetic discharge. Often,
the clinical responses to autonomic drugs
reflect not only the direct effects of the
drug, but also the secondary effects induced
by activation of the baroreceptor reflex.
(LO Physiology, Question 4)
There are sensors (neurons) in the carotid
sinus and the aorta that only sense
pressure. When it gets too high, they
become active. They take sensors to the
brain, activate the neurons, and now know
that pressure has gone up. It sensed it. The
brain senses that pressure has gone up.
The reflex response is to withdraw
sympathetic activity and activate
sympathetic activity. The inverse is also
true. In states of hemorrhage (when there
is a drop in blood pressure), there is an
increase in sympathetic activity and a
decrease in parasympathetic activity.

We can view the change in blood pressure
in experimental studies. In one study,
they infused phenylephrine into mouse
subjects and looked at the heart rate and pulse pressure. They noted that
the heart rate and pulse pressure increased during phenylephrine infusion
and dropped after halting the infusion.
Phenylephrine is an alpha-1-agonist, and the
mechanism of action translated to a systemic effect.

Orthostatic hypotension, also known as postural
hypotension, is a form of low blood pressure that
happens when you stand up from sitting or lying
down. Orthostatic hypotension can make you feel
dizzy or lightheaded, and maybe even faint. This is
due to an inappropriate response of the baroreflex.
(LO Physiology, Question 4)

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42
The following is a general summary in the review of the autonomic nervous
system.
1. The pharmacological response to a class of autonomic drugs can be
predicted if the organ innervation and receptor classification are
known.
2. Drugs alter autonomic function by mimicking the activity of an
endogenous agonist, by preventing the synthesis or release of an
endogenous agonist, by preventing the degradation of an
endogenous agonist or by blocking specific receptors normally
stimulated by an endogenous agonist.
3. The pharmacological effect of an agonist is proportional to the dose
administered.
4. The pharmacological effect of an antagonist is proportional to both
the dose administered and the intensity of receptor stimulation by
the endogenous agonist.
5. The structure of an endogenous agonist can be modified to increase
both receptor specificity, duration of action, and lipid solubility.
6. Preventing its inactivation can increase both the intensity and
duration of stimulation by an endogenous agonist.
7. If a drug inhibits the activity of one limb of the autonomic nervous
system in a dually innervated organ, the side-effects associated with
that drug will be caused by the unopposed activity of the other limb
of the autonomic nervous system.
8. Any peripherally acting drug, which lowers blood pressure and does
not interfere with the function of cardiac beta-adrenergic receptors
will elicit a baroreflex-mediated tachycardia.
Case Study (adapted from Laurie Kelly McCorry,
Case Studies, 2006)
Joe leaves for work at 5:00 AM when it is still quite dark outside. On
Halloween Eve, his neighbors son Johnny placed Matilda, a fully
articulated human skeleton, in the drivers seat of Joes pickup truck.
Halloween morning, Joe arose at 4:45 AM, poured coffee, got ready for
work and walked out to his truck in the driveway.

Completely unsuspecting, when Joe opened the truck door, the sound of
Aghhhh!!! shattered the quiet of the morning. Poor Joe stood by his
truck wide-eyed and clutching his chest. Several events occurred in his
body at once. His heart began racing, his blood pressure increased, his
pupils dilated, he began sweating, the hair on his arms and the back of his
neck stoof on end, and he felt a surge of adrenaline. The neighbors son
Johnny jumped out from where he was hiding and cheerfully wished Joe a
Happy Halloween!

What happened to Joe?

Answer: He essentially had a sympathetic overdrive.
43
Lecture VI
Sympathetic Pharmacology
Lecturer: Dr. Meredith Hay, PhD
Learning Objectives
1. To understand the basic mechanisms underlying the
pharmacological effects of sympathomimetic drugs.
2. To identify the organ location and function of alpha-adrenergic
receptor subtypes.
3. To review the classes and pharmacological effects of
sympathomimetic and sympatholytic alpha-adrenergic drugs.
4. To review the clinical uses for some alpha-adrenergic drugs.
5. To identify the organ location and function of beta-adrenergic
receptor subtypes.
6. To review the classes and pharmacological effects of
sympathomimetic and sympatholytic beta-adrenergic drugs.
7. To review the clinical uses for some beta-adrenergic drugs.
Lecture
So, for any neurotransmitter
system that we talk about,
whether it is adrenergic or
cholinergic or serotonergic,
drugs are going to target one of
the six sites. The following
illustration describes the six
potential sites involved in
neurotransmission as well as
the potential sites of drug
action. We can observe this with the synthesis of norepinephrine (LO S.
Pharmacology, Question 1):
1. Synthesis of a Neurotransmitter: In norepinephrine, drugs can
block the hydroxylation of tyrosine, the rate-limiting step in
synthesis of norepinephrine. There are drugs that will inhibit the
synthesis of epinephrine or norepinephrine.
2. Uptake Into Storage Vesicles: Neurotransmitters have to be packed
into a storage vesicle. In the neuron, dopamine enters a vesicle and
is converted to norepinephrine. Norepinephrine is protected from
degradation in the vesicle. The transport into the vesicle is inhibited
by reserpine.
3. Release of Neurotransmitter: The release of calcium causes fusion
of the vesicle with the cell membrane. The neurotransmitter has to
be release. A major way to inhibit the release of neurotransmitter is
44
to inhibit the influx of calcium. Drugs such as guanethedine and
bretylium can block the release.
4. Binding to Receptor: the binding of the neurotransmitter activates
Postsynaptic receptor. A majority of drugs will block binding to the
receptor. There are direct acting blockers that will block binding.
Receptors also take into account the selectivity.
5. Removal of Neurotransmitter: After release, the neurotransmitter
gets taken up (reuptake) or removed. The releases norepinephrine
is rapidly taken into the neuron.
Drugs such as cocaine and
imipramine can inhibit the
reuptake.
6. Metabolism: In this example,
norepinephrine is methylated by
C0MT and oxidized by
monamine oxidase (MAO).

To understand norepinephrine it is
important to understand the synthesis
of catecholamines. Tyrosine gets taken
into the synaptic cleft. It is converted to
dopa by tyrosine hydroxylase. Dopa is
converted to dopamine by dopa-beta-
decarboxylase. Individuals have made
dopa to produce dopamine. Dopamine is
converted to noradrenaline by dopamine
beta-hydroxylase. In summary, the
neurohumoral transmission process is
simply this:
1. Synthesis and Storage of
Neurotransmitter
2. Release of neurotransmitter
3. Interaction with Postjunctional
Cell and Initiation of Activity
4. Deactivation

This can also be shown in a diagrammatic form. Tyrosine is actively
transported into the terminal. Tyrosine is converted to Dopa and Dopa is
converted to Dopamine. Dopamine is converted to norepinephrine,
packaged into these vesicles. The vesicles, with the influx of calcium
cations, merge with the terminal, release the contents. The contents either
binds to the receptor, get taken back up, or become metabolized. The
catecholamines can be endogenous or exogenous. Epinephrine (Epi),
norepinephrine (NE), dopamine (DA), and isoproterenol (synthetic
catechol) are biogenic amines. Epi, NE, and DA are considered endogenous
agonists, meaning that the body makes it itself. Isoproterenol, however, is
an exogenous agonist. These direct sympathomimetic catecholamiens can
be remembered by the mnemonic DINED:
45
" D Dopamine
" I Isoproterenol
" N Norepinephrine
" E Epinephrine
" D - Dobutamine

Different cardiovascular responses are seen with Epi, NE, and Iso due to
differences in the ratios of the alpha and beta-receptor affinities.
Predicting the receptor response is mainly on the receptor itself. In the
vasculature, we are thinking about expression of beta-1 receptors. It
means that the ratio leans towards beta-1 receptors. However, in the
smooth muscle, there is a predominant expression of beta-2 receptors.
Dopamine is a precursor to norepinephrine and is known to increase
norepinephrine release. At low doses, dopamine activates DA1 receptors in
some vascular beds to cause vasodilation. Dobutamine is a
sympathomimetic drug used in the treatment of heart failure and
cardiogenic shock. Dobutamine is a synthetic catecholamine known to
selectively activate beta-1 receptors involved in contractility vs.
chronotropy. They can be summarized in the following table:
Receptor Typical Locations Result of Ligand Binding
Alpha-1 Postsynaptic effector cells, especially smooth muscle.
Alpha-1 receptors are predominantly post-synaptic,
especially in the smooth muscle (particularly smooth
muscle of vasculature.
" Formation of IP3 and DAG
" Increase intracellular calcium
Alpha-2 Presynaptic adrenergic neruron terminals, platelets,
lipocytes, smooth muscle, and CNS. It essentially
inhibits transmitter release.
" Involved in inhibition of
adenylate cyclase
" Decrease cAMP
Beta-1 Postsynaptic effector cells, especially the heart,
lipocytes, brain, as well as presynaptic cholinergic and
adrenergic terminals.
" Stimulation of adenylate
cyclase.
" Increase cAMP.
Beta-2 Postsynaptic effector cells, especially smooth muscle
and cardiac muscle, but mainly smooth muscle in
bronchiole and GI tract. They activate a calcium
activated potassium channel to relax and cause
bronchodilation
" Stimulation of adenylate
cyclase
" Increase cAMP.
.
Beta-3 Postsynaptic effector cells, especially lipocytes. " Stimulation of adenylate
cyclase
" Increase cAMP.
D1 (DA1),
D5
Brain, effector tissues, especially smooth muscle of the
renal vascular bed
" Stimulation of adenylate
cyclase
" Increase cAMP.
D2 (DA2) Brains, effector tissues, especially smooth muscle,
presynaptic nerve terminals.
" Inhibition of adenylate cyclase
" Increased potassium
conductance
D3 Brain " Inhibition of adenylate cyclase
D4 Brain, Cardiovascular System " Inhibition of adenylate cyclase
When considering the hemodynamic alterations produced by
catecholamines and sympathomimetic amines, the information
is more easily understood and retained if attention is given to:
1. The selectivity of each agent for the different of
adrenoreceptors. It is important to discuss the affinity of
a drug to certain types of receptors.
2. The direct agonistic effects of each agent in the various
parts of the circulatory system.
3. The events, which occur secondary to the activation of
the cardiovascular baroreflexes. It is important to NOT
46
forget the baroreflex.

Now it is important to discuss the sympathetic nervous system and the
effector organs, receptor, and action. In the eye, we can look at the alpha-1
receptors in the iris. They are involved in pupil dilation. We know that it is
the muscles contracting. Beta-1 receptors are predominantly in the heart.
Beta-2 is predominantly in the lung. Blood vessels are predominantly
alpha-1. Beta-2 receptor activation will be involved in relaxation in
skeletal muscle. Alpha-1 is on the sphincter, causing constrction. Alphas
and beta-2 are equally expressed, but predominantly decreasing.
Sphincters are alpha-1 to constrict. The bladder wall contains bladder wall
to facilitate relaxation. The penis and seminal vesicles have alpha-1 to
facilitate ejaculation. The adrenal medulla is nicotinic. There is no
synapse. The intermediate lateral horn branches a nerve out and the
nerve goes into the gland.
Effector Organs Receptor Action
Eye Radial Muscle (Iris) Alpha-1 Contraction (Mydriasis)
Ciliary Muscle Beta-2 Relaxation.
Heart SA Node Beta-1 Increased heart rate
AV Node Beta-1 Increased conduction velocity
Contractility Beta-1 Increased force of contraction.
Lung Bronchial Muscle Beta-2 Relaxation (Bronchodilation)
Blood Vessels Most Blood Vessels Alpha-1 Constriction
Skeletal Muscle Beta-2 Relaxation
Gastro-
intestinal
Tract
Sphincter Alpha-1 Constriction
Motility and Tone Alpha-1, Alpha-2, and
Beta-2
Decrease
Genito-
Urinary
Tract
Sphincter Alpha-1 Constriction
Bladder Wall Beta-2 Relaxation
Penis and Seminal
Vesicles
Alpha-1 Ejaculation
Secretory
Glands
Sweat Alpha-1 Localized Secretion
Intestinal Alpha-2 Inhibition to moderate secretion.
Bronchial
Lacrimal
Metab-olism Adrenal Medulla Nicotinic Secretion of catecholamines
Kidney Beta-1 Increase renin release
Skeletal Muscle Beta-2 Glycogenolysis
Pancrease (Beta-Cell) Alpha-2 Decrease insulin release
Fat Cells Beta-3 Lipolysis
(LO S. Pharmacology, Question 2, 5):
Sympathomimetics mimic the effects of transmitter substances of the
sympathetic nervous system. We have three different types of
sympathetic drugs actions:
1. Direct Acting such as epinephrine, dobutamine, phenylephrine,
norepinephrine, isoproterenol, and clonidine.
2. Indirect Acting, such as tyramine, amphetamine, and cocaine.
3. Mixed acting, such as dopamine, ephedrine, amphetamine,
metaraminol, and phenylpropanolamine.

We can first discuss directly acting agonists. Directly acting agonists are
agents that interact directly with adrenoreceptors. The following is a table
of directly acting agonists and their affinities:
Drug Receptor Affinity
Norepinephrine (Levarterenol) A > B1 > B2
Epinephrine (Adrenalin) B2 > B1 > A
47
Dopamine (Intropin) D1 > B1 > B2 > A1
Phenylephrine (Neo-synephrine) A1 ONLY! This means that is selective to A1!
Oxymetazoline (Afrin) As only
Tetrahydrozoline (Visine) As only
Dobutamine B1 > B2 and A1
Isoproterenol (Isuprel) B1 = B2 (Non-selective agonist)
Albuterol (Ventolin) B2 >> B1
Terbutaline (Brethine) B2 >> B1

We can summarize the sympathetic agonists/sympathomimetic and their
receptor affinities into the following table:
Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2
Phenylephrine Methyldopa Epinephrine Dobutamine Metaproterenol
Methoxamine Clonidine Norepinephrine Terbutaline
Oxymetazoline Guanabenz Dopamine Albuterol
Mitodrine Guanfacine Ibopamine Isoetharine,
Pilbuterol
Metaraminol Bitolterol, Fenoterol
Procaterol
Alpha-1 and Alpha-2 Beta-1 and Beta-2
Naphazoline
Tetrahydrozoline

We observe that the drug affinity or selectivity for a different type of
receptor. We notice that epinephrine, norepinephrine, and dopamine are
endogenous ligands. Phenylephrine is a selective alpha-1 agonist. It is
very popular for OTC medications. It is often used for decongestants.
Clonidine and guanfacine are alpha-2 selective agonists. Clonidine
stimulates the alpha-2 receptor, but mainly acts in the brain. It has been
used for lowering blood pressure. It has also been approved for ADHD
treatments, acting on cortical receptors. It is also used as a sedative in
veterinary practice. Guanfacine lowers both systolic and diastolic blood
pressure. It does the same, but affects peripherally, decreasing the
sympathetic drive in blood vessels. Tetrahydrozoline (Visine) is non-
selective for alphas. It is also used in nasal sprays to spur vasoconstriction
and minimize swelling. Albuterol is the predominantly beta-2 agonist.
There are also special sympathomimetics:
1. Cocaine is one of them. Cocaine was used as a local anesthetic.
Cocaine inhibits uptake 1. Consequently, it increases the availability
of norepinephrine and cause increase in blood pressure, heart rate,
and excitability. It also blocks peripheral sympathomimetic action.
In the Central Nervous System, it inhibits reuptake of dopamine into
neurons in the pleasure centers of the brain.
2. Tyramine is an indirect sympathomimetic because it gets packaged
and released similar to norepinephrine. It is normally a by-product
of tyrosine metabolism. It is found in fermented foods such as
cheese and red wine. It is metabolized by monoamine oxidase. It is
involved in the release of stored catecholamines, giving indirect
sympathomimetic action.
(LO S. Pharmacology, Question 3)
There are also therapeutic uses of alpha-adrenergic agonists:
48

1. Use with local anesthetics: Epinephrine is commonly used as a
vasoconstrictor agent with local anesthetic drugs. It causes
pronounced local
vasoconstriction and thereby
localizes the action and delays
the absorption of the anesthetic.
Since norepinephrine is less
potent an agonist than
epinephrine, it is infrequently
used in local anesthetic
solutions.
2. Local hemostatic:
vasoconstrictor effects of
epinephrine may be used to
control superficial bleeding of
mucosal subcutaneous regions
by application of moistened
gauze sponges or by aerosol
sprayed onto damaged region.
Epinephrine solutions have
been used topically during
ophthalmic surgeries and
dental extractions.
Epinephrine is effective only
against hemorrhage from
capillaries and small arterioles and should not be used to control
bleeding from major vessels. Epinephrine is often used in
combination of local anesthetic agents to prolong the duration of
anesthetic action. This would include articaine, bupivacaine, or
lidocaine. This combination is used because epinephrine can induce
vasoconstriction, thus limiting the diffusion of the local anesthetic
from the site of injection.
3. Hypotension: Pressor amines are often used to maintain blood
pressure during spinal surgery, and epinephrine is quite effective in
treating hypotension associated with anaphylactic shock.
4. Cardiac Effects: Catecholamines are indicated in treatment of
certain cardiac disorders such as cardiac arrest and
atrioventricular block. During cardiac arrest, if CPR fails to restore
heartbeat, epinephrine or isoproterenol may be given in an attempt
to restore contractions.
5. Anaphylactic and Allergic Reactions: Epinephrine is extremely
effective and often lifesaving in treatment of acute anaphylactic
shock. It quickly reverses the fall in blood pressure and cardiac
irregularies associated with this type of syndrome. Bronchiolar
passageways are dilated by epinephrine as the results of relaxation
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49
of smooth muscle, and dyspnea is quickly counteracted. When you
have constriction of the bronchioles, you need to active beta-2 to
dilate the bronchioles.
6. Bronchial Asthma: Isoproterenol and epinephrine have been useful
for providing immediate relief from bronchial asthma. These agents
activate beta-2 receptors of the bronchial smooth muscle cells,
causing relaxation and prompt relief by dilating the airways.
(LO S. Pharmacology, Question 4):
When we think about the transmitter getting into the vesicles, we now
have an idea where these drugs act. A sympatholytic/sympathoplegic
drug is a medication, which inhibits the postganglionic function of the
sympathetic nervous system. Adrenergic blocking drugs are used in
reference to a very explicit mechanism of action. These drugs interact
with the adrenergic receptors by occupying these sites and do not allow an
adrenergic agonist access to the receptor. They are binding to the
receptor, preventing norepinephrine or epinephrine to bind to the
receptor.
Drug Receptor Affinity
Phenoxylbenzamine (Dibenzyline) A1 >> A2
Phentolamine (Regitine) A1 = A2
Prazosin A1
Labetalol A1
Yohimbine A2

The sympatholytics can be summarized into the following table:
Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2
Prazosin, Terazosin Yohimbine Labetalol Metoprolol Butoxamine
Ketanserin,
Alfuzosin
Carvedilol Atenolol
Bunazosin,
Tamsulosin
Acebutolol
Betaxolol
Celiprolol
Esmolol
Alpha-1 and Alpha-2 Beta-1 and Beta-2
Phenoxybenzamine
Phentolamine
(LO S. Pharmacology, Question 6):
Yohimbine reverses clonidine sedation and acts on the Central Nervous
System. It is clinically used to offset the effective clonidine. Prazosin is a
selective alpha-1 antagonist, designed to control blood pressure. It has
been approved for PTSD and anxiety for its actions in the CNS. We can
have orthostatic intolerance as a side effect. Phenoxybenzamine and
phentolamine are non-selective alpha antagonists.

Phenoxybenzamine is an irreversible noncompetitive blocker for 14-48
hours. It inhibits norepinephrine reuptake. It blocks H1, Ach and
serotonin receptors. It blocks catecholamine-induced vasoconstriction. It
is involved in epinephrine reversal. The clinical indications for
phenoxybenzamine include (1) pheochromocytoma, (2) male erectile
dysfunction, and (3) peripheral vascular diseases. Advanced effects
include postural hypotension and tachycardia.

50
Phentolamine is a competitive antagonist, lasting for four hours. It is also
involved in epinephrine-reversal. It reduces PVR. It is involved in cardiac
stimulation, activating the baroreflex and increase in norepinephrine
release. It inhibits serotonin responses. It is indicated for
pheochromocytoma and male erectile dysfunction. Adverse effects can
include severe tachycardia, arrhythmias, myocardial ischemia, and
gastrointestinal stimulation.

An important limitation to therapy with non-selective alpha-blockers such
as phentolamine and phenoxybenzamine is their paradoxical
sympathomimetic activity, especially in the heart. There is a baroreceptor
reflex when youre giving a drug. When we give an alpha-blocker, you get
an increase in heart rate. It is not because the alpha-receptor is affecting
the heart. It is because of the blood vessel dilation. The baroreflex
responds to the blood vessel dilation/decreased blood pressure causing it to
spur epinephrine release. Administration of alpha-blockers can result in
cardiac excitation and increased plasma concentration of epinephrine and
norepinephrine. Historically, these effects were attributed to a triphasic
adjustment in autonomic nerve activity instigated reflexly by the
hypotensive response to inhibition of alpha-vasoconstrictor. These three
phases in response to alpha blockade are:
1. Increased sympathetic efferent traffic over the cardioaccelerator
nerves
2. Decreased vagal impulses to the sinoatrial node (pacemaker).
3. Increased sympathetic firing to the adrenal medulla.

The cardiovascular effects of alpha-adrenergic blocking agents are:
1. Epinephrine reversal: alpha adrenoreceptor antagonists convert
the increase in mean arterial pressure, caused by epinephrine into a
decrease in mean arterial pressure.
2. Yohimbine is highly lipid soluble and blocks central alpha-2
receptors and has some CNS stimulatory effect. It is sometimes used
to reverse the effects of xylazine (a sedative that acts at CNS alpha-2
receptors) in dogs.
3. Some of the more selective alpha-antagonists have been used with
varying degrees of success to reduce vasoconstriction in the
treatment of peripheral vasospasm,
hypertension, pheochromocytoma
in humans.

A pheochromocytoma is a neuroendocrine
tumor of the medulla of the adrenal glands
(originating in the chromaffin cells), or
extra-adrenal chromaffin tissue that failed
to involute after birth, and secretes
excessive amounts of catecholamines. They consequently cause the
increase in synthesis and release of norepinephrine and epinephrine into
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51
the circulation. It results physiological in an increase in blood pressure
and increased heart rate and a hypertensive crisis. Treatment is surgical
removal for solid tumor. Pharmacologically we can use alpha and beta-
blockers such as labetalol. We can use an alpha-blocker such as
phenoxybenzamine or phentolamine. We can use an inhibitor of tyrosine
hydroxylase such as alpha-methyl-p-tyrosine. We can also use a beta-
blocker only after an alpha-blockade. We can use beta-adrenergic blocking
agents (beta-blockers) to address blood pressure. Example of beta-
adrenergic blocking agents (shown with the suffix olol) are shown in the
table:
Drug Receptor Affinity
Propranolol (Inderal) B1 = B2
Timolol (Blocadren) B1 = B2
Nadolol (Corgard) B1 = B2
Metoprolol (Lopressor) B1 >> B2
Atenolol (Tenormin) B1 >>> B2

It can be shown by the previous shown table:
Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2
Prazosin, Terazosin Yohimbine Labetalol Metoprolol Butoxamine
Ketanserin,
Alfuzosin
Carvedilol Atenolol
Bunazosin,
Tamsulosin
Acebutolol

Betaxolol
Celiprolol
Esmolol
Alpha-1 and Alpha-2 Beta-1 and Beta-2
Phenoxybenzamine
Phentolamine

To remember beta-blockers, the -olols that start from A to M are
cardioselective (beta-1), while the -olols that start from N to Z are non-
selective (beta-1 and beta-2). Labetalol and carvedilol are exceptions,
which are both alpha and beta blockers. There are obvious clinical uses to
beta-blockers. We can use it in angina (with non-selective or beta-1-
selective). Beta-blockers are often given to address the workload of the
heart. If you decrease the workload, due to cytokines released, you can
increase the O2 demand. In the cardiac theatre, you can decrease oxygen
demand more than oxygen supply. It is also used in arrhythmias
(especially for beta-1-selective, LA-action). It keeps the heart from
becoming dysrhythmic and keeps it constant. It decreases catecholamine-
induced increases in conductivity and automaticity in the heart, and
decreases the serum potassium cations (action in skeletal muscle). Non-
selective beta-blockers are used in glaucoma to decrease aqueous humor
formation, especially with Timolol. Other uses of beta-blockade include the
block of tremor of peripheral origin, especially with beta-2A receptor in
skeletal muscle. It is used as a prophylaxis for migraines, but the
mechanism is unknown. It is used in the treatment of panic attacks and
stage fright. In sympatholytic drugs, all of these agents directly or
indirectly decrease the release of norepinephrine from peripheral
52
sympathetic neurons and thus lower blood pressure by reducing total
peripheral resistance and/or cardiac output.
1. Reserpine (Serpasil) blocks the uptake and can be a
sympathomimetic, but would deplete the terminal norepinephrine.
It is a catecholamine-depleting agent that blocks the uptake of NE. It
is slow-onset with a half-life of 75 hours.
2. Guanethidine (Ismelin) is an intravenous administration that
causes immediate release of norepinephrine from terminals. This is
followed by a blockade of norepinephrine uptake. After a few hours,
guanethidine also inhibits voltage-dependent release of
norepinephrine.
3. Bretylium (Bretyolol) blocks norepinephrine release from the
terminals. It sdoes not deplete norepinephrine concentration in
terminals.
(LO S. Pharmacology, Question 7)
The sympatholytics have limited use in humans as an antihypertensive. It
has no use in veterinary medicine, except when used as a pharmacological
tool in experimental animals. Drugs that inhibit norepinephrine
metabolism include
1. Cocaine: blocks norepinephrine uptake thus increases
norepinephrine in synapse.
2. Monoamine Oxidase Inhibitors/ MAO Inhibitors ! Deprenyl
(Eldepryl) is used to treat Parkinsons disease. Phenelzine (Nardil)
is the last choice of drug in the treatment of depression.
3. Tricyclic antidepressants (e.g. imipramine (Tofranil)): Imipramine
is a tricyclic antidepressant. It inhibits norepinephrine and
serotonin uptake. Orthostatic hypotension can occur due to alpha-
receptor blockade. It is used also in sedation as a mild analgesic.
Study Questions
What is the effect of timolol and other beta-blockers on the eye? Lungs? Heart?
Blood Vessels? Glands? Bladder? GI Tract?
Beta-1
Selective
Blocker
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Acebutolol No change. No change. Decreased
heart rate,
conduction
velocity,
and
decreased
force of
contraction.
No change. No change. No change. No change.
Betaxolol
Celiprolol
Esmolol
Atenolol
Metoprolol
Propranolol

Non-
Selective
Beta-
Blocker
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Timolol Decrease
intraocular
pressure,
increased
Increased
broncho-
constriction
Decreased
heart rate
and force of
contractility
Decreased
blood
pressure
from beta-
No
change.
Relaxation
of bladder
wall.
Decreased
GI motility
and tone.
Nadolol
Propranolol
53
contraction
of ciliary
muscle.
blockade.
Relaxation
of skeletal
muscles in
blood
vessel.
What is the effect of albuterol and other beta-2 agonists on the eye? Lungs? Heart?
Blood vessels? Glands? Bladder? GI Tract? (Usually, only blood pressure and heart
effects are discussed remember beta-agonists are selective, but not perfectly
selective and you can get some interaction between receptor subtypes).
Beta-2 Agonist Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Albuterol Increased
relaxation
of ciliary
muscle.
Relaxation
of
bronchial
muscles.
No
change.
Increased
relaxation
of skeletal
muscles.
No
change.
Relaxation
of bladder
wall.
Decreased
motility
and tone.
Metaproterenol
Terbutaline
Isoetharine
Pilbuterol
Bitolterol
Fenoterol
Procaterol
What is the effect of EPI, NE, and DA on the eye? Lungs? Heart? Blood vessels?
Glands? Bladder? GI Tract? Kidney?
Endogenou
s Agonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Epinephrine
(B2>B1>A)
Contraction
of radial
muscle
(mydriasis)
, relaxation
of ciliary
muscle.
Relaxation
of
bronchial
muscles.
Increased
heart rate,
conduction
velocity,
and force
of
contractio
n.
Constriction
of blood
vessels and
relaxation
of skeletal
muscle.
Localized
secretion,
inhibition
of
intestinal
and
bronchial
secretion,
and
lacrimal
secretion.
Re-
laxation
of
bladder
wall.
Sphincter
constriction,
and
decreased GI
motility and
tone.
Nor-
epinephrine
(A>B1>B2)
Dopamine
(D1>B1>B2>
A1)
What is the effect of methoxamine, phenylephrine, and other alpha agonists on the
eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? Baroreceptor
reflex?
Alpha-1
Agonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Phenylephrine Contraction
(Mydriasis)
of radial
muscle.
No
change.
No
change.
Constriction
of most
blood
vessels.
Localized
secretion
of sweat
glands.
Inhibition-
Moderate
Secretion.
Constriction
of sphincter
and
ejaculation
from penis
and seminal
vesicles.
Constriction
of
sphincter.
Decreased
GI Motility
and Tone.
Methoxamine
Oxymetazoline
Mitodrine
Metaraminol

Alpha-2
Agonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract
Methyldopa No change. No change. Lowers
blood
pressure
by
decreasing
cardiac
output and
peripheral
vascular
resistance.
No change. Inhibition-
Moderate
Secretion
No change. Decreased
GI motility
and Tone.
Clonidine
Guanabenz
Guanfacine

54
What is the effect of non-specific alpha agonists on the eye? Lungs? Heart? Blood
vessels? Glands? Bladder? GI Tract? Baroreceptor reflex? What role does
orthostatic hypotension play with these drugs? Name the other drugs discussed in
this lecture which may cause orthostatic hypotension?
Non-Specific
Alpha
Agonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract Orthostatic
Hypotension
Naphazoline No
Change.
No
Change.
No
Change.
No
Change.
Inhibition
to
moderate
secretion
from
intestinal,
bronchial,
and
lacrimal
glands.
No
Change.
Decreased
GI
Motility
and tone.
No Change.
Tetrahydro-
zoline
What is the effect of alpha antagonists on the eye? Lungs? Heart? Blood vessels?
Glands? Bladder? GI Tract? Baroreceptor reflex? Orthostatic hypotension?
Alpha-2
Antaonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract Orthostatic
Hypotension
Yohimbine No
change.
No
change.
No
change,
but
higher
doses can
cause
rapid
heart
rate, high
blood
pressure.
Higher
doses can
cause high
blood
pressure.
Otherwise,
no change.
No
change.
No
change.
Relaxation
of GI
Sphincter.
Increased
GI Motility
and Tone.
Possible
orthostatic
hypotension
from low
peripheral
blood
pressure.

Non-
Specific
Alpha
Antaonist
Eye Lungs Heart Blood
Vessels
Glands Bladder GI Tract Orthostatic
Hypotension
Phenoxy-
benzamine
No
change.
No
change.
No change,
but there
will be an
increased
heart rate
due to
baroreflex.
Relaxation
of most
blood
vessels.
No
change.
No
change.
Relaxation
of GI
Sphincter.
Increased
GI Motility
and Tone.
Possible
orthostatic
hypotension
from low
peripheral
blood
pressure.
Phen-
tolamine


55
Lecture VII
Parasympathetic/Cholinergic Pharmacology
Lecturer: Dr. Meredith Hay
Lecture Objectives
1. To understand the basic mechanisms underlying the
pharmacological effects of parasympathetic drugs.
2. To review the cholinergic receptor classes and their organ location
and function.
3. To review the classes and clinical uses of muscarinic and nicotinic
agonists.
4. To review the classes and clinical uses of muscarinic and nicotinic
antagonists.
5. To review the indirectly acting parasympathomimetic drugs.
Lecture
Acetylcholine is the neurotransmitter released from nerve endings which:
1. Innervate cells of the autonomic ganglia ! Acetylcholine is the
primary neurotransmitter of the somatic nervous system. It is also
the primary neurotransmitter innervating the adrenal medulla. It is
the common neurotransmitter for both the sympathetic and
parasympathetic nervous system.
2. Innervate parasympathetic neuroeffector junctions (target organs).
The first neuron comes out innervates nicotinic receptors.
3. Somatic neuromuscular neuromuscular junctions, with neurons that
innervate skeletal muscle with the primary transmitter
acetylcholine.
4. Innervate the adrenal medulla. Even with the sympathetic site of
the adrenal medulla, acetylcholine does go through the sympathetic
chain.
5. Innervate some sympathetic neuroeffector junctions, such that you
will have parasympathetic innervation of a presynaptic junction of a
sympathetic neuron.
6. Innervate some CNS regions. Therefore,
it has a major CNS role.

Understanding of the parasympathetic nervous
system allows us to create
parasympathomimetic agents.
Parasympathomimetic agents cover
specifically pharmacological agents that are used in reference to an
acetylcholine-like effect on effector cells innervated by postganglionic
neurons of the parasympathetic nervous system. Essentially, these are
drugs that mimic the parasympathetic nervous system. Another term
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56
utilized is a cholinergic agent. Cholinergic agents describe an
acetylcholine-like effect without distinction to the anatomic site of action.

The focus this time is specifically on the cholinergic synapses and the
cholinergic release on the efferent junction and dont forget the somatic
nervous system, activating into nicotinic-2 receptors. There are
fundamentally different types of receptors. The nicotinic channels are
ligand-gated ion channels. There are five subunits that make up the ion
channel, spanning the entire channel. When two acetylcholine molecules
bind, there is a change in the structure of the channel, allowing sodium to
enter, depolarizing the post-synaptic membrane and allowing propagation
of the action potential. Nicotinic-1 and Nicotinic-2 are similar, but are
different in the affinities for acetylcholine and other drugs in other sites.
Muscarinic receptors are G-protein coupled receptors. There are different
types of muscarinic receptors associated with different G-Protein coupled
receptors. There are different types of action associated with the receptors
due to different second messenger systems.

In the smooth muscle, the M1 and M3 receptors is linked to a Gq protein,
activating inositol-triphosphate, releasing calcium and causing calcium-
dependent contractions. When you activate the parasympathetic nervous
system in the gut, gut motility increases. You already know that there is
M1 or M3 receptors in the gut.
However, in the heart, there are M2
receptors, which activates potassium
channels. When the parasympathetic
nervous system is activated, heart
rate decreases. Contraction is
inhibited by potassium by
hyperpolarization.

We can start at the top with
cholinergic synapses. We can break down the possible sites of drug
targeting once again into six major steps:
1. Synthesis of Acetylcholine ! Transport of choline is inhibited by
hemicholinium.
2. Uptake Into Storage Vesicles ! Acetylcholine is protected from
degradation in the vesicle. Acetylcholine is packed into synaptic
vesicles, and these synaptic vesicles have to fuse with the
presynaptic membrane and release its contents.
3. Release of Neurotransmitter ! Remember that this is done by
membrane fusion with the vesicle. The release is blocked by
botulinum toxin, and spider venom causes release of acetylcholine.
4. Binding to the Receptor ! binding of the neurotransmitter
activates Postsynaptic receptor.
5. Degradation of Acetylcholine ! Acetylcholine is rapidly
hydrolyzed by acetylcholinesterase in the synaptic cleft. If you
block acetylcholinesterase, acetylcholine binds to the receptor.
57
6. Recycling of Choline ! Choline is taken up by the neuron, and
recycled to make more acetylcholine.
(LO P. Pharmacology, Question 1)
The botulinum toxin (BOTOX) works by inhibiting the SNARE proteins to
promote vesicular fusion. It is a toxin made from a bacteria. Once again,
we can summarize it into four major actions:
1. Synthesis and Storage of Neurotransmitter
2. Release of Neurotransmitter
3. Interaction with Postjunctional Cell and Initiation of Activity
4. Deactivation

Similar to the last time, were going to talk
about the parasympathetic ganglionic
synapse. The parasympathetic ganglionic
synapse is located in the end organ. Most of
them start in the medulla, travel to the
organ that it is innervating and release
acetylcholine (neurotransmitter).
Acetylcholinesterase is here as well.

Here is another diagram of the muscarinic
receptor. The M1 receptors are primarily in
the Central Nervous System and autonomic ganglia. M2s are found in the
heart, and the M3s are found in glands and smooth muscle. M1 and M3
are linked to Gq that activates inositol-triphosphate that increase calcium
and cause contraction. There is increased gland activation to spur releases
of tears, sweat, or fluids. In the smooth muscle, there will be increased
calcium to cause contraction of the smooth muscle. The following table can
summarize the acetylcholine receptors:
Receptor Type Location Postreceptor Mechanism
M1 Nerves IP3 and DAG cascade
M2 Heart, Nerves, and Smooth
Muscles
Inhibition of cAMP production and activation of K
+

channels
M3 Glands, Smooth Muscle,
Endothelium
IP3 and DAG cascade
M4 ? CNS Inhibition of cAMP production
M5 ? CNS IP3 and DAG cascade
NM Skeletal Muscle
Neuromuscular Junction
Na
+
, K
+
depolarizing ion channel
NN Postganglionic Cell Body and
Dendrites
Na
+
, K
+
depolarizing ion channel

With these receptors, they are also distributed differently, depending on
the organ.
Effector Organs Receptor Action
Eye Circular Muscle M3 Contraction (Miosis)
Ciliary Muscle Contraction (Accomodation)
Heart SA Node M2

Decreased heart rate
AV Node Decreased conduction velocity
Contractility Decreased contraction
Lung Bronchial Muscle M3 Contraction
Blood
Vessels
Most blood vessels - -
(For the most part, there is not really
parasympathetic innervation of the blood vessels. If
you give acetylcholine, there are acetylcholine
Skeletal Muscle
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58
receptors on the blood vessels smooth muscle but no
parasympathetic innervation. There is vasodilation
consequently due to release of nitric oxide)
GIT Sphincter M3

Relaxation
Motility and Tone Increased
GUT Trigone and Sphincter
Muscles
M3

Relaxation
Bladder Wall and Detrusor
Muscle
Increase
Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide
Secretory
Glands
Sweat M Generalized Secretion
Intestinal M3 Increased secretion
Bronchial M Increased secretion
Lacrimal M Profuse Secretion
(LO P. Pharmacology, Question 2)

There are many clinical preparations for these agents. Cholinergic
receptor agonists are utilized. However, acetylcholine itself is not use as
systemic therapeutic agents because (1) it is non-receptor selective and
affects multiple organs, and (2) it is rapidly degrade by cholinesterases. If
you give it intravenously, you can see a transient decrease in Mean
Arterial Pressure. This is due to activation of muscarinic receptors on the
endothelial cells of the vasculature. The endothelial cells then release NO
which diffuses to the vascular smooth muscle to cause vasodilation.
Acetylcholine (marketed as Micohol) can be used to produce rapid and
complete miosis before or after surgery involving the anterior portion of te
eye. Carbochol (Isopot Carbachol) has been used in the past, and is
selective for both muscarinic and nicotinic receptors. It causes miosis
after surgery in the anterior chamber of the eye. It is used in the
treatment of severe glaucoma.

Parasympathetic agents prevent acetylcholine producing its characteristic
effects in structures innervated by postganglionic parasympathetic fibers.
They also inhibit the effects of acetylcholine on smooth muscle that
respond to exogenous acetylcholine but lack cholinergic innervation.
Muscarinic antagonists include atropine, scopolamine, homatropine
(shorter acting than atropine with fewer gastrointestinal effects), and
propantheline (quaternary compound with no effects on Central Nervous
System). Homatropine and propantheline are selective muscarinic
antagonists with lesser side effects. If it does not exert CNS effects, then it
cannot cross the blood-brain barrier. Clinically, atropine is routinely used
in the following:
1. Atropine is routinely used as an adjunct to general anesthesia to
decrease salivary and airway secretions.
2. Atropine is routinely used in ophthalmic
examinations and treatment of ocular
disorders.
3. Atropine is the primary and essential
antidote to anticholinesterase poisoning.
4. Parasympatholytic drugs are frequently
used to control smooth muscle spasm and
are used to decrease GI hypermotility.
59

Atropine and scopolamine are competitive antagonists. They both compete
with acetylcholine for the muscarinic receptor and have atropine as a
sympathomimetic, mainly because it gives the sympathetic nervous
system a free-run.

Atropine is a prototype and an isolate of the belladonna alkaloid. It has a
high affinity for muscarinic receptors. It is also a central and peripheral
muscarinic blocker. It causes reversible (surmountable) blockade of the
actions of cholinomimetics at muscarinic receptors. IT causes reversible
blockade of the actions of cholinomimetics at muscarinic receptors, giving
unopposed sympathetic action.

Anticholinergic effects can be remembered with this:
" DRY AS A BONE Dry mucous membranes, urinary retention,
constipation
" MAD AS A HATTER Restlessness, tachycardia, palpitations, HA,
dizziness
" RED AS A BEET Flushed, hot, and dry skin
" BLIND AS A BAT Pupillary dilation (mydriasis), blurred vision
(cycloplegia), photophobia.

Other muscarinic agonists include methacholine (provocholine), which is
selective for muscarinic receptors, but can bind to nicotinic receptors at
high enough doses. Bethanechol (Urecholine) has a selective effect on the
gastrointestinal and genitourinary smooth muscle. It can be used to treat
bowel stasis, postoperative paralytic ileus, and urinary retention. The use
of these drugs for colic and impactions should be closely monitored.
Excessive peristalsis in a patient suffering from severe obstruction can
promote rupture. Pilocarpine (Pilorcar) is extremely selective for
muscarinic receptors over nicotinic receptors and are used for glaucoma.
What is unique about it is that it is insensitive to acetylcholinesterase,
giving it a longer half-life. It is in naturally occurring plant alkaloids
primarily used in the treatment of acute glaucoma. (LO P.
Pharmacology, Question 4)

Autonomic Ganglionic Blocking Drugs (or nicotinic antagonists are agents
that act by competitive blockade of NN-cholinergic receptors at the
autonomic ganglia and prevent all sympatheticparasympathetic nerve
activity from reaching the end organs. They are competitive antagonists.
If you are blocking a nicotinic receptor between the preganglionic and post-
ganglionic neuron, it will affect parasympathetic and sympathetic nervous
system. The pharmacological effects are easy to predict if the predominant
autonomic tone to each organ is considered. Some nicotinic antagonists
include:
1. Hexamethonium: used to treat chronic hypertension, but the non-
specificity of such treatment led to its discontinuation.
60
2. Trimethaphan (Arfonad): used to produce controlled hypotension
during vascular, ocular, and neurologic surgeries. It lowers blood
pressure, and provides a controlled drop in blood pressure.
3. Chlorisondamine

We can summarize it into the following table:
Susceptibility to
cholinesterase
Muscarinic Effects Nicotinic Effects Therapeutic
Effects
Ach + +++ +++ Miotic
Metacholine + ++++ + Dx of bronchial
hyperactivity
Carbachol - +++ ++ Miotic
Betanechol - ++ - Non-obstructive
urinary retention

Drugs that affect acetylcholinesterase are also an indirectly acting
parasympathomimetic. The pharmachological effects of cholinesterase
inhibitors can be explained almost entirely by their characteristic
inhibitory action on acetylcholinesterase. If you block
acetylcholinesterase, you give an exacerbated response of the
parasympathetic nervous system. There are two main types of
acetylcholinesterase inhibitors: reversible (anticholinesterases) and
irreversible (organophosphates). Remember that acetylcholine breaks
down into choline and acetic acid in the presence of cholinesterase, and an
anticholinesterase will inhibit cholinesterase, increasing the concentration
of acetylcholine !"#$%&"!!"#$%
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Reversible inhibitors include:
1. Physostigmine (Antilirium): Physostigmine inhibits the CNS and
consequently has CNS. This is because it is lipophilic and freely
enters CNS. Therapeutic uses include glaucoma, atropine overdose,
and Alzheimers disease.
2. Neostigmine (Prostigmin): Neostigmine is not active in the Central
Nervous System. It is a partial agonist at Nicotinic-2 receptors. The
therapeutic uses include atony of gastrointestinal and genitourinary
smooth muscles, postoperative paralytic ileus, reversal of the action
of neuromuscular blocing agents.
3. Edrophonium (Tensilon): It is not active in Central Nervous System,
and a partial agonist of Nicotinic-2 receptors.
(LO P. Pharmacology, Question 3)

It can be described further in this table:
Inhibitor Description CNS? DOA
(hrs.)
Therapeutic Uses Adverse Effects
Physo-
stigmine
Alkaloid,
tertiary
ammonium
grp
Enters the
CNS
0.5 to 2 " Atony of
intestines and
bladder
" Glaucoma !
Lowers IOP
" Antidote !
Atropine,
phenothiazines,
TCA
" NDMR
" Convulsions
" Bradycardia
" CO
61
(Tubocurarine)
Reversal
Neo-
stigmine
Quaternary
Ammonium
grp
Does not
enter the
CNS !
peripheral
0.5 to 2 " Atony of
intestines and
bladder
" Myasthenia
Gravis
" NDMR
(tubocurarine)
Antidote
" Salivation
" Flushing
" Decreased blood
pressure
" Nausea
" Abdominal Pain
" Diarrhea
" Bronchospasm
Edro-
phonium
Quaternary
amine
Does not
enter the
CNS !
Peripheral
0.5 to 2 " Diagnosis of
myasthenia
gravis
" NDMR
(tubocuraine)
antidote
" Arrhythmias
(SVT)
" Antidote for
atropine
poisoning
" Salivation
" Flushing
" Decreased Blood
Pressure
" Nausea
" Abdominal Pain
" Diarrhea
" BRonchospasm

There are also irreversible inhibitors of acetylcholinesterase. These
compounds were developed to function as insecticides or nerve gases for
chemical warfare. Organophosphates act as irreversible inhibitors of the
cholinesterases in mammals. Organophosphates irreversibly
phosphorylate acetylcholinesterase, because it is irreversible. The side
effects of organophosphate poisoning are severe. These compounds
irreversibly phosphorylate both acetylcholinesterase and
pseudocholinesterases. Classic symptom includes extreme overexcitation
of parasympathetic nervous system. Because endogenous acetylcholine is
not inactivated, the resulting effects are due to the excessive preservation
and accumulation of acetylcholine. Some organophosphates include:
Organophosphate Uses
Malathion and Parathion Insecticides for plants and livestock
Dimpylate (Diazinon) Insecticide
Carbaryl (Sevin) Insecticide (is slowly reversible carbomoylation)
Dichlorvos Oral anthelmintic, pesticide
Soman, Serin Nerve gas

Organophosphate poisoning has diffuse cholinomimetic
effects; with these signs reflect excess activation of
muscarinic and nicotinic receptors of postganglionic
parasympathetic neuroeffector junctions. The signs and
symptoms include: (1) miosis, (2) salivations and frothy
secretions, (3) sweating, (4) bronchial constriction, (5)
vomiting and diarrhea, and (6) muscle fasciculation
(muscle twitches in the face). Organophosphate
poisoning is treated with therapy. It involves
maintenance of vital signs for respiration,
decontamination. Drugs utilize involve atropine and pralidoxime.
Atropine sulfate involves 1 to 2 milligrams intravenously every 5-15
minutes until the muscarinic effect disappears. The maximum is 1 gram
per day. Pralidoxime is utilized to help regenerate acetylcholinesterase
and help generate new enzyme. It is a cholinesterase enzyme regenerator
compound, and it is usually 1 to 2 grams given over thirty minutes by
intravenous infusion. You can know this with SLUDGE BAM:
62
" S: Salivation
" L: Lacrimation
" U: Urination
" D: Defecation
" G: Gastrointestinal Distress
" E: Emesis
" B: Breathing Difficulty
" A: Arrhythmias
" M: Miosis

Nicotinic effects can be remembered with the days of the week:
" M: Mydriasis
" T: Tachycardia
" W: Weakness
" H: Hypertension & Hyperglycemia
" F: Fasciculations

Myasthenia gravis causes weakness of the voluntary (skeletal) muscles.
Voluntary muscles are those that are under your control. In other words,
you think about moving your arm, and it moves. The muscle weakness of
myasthenia gravis worsens with activity and improves with rest. The
muscle weakness can lead to a variety of symptoms, including (1)
difficulty breathing because of weakness of the chest wall muscles, (2)
chewing or swallowing difficulty, causing frequent gagging, choking, or
drooling, and (3) facial paralysis or weakness of the facial muscles.
Medications that may be prescribed include neostigmine to improve the
communication between the nerves and the muscles.
(LO P. Pharmacology, Question 5)
Cholinergic Pharmacology Study Questions
Briefly discuss the synthesis and metabolism of acetylcholine.
We can start at the top with cholinergic synapses. We can break down the
possible sites of drug targeting once again into six major steps:
1. Synthesis of Acetylcholine ! Transport of choline is inhibited by
hemicholinium.
2. Uptake Into Storage Vesicles ! Acetylcholine is protected from
degradation in the vesicle. Acetylcholine is packed into synaptic
vesicles, and these synaptic vesicles have to fuse with the
presynaptic membrane and release its contents.
3. Release of Neurotransmitter ! Remember that this is done by
membrane fusion with the vesicle. The release is blocked by
botulinum toxin, and spider venom causes release of acetylcholine.
4. Binding to the Receptor ! binding of the neurotransmitter
activates Postsynaptic receptor.
63
5. Degradation of Acetylcholine ! Acetylcholine is rapidly
hydrolyzed by acetylcholinesterase in the synaptic cleft. If you
block acetylcholinesterase, acetylcholine binds to the receptor.
6. Recycling of Choline ! Choline is taken up by the neuron, and
recycled to make more acetylcholine.
Where in the ANS are the cholinergic receptors located?
The parasympathetic ganglionic synapse is located in the end organ. Most
of them start in the medulla, travel to the organ that it is innervating and
release acetylcholine (neurotransmitter). Acetylcholinesterase is here as
well. It will typically originate in the medulla of the Central Nervous
System.
Outline the effect of activating muscarinic receptors in the heart, lung, eye, glands,
GI.
Receptor Heart Lung Eye Glands GI
Muscarinic Decreased heart
rate, conduction
velocity and
contraction.
Contraction of
bronchial
muscle.
Contraction of
the circular
muscle and
ciliary muscle.
Increased
generalized
secretion.
Relaxation of the
sphincter and
increased motility
and tone.
Classify cholinergic receptors.
The focus this time is specifically on the cholinergic synapses and the
cholinergic release on the efferent junction and dont forget the somatic
nervous system, activating into nicotinic-2 receptors. There are
fundamentally different types of receptors. The nicotinic channels are
ligand-gated ion channels. There are five subunits that make up the ion
channel, spanning the entire channel. When two acetylcholine molecules
bind, there is a change in the structure of the channel, allowing sodium to
enter, depolarizing the post-synaptic membrane and allowing propagation
of the action potential. Nicotinic-1 and Nicotinic-2 are similar, but are
different in the affinities for acetylcholine and other drugs in other sites.
Muscarinic receptors are G-protein coupled receptors. There are different
types of muscarinic receptors associated with different G-Protein coupled
receptors. There are different types of action associated with the receptors
due to different second messenger systems. The M1 receptors are
primarily in the Central Nervous System and autonomic ganglia. M2
receptors are found in the heart, and the M3 receptors are found in glands
and smooth muscle. M1 and M3 are linked to Gq that activates inositol-
triphosphate that increase calcium and cause contraction. There is
increased gland activation to spur releases of tears, sweat, or fluids. In the
smooth muscle, there will be increased calcium to cause contraction of the
smooth muscle. The following table can summarize the acetylcholine
receptors:
Receptor Type Location Postreceptor Mechanism
M1 Nerves IP3 and DAG cascade
M2 Heart, Nerves, and Smooth
Muscles
Inhibition of cAMP production and activation of K
+

channels
M3 Glands, Smooth Muscle,
Endothelium
IP3 and DAG cascade
M4 ? CNS Inhibition of cAMP production
M5 ? CNS IP3 and DAG cascade
NM Skeletal Muscle
Neuromuscular Junction
Na
+
, K
+
depolarizing ion channel
64
NN Postganglionic Cell Body and
Dendrites
Na
+
, K
+
depolarizing ion channel

With these receptors, they are also distributed differently, depending on
the organ:
Effector Organs Receptor Action
Eye Circular Muscle M3 Contraction (Miosis)
Ciliary Muscle Contraction (Accomodation)
Heart SA Node M2

Decreased heart rate
AV Node Decreased conduction velocity
Contractility Decreased contraction
Lung Bronchial Muscle M3 Contraction
Blood
Vessels
Most blood vessels - -
(For the most part, there is not really
parasympathetic innervation of the blood vessels. If
you give acetylcholine, there are acetylcholine
receptors on the blood vessels smooth muscle but no
parasympathetic innervation. There is vasodilation
consequently due to release of nitric oxide)
Skeletal Muscle
GIT Sphincter M3

Relaxation
Motility and Tone Increased
GUT Trigone and Sphincter Muscles M3

Relaxation
Bladder Wall and Detrusor
Muscle
Increase
Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide
Secre-
tory
Glands
Sweat M Generalized Secretion
Intestinal M3 Increased secretion
Bronchial M Increased secretion
Lacrimal M Profuse Secretion
Classify cholinergic drugs.
Cholinergic drugs are classified by the following:
1. Acetycholine Receptor Agonists (Pilocarpine, Muscarine, Nicotine)
2. Acetylcholinesterase Inhibitors (Neostigmine, Physostigmine,
Edrophonium, Organophosphates)
What is myasthenia gravis?
Myasthenia gravis causes weakness of the voluntary (skeletal) muscles.
Voluntary muscles are those that are under your control. In other words,
you think about moving your arm, and it moves. The muscle weakness of
myasthenia gravis worsens with activity and improves with rest. The
muscle weakness can lead to a variety of symptoms, including (1)
difficulty breathing because of weakness of the chest wall muscles, (2)
chewing or swallowing difficulty, causing frequent gagging, choking, or
drooling, and (3) facial paralysis or weakness of the facial muscles.
Name one cholinergic drug used to treat myasthenia gravis.
Medications that may be prescribed include neostigmine or another
anticholinesterase inhibitor to improve the communication between the
nerves and the muscles.
Classify anti-cholinergic drugs (atropine substitutes) according to therapeutic use.
Anti-cholinergic drugs are classified by the following:
1. Muscarinic Antagonists (Atropine, Scopolamine, Homatropine,
Propantheline)
2. Nicotinic Antagonists (Hexamethonium, Trimethaphan,
Chlorisondamine)
65
Write short notes on (a) Pilocarpine (b) Physostigmine (c) Neostigmine (d)
Edrophonium (e) Atropine (f) Treatment of Acute Glaucoma
Drug Description
Pilocarpine Pilocarpine (Pilorcar) is extremely selective for muscarinic receptors over nicotinic receptors
and are used for glaucoma. What is unique about it is that it is insensitive to
acetylcholinesterase, giving it a longer half-life. It is in naturally occurring plant alkaloids
primarily used in the treatment of acute glaucoma.
Physostigmine Physostigmine inhibits the CNS and consequently has CNS. This is because it is lipophilic and
freely enters CNS. Therapeutic uses include glaucoma, atropine overdose, and Alzheimers
disease.
Neostigmine Neostigmine is not active in the Central Nervous System. It is a partial agonist at Nicotinic-2
receptors. The therapeutic uses include atony of gastrointestinal and genitourinary smooth
muscles, postoperative paralytic ileus, reversal of the action of neuromuscular blocing agents.
Edrophonium It is not active in Central Nervous System, and a partial agonist of Nicotinic-2 receptors.
Atropine Atropine is a prototype and an isolate of the belladonna alkaloid. It has a high affinity for
muscarinic receptors. It is also a central and peripheral muscarinic blocker. It causes
reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors.
It causes reversible blockade of the actions of cholinomimetics at muscarinic receptors, giving
unopposed sympathetic action.
Treatment of
Acute
Glaucoma
Carbochol (Isopot Carbachol) has been used in the past, and is selective for both muscarinic
and nicotinic receptors. It causes miosis after surgery in the anterior chamber of the eye. It is
used in the treatment of severe glaucoma.
Discuss the steps of management of organophosphate poisoning.
Organophosphate poisoning is treated with therapy. It involves
maintenance of vital signs for respiration, decontamination. Drugs utilize
involve atropine and pralidoxime. Atropine sulfate involves 1 to 2
milligrams intravenously every 5-15 minutes until the muscarinic effect
disappears. The maximum is 1 gram per day. Pralidoxime is utilized to
help regenerate acetylcholinesterase and help generate new enzyme. It is
a cholinesterase enzyme regenerator compound, and it is usually 1 to 2
grams given over thirty minutes by intravenous infusion.

66
Lecture VIII
Review and Case Studies
Lecturer: Dr. Meredith Hay
Application of the ANS to the Understanding of
Human Health
True understanding of autonomic physiology and pharmacology requires
more than simply memorizing receptors, transmitters, and drugs.
Applying your new knowledge to understanding how the ANS is altered
during disease and how ANS drugs are used in therapy is essential for a
deep understanding of the ANS. The case studies serve to separate
students who have simply memorized aspects of the ANS from students
who have a more thorough understanding of this system. Successful
completion of the case studies requires higher level critical-thinking and
problem-solving skills.
Case#1: Insecticide Poisoning
CD is a 44-year-old woman who had spent much of the day working in her
garden. A blustery wind caused her to unintentionally inhale the
insecticide that she was spraying throughout the garden. When she began
wheezing severely, she was taken to the emergency room. The attending
physician observed other symptoms including constricted pupils and a
slowed heart rate. CD was trated with the intravenous administration of
atropine sulfate.
Insecticides contain organophosphates, which inhibit acetylcholinesterase. What is the
function of acetylcholinesterase?
Acetylcholinesterase is a serine protease that hydrolyzes the
neurotransmitter acetylcholine. Its activity serves to terminate synaptic
transmission.
Which types of autonomic receptors are excessively stimulated as a result of this
inhibition?
The receptors of the parasympathetic division of the autonomic nervous
system are excessively stimulated due to the accumulation of
acetylcholine in the synaptic terminals. The muscarinic receptors are
excessively stimulated.
Which division of the ANS has been primarily affected, the sympathetic or the
parasympathetic?
The parasympathetic branch of ANS is affected.
Under what conditions does this division of the ANS normally predominate?
The conditions this division of the ANS normally predominate is typically
in a rest and digest situation.
67
Explain how the insecticide resulted in her presenting symptoms.
The organophosphates in the insecticide irreversibly inhibit
acetylcholinesterase. The acetylcholine accumulates in the synaptic
terminal, causing excessive parasympathetic stimulation. Remember the
table.
Effector Organs Receptor Action
Eye Circular Muscle M3 Contraction (Miosis)
Ciliary Muscle Contraction (Accomodation)
Heart SA Node M2

Decreased heart rate
AV Node Decreased conduction velocity
Contractility Decreased contraction
Lung Bronchial Muscle M3 Contraction
Blood
Vessels
Most blood vessels - -
(For the most part, there is not really
parasympathetic innervation of the blood vessels. If
you give acetylcholine, there are acetylcholine
receptors on the blood vessels smooth muscle but no
parasympathetic innervation. There is vasodilation
consequently due to release of nitric oxide)
Skeletal Muscle
GIT Sphincter M3

Relaxation
Motility and Tone Increased
GUT Trigone and Sphincter
Muscles
M3

Relaxation
Bladder Wall and Detrusor
Muscle
Increase
Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide
Secretory
Glands
Sweat M Generalized Secretion
Intestinal M3 Increased secretion
Bronchial M Increased secretion
Lacrimal M Profuse Secretion
What effects may the insecticide have on the gastrointestinal system? Explain.
It can cause relaxation of the sphincter of the gastrointestinal tract as well
as cause increased gut motility and tone, causing nausea and diarrhea.
What effect may the insecticide have on generalized sweating in the patient? Localized
sweating? Explain.
It will have generalized sweating due to muscarinic activation in the
secretory glands.
If exposed to high enough doses, what effect might the insecticide have on the patients
skeletal muscles?
Excessive acetylcholine will cause contraction of the patients skeletal
muscles due to the nicotinic receptors in the skeletal muscle.
Would the administration of a beta-adrenergic receptor antagonist be useful in the
treatment of this patient? Why or why not?
A beta-adrenergic receptor antagonist would not be useful in the treatment
of the patient because organophosphate toxicity presents with decreased
heart rate, blood pressure, and force of contractility. It would be more
damaging to give a beta-adrenergic receptor antagonist as a mode of
treatment for a patient with this condition.
Would the administration of a beta-adrenergic receptor agonist be useful in the treatment
of this patient? Why or why not?
It will be useful to increase heart rate, blood pressure, and force of
contractility of the heart while administering atropine and pralidoxime.
68
Why is atropine an appropriate treatment?
Atropine is an appropriate treatment because it is a competitive antagonist
to the muscarinic receptor. It will compete with acetylcholine for the same
binding site.
The nerve gas, sarin, is a potent, irreversible organophosphate. What is the likely cause
of death resulting from exposure of this extremely toxic agent?
The likely cause of death resulting from exposure of this extremely toxic
agent is due to asphyxiation by excessive salivation and
bronchoconstriction.
Case #2: Pheochromocytoma
AF is a 55-year-old woman who had been experiencing hearts palpitations,
a throbbing headache, sweating, pain in the abdomen, nausea, and
vomiting. Because these symptoms had failed to subside, she went to see
her primary care physician. A urinalysis revealed the presence of
catecholamines and their metabolites, including vanillylmandelic acid
(VMA). A subsequent CT scan confirmed the presence of a tumor in the
adrenal medulla. Surgery to remove the tumor was scheduled.
What is a pheochromocytoma?
A pheochromocytoma is a neuroendocrine tumor of the medulla of the
adrenal glands, secreting excessive amounts of catecholamines, usually
norepinephrine and epinephrine.
What are the catecholamines? Which is the predominant compound?
The major catecholamines in the body are norepinephrine, epinephrine,
and dopamine. Norepinephrine is the predominant compound.
Norepinephrine is 80%, while epinephrine is 20%.
Describe the relationship of the adrenal medulla to the autonomic nervous system. Under
what conditions are the catecholamines typically released?
Catecholamines are typically released under fight or flight conditions,
where survival is necessary.
How are catecholamines normally eliminated from the blood?
Catecholamines are normally eliminated from the blood by methylation by
catechol-O-methyltransferases (COMT) or by deamination by monoamine
oxidase (MAO). Amphetamines and MAOIs bind to MAO in order to inhibit
its action of catecholamine breakdown. Amphetamines not only cause a
release of dopamine, epinephrine, and norepinephrine into the blood
stream but also suppress re-absorption.
Is heart rate slower or faster than average in this patient? Why? What autonomic
receptors are involved with this change in heart rate?
Heart rate will increase because the catecholamines are acting on the beta-
1 receptors.
Is blood pressure likely to be lower or higher than average in this patient? Why? What
autonomic receptors are involved with this change in blood pressure?
BP is high because of vascular constriction.
69
Describe the mechanism of excessive sweating in the patient. What autonomic receptors
are involved with this sweating?
Effector Organs Receptor Action
Eye Radial Muscle (Iris) Alpha-1 Contraction (Mydriasis)
Ciliary Muscle Beta-2 Relaxation.
Heart SA Node Beta-1 Increased heart rate
AV Node Beta-1 Increased conduction velocity
Contractility Beta-1 Increased force of contraction.
Lung Bronchial Muscle Beta-2 Relaxation (Bronchodilation)
Blood Vessels Most Blood Vessels Alpha-1 Constriction
Skeletal Muscle Beta-2 Relaxation
Gastro-
intestinal
Tract
Sphincter Alpha-1 Constriction
Motility and Tone Alpha-1, Alpha-2, and
Beta-2
Decrease
Genito-
Urinary
Tract
Sphincter Alpha-1 Constriction
Bladder Wall Beta-2 Relaxation
Penis and Seminal
Vesicles
Alpha-1 Ejaculation
Secretory
Glands
Sweat Alpha-1 Localized Secretion
Intestinal Alpha-2 Inhibition to moderate secretion.
Bronchial
Lacrimal
Metabolism Adrenal Medulla Nicotinic Secretion of catecholamines
Kidney Beta-1 Increase renin release
Skeletal Muscle Beta-2 Glycogenolysis
Pancrease (Beta-Cell) Alpha-2 Decrease insulin release
Fat Cells Beta-3 Lipolysis

The excessive sweating is due to the binding of catecholamines to alpha-1
and alpha-2 receptors of secretory glands. There is an expectation of
localized sweating, but the diaphoresis becomes generalized as more sweat
glands are activated.
Would you expect the patients pupils to be constricted or dilated when her other
symptoms are at a peak? What is the clinical term used to describe this condition?
Patients pupils will dilate because the muscles contract and the receptors
are alpha-1 in the radial muscles of the eye. This is known as mydriasis.
How does the duration of activity of the circulating catecholamines compare to that of
neuronally released norepinephrine? Explain.
Because there is more epinephrine and norepinephrine being secreted and
not localized in a neuronal synapse, the effect of the systemic activity will
be longer in duration.
How does the breadth of activity of the circulating catecholamines compare to that of
neuronally released norepinephrine? Explain.
Breadth of activity would be the larger compared to neuronally released
norepinephrine. Youre activating more and systemic and longer.
In order to prepare the patient for surgery, what types of autonomic nervous system
medications may be used to stabilize her blood pressure within the normal range?
Treatment is surgical removal for solid tumor. Pharmacologically we can
use alpha and beta-blockers such as labetalol. We can use an alpha-blocker
such as phenoxybenzamine or phentolamine. We can use an inhibitor of
tyrosine hydroxylase such as alpha-methyl-p-tyrosine. We can also use a
beta-blocker only after an alpha-blockade. We can use beta-adrenergic
blocking agents (beta-blockers) to address blood pressure.
70
Clinical Implications of ANS Pharmacology
Understanding the clinical implications of ANS Pharmacology will be
applicable to many different occupations including human medicine,
veterinary medicine, pharmacy, nursing, or a physiologist or
pharmacology researcher.

The tables below displays exercises that will help you logically think
through the effect of different ANS drugs on an induced physiological state
or drug overdose. REMEMBER TO CONSIDER NOT ONLY THE DIRRECT
EFFECT OF EACH DRUG OR PHYSIOLOGICAL STATE, but THE ROLE
BAROREFLEX RESPONSE AS WELL.

Fill in the following blanks with the symbols +, -, or NC to denote an
increase, decrease, or no change, respectively, in the blood pressure of an
awake cat. Each row represents the effects in a different animal. Assume
that the effect of the antagonist lasts throughout the experiment.
Cats
Pretreated
With
Cats collar
is restricting
blood flow to
the head
Dog
enters
clinic and
cat tries
to kill
dog.
Cat presents in
clinic with bee
sting allergy.
You overdose
with too much
epinephrine.
Cat presents in clinic
after eating half the
clients cocaine stash.
(Cocaine blocks uptake
of norepinephrine and
epinephrine)
Cat presents in
clinic after eating
three flea collars
(its a big cat)
Nothing
(Control)
+ + + + -
Trimethaphan
(Nicotinic
receptor
antagonists !
Both SNS and
PSNS are
blocked.)
N.C. N.C. ++ (there is no
baroreflex to
bring it down)
+ -
Bretylium
(blocks NE
release)
N.C. N.C. + N.C. -
Prazosin
(blocks alpha-
1)
N.C. N.C., but
HR +
N. C. N.C. -
Phentolamine
(Alpha-1 and
Alpha-2
blocker)
N.C. N.C., but
HR +
N.C. but HR +
due to reflex
tachycardia
+ N.C.
Atropine
(comp.
antagonist for
muscarinic
receptors)
+ + + + -
Atenolol
(Beta-
blocker)
+ + + + N.C.
Labetalol
(Beta-
blocker)
+ + + + N.C.
Trimethephan
and
Phentolamine
N.C. N.C. ++ + -
Atropine,
Bretylium,
and
Phentolamine
N.C. N.C. N.C. N.C. N.C.


71

Lectures IX
Cardiovascular Disease Pharmacotherapy #1
Lecturer: Dr. Joseph S. Alpert, M.D.

What are the different kinds of cardiovascular diseases that are treated
with pharmacological agents, that is, drugs? We need a little background,
because if you dont know the diseases and its manifestations, we wont be
able to understand the drugs. Disease is often a state of abnormal
physiology, and drugs are utilized to reverse the damage associated with
such abnormal physiology. In cardiovascular pharmacology, we often use
drugs to treat these cardiovascular disorders (and many more):
" Hypertension
" Lipid (fats in the blood) disorders
" Atherosclerotic disease myocardial infarction (MI), angina, stroke
(CVA)
" Heart failure (CHF)
" Cardiac arrhythmias
" Valvular heart disease
" Cardiomyopathy
" Congenital heart disease

Atherosclerosis is often known as the
disease of industrial societies. It is the
number one cause of death in the world.
The cause of heart attacks is typically the
change in diet, a transition from fresh
vegetables and high-quality foods to
hamburgers, pizza, and other junk food.
There are genetic propensities, but those
were not really translated to a phenotype
mainly because individuals were not
engaged into poor nutrition or a sedentary lifestyle. Cigarettes were not as
plentiful and smoked as much before as it is today. It is seen all over the
world, with 2,102,000 in North America, 6,044,000 in Europe, 3,564,000
in Asia, 1,116000 in Oceania, 436,000 in Africa, and 1,538,000 in South
America. You can note that this is not a very small problem.

So, lets discuss myocardial infarction. The Myocardial refers to muscle
of the heart and infarction means death of tissue from lack of blood flow.
Lots of things can injure the heart and kill heart cells, such as trauma
(injury) or viral infection (inflammation). However, a heart attack must
have a lack of blood flow. It is caused by a sudden blockage of blood flow in
a coronary artery by a blood clot leading to death of the heart muscle.
Atherosclerosis is almost always the cause of the formation of the blood in
the artery. The damaged heart often survives the myocardial infarction
!"# %&' ()*+#,-./ 0**1)2 3*.-+#*.#
1,538,000
6,044,000
1,116,000
2,102,000
Adaptedfrom American Heart Association: Adaptedfrom American Heart Association: Heart andStroke Stati stical Update, 1998 Heart andStroke Stati stical Update, 1998..
3,564,000
Incidence rates based on 1995 data Incidence rates based on 1995 data
436,000
72
but may have reduced function, causing shortness of
breath, leg swelling, and even arrhythmias that can
cause sudden death at a later point in time. Often, a
manifestation of myocardial infarction is sudden
death. An individual can be perceived as healthy, but
can suddenly die. Extensive programs are offered for
emergency resuscitation and education in the
community, as well as the availability of portable defibrillators in public
areas. Many people are alive in public areas where they have cardiac
arrests due to defibrillators that readily shock individuals
back to a normal rhythm.

So, here is the atherosclerotic process. It starts off with a
normal blood vessel, and then gradually, there is the
atherosclerotic change. Eventually, there will be blood
flow, but to the point of significant encroachment on the
channel. What happens is that when the heart needs to
do more work, the heart will work harder and not enough
blood goes through. It can lead to angina, which is
essentially a signal that the body is not getting
enough fuel. Atherosclerosis starts in early
childhood, and progresses in some people to the
point of excessive buildup. However, not
everybody reaches that point. As you get older,
especially towards middle life, the blood vessels
begin to dilate. There is no guarantee that the
blood vessels will have excessive buildup.

Remember that acute myocardial infarction is defined as myocardial cell
death due to prolonged myocardial ischemia (lack of blood flow). A blocked
artery causes a section of the heart to become hypoxic and killed due to
lack of oxygen and nutrition. This can be seen in autopsied sections of
coronary vessels. You can see the normal coronary artery, and you can
see a fibrous tissue cap and this cholesterol and inflammatory cell buildup.
The fibrous tissue cap tends to rupture and the circulatory system will
build a clot. Individuals with long-standing atherosclerosis will have very
thick fibrous (scar) tissue over the atherosclerosis, and tends not to
rupture. In older individuals, the heart attacks are smaller, because you
dont suddenly block the whole channel, whereas in younger individuals,
the fibrous cap is smaller and is more likely to rupture. When the fibrous
cap ruptures, it essentially sets off a cascade of clotting reactions. We have
a very complex clotting system in order to address trauma and an
important survival mechanism. However, it is not very useful in intrinsic
trauma. You can also see an atherosclerotic lesion, with cracks, due to
increased blood pressure, inflammatory cell action, and other factors not
yet known. When the lesion cracks and the clot forms, it can eventually
lead to occlusion in the artery and the heart muscle oxygenated by that
artery is dead.






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A stroke (or cerebrovascular accident) is caused by
sudden blockage of blood flow in an artery to the
brain or in the brain leading to the death of brain
tissue. Atherosclerosis is the most common cause
of the formation of the blood clot in the artery. The
damaged brain often survives the cerebrovascular
accident but may have reduced function leading to
disability. For example, a stroke can cause the
inability to move one leg or one arm. Elderly
individuals tend to not wish for a stroke because it
often robs their independence. A little clot in the heart may not be as bad
as a clot in the brain. A clot in the brain can cause major deficits. What are
the factors that lead to atherosclerosis?
" Increased low-density lipoprotein (LDL) Cholesterol
" Decreased HDL (high-density lipoprotein) Cholesterol
" Cigarette Smoking
" Hypertension (affects a third of Americans)
" Increased Age
" Diabetes
" Estrogen and Oral Contraceptive Agents ! Studies have shown that
OCAs can lead to an increased risk for heart attacks due to
estrogens effects in clotting. If clotting factors are excessive,
women can have pulmonary emboli. Estrogen itself does decrease
the risk of atherosclerosis, but excessive quantities can lead to the
clotting cascades.
" Physical Inactivity

These risk factors are associated with the Western lifestyle. Stress is also
a factor, but not exactly quantifiable. However, it is associated with the
Western lifestyle. Additional risk factors that are difficult to address
include:
" Men
" Obesity
" Type A Personality
" Positive Family History: Family History of heart attacks is often
associated with the problem of heart attacks.

So, this is the atherosclerotic process. It is now known to be an
inflammatory process. Something injures the lining of the blood vessel,
causing cholesterol in the blood to get into the wall and causes an
inflammatory action. Inflammatory cells get in, and they start eating the
cholesterol. Some die, and fibrous tissue builds up. There is a very thick
fibrous cap. You may have some angina, but the plaque will not rupture. If
the cap is thinner, there may be rupture and clotting. What are the ways
to prevent this from occurring? The American Heart Association laid out
some prevention guidelines:
" Smoking Cessation
!"#$%& ()* +& ,&-).")"/*0
74
" Blood Pressure Management
" Physical Activity (Exercise should be fixed into your schedule every
day)
" Weight Control
" Diabetes Mellitus Management ! The more controlled, the less
likely to have complications.
" Antiplatelet/Anticoagulant Therapy to prevent further clotting
" Angiotensin Converting Enzyme (ACE) Inhibitors ! Have to do with
Renin-Angiotensin-Aldosterone System
" Beta-Blockers ! Block adrenaline effects
" Lipid Management
" No Hormone Replacement Therapy post-menopause, but it is still a
large debate.

What is the leading cause of death in the United
States? So far, it is cardiovascular disease, taking 1.3
million people. Cardiovascular disease kills more
people each year than Alzheimers, accidents, and
cancer combined. It has surpassed infectious diseases
as the common cause of death. There are 1.3 million people killed each
year in the United States. This translates roughly to about 3,500 people
per day. There is one death every thirty seconds, and 1 in 3 will die from
cardiovascular disease. What is the leading risk for cardiovascular
disease? It is abnormal cholesterol and other lipids in the blood.
Approximately 50% of adult Americans have high cholesterol levels, which
is over 100 million people. It could be said that high cholesterol is almost
always associated with cardiovascular disease. For many, the first sign of
a problem is sudden death. Hyperlipidemia is high levels of various fats in
the blood. There are several types of fats in the blood, including total
cholesterol (contains the good and bad components), LDL cholesterol
(bad), HDL cholesterol (good), triglycerides (commonly elevated in
diabetics), and other components. This is an area of intense investigation.
It absolutely has something to do with diet, but also with genetics.
Hyperlipidemia increases the risk for myocardial infarction, congestive
heart failure, and cerebrovascular accidents. It is related in part to
heredity and in part to diet and lifestyle, for example, over eating and
inactivity leading to obesity. As you can see, the relative risk for first
heart attack and total blood cholesterol has a relationship. The
Framingham Study showed that high cholesterol is a etiologic factor in the
cause of heart attacks. This led to efforts towards lipid management. LDL
(low-density lipoprotein) cholesterol is the bad cholesterol that gets into
the lining of blood vessels and causes the inflammatory response.
Cholesterol testing can be done to monitor hyperlipidemia and the risk for
stroke. Sometimes diet modification and pharmacological agents may be
used depending on the severity.

Evidence-based medicine is opposed to eminence-based medicine.
Evidence-based medicine means proven by carefully done blinded clinical
75
trials. Evidence-based medicine is based on facts and research, while
eminence-based medicine is based on opinion and expertise.
Pharmacology is central to these drugs because many of these trials are
drug trials. The drugs that have the greatest reduction in major acute
ischemic coronary events (MACE) of all agents used to prevent an initial or
a second myocardial infarction (heart attack) are statins. What do statins
do? Statins block the liver enzyme, HMG-CoA reductase, needed to
synthesize cholesterol in the liver. Blockage of this enzyme leads to
increased numbers of LDL receptors on the surface of the liver cell.
Pharmaceutical companies invest $25 billion per year attempting to lower
patients cholesterol levels. The top two prescription drugs sold worldwide
are cholesterol-lowering medications (simvastatin and lovastatin). Most
inhibit cholesterol production in the liver. Lipid-lowering Therapies are as
follows:
LDL-C HDL-C TG
Statins (atorvastatin, fluvastatin, lovastatin, pravastatin,
rosuvastatin, simvastatin)
# 18-63% $ 5-15% # 7-30
Bile Acid Sequestrants (Colesevalem, cholestyramine, colestipol) # 15-30% $ 3-5% 0 or $
Nicotinic Acid # 5-25% $ 15-35% # 20-50%
Fibric Acid Derivatives (Gemfibrozil, Fenofibrate) # 5-20 or $ $ 10-20% # 20-50%
Cholesterol Absorption Inhibitor (Ezetimibe) # 18% $ 1% # 7%
Omega-3 Fatty Acids (Fish Oil) (Prescription Strength Only) ? $ 9% # 45%
So, in people who cannot tolerate the statins, there is consideration for
herbal products with flaxseed (in pill or as the seeds). There are relatively
modest changes. Red rice yeast has lovastatin, but in very low doses. The
average lovastatin pill is 40 mg, and the pill of red rice yeast contains 1-2
mg of lovastatins. Statins were discovered in fungi, just like penicillin was
found in a mold. The problem with the herbal products is that they are not
standardized. The label may say it has these active ingredients, but you do
not know what is actually in it and the amount of the active ingredients
varies. Pharmacological agents originated as herbal products, but the
problem with herbal products is that we cannot regulate the dose and the
FDA does not control it so you do not know what you are getting. It is not a
controlled environment. However, some natural products are helpful, but
in fact that there is a prescription level and an over-the-counter level.
Consumers need to be careful of what manufacturers are making these
products. The problem is the need of the intelligent consumer towards
safety during use. This diagram displays the whole variety of pathways of
fats and cholesterol and the action of the different drugs:

76
Statins is an HMG-CoA reductase inhibitor. Bile acid sequestrants (BAS)
increase the amount of bile transferred to the feces. Ezetimibe blocks
NPC1L1. Fibrates work in CMr-C and IDL-C. Niacin is seen working in
VLDL-C. All these processes have multiple steps, and these engineers are
working on blocking at different levels. The end-result is the same. You
will see multiple things like this, but there are multiple ones, but the best
are the statins. This is because of the double blind, randomized trials
showed the statins as the most effective and the most tolerated. Drugs are
designed to be effective, but also minimal side effects. Why? This is
because most of these drugs may have to be taken by the patient for the
rest of their lives. LDL cholesterol lowering drugs (statins) decrease the
rate of production of lipids by the liver and remove LDL from the blood
vessels. You can also see cholesterol synthesis in the following reaction:

LDL cholesterol lowering drugs (statins) decreased production of
cholesterol by the liver and increase removal of LDL. Serious side effects
can include liver damage (rarely) and pain and weakness muscle damage
(very rarely). Blood testing monitors this. They are extremely well
tolerated, but not tolerated by all.

However, it can be observed that there is
major coronary heart disease risk reduction
with statin therapy. Statins decreased
major coronary events by 30%. There were
coronary deaths reduced by 30%, and
cardiovascular deaths reduced by 30%, and
no changes in noncardiovascular events.
All in all, there were major improvements
with the use of statins. There is a log-linear relationship between LDL-C
levels and relative risk for coronary heart disease
(CHD). This relationship is consistent with a large
body of epidemiologic data and data available from
clinical trials of LDL-C-lowering therapy. These data
suggest that for every 30-mg/dL change in LDL-C, the
relative risk for CHD is changed by about 30%. The
relative risk is set at 1.0 for LDL-C = 40 mg/dL. It is
!"#$%&'%(#$ *+,'"%&-&
39
CHD Risk Reduction with Statin Therapy
La Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern
Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.
Endpoints +20 35 30 25 0 5 10 15 20
Relative Risk Reduction (%)
40 45 50
Major coronary events

Coronary deaths

Cardiovascular deaths

Noncardiovascular events


Total mortality

Strokes

Intermittent claudication

Angina
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by abouL 30.
1he relaLlve rlsk ls seL aL 1.0 for
LuL-C = 40 mg/dL.

LuL-C = low-denslLy llpoproLeln cholesLerol, CPu = coronary hearL dlsease.

8eprlnLed wlLh permlsslon from Crundy SM, Cleeman !l, Merz Cn8, eL al. lmpllcaLlons of recenL cllnlcal Lrlals for
Lhe naLlonal CholesLerol LducaLlon rogram AdulL 1reaLmenL anel lll guldellnes. !"#$%&'(")*+ 2004,110:227
239.
LDL-C, mg/dL
Relative Risk
for CHD,
Log Scale
40 70 100 130 160 190
1.0
1.3
1.7
2.2
2.9
3.7
77
important to think about a typical patients LDL
and the normal LDL. You can also see that the
statins reduced the risk for death and MI from
unstable angina, a previous myocardial infarction,
post-angioplasty, post-coronary artery bypass
graft, and individuals with elevated cholesterol.
There is real science that says it works, not just
opinion.

High-density lipoprotein (HDL) is considered the good cholesterol. They
can be increased with exercise and diet. A number of clinical studes show
that high levels reduce risk of cardiovascular disease.

It is important to remember that statins inhibit cholesterol synthesis in
the liver and increase LDL receptors. It causes a 24-40% relative
reduction in coronary events. The potential side effects include myopathy
and elevated liver enzymes. Contraindications are for active liver disease.
It should be used with caution with other drugs. Lowering LDL-Stating
Drugs include:
" Crestor (Rosuvastatin)
" Lescol (Fluvastatin)
" Lipitor (Atorvastatin)
" Mevacor (Lovastatin)
" Pravachol (Pravastatin)
" Zocor (Simvastatin)

Atorvastatin (Lipitor) is the number one selling drug in the world. Lipitor
lowers LDL cholesterol in one way: by inhibiting cholesterol production in
the liver. It is sold by Pfizer Pharmaceutical and represents 20% of total
company revenues. Simvastatin (Zocor) is the second largest selling drug
in the world sold by Merck/Schering-Plough. It lowers LDL cholester one
way, by inhibition of cholesterol production in liver. The following
describes a comparative efficacy of the statins:

The following describes the pharmacokinetics of the HMG-CoA reductase
inhibitors, that is statins:
Agent Major
Metabolic
Isoenzymes
Lipophilic Bioavailability
(%)
Protein
Binding (%)
Active
Metabolites
Half-life
(hrs)
Fluvastatin 2C9 Yes 19-29 >98 No 3
Rosuvastatin 2C9, 2C19 No 20 88 Yes 20
Pravastatin None No 18 50 No 2
Lovastatin 3A4 Yes 5 >95 Yes 2
Simvastatin 3A4 Yes 5 >95 Yes 3
Atorvastatin 3A4 Yes 14 >98 Yes 14
STELLAR Trial: Jones PH et al. Am J Cardiol. 2003;92:152.
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Statins in Cardiovascular Disease
78
You can also note that pravastatin is not metabolized in the liver, and can
be considerably safer to use with individuals with compromised livers in
comparison to the other statins. With any drug, there are some
characteristics that can predict toxicity with the statins:
" Females > Males
" Advanced Age (>80 years)
" Small body size or frailty
" Diminished renal and hepatic function
" Multiple comorbities or medications
" Hypothyroidism
" Perioperative Periods
" Alcohol Abuse

The next question in lipid management is what to do if statin therapy does
not lower the lipids enough. Combining statins with other lipid lowering
medicines is the next step. For example, ask the patient to take
gemfibrozil or fenofibrate tablets in addition to the statin. The combination
is more effective than either drug alone, but complications and side effects
are more common with the combination program. One of the complications
is rhabdomyolysis with statin/fibrate combination therapy. There is an
increased risk of myopathy and rhabdomyolysis with statin/fibrate
combination therapy. However, statin/fibrate combination therapy is NOT
contraindicated.

Fish oils plus statins may often be an alternative to fibrate or niacin plus
statin. Fish oils may have other cardiovascular effects complementary to
those of statins, such as:
" Reduction in malignant ventricular dysrhythmias
" Increased heart rate variability
" Antithrombotic effects
" Improved endothelial reactivity/relaxation
" Anti-inflammatory effects
" Slight lowering of blood pressure

The omega-3-acid ethyl esters (fish oil) may
reduce the synthesis of triglycerides (TG) in the
liver because EPA and DHA are poor substrates
for the enzymes responsible for TG synthesis, and EPA and DHA inhibit
esterification of other fatty acids. There are reduced very high
triglycerides (TG) in patients with triglycerides (TG) greater than or equal
to 500 mg/dL. It led to a reduction in non-HDL-C by 14%, a raise in HDL-C
by 9%, and reduction in triglycerides by 45%. The most common adverse
events reported were eructation (burping), infection, flu syndrome,
dyspepsia, taste perversion, back pain, and rash. The dosing is typically
four 1-gram capsules once daily. The 90% omega-3-acid ethyl esters are
available by prescription only. When added to simvastatin therapy
(COMBOS) there is essentially a doubling in the percentage of patients who
achieved the non-HDL-C goal. There are safety concerns with both Omega-
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79
3 fatty acids and fish oils. With omega-3 fatty acids, there are no
antithrombotic effects, but it is also not proven to increase bleeding risk.
The rigorous manufacturing purification processes reduce risk of
hypervitaminosis and exposure to environmental toxins (e.g., mercury,
dioxin). The fish oils do not require USP verification not required for all
products. It is not equal to the prescription omega-3 fatty acids, because
the omega-3 fatty acids require regulation.

Now, a final question arises, what is a normal
human cholesterol value in a free-living
human being and where would you find such
a person? The total cholesterol is
approximately 70-80 mg. The average total
cholesterol is around 150-180 mg. The
closest humans have reached are in tribes
living in the highlands of New Guinea or deep
in the Amazon River basin. There is now an
advertisement from your family friendly cardiologist. Patients who
survive a myocardial infarction and who are clinically stable but continue
to smoke have a six-fold increased risk of dying during the next five years.
Cigarette smoking is a major, worldwide cause of coronary heart disease.
There is some good news, however. There are marked reductions of deaths
due to coronary heart disease. This is often attributed to lifestyle
modifications.
Case Examples
Case 1:
A 60-year-old man suffers an MI (heat attack). His lipids are abnormal:
high total and high LDL cholesterol. Which of these drugs would be
indicated?
A. Penicillin
B. Advil
C. Rolaids
D. Geritol
E. Atorvastatin
Case 2:
A 42-year-old father with three children suffers a myocardial infarction
(heart attack). His cholesterol is markedly elevated, but he has tried a
statin drug in the past and it gave him terribly painful muscle cramps.
Which of the following drugs would you NOT prescribe?
A. Pravastatin
B. Omega 3 fish oil capsules
C. Gemfibrozil
D. Fenfibrate
E. Cholestyramine
!"#$ &""' ($)*
80
Lecture X
Cardiovascular Disease Pharmacotherapy #2
Lecturer: Dr. Joseph S. Alpert, M.D.

One of the guidelines in the American Heart Association in the prevention
of heart attacks and stroke is to manage blood pressure. There are a
multitude of drugs that work against hypertension, but it continues to be a
serious illness with fatal consequences. In order to discuss blood pressure
medications, it is important to discuss the pathophysiology of
hypertension. You can think of a blood vessel as a pipe and there needs to
be a pressure to pump blood through the blood vessel. If we think of Ohms
law and translate it into the circulation, we can convert ! ! !!! to the
formula !"##$ !"#$$%"# ! !"#$%"& !"#$"# ! !"#$%&"' !"#$#%&'(" . Patients
with hypertension have increased vascular resistance, which leads to
increase blood pressure, that is, hypertension. Approximately one-third of
Americans have hypertension. About a third of Americans have our blood
pressure set too high. The resistance is too high. There is an advantage to
blood pressure for athletes, but the problem is the system is worn out over
time. The heart is essentially overworked and there are long-term
consequences. Patients with high blood pressure have increased vascular
resistance. Chronic hypertension causes many complications:
" Stroke (CVA)
" Myocardial Infarction (MI = heart attack)
" Heart failure shortness of breath, fatigue, swelling of legs ! the
heart is not pumping efficiently, there is eventually a point where
the heart is worn out.
" Kidney failure
" Dementia decreased intellectual capacity due to damaged neurons
in the brain
" Arrhythmias atrial fibrillation ! the atria is quivering in the heart
and appears in Emergency Rooms. It seen commonly in the elderly
and accompanied by other heart disease. Everyone has
arrhythmias. Most are monitored to address recurrent
arrhythmias. Of young people, it is 1 in 10,000 that have malignant
arrhythmias.
" Shortened life expectancy

The consequences of uncontrolled hypertension can be
shown in the graph. The problem with uncontrolled
hypertension is that it can lead to extremely
dangerous flow of vasculature, especially to the brain.
It can lead to strokes, which can also be hemorrhagic. This is what
contributed to the death of Franklin Delano Roosevelt towards the end of
World War II. President Franklin Delano Roosevelt had around normal
blood pressure but over time, but the blood pressure progressively
increased, due to post-polio states and stress. They soon found that he
Consequences of Uncontro||ed nypertens|on
Messer|| I. N Lng| I Med 199S,332:1038-1039 Copyr|ght 199S
Massachusetts Med|ca| Soc|ety. A|| r|ghts reserved.

81
passed from a cerebral hemorrhage from stroke and severe hypertension.
They gave him a series of early (1930)
antihypertensive therapies, which were
empirical and poorly regulated, but now
we have other medications that are
evidence-based. Some of these drugs
work in a certain population, and some
drugs in other populations. What about
the public health statistics? The study
showed that the number of people identified with hypertension has
increased. There are individuals that are better treated for hypertension.
Physicians are detecting patients better. However, adequate control is
only about 50% in the 2005-2008 period, which means that there is still
much work in controlling hypertension. Now the question remains: what
approaches can be used to improve detection and control of hypertension?
There are populations that are at higher risk and require treatment. There
is a multitude of patient characteristics associated with high-risk
hypertension:
" High baseline blood pressure ! Individuals in high school with
elevated blood pressure can be considered at risk for developing
hypertension.
" Older age
" Obesity
" Excessive dietary salt ingestion: the American diet is high in salt
content
" Chronic kidney disease ! The kidney is the major regulator of blood
pressure.
" Diabetes ! due to decrease insulin sensitivity and consequent action
in the blood pressure.
" Left ventricular hypertrophy ! inadequately treated blood pressure
" African American race ! particularly prone to nasty hypertension
" Female gender ! Women tolerate hypertension less than men.
" Residence in Southeastern United States ! Stroke Belt, not so
much due to the prevalence of African-Americans but more due to
the diet, which contains copious amounts with salt, fat, and lack
fiber and organics, and possibly due to socio-economic factors.
There are also lifestyle factors contributing to hypertension, which can
modified and are considered in therapy:
" Obesity or overweight ! Weight loss will help reduce risk, but is a
challenging problem.
" High salt diet ! Decreasing salt intake can help reduce your risk for
hypertension.
" Physical inactivity ! Exercise can decrease risk for hypertension.
" Ingestion of low-fiber, high-fat diet. ! The opposite can reduce the
risk.
" Heavy alcohol ingestion ! Alcohol cessation can halt the
progression of hypertension.

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82
Pharmacological therapy is usually considered in
individuals with blood pressure that is consistently
greater than 140/80 mm Hg. Diuretics make you
urinate, essentially. Diuretics work in the nephron,
either at the ascending loop of Henle (loop diuretics)
or in the distal convoluted tubule (thiazide
diuretics). They help in the sodium movement in the
nephron. Thiazide diuretics are an excellent first line therapy alone and in
combination with other agents. This is the best therapy for the disease.
These diuretics are also generic and therefore inexpensive. The most
popular ones are the thiazide diuretics. They are shown to reduce
cardiovascular events, for example, stroke, in patients with hypertension.
The following describe common thiazide diuretics:
Absorp-
tion (%)
T1/2 Relative
Potency
Elimination (R = Renal,
H=Hepatic, B= Biliary, U=
Unknown)
Anti-hypertensive dosing
(typical)
Chlorothiazide 9-56 !1.5 0.1 R PO: 500-2000 mg/day in 2 doses
Chlorthialidone !65 !47 1 65% R, 10% B, 25% U 12.5-25 mg PO once daily
Hydro-
chlorothiazide
!70 !2.5 1 R 12.5 -50 mg PO once daily
Indapamide !93 !14 20 > 95% H 1.25-5 mg PO once daily
Metolazone !65 4-5 10 80% R, 10% H, 10% B 2.5-5 mg po once daily For
Mykrox: 0.5-1 mg PO QD

Absorption is essentially how well the body is
absorbing the drugs. Hydrocholorothiazide is
considered the best one out there. It is absorbed
very well in the stomach and stays in the blood
for approximately 2.5 hours and is considered
the gold standard. Its potency is 1, which
means you can give a normal dose, compared to
indapamide where you have to give a smaller dose. The drugs to
remember are hydrocholorothiazide and chlorthalidone. Chlorthalidone is
slightly more potent and gives off slightly more side effects. There are
major antihypertensive effects of hydrochlorothiazide versus
chlorthalidone on blood pressure. There are statistically significant
reductions in average systolic blood pressure. This made diuretics the mot
prescribed medication. With chlorthalidone, there was statistically more
significant reduction. It is a lot more effective, but hydrochlorothiazide is
used more. However, there are adverse effects of thiazide diuretics:
" Hypokalemia (dose-related and can affect clinical outcome) !
Diuretics tend to wash potassium, so there is muscle pain. This can
be ameliorated with potassium supplementation.
" Glucose Intolerance (diabetic tendency)
! Pushes individuals towards diabetes.
What thiazide diuretics do is induce
insulin resistance, so all cells become
insulin resistant due to thiazides.
" Gout ! Joint problems and precipitation
of uric acid.
" Kidney Damage
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83
There are also less-commonly recognized substances impeding blood
pressure control. Alcohol is a common interference to blood pressure.
Alcohol raises blood pressure transiently, and can raise blood pressure
even with pharmacological agents. Antidepressants also raise blood
pressure. Ma huang (ephedra), bitter orange, blue cohosh, ginsent,
guarana are over-the-counter and can also raise blood pressure. Some of
the anticancer drugs (bevacizumab,
sorafenib, and sunitinib), which inhibit
vascular endothelial growth factor, can raise
blood pressure. NSAIDs can also raise blood
pressure. The drugs work in different areas.
ACE inhibitors and ARBs work by decreasing
vascular resistance. Beta-blockers decrease
the heart rate. Diuretics work on the
vascular resistance but also the filling of the
left ventricle. Beta-blockers and some calcium blockers decrease the
contractility of the heart. Some patients respond to drugs in one category
and better in another category. There are also ethnic differences. African-
Americans respond better to calcium blockers than to ACE inhibotors.
Thus, there may be ethnic concerns to address, and can be noted that it
may take more than one drug. Now, we need to discuss the renin-
angiotensin-aldosterone system. The main organ for regulating blood
pressure is the kidney. This is why patients with kidney disease often
present with hypertension. Renin is released by the kidney in response to
injury, and causes increases in blood pressure. The kidney is crucial to
blood pressure regulation the juxtaglomerular apparatus and renin
release. Renin initiates a biochemical sequence that eventually converts
angiotensinogen produced in the liver into angiotensin, a strong
vasoconstrictor. Angiostensin stimulates release of aldosterone from te
adrenal gland which causes the kidney to retain salt (NaCl) and water.
Angiotensin stimulates release of anti-diuretic hormone from the pituitary
gland, which causes the kidney to retain water. This system is part of the
bodys defense against dehydration and/or blood loss. The idea is to
restore blood volume to normal as quickly as possible. Here is a list of
common drugs that act in the Renin-Angiotensin-Aldosterone System:
Drug Commonly used ACEi and AH blockers in
treatment of HF with low EF
Initial daily dose Target dose
ACEi Captopril 6.25 mg tid 50 mg tid
Enalapril 2.5 mg bid 10-20 mg bid
Fosinopril 5-10 mg daily 40 mg daily
Lisinopril 2.5-5 mg daily 20-40 mg daily
Perindopril 2 mg daily 8-16 mg daily
Quinapril 5 mg bid 20 mg bid
Ramipril 1.25-2.5 mg daily 10 mg daily
Trandolapril 1 mg daily 4 mg daily
ARB Candesartan 4-8 mg daily 32 mg daily
Losartan 25-50 mg daily 50-100 mg daily
Valsartan 20-40 mg bid 160 mg daily
However, there are also adverse effects with ACEi and ARB as a 1
st
line
drug. With ACE inhibitors, there is kidney damage especially in
individuals with prior damage, excessive drop in blood pressure, tongue
and facial swelling due to allergic reaction. With angiotensin-receptor
!"#$#%&#'$()"#*$#%&+,(*)"-(#" /0*)"1
Angiotensinogen
Angiotensin I
Angiotensin II
AT1 Receptor
Renin
ACE
Bradykinin
Inactive Peptides
Non ACE Pathways ACE Pathways
Chymase
CAGE
Cathepsin G
t-PA
AT2-4 Receptors
Antihypertrophic,
proapoptotic ???
Cell
Growth
Sodium &
Fluid Retention
Sympathetic
Activation
Vasoconstriction Aldosterone
Release
Vagal
Inhibition
Thirst
Stimulation
AII-Receptor Blockers
ACE-I
84
blockers, there is kidney damage especially in
individuals with prior damage and excessive drop
in blood pressure.

Another set of drugs involved in the management
of hypertension is known as aldosterone
antagonists. Their mechanism of action involves
the block of aldosterone binding at receptors in
kidney, heart, blood vessels, and brain. The
blockade of aldosterone in the renal tubule causes
increased NaCl and water excretion and potassium
retention. One known aldosterone inhibitor is
spironolactone, which is a competitive antagonist
of the aldosterone receptor, giving effects on myocardium, arterial walls,
and kidney. It decreases retention of sodium cations and water
(decreasing edema). It also decreases the excretion of potassium and
magnesium cations (decreasing arrhythmias) and decreases collage
deposition (decreasing fibrosis of myocardium vessels).

Beta-blockers slow the heart rate and block sympathetic nerve stimulation
to the kidney (decreasing renin release) and the peripheral nerves
(decreasing vascular resistance). They are 2
nd
line agents for
hypertension. They were discussed in sympathetic pharmacology in their
function, mainly to decrease epinephrine binding to the beta-1 receptor of
the heart and consequently decrease the rate of SA node firing. Beta-
blockers are listed below:
Selec-
tivity
Lipid
Solubility
Bioavailbility
(%)
Protein
Binding (%)
T1/2
(h)
Primary (secondary)
Elimination R=Renal, H=Hepatic
Nadolol "1"2 L 30 25-30 20-24 R
Propranolol "1"2 H 30 90 3-5 H
Timolol "1"2 L-M 75 < 10 4 H(R)
Pindolol "1"2 M 90 57 3-4 H(R)
Atenolol "1 L 50-60 < 5-10 6-9 R(H)
Metoprolol "1 M 50(77-XL) 10-12 3-7 H/R
Bisoprolol "1 L 80 26-33 9-12 R(H)
Acebutolol "1 L 40 15-25 3-4 H(R)
Labetalol "1"2!1 M 18-30 50 5.5-8 R(H)
Carvedilol "1"2!1 M 25-35 98 7-10 Bile
Adverse events of beta-blockers include fluid retention and worsening
heart failure, but are more likely to occur during initiation and first several
months. It requires daily weight and careful adjustment of diuretics.
Hypotension is more likely with carvedilol, and consequently must be
administered with food. It has been suggested to administer ACE inhibitor
or temporarily reduce ACE-I. There is a risk of bradycardia and heart
block and a risk of 5-10% as dose is increased. There is also fatigue and
weakness, which may resolve with time or reduction in dose.

Calcium channel blockers dilate arterioles (resistance vessels) and thereby
decrease vascular resistance. The mechanism of action involves
relaxation of vascular smooth muscle and thereby dilates arterioles and
decrease vascular resistance. There are two forms: dihydroperidine and
non-dihydroperidine. Dihydroperidine forms (such as nifedipine,
!"#$ !&'()*+, -,"+#.
Non-Selective Selective*
Alpha-Blocking
Activity
Nadolol
Propranolol
Timolol
Sotalol
Pindolol
Carteolol
Penbutolol
Atenolol
Metoprolol
Esmolol
Betaxolol
Bisoprolol
Nevibolol
Acebutolol
Celiprolol
Labetalol
Carvedilol
Bucindolol
- ISA + ISA + ISA - ISA
With
*Beta-1
Cardioselective
ESC Expert Consensus Document on B-adrenergic Receptor Blockers. Eur Heart J 2004:25;1341-1362

ALDOSTERONE
< Retention Na
+

< Retention H
2
O

< Excretion K
+

< Excretion Mg
2+
Collagen
deposition

Fibrosis
myocardium
vessels
Spironolactone
< Edema
< Arrhythmias
Competitive antagonist of the
aldosterone receptor
(myocardium, arterial walls, kidney)
Aldosterone Inhibitors
-
85
amilodipine, and nicardipine), at the doses used in humans, only dilate
arterioles. There is no effect on the electrical system of the heart (the
conduction system). Non-dihydroperidine calcium blockers (such as
diltiazem and verapamil) dilate arterioles and also decrease the rate of
passage of electrical impulses in heart muscle. Because of their effect on
the electrical activity of the heart, they are often used to control
arrhythmias. Other drugs that are used to treat hypertension include:
" Minoxidil is a very potent vasodilator, but is also used to grow hair.
" Clonidine blocks sympathetic nerve activity in the brain and leads
to less sympathetic nervous system increase
in vascular resistance.
" Peripheral sympathetic receptor blockers in
vascular smooth muscle alpha-receptor
blockers ! these are not utilized as much
due to reflex tachycardia.

As you can note, there is an ascending ladder. The
first-line of therapy involves lifestyle modifications.
If that does not work, then there is consideration
for the use of diuretics, beta-blockers, calcium
blockers, or ACE inhibitors. Then you can consider
either adding a second drug, increasing the dose of
the first drug, or substituting another drug. Then if
that is unsuccessful, there may be addition of a different class or
substitution of the second drug. Finally, there is further evaluation and
referral or the addition of a third or fourth drug. Attempts should be made
to step-down therapy and continue nonpharmacological approaches. As
you can also note, there may be a number of antihypertensive agents
necessary to achieve the target blood pressure. The average number of
anti-hypertensive agents needed to achieve target blood pressure is
between 3-4, and researchers and clinicians are making considerable
efforts to reduce the number of drugs utilized to counter hypertension.
Case Examples
Case #1
A 21-year-old U of A student is referred to you for evaluation of high blood
pressure found in screening at a local mall. The blood pressure reading
there was 145/90 mm Hg. What is your approach to this patient?
Answer:
Re-check the blood pressure, because the screening itself is extremely
random in comparison, and perform a history and physical. Consider only
lifestyle modifications rather than pharmacological agents.
Case #2
A 55-year-old African American woman reports many years of
hypertension treatment with less than ideal blood pressures. In your office
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1. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.2. Estacio RO et al. Am J Cardiol. 1998;82:9R-14R.
3. Lazarus JM et al. Hypertension. 1997;29:641-650.4. Hansson L et al. Lancet. 1998;351:1755-1762.
5. Kusek JW et al. Control Clin Trials. 1996;16:40S-46S.6. Lewis EJ et al. N Engl J Med. 2001;345:851-860.7. ALLHAT. JAMA. 2002;288:2998-3007.
1
No. of Antihypertensive Agents
2 3 4
SBP 140/DBP 90 ALLHAT7
SBP 135/DBP 85 IDNT6
MAP 92 AASK5
DBP 80 HOT4
MAP 92 MDRD3
DBP 75 ABCD2
DBP 85 UKPDS1
Target BP
(mm Hg)
Trial
86
her blood pressure is 160/98 mm Hg. She says she takes her medicines
regularly and faithfully. She takes small doses of an ACEi and small doses
of a beta-blocker. What is your strategy here?
Answer:
You can do many things. You can increase the dosages of the ACEi and/or
beta-blocker, or you can give the patient (as she is African-American) an L-
type calcium channel blocker, such as verapamil or amilodipine, and
consider decreasing the doses (or discontinuing) the ACEi or beta-blocker.
Case #3
A 60-year-old patient seeks your advice for his poorly controlled blood
pressure. He tells you that almost all of the medicines that have been tried
cause him terrible side effects and that is why his blood pressure is so
poorly controlled. He just cannot take the medicines without some bad
thing happening. What is your strategy here?
Answer:
Ask the patient the specifics of some bad thing happening. The bad
thing happening can either be an adverse effect or simply lack fo
compliance.
Case #4
A 56-year-old woman reports poor control of her blood pressure that
recently led to an episode of heart failure treated in the hospital. She tells
you that she has no medical insurance and that the blood pressure
medicines her doctor prescribed were costing way too much for me to able
to take them every day. What is your strategy here?
Answer:
Consult with medical services for the underprivileged or discuss with a
medical director on the financial course of action.
Case #5
A 25-year-old friend of yours has a very extensive family history of
hypertension with many relatives suffering strokes and heart attacks in
40-50 years of age. He tells you that his doctor tells him that he also has
high blood pressure with readings often in excess of 160/100 mm Hg. His
doctor prescribed medicines for him but he thinks that some herbs he
purchased at the health food store will control his blood pressure better
than the medicines his doctor gave him. What is your advice?
Answer:
Tell the patient that the herbs do not have enough regulation to ensure
that his blood pressure will be maintained. Many of the drugs contain
herbal origins, but are regulated enough to provide a much better effect in
comparison to the herbs.
Case #6
An 82-year-old female was diagnosed with hypertension six months ago in
January. She is taking lisinopril (an ACEi vasodilator) with excellent
87
control of her blood pressure. She lives here in Tucson all year. Recently
on July 5
th
she tells you that she nearly passed out when getting out of bed
in the morning. The same thing happened again later in the morning when
she went shopping. What should be done with her medicines?
Answer:
Her medication should be reduced to account for Tucson Summer
Syndrome. Tell the patient also to drink a lot of water.
Questions
Question #1
Doctor, my blood pressure readings are all over the map. I never get the
same reading two times in a row. What is your response and how can you
help this patient?
Answer:
Tell that patient that blood pressure fluctuates throughout the day, and
that they should consider taking blood pressure readings around a specific
time throughout the day. If the blood pressure is consistently high, then it
may be a better time to consult a physician.
Question #2
A 350-pound woman seeks your advice about her planned bariatric
surgery. She has been hypertensive for years and is taking four different
medicines with rather poor blood pressure control. She tells you that her
friend had the bariatric operation 4 years ago and now does not need to
take any medicines for blood pressure control. Can she expect the same
thing to happen to her?
Answer:
No. She may expect some weight loss, but lifestyle modifications will be
needed to reach her goals.
Question #3
What is the best class of medicine to control blood pressure in a 44-year-old
diabetic man with hypertension? His blood pressures at home runs
around 155/90 mm Hg.
Answer:
ACE inhibitors or ARBs are considered best to help manage his high blood
pressure. However, the diabetes must also be managed, as blood pressure
is difficult to manage with uncontrolled diabetes.
Question #4
Which of the following medicines is not used for the treatment of
hypertension?
A. Propranolol
B. Lisinopril
C. Losartan
88
D. Tamoxifen
E. Nifedipine
Question #5
Are there street drugs that can cause hypertension? Are there products
in the supermarket that can cause or worsen hypertension?
Answer:
Yes. Cocaine and methamphetamine can cause severe rises in blood
pressure. Coffee, energy drinks, and herbal medicines that are given in the
supermarket can also increase blood pressure.
Question #6
Are most patients very faithful about taking their medicines for
hypertension as prescribed by their physician or nurse clinician?
Answer:
Not always, but we can always detect ways to determine if they are faithful
in taking their medications through blood tests, toxicology screens, or even
just counting the number of pills in the container.
Question #7
Which of the following classes of drugs are considered first line for the
treatment of hypertension?
A. Beta blockers
B. Calcium channel blockers
C. Angiotensin receptors blockers
D. Thiazide diuretics
E. Central nervous system sympathetic blockers
Question #8
Are there lifestyle changes that should be made by patients with
hypertension who have been started on medication to control their
elevated blood pressure?
Answer:
Yes! Some lifestyle changes that have been shown to benefit patients with
hypertension alongside their medicines include weight loss, regular
exercise, decreasing dietary salt consumption, mind body exercises such
as meditation, and decreasing alcohol intake
Question #9
Which of the following foods are high in salt and therefore might increase
blood pressure?
A. Ketchup
B. Mustard
C. Canned Soups
D. V8 Tomato Juice Cocktail
E. Dill Pickles
F. All of the Above

89
Lecture XI
Cardiovascular Disease
Pharmacotherapy #3 Myocardial Infarction and Heart Failure
Lecturer: Dr. Joseph S. Alpert, M.D.

Heart attacks are the most commonly diagnosed diseases covered by
Medicare, and the number one cause of death in the United States. In
2007, the American Heart Association released the statistics on heart
disease and stroke. In 2004, the number of strokes per year was 700,000.
The number of fatal strokes was 150,000, giving a fatality rate of
appxoimately 21%. Myocardial infarctions lead to two million deaths per
year. The same statistics revealed that the number of heart attacks per
year was 865,000. The number of fatal heart attacks reached 158,000,
with a fatality rate of 18%. The total number of deaths due to coronary
artery disease reached 452,000.

Atherosclerosis starts when there is an injury to
the inner lining of the blood vessel
(endothelium). From there, lipids are able to
enter the endothelium, setting off the
inflammatory process. Inflammatory cells come
in, ingesting cholesterol and inflammatory cells,
depositing into the lining. It causes the
spiraling inflammatory cascade. There are a lot of things that can injury
the lining, such as high blood pressure diabetes mellitus, viral infection,
and tobacco use. What sets off atherosclerosis to a myocardial infarction
(death of heart tissue from hypoxia) is a tear in the atherosclerotic plaque.
When that happens, the first defense is the adhesion of platelets, which set
off clotting factors and further platelet aggregation and clotting cascade.
The clotting cascade yields several
efforts to halt bleeding and injury.
Lack of some of these factors is
associated with hemophilia and
disease. However, too much clotting
activity can cause clots to occur inside
the circulatory system, because they
can do mischief. On the venous side,
they can cause pulmonary embolism,
which can be fatal. On the arterial
side, they can cause heart attacks
(MI), strokes, and kidney damage.
There is a long list of unpleasantries
when there are clots in the
cardiovascular system.

90
What happens is the following: when the vessel wall is damaged. Platelets
begin to adhere, causing the initiation of this cascade of clotting factors,
leading to the product (thrombin), which joins with release of mediators
and platelet aggregates to form fibrin (which is essentially an intrinsic
scab/thrombus. Fibrin consists of strong protein strands, which is the end-
stage step, which traps erythrocytes and platelets to yield thrombus. You
have to have something to dissolve the clot. There are enzymes to dissolve
the fibrin, and you are able to
measure fibrin degradation
products in a diagnostic
laboratory (known as a D-
Dimer). Venous clots are rather
silent in comparison to arterial
clots (which are seen by
weakness in the face, arms,
chest pain, or legs).

You can see the entire clotting
cascade, which is a lot more
complicated. This is an area of
considerable research and
interest, because so many cardiovascular diseases are associated with
clots. There are a lot of attempts to block this in various points of the
clotting cascade. The major risk of blocking the clotting cascade is
hemorrhage. There is a fine line between bleeding out and clotting.
Consequently, the dosage is extremely controlled. In an atherosclerotic
blood vessel, there is a build up of lipids and inflammation, and can
rupture, causing clotting and occlusion of the artery. Depending on the
location, it can lead to heart attacks and stroke. Remember the risk
factors for heart attack and stroke:
" Increased LDL Cholesterol
" Decreased HDL Cholesterol
" Cigarette Smoking
" Hypertension
" Increased Age
" Diabetes (Less controlled diabetes can lead to greater risk of heart
attack and stroke)
" Estrogen, Oral Contraceptive Agents
" Physical Inactivity

Medication can often offset the risk for heart attacks and strokes. The
therapeutic goals in patients with myocardial infarction is to:
" Improve blood flow into the heart muscle with thrombolytic agents,
anticoagulants, anti-platelet drugs with or without angioplasty.
" Prevent further thrombosis, that is, blood clot formation
" Decrease the work of the heart during the acute and chronic phase
of the illness.
" Correct atherosclerotic risk factors.
91

Thombolytic agents dissolve the fibrin skeletal structure of blood clots. On
average, these drugs open 60-70% of thrombosed (clotted) coronary
arteries. However, angioplasty is 95% effective. The earlier in the
myocardial infarction they are administered, the more effective they are.
How much the heart is pushing will vary. Therefore, it is important to
open the artery within two hours of onset. These thrombolytic agents are
given intravenously. Some thombolytic agents include streptokinase,
tissue plasminogen activator (tPA), and its cousins, urokinase.

Anticoagulants can be oral, intravenous, or subcutaneous. Heparin (IV or
subcu) blocks the clotting cascade by its action on antithrombin 3, a
component of the clotting cascade. Warfarin is given orally and blocks the
synthesis of clotting factors II, VII, IX, and X in the liver. It is used in the
management of pulmonary embolism, deep vein thrombosis, or atrial
fibrillation to prevent further clotting. Atrial fibrillations can develop clots
in the heart. However, it is not given
for myocardial infarction. It has a
very narrow therapeutic window,
giving rise to under and overdosing. A
rare adverse event is skin necrosis on
the chest, but is extremely rare. A
refined form of heparin (enoxaparin)
contains the part of the molecule that is
active in anticoagulation. Since the active
site is preserved, the therapeutic window
essentially becomes wider, preventing
some degree of over and under-dosage of
the drug. Enoxaprin (low molecular
weight heparin) is also given
subcutaneously, while unfractionated
heparin (UFH) is given intravenously. EnoXaprin only acts on factor Xa.
Newer anticoagulants include dabigatran, rivaroxaban and apixaban.
Dabigatran bocks factor IIa in the clotting cascade. It is used to prevent
stroke in atrial fibrillation and not used in myocardial infarction patients.
Rivaroxaban and apixaban block factor
Xa in the clotting cascade. It is used to
prevent stroke in atrial fibrillation and
not used in MI patients. Rivaroxaban is
also used in patients with venous
thrombosis and pulmonary embolism.

Antiplatelet agents include aspirin,
clopidogrel (Plavix), dipyridamole, as well
as newer agents (prasugrel and ticagrelor). Aspirin is the most common
oral anti-platelet agent, blocking platelet activation permanently.
Clopidogrel is an oral, reversible platelet inactivator. Dipyridamole is an
oral antiplatelet agent utilized for stroke or transient ischemic attack. It is
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a reversible agent that is combined with aspirin. Newer agents, such as
prasugrel and ticagrelor) are also oral and reversible. The use of aspirin
permitted marked reductions in incidences of death and myocardial
infarction.

Another treatment focus is to decrease the work of the heart, particularly
in the left ventricle (larger, muscular portion) of the heart. Beta-blockers
slow the heart rate and lower blood pressure thereby decreasing the heart
work. ACE inhibitors and angiotensin-receptor blockers decrease blood
pressure. Nitrates such as nitroglycerin or its longer acting cousins,
isosorbide dinitrate or isosorbide
mononitrate, shrink the heart and thereby
lower wall stress and heart work. They also
dilate small collateral (reserve) blood
vessels. ACE inhibitors and angiotensin
receptor blockers decrease blood pressure
and decrease the work of the heart by
dilating arteries. The major side effects
include cough, dizziness, and hypotension,
and ACE inhibitors and angiotensin-receptor blockers are contraindicated
in pregnancy. Major ACE inhibitors and ARBs include:
" Accupril (Quinapril)
" Altace (Ramipril)
" Lotensin (Benazepril)
" Vasotec (Enalapril)
" Zestril, Prinivil, Monopril
(Lisinopril)
" Avapro (Irbesartan)
" Atacand (Candesartan)
" Cozaar (Losartan)

With the use of ACE inhibitors, there is a
reduction in the incidences of myocardial
infarction and death with health management with ACE inhibitors.
Another major trial, the SAVE trial, there is a higher mortality in the trial
group with the placebo (control) in comparison to the group with captopril.

Beta-blockers decrease the work of the heart by decreasing the heart rate,
decreasing blood pressure, and decreasing the force of contraction. Side
effects include fatigue, dizziness, cold hands/feet, and impotence. It is
contraindicated in those patients with asthma and severe chronic
obstructive lung disease. Beta-blockers have
markedly reduced the incidence of death and
myocardial infarction in patients with
myocardial infarction.

Management also requires the minimization
of atherosclerotic risk factors:
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" Treatment of hyperlipidemia (abnormal LDL cholesterol levels)
" Treatment of hypertension
" Treatment of smoking addiction
" Treatment of diabetes mellitus and decrease glucose intolerance

The LDL cholesterol treatment goal is less than 100 milligrams, and
pharmacotherapy is indicated for LDL cholesterol that is greater than 130
milligrams. Current LDL-lowering drugs (statins) include:
" Crestor (Rosuvastatin)
" Lescol (Fluvastatin)
" Lipitor (Atorvastatin)
" Mevacor (Lovastatin)
" Pravachol (Pravastatin)
" Zocor (Simvastatin)

Low HDL levels (below 40 in men and below 50 in women) are associated
with increased risk of death from cardiovascular disease. Increasing HDL
levels decreases the risk of cardiovascular disease. The average HDL in US
Adults is 51. Increasing HDL levels can be done with drugs, such as
Niaspan (Niacin), Lopid (Gemfibrozil), Tricor (Fenofibrate), and statins.
However these increases are not very effective in increasing HDL (around
10%). HDL levels can also increase with lifestyle modifications, such as
regular exercise, smoking cessation, weight control, moderate alcohol
consumption, and decreased dietary fat. Statins have markedly reduced
the risk of cardiovascular disease in all groups. The Hypertension
Treatment Guidelines are once again as follows:
Normal BP <120/80
Pre-Hypertension 120-139/80-89
Hypertension > 140/90

Aspirin has been used to prevent heart attacks and stroke since the 1950s,
but the association was not established until the 1970s. In 1950,
Lawrence Craven, MD, a general practitioner presented data that one
aspirin tablet per day prevented heart attacks in men with risk factors. In
1956, he reported that aspirin also prevented strokes and mini-strokes.
When he presented such data, the medical community met him with
skepticism. No one believed him until the 1970s and 1980s when
randomized clinical trials proved him to be correct. However, another
controversy remains: whats the right dose? All the physicians agree that
the correct dose is either:
" 81 milligrams (one baby aspirin)
" 162 milligrams (two baby aspirin)
" 325 mg (one adult aspirin)

The major side effect of aspirin is bleeding. In randomized clinical trials,
the incidence of major bleeding is the same for 81 milligrams/day and for
162 milligrams/day. Bleeding rates were higher with 325 milligams/day.
There were 1 to 2 cases per 1,000 years of treatment. Another question is
who should take aspirin? In the absence of contraindications:
94
" Patients with known cardiovascular disease
" Adults with diabetes
" Those with cardiovascular risk factors
" Men age >50
" Post-menopausal women, but this is controversial, because aspirin is
less beneficial in women.

Another groups of cardiovascular diseases are transient ischemic attacks
(TIAs) and stroke. 15% of all strokes are preceded by a transient ischemic
attack. TIAs are referred to as a mini-stroke. Symptoms include: partial
loss of vision, weakness of arm or leg, speech or swallowing difficulty. The
symptoms last less than 24 hours, and require prompt evaluation by a
physician. There is evidence-based medical therapy proven to benefit
patients following a myocardial infarction, with these drugs:
" ACE inhibitors and angiotensin receptor blockers (lisinopril and
losartan)
" Aspirin, other platelet acting drugs such as clopidogrel
" Beta blockers (metoprolol)
" Statins and other lipid-lowering agents (pravastatin)
" Anticoagulants in selected patients, such as for patients with atrial
fibrillation.

The evidence-based medicine once again proves its point. There is a
decrease in mortality as the number of recommended therapies increase.
The death rate goes down. As hospitals increase in guideline adherence,
there is also a decrease in mortality. The American Heart Association
Prevention Guidelines include:
" Smoking
" Blood Pressure
" Physical Activity
" Weight Control
" Diabetes Mellitus
" Antiplatelet/Anticoagulant Agents
" ACE Inhibitors
" Beta Blockers
" Lipid Management
" Cessation of Hormone Replacement Therapy

Heart failure is when one of the ventricles (usually the left) cannot pump
enough blood to satisfy the amount of blood flow that is required for daily
activities. The body responds with compensatory mechanisms as if there
were a state of dehydration or hemorrhage. Salt and water are retained in
an attempt to correct the deficit in circulating blood volume with resultant
shortness of breath and swelling, usually of the legs. Diuretics are usually
given. Drugs in heart failure should be used to effectively control fluid
retention. It is essential for fluid overload with resultant symptoms. The
other drugs used attempt to improve heart function by decreasing heart
95
work and facilitate heart emptying. The following list once again describes
the commonly used diuretics in heart failure:
Absorp-
tion (%)
T1/2 Relative
Potency
Elimination (R = Renal,
H=Hepatic, B= Biliary, U=
Unknown)
Anti-hypertensive dosing
(typical)
Chlorothiazide 9-56 !1.5 0.1 R PO: 500-2000 mg/day in 2 doses
Chlorthialidone !65 !47 1 65% R, 10% B, 25% U 12.5-25 mg PO once daily
Hydro-
chlorothiazide
!70 !2.5 1 R 12.5 -50 mg PO once daily
Indapamide !93 !14 20 > 95% H 1.25-5 mg PO once daily
Metolazone !65 4-5 10 80% R, 10% H, 10% B 2.5-5 mg po once daily For
Mykrox: 0.5-1 mg PO QD

Loop diuretics primarily act in the thick
ascending limb, which is also the site of the
greatest sodium cation capacity (25% of the
filtered sodium load). Nephron segments past
this site do not possess reabsorptive capacity
to reabsorb this high volume of fluid and salt.
It is effective despite reduced kidney function.
Thiazide iuretics are better antihypertensives than loop diuretics. They
are supported by hard outcome data in hypertensive patients, with long-
term reduction in vascular resistance. There is less electrolyte
disturbances and attractive in mild heart failure particularly if there is
concomitant hypertension. The initiation and maintenance of diuretics
involves this: once fluid retention is resolved, a maintenance dose should
be continued with dose reassessed and adjusted periodically. Patients
should be educated on self-adjustment based on weight and symptoms.
Physicians may need to use two or more diuretics (thiazide and loop) in
combination for enhanced effect.

Beta-blockers (particularly metoprolol, bisoprolol, and carvedilol) have
been proven effective in heart failure. The following once again shows the
pharmacokinetic properties of select beta-blockers:
Selec-
tivity
Lipid
Solubility
Bioavailbility
(%)
Protein
Binding (%)
T1/2
(h)
Primary (secondary)
Elimination R=Renal, H=Hepatic
Nadolol "1"2 L 30 25-30 20-24 R
Propranolol "1"2 H 30 90 3-5 H
Timolol "1"2 L-M 75 < 10 4 H(R)
Pindolol "1"2 M 90 57 3-4 H(R)
Atenolol "1 L 50-60 < 5-10 6-9 R(H)
Metoprolol "1 M 50(77-XL) 10-12 3-7 H/R
Bisoprolol "1 L 80 26-33 9-12 R(H)
Acebutolol "1 L 40 15-25 3-4 H(R)
Labetalol "1"2!1 M 18-30 50 5.5-8 R(H)
Carvedilol "1"2!1 M 25-35 98 7-10 Bile

Beta-blockers mechanism of action involves
cardiac myocyte protection of receptors from
catecholamines and prevents binding of
autoantibodies to adrenoceptors. Studies have
shown that it caused a 34-35% reduction in risk
for mortality in heart failure with reduced left
ventricular ejection fraction. Its effects are in
three areas:
Sodium Reabsorption Sites in the Nephron
70% Proximal
Tubule
5% Distal
Tubule
1-4%
20% Loop
of Henle
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Esmolol
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96
" Improved (diastolic) coronary
artery flow and greater myocardial
oxygenation.
" Improved force-frequency
relationship
" Cardiac myocyte energy
conservation.

ACE inhibitors remain the cornerstone of anti-renin-angiotensin-
aldosterone-type therapy in heart failure with reduced heart function.
ACE inhibitors and/or ARBs can be used in patients with moderate kidney
disease. It is used in first-line therapy for the treatment of heart failure.
The following are the ACE inhibitors and ARBs:
Drug Commonly used ACEi and AH blockers in
treatment of HF with low EF
Initial daily dose Target dose
ACEi Captopril 6.25 mg tid 50 mg tid
Enalapril 2.5 mg bid 10-20 mg bid
Fosinopril 5-10 mg daily 40 mg daily
Lisinopril 2.5-5 mg daily 20-40 mg daily
Perindopril 2 mg daily 8-16 mg daily
Quinapril 5 mg bid 20 mg bid
Ramipril 1.25-2.5 mg daily 10 mg daily
Trandolapril 1 mg daily 4 mg daily
ARB Candesartan 4-8 mg daily 32 mg daily
Losartan 25-50 mg daily 50-100 mg daily
Valsartan 20-40 mg bid 160 mg daily

Another method of reducing work on the heart is with aldosterone
inhibitors, such as spironolactone, which is a competitive antagonist of the
aldosterone receptor in the myocardium, arterial walls, and kidney. They
ultimately decrease the retention of water and sodium (reducing edema)
as well as decrease the excretion of potassium and magnesium (reducing
arrhythmias). It has also been known to decrease collagen deposition
(fibrosis) in the myocardium and the vessels. Aldosterone antagonists
work by blocking aldosterone binding in two areas: (1) at the
mineralocorticoid receptors in kidney, heart, blood vessels, and brain, and
at (2) the distal renal tubule, causing increased sodium chloride and water
excretion and potassium retention. Spironolactone has shown efficacy in
heart failure, reducing total mortality by 30% over 2 years in NYHA late III
and IV patients (fairly late heart failure) and reduced need for
hospitalization.

A final medication utilized in the management of heart failure is a digitalis
glycoside known as digoxin. Digitalis is from the foxglove plant. It is a last
resort drug due to its ineffectiveness in comparison to beta-blockers, ARBs,
and ACE inhibitors. Digoxin works by inhibition of sodium-potassium
ATPase in three areas:
" Cardiac Cells (increasing contractility)
" Non-Cardiac Cells (sensitization of cardiac baroreceptors and
decreasing sympathetic CNS outflow)
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
Relative risk and 95% confidence intervals
CIBIS-II 1.3 years
placebo 228/1320 (17%) bisoprolol 156/1327 (12%)
MERIT-HF 12 months
placebo 217/2001 (11%) metoprolol-XL 145/1990 (7%)
COPERNICUS ~ 12 months
Placebo 190/1133 (18.5%) carvedilol 130/1156 (11.4%)
P = 0.0001
P = 0.0062
P = 0.0014
!"#$%$&'"("')*+ !-.+/*() 01"'$23
"##$%&'() *+,-&#.-/ .0 12 3.-4 ,)5'6)5 7892
RR


34%



34%
35%


CIBIS-II Investigators and Committees. Lancet 1999; 353:9-13.
The Metoprolol CR/XLRandomised Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA2000;283:1295-1302.
Packer et al. For The COPERNICUS Trial Study Group. N Engl J Med 2001;344:1651-8.

97
" Renal Cells (reduction in renal tubular absorption of sodium and
increased presentation to distal tubules) ! suppression of renin
secretion

Studies have shown that digitalis has
been associated with an increased force of
contraction, which can be seen with
comparison of Starling Curves. One large
randomized trial that confirmed the
effectiveness of digoxin was the DIG Trial.
The DIG Trial was done to evaluate the
effects of digoxin in patients with normal
sinus rhythm with heart failure with
reduced left ventricular function. The
study found that there were no statistical
differences. It did not decrease mortality,
and did not decrease mortality was due to
cardiovascular causes and worsening
heart failure. The improvement was in
symptoms, but not in mortality. However
there were two findings in favor of
digoxin. It decreased hospitalizations for
worsening heart failure and
hospitalization for any cause. Essentially,
it was not effective as ACE inhibitors,
beta-blockers, and ARBs. Physicians often do not use it, or use it as a third-
line therapy. Individuals who had low levels did better in comparison to
high levels, because higher levels are associated with complications.

In summary, treatment of Heart Failure is in ABCDE:
" A: ACE Inhibitors/Angiotensin-Receptor Blockers
" B: Beta-blockers
" C: Calcium channel blockers
" D: Diuretics
" E: Endothelin-converting enzyme inhibitors

Initiation and monitoring requires low doses of 0.125 milligrams to 0.250
milligams daily. Digoxin is mostly eliminated by the kidney in the urine,
with a long half-life (18 hours), with distribution and levels. It is
important for physicians to check baseline digoxin blood levels and again if
there are changes in clinical condition, suspicion of toxicity, changes in
renal function, and addition of an interacting drug (such as amiodarone).
In conclusion, pharmacological heart failure therapy has improved
tremendously during the last forty years. Survival of these patients is
better than in the past but is still markedly reduced. Intense research
continues in this area in an attempt to improve the function of the failing
heart.
Rathore S., et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA.
2003;289:8710878. Copyright 2003. American Medical Association. All rights reserved.
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!&,7 85/93/:&(:'5/
98
LECTURE XII
Cardiovascular Disease Pharmacotherapy #4
Lecturers: Joseph S. Alpert, MD and Michelle Kaczynski, PharmD
Case #1:
A 45-year-old man is being treated for hypertension and diabetes mellitus.
What is the most feared complication of this combination of diseases and
which drugs would you likely choose for this patient?
Answer
The most feared complications of this combination of diseases are
cardiovascular diseases, mainly stroke and heart attack.

Address the hypertension with beta-blockers or ACE inhibitors, and
address the diabetes mellitus with antihyerglycemic agents, namely
Metformin.
Case #2 (1):
An 86-year-old patient with hypertension and mild dementia is taking
metoprolol, lisinopril, HCTZ, nifedipine, lovastatin, aspirin, clopidogrel,
warfarin, and valium. What do you think of this program?
Answer
There are too many drugs to address the hypertension, and the mild
dementia can possibly be associated with drug-drug interactions.
Case #2 (2):
During July in Tucson, the patient reports fainting once and feeling faint
on many occasions in the last few weeks. What might be the problem here
and how would you correct it? Remember that the patient is 86-years-old
and has some dementia.
Answer
Reduce the dosage and number of medications. Encourage hydration. It is
important to also observe environmental influences.
Case #3:
A 27-year-old homeless man who smokes heavily and has used crystal
meth frequently in the past reports severe, squeezing chest pain
whenever he walks up a slight hill.
Part 1.
What is the likely diagnosis?
99
Answer
Angina secondary to methamphetamine use.
Part 2.
What sudden life-threatening event might happen to this man?
Answer
Myocardial Infarction.
Part 3.
What pharmacological therapy does he probably require?
Answer
Discontinuation of methamphetamine use and administration of beta-
blockers and/or ACE inhibitors or ARBs.
Case #4
A 60-year-old man with hypertension tells you that he does not want to
take his prescribed medicines because they are artificial chemicals that
cause cancer. Instead he is taking twelve different herbal preparations
from the health food store. What is your advice and why?
Answer
Tell him that the herbal preparations are not regulated.
Case #5:
A 47-year-old woman with long standing hypertension tells you that she
cannot tolerate any of the medicines she has received from her doctor in
the past. She is obese, loves salted chips pretzels, and peanuts. What
advice would you give her and what pharmacological therapy might you
suggest?
Answer
Choose most benign drug and get her started with that drug. Tell her also
that she needs to engage in lifestyle modifcations to improve her tolerance
to pharmaceutical agents.
Question?
Are there street drugs that can cause hypertension?
Answer
Yes. Methamphetamines and cocaine.
Are there products in the supermarket that can cause or worsen
hypertension?
Answer
Yes. Alcohol, licorice, caffeine, ginseng, NSAIDs, salt, spam? Anything
with sympathomimetic amines.

100
Which of the following classes of drugs are considered first line for the
treatment of hypertension?
A. Beta blockers
B. Calcium channel blockers (indicated for African Americans)
C. Angiotensin receptor blockers
D. Thiazide diuretics
E. Central nervous system sympathetic blockers

Which of the following foods are high in salt and therefore might increase
blood pressure?
A. Ketchup
B. Mustard
C. Canned soups
D. V8 Tomato Juice Cocktail
E. Dill Pickles
F. All of the Above
Case #6
A 56-year-old woman reports poor control of her blood pressure that
recently led to an episode of heart failure treated in the hospital. She tells
you that she has no medical insurance and that the blood pressure
medicines her doctor prescribed were costing way too much for [her] to
able to take them every day. What is your strategy here?
Answer
Consult with free clinics and financial services to manage costs for patient.
Question?
Are most patients very faithful about taking their medicines for
hypertension as prescribed by their physician or nurse clinician?
Answer
Patient compliance is (at best) around 50%.
Case #7
A 74-year-old man has heart failure and is receiving digoxin therapy
among other drugs. He develops an arrhythmia and is started on oral
amiodarone, a drug that binds with great intensity to proteins. Two weeks
after starting amiodarone, the man reports severe nausea, changes in
color vision, and two fainting spells. What has happened to the patient?
Answer
Drug interactions. Digoxin and amiodarone are not to mix. Discontinue
the digoxin.
101
Case #8
A 79-year-old woman is taking the oral anticoagulant, warfarin, because of
a previous stroke. The patient regularly takes aspirin for her arthritis.
Early this morning, she became nauseous and vomited bright red blood isn
copious amounts. Why might this have occurred?
Answer
Hemorrhage due to antiplatelet and anticoagulant agents.
Case #9
A fifty-year-old man with severe, end stage liver disease from chronic
alcohol abuse develops pneumonia and is admitted to the hospital. He has
severe degenerative osteoarthritis and complains of severe back pain. He
is given intravenous morphine and 15 minutes later, he stops breathing.
What happened?
Answer
Overdose of morphine in individual with severe, end stage liver disease.
Question?
Which of the following drugs would NOT be appropriate for a patient with
heart failure?
A. Beta-blocker
B. Angiotensin Receptor Blocker
C. Digoxin
D. Furosemide
E. Penicillin

Which of the following drugs would be appropriate for a patient with
hypertension and what is their mechanism of action:
A. Beta-blocker-Blocking the SNS action
B. Angiotensin Converting Enzyme Inhibitor modulation of RAA
Axis.
C. Methotrexate
D. Prednisone
E. Furosemide
Case #10
A 69-year-old man suffers an acute myocardial infarction (heart attack).
His lipid tests were as follows: total cholesterol = 270 mg%, LDL cholesterol
= 160 mg%; HDL cholesterol = 35 mg%. What class of medication should he
receive and why?
Answer
Statins to regulate cholesterol levels.

102
What is the mechanism of action of statin drugs? In other words, how do
they lower cholesterol levels?
Answer
Statins are beta-hydroxy-beta-methylglutarate coenzyme A reductase
inhibitors.
Question?
Which of the following diseases is the #1 cause of death in the world?
A. Cancer
B. Pneumonia
C. HIV/AIDS
D. Cirrhosis
E. Trauma
F. Cardiovascular Disease

Which of the following is NOT a cause of myocardial infarction (heart
attack)?
A. Cigarette Smoking
B. High Blood Pressure
C. Diabetes Mellitus
D. Cancer
E. High Blood Pressure
Case #11
A 45-year-old man develops severe central chest pain early in the
morning. He is nauseated and sweaty. He calls 911 and is brought to the
emergency ward. What treatment would be best for him if he is found to be
having a heart attack?
Answer
Get him into the cardiac catheterization lab, as it is 90% effective in
elimination of blockage.
Case #12
A 99-year-old man has severe valvular heart disease and severe heart
failure. He has advanced kidney failure and Alzheimers disease. His
family wants everything possible done for him. What therapy would you
recommend?
Answer
Conservative/supportive therapy and pain management in an effort to
permit nature to take its course painlessly ! With such advanced heart
and kidney disease, there is not much possibly to do.
103
Case #13
A 29-year-old man with severe familial hypertension always has elevated
blood pressures when he comes into the office. What questions would you
ask him?
Answer
Calm the patient down and ask him about his lifestyle.
Case #14
The 33-year-old father of a 5-year-old girl has an acute heart attack and
survives. His total cholesterol = 356 mg% and his LDL cholesterol = 201
mg%. You are the girls pediatrician. What would you recommend to the
parents?
Answer
Measure her cholesterol levels and possibly focus on reduction of
cholesterol levels with lifestyle modification or pharmacological agents.
Question?
Which of the following values for total and LDL cholesterol are seen in
natives living in the rain forest highlands of New Guinea?
a. Total chol = 180 mg%; LDL = 98 mg%
b. Total chol = 80 mg%; LDL = 40 mg%
c. Total chol = 200 mg%; LDL 140 mg%
d. Total chol = 20 mg%; LDL 10 mg%
Case #15
A fifteen-year-old male reports that he develops a fast irregular heart rate
following his daily 2-hour vigorous workout. You are his doctor. What
would you suggest for this patient?
A. Record his heart beats for 24 hours with a portable ECG recorder.
B. Do nothing and reassure the patient.
C. Treat the patient with oral amiodarone.
D. Suggest a consultation with a cardiac surgeon.
E. Treat the patient with a beta-blocker, and an angiotensin receptor
blocker.
Case #16
A 44-year-old homeless woman has had two heart attacks in the past and
reports shortness of breath while walking quietly as well as swollen ankles.
Part 1.
Can this patient get the drug therapy she needs?
104
Answer
Only if she can reach the appropriate financial services, including family.
Most likely she will be unable to attain the drug therapy mainly because of
her homeless status, inaccessibility to services, and lack of social support
in management of drug therapy.
Part 2.
What drugs should be given?
Answer
Beta-blockers
ACE Inhibitors or ARBs
Digoxin (third-line)
Loop diuretics or thiazide diuretics
Aldosterone Inhibitors (Spironolactone)
Question?
Which of the following drugs can worsen kidney function in a patient with
pre-existing kidney disease?
A. Digoxin
B. Angiotensin receptor blocker
C. Ibuprofen (Motrin/Advil)
D. Furosemide (a diuretic)
E. Penicillin

Which of the following drugs has been shown in randomized, double-blind
clinical trials to decrease the risk of death in patients with angina and
coronary artery disease?
A. Beta-blockers
B. HCTZ
C. Angiotensin Converting Enzyme Inhibitor
D. Aspirin

105
Lectures XIII
Drugs Targeting Central Nervous System
Lecturer: Dr. Edward French, Ph.D.
Introduction
Vertebrate animals have developed unique anatomical and neurochemical
systems that reinforce goal-directed behaviors such as feeding, drinking
and sex. These behaviors seem to have evolved to ensure the survival of
the individual and the continued existence of the species. The successful
attainment of each goal leads to a rewarding stimulus (good feelings,
pleasure, etc.), which further reinforces the behavior, making it more
likely to be repeated. This I will call positive-reinforcement. Later on we
can discuss how negative consequences can also make it more likely that
some behaviors will be repeated.

There is considerable evidence to suggest that drugs of abuse activate the
same biochemical pathways as natural rewards such as a palatable meal or
a stimulating social interaction. In fact, drugs such as cocaine may activate
these systems so strongly that the individual spends increasing amounts of
time acquiring and administering the drug. Natural rewards can become
insignificant or unimportant compared to the euphoria or rush produced
by the supraphysiological reinforcements of some drugs of abuse.

Drug Addiction

Drug addiction is a complex biochemical and behavioral syndrome that
exists along a continuum from minimal use, to abuse to addiction (OBrien,
1996). Addiction is defined as a chronic, relapsing brain disease
characterized by compulsive drug seeking and use, despite harmful
consequences (eg. significant health, economic and/or social costs to the
individual). In a nutshell, addiction is commonly thought of as a loss of
106
control. The addiction cycle has been characterized by: impulsivity
(binge/intoxication) leading to withdrawal/negative effects causing
preoccupation/anticipation, thus shifting from impulsivity to compulsivity
to addiction.

Generally, addictive drugs can act as positive reinforcers (producing
euphoria) or as negative reinforcers (alleviating symptoms of withdrawal
or dysphoria).

It is considered a brain disease because drugs change the brainthey
change its structure and how it works. Brain imaging studies from drug-
addicted individuals show physical changes in areas of the brain that are
critical to judgment, decision making, learning and memory and behavior
control. These brain changes can be long lasting, and can lead to the
harmful behaviors seen in people who abuse drugs.

Other terms are often associated inappropriately with addiction. Terms
such as tolerance and physical dependence are frequently mentioned.
Tolerance refers to a reduction in a particular effect produced by a given
drug following repeated administration of that same drug. Higher doses of
the drug are needed to produce the original level of effect. Physical
dependence is a physiological response to continued drug administration.
The body compensates in an effort to return it to homeostasis. If the drug is
suddenly withdrawn, a physical withdrawal syndrome may occur. This
withdrawal syndrome may produce effects which are opposite to those
produced by the drug. Sometimes this is referred to as the abstinence
syndrome, which occurs following cessation of drug taking (abstinence
from the drug). A withdrawal syndrome can also often be produced by
administering an antagonist to the drug (precipitated abstinence).
Heroin is an excellent example of a commonly abused drug, which
produces all of the effects listed above. The administration of heroin
produces euphoria, which leads to further heroin use (positive
reinforcement). Repeated exposure to the same dose of heroin then
results in a progressive decrease in the euphoric effect (tolerance). In
order to achieve the same degree of euphoria the user must take a larger
dose. Substituting a different opiate (eg. oxycodone) for heroin in an
attempt to elicit the same degree of euphoria similarly shows a decreased
level of effect - this is an example of cross-tolerance between heroin and
the other opiate. Repeated exposure to heroin also can produce physical
dependence. The user needs heroin in order to maintain a newly
established level of homeostasis and to prevent withdrawal from the drug.
Heroin withdrawal produces an abstinence syndrome which is
accompanied by a wide variety of autonomic signs including sweating,
chills, piloerection which makes the skin look like gooseflesh (hence, the
term, cold-turkey), diarrhea, and involuntary muscle spasms (thus,
kicking the habit). The gastrointestinal response is an example of the
adaptation made by the body to counteract the effects of an opiate. Heroin
and other opiates are famous for producing constipation and, in fact the
107
two accepted medical uses of opiates are as analgesic agents and as
antidiarrheal medications. Withdrawal from opioid dependence can also be
precipitated by administration of naloxone, an opioid receptor
antagonist.
It is important to realize that in many cases tolerance and physical
dependence are present but neither is necessary or sufficient for a
diagnosis of addiction (OBrien, 1996). A person with chronic back pain,
for example, may be treated over a long period of time with an opioid
resulting in tolerance and physical dependence. It is unlikely, however,
that the patient will develop the behavior of compulsive drug use.
Although sometimes this can and does occur.

As mentioned, there are many factors that contribute to drug addiction.
Such diverse factors as the availability of a particular drug, the route of
administration, the social setting and the availability of non-drug
reinforcers can all influence an individuals pattern of drug use. The
primary driving force behind drug addiction, however, is the
reinforcing actions of the drug. The drug produces a sense of well being,
euphoria or some other behavioral change that makes the person want to
repeat the experience.

In order to understand how drugs of abuse produce their reinforcing
effects, an understanding of the neurobiology of reward is essential. Much
of what is known about the mammalian reward system is derived from
animal research using procedures such as intracranial self-stimulation
(ICSS) and drug self-administration.

Intracranial Self-Stimulation (ICSS)
In the early 1950s, James Olds and Peter Milner were investigating
whether electrical stimulation of the rat reticular activating system would
increase attention and learning. Small electrical currents were delivered to
this brain region via a chronically implanted small wires. They observed
that one of the rats kept returning to the place on a table top enclosure
where it had received a small electrical stimulation.

Fortunately, they decided to pursue the observation. They checked the
location of the electrode and found that they had placed it by accident near
the anterior commissure (you do not need to know the neuroanatomy).
They implanted additional rats with electrodes in a variety of brain regions
and made the electrical stimulation contingent on the rats pressing a lever.
In some brain regions rats would press the lever thousands of times in an
hour while neglecting natural rewards such as food or a receptive mate.
The studies in rats were also extended to include ICSS behavior in goldfish,
guinea pigs, dolphins, dogs and monkeys, suggesting that there is a reward
system in place for probably every vertebrate species.

108
There have also been several reports of humans undergoing therapeutic
electrical stimulation in deep brain structures. They have reported
pleasurable feelings from the stimulation. In fact, patients will perform a
nominal task to receive this stimulation. Many of the same structures that
support ICSS in rats, such as the lateral hypothalamus, also produce
subjective effects of pleasure when stimulated in humans. Though these
studies were interesting, there were alternative explanations for the
observed behavior. The implantation of the electrode, for example, could
have produced a painful state that was relieved by the electrical
stimulation. It took many additional studies to validate the procedures and
advance our understanding of the brains reward systems.

Initial studies focused on the anatomical sites in the brain that supported
ICSS behavior. Not surprisingly, a number of these areas were located in
what is called the limbic system (a primitive collection of neuronal nuclei
involved in the very basics of survival behaviors). This includes the septal
area, nucleus accumbens, (often referred to as the ventral striatum)
lateral hypothalamus, areas in the amygdala and the cingulate cortex. It
should be noted that stimulation of other regions produces neutral or
aversive stimuli (e.g. spinothalamic tract).

Stimulation of the lateral hypothalamus, in particular, supported robust
ICSS. The medial forebrain bundle (MFB) is one of the transversing neural
pathways in the hypothalamus and contains the neurotransmitters
dopamine (DA), norepinephrine (NE) and serotonin (5-HT) nerve fibers
that originate in brainstem nuclei and terminate throughout the limbic
system (see Figure 1). When electrodes were implanted anywhere along
the MFB, robust ICSS behavior could be
elicited.

In Panel A, animals are trained to press a
lever to obtain a drug or saline (self-
administration) or to receive intracranial
current in brain-rewarding loci (ICSS). In
Panel B, the animal is placed in a box with
two discrete chambers (environments), and
then injected with a drug (eg. on days 1, 3
and 5) in one chamber and then with saline
(eg. on days 2, 4, and 6) in the other
chamber. On the drug-free test day (day 7)
the animal is allowed access to both
chambers, and the amount of time spent in
each is recorded. If the drug is positively
reinforcing the animals will spend more time
in the chamber in which it received the drug
and less in the chamber in which it received
saline. This is called place preference.

109
The widespread MFB innervation of the limbic system suggested that this
system was involved with regulation of the autonomic nervous system,
drives and emotions. The observation that ICSS is increased in hungry
animals and decreased in satiated animals further indicated that there was
a close relationship between the physiological state of the animal and its
sensitivity to natural rewards.

The mesolimbic circuit includes projections from the ventral tegmental
dopamine neurons to the nucleus accumbens, amygdala and hippocampus.
This circuit has been implicated in acute reinforcing effects, memory, and
craving. The mesocortical circuit includes projections from the ventral
tegmental dopamine neurons to the prefrontal cortex, orbitofrontal cortex
and anterior cingulated. It is involved in conscious experience of the
effects of drugs, craving, and compulsion to take drugs.

The important issue of which neurotransmitters regulate the reward
pathway and ICSS behavior, was studied through the use of specific
chemical antagonists and neurotoxins. Stimulation of the locus coeruleus,
which gives rise to NE axons in the MFB, did not support ICSS.
Furthermore, destruction of NE neurons in the locus coeruleus or selective
blockade of NE receptors with antagonists had no effect on MFB ICSS.
Similar studies using 5-HT antagonists saw a slight increase in MFB ICSS,
suggesting that 5-HT inhibits this system.

Studies that manipulated DA levels on the other hand, played a critical role
in ICSS. Dopamine agonists facilitated ICSS while lesions of DA neurons in
the midbrain and the administration of DA antagonists, dramatically
reduced ICSS. In conclusion, it became apparent that the neurotransmitter
dopamine was critical to ICSS.

With the development of the ICSS procedures it was logical to ask what
effect, if any, do drugs of abuse have on ICSS? One might predict that if
cocaine makes a rat feel good, then the rat might not press for ICSS as
much. On the other hand, rats, like humans, are hedonists and might push
110
the lever as much or more under the influence of cocaine. Experiments
confirmed the second hypothesis. If you give a rat an injection of cocaine
before its test session, you get a dramatic increase in lever pressing for
ICSS. Other drugs of abuse also increased pressing. The interaction
between drugs of abuse and ICSS makes better sense if you consider that
the rate of lever pressing is related to the intensity of the electrical
stimulus. The greater the electrical current (up to the point that you start
getting tissue damage), the faster the rats press the lever. It was concluded
that drugs like cocaine and morphine were affecting neurotransmission,
and like the stimulating electrodes, effectively increasing the output of
these neurons to produce a more rewarding stimulus.
Drug Self-Administration Studies
Contemporaneous with the experiments of Olds and Milner, other
experimenters were searching to explain how various drugs acted in the
central nervous system to alter behavior. In particular, why do humans
find some drugs pleasurable? Through the use of the animal model of self-
administration of drugs it became possible to begin assessing the role of the
neurotransmitters norepinephrine, serotonin and dopamine in drug taking
behavior. As before, the same limbic structures and the catecholamine
neurotransmitter dopamine were found to be involved. For example:
1. In rats trained to lever press for the intravenous infusion of a drug,
pretreatment with a selective antagonist of dopamine receptors
blocks the self-administration of amphetamine, cocaine, heroin and
other abused substances. Dopamine antagonists also prevent the
euphoric effects of these drugs in humans, as well as the pleasurable
effects of naturally rewarding stimuli. Norepinephrine receptor
blockers do not.
2. Selective depletion of dopamine from the nucleus accumbens by the
neurotoxin 6-hydroxydopamine disrupts cocaine and amphetamine
self-administration in animals.
3. Injections of dopamine antagonists directly into the nucleus
accumbens blocks intravenous cocaine self-administration in ani-
mals.
4. Rats will press a lever for injections of cocaine or amphetamine
directly into the nucleus accumbens or prefrontal cortex. This effect
can also be blocked by the peripheral injection of a dopamine
receptor blocker.
5. Rats will self-administer morphine
directly into the ventral tegmental
area, the collection of dopamine
neurons providing dopamine
innervations to the mesolimbic
forebrain structures. Morphine
stimulates those cells and increases
dopamine release in the nucleus
accumbens.
111
6. Intra-ventral tegmental area injections of morphine will also
facilitate ICSS.
7. Naloxone injections directly into the ventral tegmentum will prevent
the intravenous self-administration of morphine and heroin.

Thus, the mesolimbic (nucleus accumbens) and mesocortical (prefrontal
cortex) dopamine systems appear to serve as a central pathway in
mediating the positive reinforcing properties of a number of behaviors
including addictive drug use.

The problem with attempting to develop a unifying theory for addiction
based upon dopamine neurotransmission in limbic areas is that the various
classes of drugs of abuse act on different receptors, localized in different
parts of the brain, and they may produce totally opposite effects on
neuronal excitability (e.g., heroin and cocaine; alcohol and amphetamine;
nicotine and marijuana) (See Table 1). Nevertheless, a theory of addiction
was developed that centered on a factor common to all the major classes of
abused drugs and other rewarding behaviors (food, thirst, sex): (1) they
increase dopamine levels in limbic structures and (2) they elicit approach
or forward locomotion. In rats, approach behaviors and positive
reinforcement can be elicited by electrical stimulation of the MFB, and
drugs, which serve as positive reinforcers, elicit forward locomotion. This
notion has been called the psychomotor stimulant theory of addiction with
the mesolimbic-mesocortical dopamine structures (nucleus accumbens,
prefrontal cortex and ventral tegmental area) serving as the substrates for
the rewarding properties of drugs of abuse.
The Psychomotor Stimulant Theory
If we administer a dopamine antagonist to animals,
we can block cocaines reinforcing effects. In
addition, dopamine antagonists can block, or
attenuate, the reinforcing effects of almost any
drug of abuse or natural reward. This includes
morphine, THC, PCP, nicotine and sexual behavior.
In addition, it is possible to measure neuronal activity and neurotransmit-
ter release in discrete brain regions. For this reason, it has been
hypothesized that drugs of abuse or natural rewards increase dopami-
nergic activity and the release of dopamine in the reward system. The
psychomotor stimulant theory of addiction incorporated the above findings
into a workable hypothesis. Although drugs of abuse have many different
primary mechanisms of action, they all increase CNS levels of dopamine.
Furthermore, any event that elicits approach or forward locomotion (49-5)
will serve as a positive reinforcer (psychomotor stimulant). It is thus
hypothesized that certain stimuli (food, drugs of abuse, etc.) increase the
animals level of arousal, elicit approach behaviors and reinforce the
interaction by activating dopamine reward systems. Dopamine may play
an important role in directing the animals attention to motivationally
112
relevant stimuli. This theory also has important ramifications with regard
to drug abuse. One addictive drug could produce the same general type of
stimuli that a different drug produces. This could explain why many drug
users are polydrug users. Furthermore, a recovering heroin addict may be
prone to relapse if he or she drinks alcohol. It is worth noting here that all
the major drugs of abuse lower the threshold for ICSS and are self-
administered. For the clinician, then, it is important to realize that for an
individual in a drug rehabilitation program (say for heroin addiction), that
they may be susceptible to other drugs for which they are not being treated
but which may activate the same neural circuitry as heroin and thus put
the ex-addict at risk of relapse.

An important question is How does an inhibitory drug of abuse such as
alcohol or heroin increase dopamine release? One explanation is that
these drugs inhibit tonically active inhibitory interneurons in the VTA, i.e.,
inhibiting the inhibitory neuron (see Figure 2). This is termed disinhibition
and leads to an increase in activity of the neurons (in this case a dopamine
neurons) that project to the limbic structures via the MFB.
Drugs as Surrogates of Natural Reward
How do addictive drugs fit into the natural reward systems? Lets use
cocaine as an example. A group of friends suggest that you try cocaine at a
party. This might activate the dopamine system enough for you to become
interested and approach the table (fig. 3). If you decide to try the drug you
are likely to further stimulate the dopamine reward system and associate
the drug (primary incentive) and the environment (secondary incentive)
with a sense of well-being. Continued use of the drug will further
strengthen the bonds between primary and secondary incentives of the
drug use and a sense of pleasure. You can also get an appreciation of how
hard it might be to break an addiction, even after you separate yourself
from the drug and the social group that you were involved with. The sight
of a white powder, for example, may bring back a flood of good memories
that triggers an intense craving for the drug.

Of course, there are differences between stimuli such as food and cocaine.
The primary incentive properties of cocaine, for example, (bitter taste,
lack of smell, white chalk-like powder) may not be as strong as it is for
food. The incentive learning phase of drug abuse thus plays an important
role in the development of drug self-administration behaviors, namely the
establishment of secondary incentives.
Summary
We have mentioned that behaviors essential to the survival of the
individual and the species include feeding and drinking, as well as mater-
nal, social and sexual interactions. By pairing these behaviors with
immediate feedback in the form of pleasure, natural selection has provided
113
the species with a means to increase the likelihood that the behavior will
be repeated (reinforcement). Drugs of abuse can also stimulate the reward
systems that reinforce these behaviors. What is common to almost all
drugs of abuse is their ability to directly or indirectly stimulate
dopaminergic reward systems. It is the powerfully reinforcing actions of
these drugs that can make them surrogates for natural rewards (and
possibly becoming the focus of an addiction).
Learning Objectives
List several sites in the rat CNS that support intracranial self-stimulation.
Ventral Tegmental Area
Lateral Hypothalamus
Septal area/Nucleus Accumbens
Parts of the amygdala (Posterior amygdala)
Cingulate cortex
Caudate
Name the three monoamine pathways whose axons comprise the medial forebrain
bundle.
The three major monoamine pathways whose axons comprise the medial
forebrain bundle are:
Dopaminergic
Noradrenergic
Serotonergic
Detail the neuroanatomical pathways of the mesolimbic and mesocortical dopamine
systems (i.e. where do the neurons originate, in which fiber tract do they travel and
where do they terminate).

Pathway Neuronal Origin Fiber Tract Traveled By Termination
Mesolimbic Ventral Tegmental Area of
the Midbrain
Medial Forebrain Bundle Nucleus Accumbens, limbic
cortices, septo-hippocampal
complex, and amygdala
Mesocortical Ventral Tegmental Area of
the Midbrain
Meso-cortical dopamine
projections
Cerebral Cortex (particularly the
frontal lobes), innervates
prefrontal and insular corticies
Nigrostriatal Substantia Nigra Basal Ganglia Corpus Striatum (Caudate and
Putamen)
Tubero-
infundibular
Arcuate nucleus of the
mediobasal hypothalamus
Dopamine neuronal
projections
Projection to the median
eminence
Lecture XIV
Antipsychotics
Lecturer: Edward D. French, Ph.D.
Psychosis
Psychosis is a severe syndrome principally characterized by disordered
thinking, alterations in perception, affect and behavior. Its symptoms
include paranoid delusions, hallucinations (visual and auditory), loss of
affect, loss of ego boundaries and volition, and impaired interpersonal
functioning and relationship to the external world. The etiology of
psychoses can be either organic or idiopathic. Organic psychosis can occur
in response to a defined toxic (eg. methamphetamine psychosis), metabolic
or neuropathological change resulting in delirium (confusion and
disorientation) and dementia (memory deficits). In age-related dementia
some individuals show agitation and disorder thinking when the sun sets.
Idiopathic psychosis is characterized by disturbances in thought, affect
and behavior for which there is no definable underlying pathology.

Dopamine over-activity in the limbic and frontal cortical structures of the
CNS is postulated to play a pivotal role in the psychotic disorder of
schizophrenia. The resulting dopamine hypothesis for schizophrenia was
proposed and was based largely upon a number of pharmacological
observations consisting of:
1. Virtually all antipsychotic drugs block dopamine receptors in the
CNS;
2. Levodopa, a drug used to treat Parkinsons disease, augments
dopamine activity within the CNS and can elicit occasionally
schizophreniform behavior;
3. Psychomotor stimulants which act through increasing synaptic
levels of dopamine can mimic some aspects of schizophrenic
symptoms (eg. amphetamines, cocaine);
4. PET (positron emission tomography) scans in both drug-free and
neuroleptic treated patients have found increased densities of
dopamine receptors compared to nonschizophrenic subjects.

However, the dopamine hypothesis has limitations because antipsychotic
drugs do not completely eliminate all psychotic symptoms. The positive
symptoms of schizophrenia, delusions, hallucinations, bizarre behavior,
and thought disorder, appear more responsive to drugs, which block the
dopamine D-2 receptor. However, newer antipsychotic agents (clozapine,
olanzepine and risperidone) have higher affinity for other receptors (i.e.
serotonin) and are efficacious for treating a broader range of psychotic
symptoms, including the negative symptoms consisting of affective
115
blunting, poverty of speech, avolition/apathy, anhedonia and attentional
impairment This latter group of drugs has been referred to as atypical
neuroleptics, and they are often favored because their use is associated
with a lower incidence of extrapyramidal movement disorders.

Molecular cloning techniques have identified five dopamine receptors (D-1
to D-5) in the CNS. Although the relative importance of these five types in
the etiology of schizophrenia has not been determined, there is a very high
positive correlation between an antipsychotic drug's clinical potency and
its ability to bind to D2 dopamine receptors (Figure 1). The therapeutic
effect of these agents is postulated to result from a blockade of D2
receptors in the limbic and mesocortical (prefrontal) brain areas.

However, the blockade of D2 receptors in the nigrostriatal pathway is
likely the cause of the extrapyramidal movement disorders caused by
these drugs. These movement disorders are Parkinsonian-like and are
consistent with a decrease in dopamine function within the caudate-
putamen. Remember that these drugs act in all areas of the brain that
receive dopamine innervation. They do not prevent dopamine from being
released. In fact, through feedback processes they actually cause an
increase in dopamine release through their blockade of presynaptic
autoreceptors. Nevertheless, the concurrent blockade of the postsynaptic
dopamine receptor results in a net decrease in dopamine function in the
central nervous system.

Figure 1: Correlation of
clinical potency to D-2
receptor-binding activities of
neuroleptic drugs. Clinical
potency is expressed as the
daily dose used in treating
schizophrenia, and binding
activity is expressed as the
concentration needed to
produce 50% inhibition of
haloperidol binding (Synapse
1:133, 1987).

Although antipsychotic drugs
are highly selective for
dopamine receptors they also
have some affinity for alpha-adrenergic, cholinergic and histaminergic
receptors, with the newer atypicals having considerable affinity for
serotonin-2 receptors (5-HT
2
). Actions at alpha- adrenergic sites may
help control excitement, but also cause postural hypotension, while
116
blockade of histamine receptors may produce some sedation. Blockade of
muscarinic cholinergic receptors may produce the atropine-like side
effects of dry mouth, blurred vision, constipation and difficulty in
urination,. On the other hand the anticholinergic actions of neuroleptics
will reduce the intensity of the Parkinsonian-like side effects that occur
with the older types of antipsychotic agents.
Indications For Antipsychotic Drugs
Schizophrenia is the primary indication for use of neuroleptics, but not all
patients are responders and a full response occurs infrequently.
Schizoaffective disorders, which bear some resemblance to schizophrenia,
may also benefit from these drugs, which may also be used in conjunction
with antidepressants or lithium. The manic episode in bipolar affective
disorder can also be effectively treated with neuroleptics, which can be
withdrawn upon subsidence of the mania. Other conditions for the use of
neuroleptics include: intractable hiccups, the chorea of Huntington's
disease, ballism, and Tourette's syndrome, and psychotic depression.
Drug Choice
Differences between chemical structures (potency, pharmacokinetics) and
pharmacological differences (receptor affinities) between classes of
compounds may be the best rationale for choosing a given antipsychotic
medication. Past response and potential adverse effects best determine
drug selection. Remember that for schizophrenia there is virtually no
evidence that a given compound can target given symptoms. Presently,
there is an increasing tendency in psychiatry to begin treatment with one
of the atypicals such as clozapine, risperidone, olanzepine, quetiapine or
aripiprazole.
Doses
Since the range of effective doses among the various antipsychotics is so
large this must be empirically determined for each drug that is most
effective in an individual patient. With greater milligram potency (i.e.
smaller recommended dose) there is less sedation and hypotension but
generally more acute extrapyramidal reactions. Attempts to monitor the
therapeutic plasma concentrations can be so disparate from patient to
patient that it is not warranted.

The daily oral dose can be given in smaller amounts initially to minimize
adverse reactions, and then reduced to one or two doses unless there is an
adverse reaction. A single dose at bedtime is often preferred since it takes
advantage of the drugs sedative effects and decreases the incidence of
117
postural hypotension. However, long-acting depot forms of drugs, such as
fluphenazine decanoate are quite useful for treating those patients who are
non-compliant for a variety of reasons. The depot preparations can be
given intramuscularly at intervals of one to several weeks, depending upon
the release characteristics. However, adverse effects from depot injections
will be difficult to reverse.
Drug Combinations
Different antipsychotics should not be combined. However, tricyclic
antidepressants can be concurrently administered when there is clear
indication of a co-existing clinical depression.

ANTIPSYCHOTIC DRUGS - DO NOT MEMORIZE THIS TABLE
Drug Equivalent Oral
Dose
Sedation Autonomic Extrapyramidal
Reactions
Fluphenazine
Permitil
Prolixin
2 + + +++
Haloperidol
Haldol
2 + + +++
Sertindole
Serlect
4 + 0 0
Thioxene
Navane
5 + + +++
Trifluoperazine
Stelazine
5 ++ + +++
Risperidone
Risperdal
5 + +++ +
Olanzepine
*

Zyprexa
10 + 0 0
Perphenazine
Trilafon
10 ++ + ++/+++
Molindone
Moban
10 ++ + +
Pimozide
Orap
10 + + +++
Loxapine
Loxitane
15 ++ +/++ ++/+++
Aripiprazole
Abilify
15 0/+ 0/+ 0?
Acetophenazine
Tindal
20 ++ + ++/+++
Chlorprothixene
Taractan
45 +++ +++ +/++
Mesoridazine
Serentil
50 +++ ++ +
Clozapine
Clozaril
50 +++ +++ 0?
Ziprasidone
Geodon
80 + 0 0
Chlorpromazine
Thorazine
100 +++ +++ ++
Thioridazine
Mellaril
100 +++ +++ 0
Quentiapine
Seroquel
150 + ++ 0

*
Also used for treating OCD
118
Pharmacological Properties Of Neuroleptics
1. Neuroleptic Syndrome: This consists of suppression of
spontaneous movement and complex behavior, (spinal reflexes
remain intact). Neuroleptics reduce initiative and interest in one's
surroundings and they lessen displays of emotion or affect.
Psychotic patients become less agitated and restless, and withdrawn
or autistic patients sometimes become more responsive and
communicative. Aggressive and impulsive behavior diminishes, and
gradually (several days to weeks) hallucinations, delusions, and
disorganized (i.e. cognitive) thinking lessens. Remember
antipsychotic drugs do not cure the disorder, but only manage
the symptoms. Almost all drugs presently prescribed for psychosis
also have been found to produce some bradykinesia (extreme
slowness of moving), mild rigidity, and tremor that resemble that of
Parkinsons disease, and occasional subjective restlessness
(akathisia). Since all antipsychotic drugs elicit the neuroleptic
syndrome to varying degrees they are commonly lumped into the
category of "neuroleptics". Clozapine, olanzepine, risperidone,
seroquel, and ziprasidone produce fewer extrapyramidal side
effects, and for this reason are referred to as atypical neuroleptics.
Generally speaking, neuroleptic drugs are found to be very
unpleasant when given to a normal (i.e. non-psychotic) person.
2. Normalization of sleep disturbances often seen with psychoses.
Phenothiazine and thioxanthene type neuroleptics should be used
with extreme caution in untreated epileptics and in patients
undergoing withdrawal from central depressants because they can
lower seizure threshold.
3. Increase in prolactin secretion through blockade of the
hypothalamic-tuberinfundibular dopaminergic pathway. There is
little to no tolerance to this effect with neuroleptic treatments and
thus they produce breast engorgement and galactorrhea (also in
males), which reverses upon discontinuation. Clozapine does not
appear to have this effect.
4. Little effect on brain stem processes so that even large suicidal
doses usually do not produce coma or death, making them relatively
safe compounds. Exceptions: thioridazine and loxapine can be
dangerous in overdose.
5. Interactions with other drugs: potent potentiation of sedatives and
analgesics, antihistamines and cold remedies, and alcohol; may
enhance the peripheral and central effects of anticholinergics, such
as the tricyclic antidepressants and antiparkinsonian agents.
6. Prevent vomiting in nonsedative doses through the blockade of
dopamine receptors in the chemotrigger zone of the medulla and
peripherally on receptors in the stomach. However, thioridazine
does not possess anti-emetic actions.
119
7. Also chlorpromazine can be used to control intractable hiccups.
8. Management of Tourette's syndrome, which is characterized by
tics, involuntary movements, grunts, and vocalizations (often
obscene) and the choreoathetotic movements of Huntington's
disease.
Side Effects and Toxic Reactions
Autonomic nervous system
1. Moderate alpha-adrenergic blockade and weak cholinergic blockade
causing blurred vision, mydriasis, constipation and decreased
gastric secretion and motility, decreased sweating and salivation,
inhibition of ejaculation without interfering with erection,
orthostatic hypotension and reflex tachycardia, vasodilation and
antiarrhythmic effects on the heart. Abnormal electrocardiograms
are more prevalent with thioridazine (Mellaril) and pimozide
(Orap).
Endocrine effects
1. Gynecomastia and galactorrhea, amenorrhea;
2. Interference with pituitary growth hormone secretion;
3. Weight gain and increase in appetite, weak diuretic effects from
inhibition of ADH release.
4. Weight gain and an increased incidence of diabetes mellitus has been
reported in patients taking clozapine and olanzepine.
5. disruption of hypothalamic thermoregulatory control may lead the
patient to complain of being cold, or worse still develop into hypo- or
hyperthermia.
Hypersensitivity reactions
1. Agranulocytosis is uncommon, yet associated with some of the lower
potency neuroleptics, and with clozapine (Clozaril) in about 1% of
patients.
2. Dermatitis and increased pigmentation may occur with long-term
high dose therapy of low potency and neuroleptics.
3. Chlorpromazine can induce photosensitivity.
4. Pigmentary degeneration of the retina with thioridazine, resembling
retinitis pigmentosa characterized by a "browning" of vision. These
effects are reduced with lower dosage.
Neurological effects
1. Parkinsonian syndrome: characterized by a generalized slowing of
movement (akinesia) with mask facies. The most noticeable signs
are rigidity and tremor at rest, especially of the upper extremities.
Parkinsonian side effects may be mistaken for depression since the
flat facial expression and retarded movements resemble signs of
120
depression. This reaction may be self-limiting but can usually be
managed by antiparkinsonian agents with anticholinergic
properties. Levodopa is contraindicated since it may induce
agitation and worsening of the psychotic illness. Antiparkinsonian
drugs should be discontinued every few months for a reassessment
of the adverse side effects.
2. Neuroleptic malignant syndrome: resembles a very severe form of
parkinsonism with catatonia plus labile pulse and blood pressure,
hyperthermia, stupor and sometimes myoglobinemia. >10%
mortality, thus immediate medical attention is required. May be
more prevalent with the use of high doses of the more potent agents.
Dantrolene, which interferes with muscle utilization of calcium, has
been used for treatment.
3. Akathisia: strong subjective feelings of distress or discomfort, often
referred to the legs, as well as to a compelling need to be in constant
motion. It can be mistaken for agitation--the distinction is critical,
since agitation might be treated appropriately with an increase in
the dose of the antipsychotic drug, but make the situation worse.
Parenteral administration of benztropine (a muscarinic cholinergic
antagonist) allows a differential diagnosis between the two
conditions since psychosis does not respond to benztropine.
Treatment typically requires reduction of antipsychotic drug dosage,
with moderate doses of propranolol reported to be very beneficial.
Importantly, this syndrome is commonly not diagnosed and
frequently interferes with a patient's acceptance of neuroleptic
treatment.
4. Acute Dystonic Reactions: facial grimacing and torticollis (stiff
neck caused by spasmodic contraction of neck muscles drawing the
head to one side with chin pointing to the other side) which may be
associated with oculogyric crisis. They respond dramatically to
parenteral use of anticholinergic antiparkinsonian drugs.
5. Tardive Dyskinesia: a late-appearing syndrome associated with
long-term neuroleptic therapy that is characterized by stereotyped
involuntary movements consisting in sucking and smacking of the
lips, lateral jaw movements, and fly- catching dartings of the tongue.
There may be choreiform or purposeless quick movements of the
extremities. Slower, more dystonic, athetoid movements and
postures of the extremities, trunk, and neck may also be seen,
especially in younger males. These movements disappear during
sleep. They are thought to occur from an imbalance of dopamine-
cholinergic function within the caudate- putamen. Symptoms may
persist indefinitely after discontinuation of the drug, although
sometimes they will disappear with time (weeks to years). Higher
doses of neuroleptics will only mask the dyskinetic effects but
worsen its course, and antiparkinsonian drugs typically worsen this
problem. No adequate therapy has been devised for its treatment.
121
Tardive dyskinesia is hypothesized to result from compensatory
hyperdopaminergic function. Thus, antidopaminergic drugs tend to
ameliorate tardive dyskinesia, while dopaminergic agonists worsen
the condition; and antimuscarinic agents worsen it, while cholinergic
ones sometimes help. It is the opposite for those with tardive
dystonia.
Tolerance
Tolerance does not develop to the antipsychotic effects, but does develop to
many of the side effects (eg. sedation). The following table summarizes
these side effects and the mechanism by which they occur:
Type Manifestations Mechanisms
Autonomic nervous system Dry mouth; loss of accommodation;
difficulty in urinating; constipation
Muscarinic blockade
Orthostatic hypotension impotence;
failure to ejaculate
Alpha adrenergic blockade
Central nervous system Parkinson's syndrome; akathisia;
dystonia
Dopamine receptor blockade
Tardive dyskinesia Dopamine receptor
supersensitivity
Toxic confusional state Muscarinic blockade
Endocrine system Galactorrhea; amenorrhea;
secondary infertility; impotence
blockade
Hyperprolactinemia to dopamine
receptors
Learning Objectives
Describe the behavioral effects referred to as the neuroleptic syndrome that is
induced by antipsychotic drugs whose primary site of action is blockade of the D-2
dopamine receptor.
Neuroleptic syndrome is a neurological disorder that consists of
suppression of spontaneous movement and complex behavior, (spinal
reflexes remain intact). Neuroleptics reduce initiative and interest in
one's surroundings and they lessen displays of emotion or affect.
Psychotic patients become less agitated and restless, and withdrawn or
autistic patients sometimes become more responsive and communicative.
Aggressive and impulsive behavior diminishes, and gradually (several
days to weeks) hallucinations, delusions, and disorganized (i.e. cognitive)
thinking lessens. Remember antipsychotic drugs do not cure the
disorder, they only manage the symptoms. Almost all drugs presently
prescribed for psychosis also have been found to produce some
bradykinesia (extreme slowness of moving), mild rigidity, and tremor that
resembles that of Parkinsons disease, and occasional subjective
restlessness (akathisia). Since all antipsychotic drugs elicit the neuroleptic
syndrome to varying degrees they are commonly lumped into the category
of "neuroleptics". Clozapine, olanzepine, risperidone, seroquel, and
ziprasidone produce fewer extrapyramidal side effects, and for this reason
122
are referred to as atypical neuroleptics. Generally speaking, neuroleptic
drugs are found to be very unpleasant when given to a normal (i.e. non-
psychotic) person.
Describe the relationship between milligram potency of neuroleptic drugs and their
adverse effects on the autonomic nervous system.
With greater milligram potency (i.e. smaller recommended dose) there is
less sedation and hypotension but generally more acute extrapyramidal
reactions. The daily oral dose can be given in smaller amounts initially to
minimize adverse reactions, and then reduced to one to two doses unless
there is an adverse reaction.
Describe how dopamine receptor blockage increases prolactin secretion.
Dopamine receptor blockage causes increases in prolactin secretion
through blockade of the hypothalamic-tuberinfundibular dopaminergic
pathway. There is little to no tolerance to this effect with neuroleptic
treatments and thus they produce breast engorgement and galactorrhea
(also in males), which reverses upon discontinuation. Clozapine does not
appear to have this effect.

Describe the symptoms of the neuroleptic malignant syndrome and a drug that can be
used to treat it.
Neuroleptic malignant syndrome resembles a very severe form of
Parkinsonism with catatonia plus labile pulse and blood pressure,
hyperthermia, stupor and sometimes myoglobinemia. >10% mortality, thus
immediate medical attention is required. The mechanism can depend on
decreased levels of dopamine activity due to (1) dopamine receptor
blockade and (2) genetically reduced function of dopamine receptor D2.
May be more prevalent with the use of high doses of the more potent
agents. Dantrolene, which interferes with muscle utilization of calcium,
has been used for treatment. Neuroleptic malignant syndrome can be
remembered with FALTER:
" F Fever
" A - Autonomic Instability
" L Leukocytosis
" T Tremor
" E - Elevated enzymes (elevated creatine phosphokinase)
" R - Rigidity of muscles
Describe the conditions other than psychosis for which antipsychotic drugs can be
used.
Conditions other than psychosis for which antipsychotic drugs can be used
are:
" Schizophrenia
" Schizoaffective disorders
" Manic phase of Bipolar Affective Disorder
" Intractable hiccups
123
" Huntingtons chorea
" Ballism
" Tourettes Syndrome
" Psychotic Depression
List the major receptor classes mediating the therapeutic and side effects of
antipsychotic drugs.
The major receptor classes mediating the therapeutic and side effects of
antipsychotic drugs are:
" Dopamine Receptors (D1, D2, D3, D4, and D5). D2 receptors in the
limbic and mesocortical (prefrontal) brain areas is the target of
therapeutic drugs.
" Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7
" Norepinephrine: alpha-1 and alpha-2
" Muscarinic acetylcholine: mACh-1 and mACh-4
" Dopamine, norepinephrine, and serotonin transporters
" Alpha-adrenergic
" Cholinergic
" Histaminergic Receptors (Histamine: H-1 and H-2)
" NMDA-glutamate receptors

Newer atypicals having affinity for serotonin-2 receptors (5-HT2). At
therapeutic doss, the typical antipsychotics occupy >75% of dopamine D-
2 receptors. 85% occupancy is needed to get extrapyramidal side effects.
Distinguish between the positive and negative symptoms of schizophrenia.
Positive symptoms are mainly symptoms that most individuals do not
normally experience but are present in the disorder. They are attributed
to the overactivity of dopamine in limbic regions. They include:
" Hallucinations
" Delusions
" Bizarre Behavior
" Thought disorder

Negative symptoms are symptoms that are not present or that are
diminished in the affected persons but are normally found in healthy
persons. They are attributed to NMDA-glutamate hypofunction. They
include:
" Affective blunting
" Poverty of speech
" Avolition/apathy
" Anhedonia
" Attentional impairment

Positive symptoms are more responsive to drugs that block the dopamine
D2 receptor. However, newer antipsychotic agents are known to address
the negative symptoms.
124
Lecture XV
Antidepressants
Lecturer: Dr. Edward French, Ph.D.
Depression
Depression afflicts about 5% of the adult population of the U.S., with about
1-2% of adults having acute manic-depressive (bipolar) illness. About 70%
of patients respond to antidepressant therapy and can experience a
complete recovery from their depression. Electroconvulsive therapy can
help patients whose disorder is refractory to antidepressants (about 20%).
The remaining 10% of patients with depression are resistant to all known
types of therapy.
Depression is considered a heterogenous disorder with disturbances in
affect which can be generally classified as:
major depression: no previous history of psychiatric illness except for
episodes of depression or mania. It is considered a genetically determined
biochemical disorder with age of onset generally in the 30's, but episodes
can occur at almost any age. It afflicts 2-3 times as many females as males.
secondary mood disorders: occur during the course of some other primary
psychiatric or medical disorder. Sometimes referred to as reactive
depression.

The hallmark signs of major depression are given in Table 1.
Type of Symptom Depression Mania
Physical " Anhedonia (decreased interest in
things previously (inappropriate -
enjoyed; loss of sex drive)
Fatigability, loss of energy
" Social withdrawal
" Psychomotor retardation or agitation
" Insomnia with fatigue
" Somatic complaints
" Loss of appetite, loss of weight
" Decreased hygiene
" Crying spells for no significant
reason

" Increased activities and
energy buying, phoning,
driving, and sexual behavior.
" Increased gregariousness
" Increased talkativeness,
pressured speech
" Decreased need for sleep
without fatigue
" Increased intake of alcohol,
drunkenness
" Physically threatening,
combative, dangerous
behavior
Cognitive " Decreased ability to concentrate
" Indecisiveness
" Distractability
" Flight of ideas, speeded
thinking, racing thoughts, poor
jugement, impulsive actions
and decisions
Emotional " Dysphoric mood, sad thoughts or
attempts at suicide
" Hopelessness, helplessness
" Worthlessness, guilt, shame
" Elevated mood, increased self-
confidence, euphoria,
grandiosity
" Irritability, hostility
" Easily angered
TABLE 1.
125
Antidepressant Drugs
The major classes of compounds used for treating depression include:
1. Tricyclics, named for their characteristic 3-ring nucleus, eg.
amitriptyline.
2. Selective serotonin reuptake inhibitors (SSRI's, eg. fluoxetine)
3. Other agents (buproprion)
4. Monoamine oxidase inhibitors (MAOI's, eg. tranylcypromine)

Although drugs from the first three groups can be selected to begin drug
therapy for depression, the general consensus among physicians is that
SSRIs now constitute the first line of pharmacological therapy. However,
in recent studies it was found that SSRIs may be no better than tricyclics,
and in some cases no better than placebo. MAO inhibitors are used when
drugs from the other classes give unsatisfactory results or in patients with
co-existing phobias.
Basic Pharmacology
All tricyclics block the reuptake of both norepinephrine and serotonin into
nerve terminals although their potency at these two sites varies
dramatically. Since this interferes with the primary mode for inactivating
neurotransmitters, this leads to elevated synaptic levels of these
monoamines. Selective serotonin uptake inhibitors are potent blockers of
serotonin inactivation by reuptake and have very little or no effect on
norepinephrine uptake. Other cyclics have mixed effects on
norepinephrine and serotonin uptake as well as blockade of specific post-
synaptic receptors. Monoamine oxidase inhibitors (MAOIs) act by
preventing the metabolism of monoamine neurotransmitters which then
leads to elevated levels of the amines (norepinephrine, serotonin and
dopamine) in the nerve terminals and a greater amount of transmitter in
the synapse. Some agents (e.g. venlafaxine, duloxetine) have been referred
to as SNRIs (serotonin and norepinephrine reuptake inhibitors).
The original amine hypothesis of mood disorders suggested a lack of CNS
biogenic amines in depression. However, substantial research data in both
animals and humans has shown serious inconsistencies in the simplistic
amine hypothesis especially when we shift attention from acute drug
effects to the long-term adaptive changes that occur with chronic
antidepressant treatment. In particular, the biochemical effects of
antidepressant drugs occur immediately, yet their therapeutic
effectiveness is not seen for several days to weeks (Figure 1). Current
thinking is that the therapeutic benefits of antidepressants occurs through
desensitized autoreceptors and heteroreceptors on noradrenergic and
serotoninergic nerve terminals, both of which normally reduce serotonin
release but when desensitized cause elevated postsynaptic levels of
serotonin (i.e. enhancement of serotonin neurotransmission).
126

Figure 1.

Although poorly understood, the postsynaptic serotonin-1A (5HT-1A)
receptor does not desensitize (Figure 2). Thus, the current thinking is that
depression may be due to a dysregulation or diminished function of
serotonin or norepinephrine neurotransmission. In support of this
hypothesis, all clinically efficacious antidepressants augment serotonin or
norepinephrine activity. It is interesting to note that tryptophan depletion
in remitted patients who are taking serotonergic antidepressants (SSRIs)
will cause a prompt relapse of their depression as will catecholamine
depletion in patients who are taking noradrenergic acting drugs.

Figure 2. Increased synaptic levels of NE and 5-HT produced by currently
available antidepressants over a period of weeks lead to down-regulation
(subsensitive) of the presynaptic serotonin (5-HT1A/B) and presynaptic
NE (!2) receptor which then allows even more 5-HT and NE to be released.
The postsynaptic neuronal response to 5-HT (via the 5-HT1A receptor) is
apparently not down-regulated while that of the alphal and beta (not


3


All tricyclics block the reuptake of both norepinephrine and serotonin into nerve terminals
although their potency at these two sites varies dramatically. Since this interferes with the
primary mode for inactivating neurotransmitters, this leads to elevated synaptic levels of these
monoamines. Selective serotonin uptake inhibitors are potent blockers of serotonin
inactivation by reuptake and have very little or no effect on norepinephrine uptake. Other
cyclics have mixed effects on norepinephrine and serotonin uptake as well as blockade of
specific post-synaptic receptors. Monoamine oxidase inhibitors (MAOIs) act by preventing
the metabolism of monoamine neurotransmitters which then leads to elevated levels of the
amines (norepinephrine, serotonin and dopamine) in the nerve terminals and a greater amount of
transmitter in the synapse. Some agents (e.g. venlafaxine, duloxetine) have been referred to as
SNRIs (serotonin and norepinephrine reuptake inhibitors).

The original amine hypothesis of mood disorders suggested a lack of CNS biogenic amines in
depression. However, substantial research data in both animals and humans has shown serious
inconsistencies in the simplistic amine hypothesis especially when we shift attention from acute
drug effects to the long-term adaptive changes that occur with chronic antidepressant treatment.
In particular, the biochemical effects of antidepressant drugs occur immediately, yet their
therapeutic effectiveness is not seen for several days to weeks (Figure 1). Current thinking is that
the therapeutic benefits of antidepressants occurs through desensitized autoreceptors and
heteroreceptors on noradrenergic and serotoninergic nerve terminals, both of which normally
reduce serotonin release but when desensitized cause elevated postsynaptic levels of serotonin
(i.e. enhancement of serotonin neurotransmission).



Figure 1

Although poorly understood, the postsynaptic serotonin-1A (5HT-1A) receptor does not
desensitize (Figure 2). Thus, the current thinking is that depression may be due to a
dysregulation or diminished function of serotonin or norepinephrine neurotransmission. In
support of this hypothesis, all clinically efficacious antidepressants augment serotonin or
norepinephrine activity. It is interesting to note that tryptophan depletion in remitted patients
who are taking
serotonergic antidepressants (SSRIs) will cause a prompt relapse of their depression as will
catecholamine depletion in patients who are taking noradrenergic acting drugs.

127
shown) receptors is thought to be made subsensitive. Thus, it appears that
antidepressants establish an increase in serotonin neurotransmission in
the CNS.
Clinical Pharmacology of Antidepressants
Indications: Antidepressants are broad spectrum psychotropics used to
treat depression, but also used for panic or phobic disorders, obsessive-
compulsive disorder, enuresis (bed wetting), anorexia nervosa, and
bulimia. Pain specialists have also found tricyclics to have some beneficial
effects in patients with neuropathic (deafferentation) pain.

Drug choice: Initial drug selection is determined by: type of mood disorder,
past response to a particular drug, pharmacologic considerations (eg.
degree of sedation or anticholinergic effects), the patient's susceptibility to
side effects, and compatibility with other drugs the patient is taking. A
meta-analysis found that SSRI's and TCA's are in general equally effective.
However the use of SSRI's has become more prevalent. Common causes of
non-adherence include oversedation, intolerance to the anticholinergic
side effects of the tricyclics, or sexual dysfunction with SSRI's.
Tricyclic Side Effects
There are a number of side effects associated with tricyclics that are mostly due to effects
on the autonomic nervous system: These include dry mouth, blurred vision,
constipation and urinary retention and speech blocking (see Table 2 & 3)
resulting from blockade of muscarinic cholinergic receptors. However, tolerance usually
develops to these symptoms within a few weeks.
" Postural hypotension, resulting from blockade of alpha adrenergic
receptors with a resultant reflex tachycardia.
" Tachycardia, arrhythmias and ECG abnormalities; high-grade
atrioventricular block, due to antimuscarinic effects.
" Sedation is a common side effect so have patient take medication at
bedtime. Weight gain may occur because of both a remission of the
depression and central actions of the antidepressants.
" Tremor, akathisia and jittery feeling (propranolol may help).
" Sexual dysfunction (will usually resolve with time for the less
serotonergic TCA's) but may be a chronic problem with SSRI's.
SSRI Side-Effects
" Nausea, headache, nervousness and insomnia to which tolerance
develops after approximately 1-2 weeks
" Some sedation
" Anorgasmia, impotence, decrease libido
" Possible fatal interaction with MAOI's (SEROTONIN
SYNDROME). Need to allow 14 days between discontinuation of
MAOI and beginning of SSRI. Also allow 2 weeks from
128
discontinuation of SSRI (except for Prozac which should be 5 weeks)
to beginning of MAOI's. Prozac has an active metabolite with a 128
hr. half-life.
MAOI SIDE EFFECTS:
" Dry mouth, constipation and difficulty urinating even though
MAOI's do not have direct anticholinergic actions.
" Insomnia
" Weight gain
" Sexual dysfunction: erectile impotence and anorgasmia in both
males and females.
" Cardiovascular side effects: orthostatic hypotension. Nifedipine for
sublingual use in case of hypertensive "cheese-effect" crisis (N.B.
tyramine and some common sympathomimetic ingredients in over-
the counter cold remedies are the most common culprits in this
"cheese- effect".
" Serotonin-syndrome
Drug-Drug Interactions:
The depressive effects of alcohol are markedly increased by tricyclic
antidepressants and patients should be warned of this interaction
especially with regard to driving an automobile.

MAOI's enhance the effects of indirectly acting sympathomimetics, such as
tyramine. Tyramine is found in a variety of foods including cheeses, beer,
red wine, pickled herring, chicken liver, chocolates, yogurt and tomatoes.
Normally, gastrointestinal MAOs metabolize tyramine. However, if MAOIs
are present, tyramine is absorbed and enters nerve endings where it
produces a massive release of NE which can result in a hypertensive crisis,
characterized by tachycardia, severe throbbing headache, chest pain,
dilated pupils, nausea and sweating. Patients need to be advised of this
wine and cheese effect, and be given dietary restrictions.
Toxicity
A tricyclic overdose causes excitement and delirium which can be
accompanied by convulsions followed by coma and respiratory depression
lasting several days. Cardiac dysrhythmias (atrial and ventricular
extrasystoles) can occur and death from ventricular fibrillation.
Dysrhythmias are often non-responsive to beta-blockers. Most cardiac
effects can only be treated using supportive measures. However, the main
CNS effects can be treated with anticholinesterase inhibitors (eg.
physostigmine). SSRI's are generally very safe even on overdose.
Generally, seizure threshold is lowered by tricyclics, as well as by
bupropion and mirtazapine.

MAOI intoxication produces agitation, delirium, neuromuscular
excitability followed by obtunded consciousness, seizures, shock and
129
hyperthermia which is best treated by supportive measures, although
sedative phenothiazines with alpha-blocking properties (ego
chlorpromazine) may be useful.

NOTE: It has been documented that suicidal thoughts and suicidal behavior
occur in approximately 4% of children/teenagers when put on anti-
depressants. In response to these findings the FDA now requires all
antidepressants to carry a Black Box Warning.

TABLE 2. Pharmacological Properties of Antidepressants and Their
Possible Clinical Consequences
Property Possible Clinical Consequences
Blockade of
norepinephrine
uptake at nerve
endings
" Tremors
" Tachycardia
" Erectile and ejaculatory dysfunction
" Augmentation of pressor effects of sympathomimetic amines
Blockade of
serotonin uptake
at nerve endings
" Gastrointestinal disturbances
" Increase or decrease in anxiety (dose dependent)
" Sexual dysfunction
" Extrapyramidal side effects
" Interactions with L-tryptophan, monoamine oxidase inhibitors, and fenfluramine
Blockade of
dopamine uptake
at nerve endings
" Psychomotor activation
" Antiparkinsonian effect
" Aggravation of psychosis
Blockade of
histamine H1
receptors
" Potentiation of central depressant drugs
" Sedation, drowsiness
" Weight gain
Blcoakde of
muscarinic
receptors
" Blurred vision
" Dry mouth
" Constipation
" Urinary retention
" Memory dysfunction
Blockade of alpha-
adrenergic
receptors
" Potentiation of the antihypertensive effect of receptor blockers prazosin,
terazosin, doxazosin, and labetalol
" Postural hypotension, dizziness
" Reflex tachycardia
Blockade of
dopamine
receptors
" Extrapyramidal movement disorders
" Endocrine changes
" Sexual dysfunction (males)
Lithium
The primary therapeutic indication for the use of lithium is in the
treatment of the manic episodes of bipolar affective disorder. Bipolar
disorder is characterized by swings of mood (mania- depression) that are
generally unrelated to life events. A manic syndrome is characterized by:
" Inflated self-esteem or grandiosity
" Flight of ideas
" Increase in goal-directed activity
" Decreased need for sleep
" Distractibility
" Excessive talkativeness

The exact biological disturbance, although generally considered to be
genetically determined, remains unknown even though dysfunctional
130
biogenic amine mechanisms are considered prime suspects. Drugs that
increase catecholaminergic activity exacerbate mania, while drugs that
reduce their activity reduce manic symptoms.
Basic Pharmacology
Lithium is a monovalent cation most closely related to sodium. It can
substitute for sodium in generating action potentials except it is not
readily pumped out and tends to accumulate inside the neurons. This may
lead to partial depolarization of nerve cells. Lithium also affects
neurotransmitters in complex ways, but the compelling case for lithium's
mechanism of action is its effects on second messenger systems in
neuronal tissues resulting in reduced responsiveness of neurons to
muscarinic and alpha-adrenergic stimulation.
Clinical Pharmacology
Indications: Lithium carbonate is the primary therapeutic agent for the
treatment of acute mania or recurrences of bipolar manic-depressive
illness. Because its onset of action is slow, antipsychotic and
benzodiazepine drugs are often used for the immediate control of severe
manic behavior. Accumulating clinical evidence also supports lithium's use
as an alternative to tricyclic antidepressants in severe recurrent
depression (nonbipolar manic-depressive illnesses) and as a supplement to
antidepressant treatment in acute, major depression.

Treatment: Lithium has a narrow therapeutic index. This means that the
plasma concentration producing its therapeutic effects is not much less
than that associated with side effects. Lithium's narrow therapeutic serum
concentration (0.8-1.2 meq/L) makes monitoring blood levels essential.
These measurements should be made about 5 days after the start of
treatment at 10-12 hrs after the last dose.
Adverse Effects and Toxic Reactions
1. Tremor is the most common adverse effect; in addition ataxia.
Propranolol can alleviate lithium-induced tremor.
2. Decreased thyroid function in most patients; this is reversible
3. Polydipsia and polyuria are frequent but reversible; this is due
interference with ADH (anti-diuretic hormone) action in the
kidneys.
4. Edema.
5. ECG abnormalities are reversible. The sinus node is susceptible to
toxic effects of lithium, with depression of its normal pacemaker
function, and therefore, lithium is contraindicated in patients with a
"sick sinus" syndrome.
6. Lithium is excreted in breast milk and may cause lithium toxicity in
newborns.
7. Therapeutic overdoses are more common than deliberate or
accidental overdoses and usually result from an accumulation of
131
lithium caused by a change in the patient's physical status, such as
the use of diuretics, change in renal function or pregnancy. This
condition can be treated with hemodialysis or peritoneal dialysis
until plasma concentrations fall below the usual therapeutic range.
Other Drugs
Carbamazepine, valproic acid and other anticonvulsants are also being
used in some patients who experience rapid cycling of mania and
depression.
The atypical antipsychotic Olanzapine (Zyprexa) has also been FDA
approved for treatment of mania.

TABLE 3
SIDE EFFECTS OF ANTIDEPRESSANTS DO NOT MEMORIZE!
Antidepressants Cardia
c Side
Effects
Orthostatic
Hypotension
Sedation Weight
Gain
Anticholinergic
Side Effects
Gastrointestinal
Upset
Agitation/Insomnia Lower
Seizure
Threshold
T
C
A
s

(
3
O
)

Amitryptyline
(Elavil)
+++ ++++ ++++ +++ ++++ 0 0 ++
Clomipramine
(Anafranil)
+++ +++ ++ ++ +++ 0 0 +++
Doxepin
(Sinequan)
++ ++++ ++++ +++ +++ + 0 ++
Imipramine
(Tofranil)
+++ +++ ++ +++ +++ 0 + ++
Trimipramine
(Surmontil
+++ +++ ++++ +++ +++ 0 0 ++
T
C
A
s

(
2
O
)

Amoxapine
(Asendin)
++ ++ ++ + ++ 0 ++ ++
Desipramine
(Norpramin)
++ ++ + + 0 + +
Nortriptyline
(Pamelor)
++ + ++ + + 0 0 +
Protriptylene
(Vivactil)
+++ ++ + ++ 0 + ++
M
i
s
c
e
l
l
a
n
e
o
u
s

Buproprion
(Wellbutrin)
0 0 0 0 0 0 ++ ++++
Maprotiline
(Ludiomil)
++ ++ +++ ++ +++ ++ + 0/+
Mirtazapine
(Remeron)
++/++ ++++ ++ ++ 0 0 +++
Neazodone
(Serzone)
0/++ ++ +++ + 0 ++ 0 0
Trazodone
(Desyrel)
0/+ ++ +++ + 0 + 0 0
Venlafaxine
(Effexor)
0/+ 0/+ 0/+ + +++ ++ 0
Duloxetine
(Cymbalta)
0 0 + 0 0/+ +/++ 0 0
S
S
R
I
s

Fluoxetine
(Prozac)
0 0 0 0 0 + ++ 0
Fluvoxamine
(Luvox)
0 0 0/+ 0 0 ++ + 0
Paroxetine
(Paxil)
0 0 + 0 0/+ +++ ++ 0
Sertraline
(Zoloft)
0 0 0/+ 0 0 +++ + 0
Citalopram
(Celexa)
0 0 0 0 0 ++ +/0 0
Escitalopram
(Lexopro)
0 0 0 0 0 + 0 0
M
A
O
I
s

Phenelzine
(Nardil)
0 +++ + ++ + + + 0
Tranylcypromi
se (Pamate)
0 ++ 0/+ + 0 + + 0
0=none; ++ = moderate; +++ = moderate to high; +++ = high
132
Learning Objectives
Describe the major classes of antidepressants.
The major classes of antidepressants are as follows:
" Tricyclics
" SSRIs
" SNRIs
" MAOIs
" Other cyclics
Describe the general mechanism of action of tricyclic and SSRI antidepressant drugs
on biogenic amine neurotransmitters.
The general mechanism of action is to address the amine hypothesis of
mood disorders, in which a lack of CNS biogenic amines is implicated in the
onset of depression. However, current thinking is that depression may be
due to a dysregulation or diminished function nof serotonin or
norepinephrine transmission.

Class General Mechanism of Action
TCAs Block the reuptake of both norepinephrine and serotonin into nerve terminals. This leads to elevated
synaptic levels of the monoamines. However, their potency at these two sites vary dramatically.
SSRIs Potent blockers of serotonin inactivation by reuptake and have little or no effect on norepinephrine
uptake.
SNRIs Potent blockers of both serotonin and norepinephrine inactivation by reuptake.
MAOIs Act by preventing the metabolism of monoamine neurotransmitters to make elevated levels of the
amines in the nerve terminals and a greater amount of transmitter in the synapse.
Describe the major side effects of tricyclic and SSRI antidepressants.
Class Major Side Effects
TCAs " Antimuscarinic effects (dry mouth, blurred vision, constipation, urinary retention, and
speech blocking)
" Postural hypotension (due to blockade of alpha adrenergic receptors with reflex tachycardia.
" Tachycardia, arrhythmia, and ECG abnormalities; high-grade atrioventricular block ! due to
antimuscarinic effects
" Sedation
" Weight gain
" Tremor, akathisia, and jittery feeling
" Sexual dysfunction
SSRIs " Nausea, headache, nervousness, and insomnia (tolerance develops after 1-2 weeks)
" Some sedation
" Anorgamia, importence, or decreased libido
" Possible fatal interaction with MAOIs.
MAOIs " Dry mouth, constipation, and difficulty urinating
" Insomnia
" Weight gain
" Sexual dysfunction
" Cardiovascular side effects

The TCA side effects can be memorized with TCAS:
" T: Thrombocytopenia
" C: Cardiac (arrhythmia, MI, strokes)
" A: Anticholinergic (tachycardia, urinary retention, etc.)
" S: Seizures

The side effects of SSRIs can be remembered with the mnemonic SSRI:
133
" S: Serotonin Syndrome
" S: Stimulate CNS
" R: Reproductive dysfunction in males
" I: Insomnia
Describe the syndrome that can be caused by an interaction between SSRIs and
MAOIs.
Serotonin syndrome is a life-threatening drug reaction following
therapeutic drug use, inadvertent drug interactions, overdose of drugs,
and recreational use of certain drugs. It is a consequence of excessive
serotonin activity in the central nervous system and peripheral serotonin
receptors.

Serotonin Syndrome is remembered because its components cause HARM:
" H: Hyperthermia
" A: Autonomic Instability (Delirium)
" R: Rigidity
" M: Myoclonus
Understand the basis for dietary restrictions when prescribing MAOIs.
MAOIs enhance the effects of indirectly acting sympathomimetics, such as
tyramine. Tyramine is found ina variety of foods, including cheeses, beer,
red wine, pickled herring, chicken liver, chocolates, yogurt, and tomatoes.
Normally, gastrointestinal MAOs metabolize tyramine. However, if MAOIs
are present, tyramine is absorbed and enters nerve endings where it
produces a massive release of norepinephrine which can result in a
hypertensive crisis, characterized by tachycardia, severe throbbing
headache, chest pain, dilated pupils, nausea, and sweating. Patients need
to be advised of this wine and cheese effect, and be given dietary
restrictions.
Understand the importance of assessing renal function when prescribing lithium.
Lithium has an extremely narrow therapeutic index. This means that the
plasma concentration producing its therapeutic effects is not much less
than that associated with side effects. Lithiums narrow therapeutic
serum concentration (0.8-1.2 mEq/L) makes monitoring blood levels
essentials. These measurements should be made about 5 days after the
start of treatment at 10-12 hours after the last dose.

In long-term use, therapeutic concentrations of lithium have been thought
to cause histological and physiological changes in the kidney. Because it
has an extremely low volume of distribution (as it is an ion), it often will
get passed (with sodium) through the kidneys. Lithium interferes with the
regulation of sodium and water levels in the body, and can induce
dehydration, causing lithium levels to further increase. Lithium toxicity is
compounded with sodium depletion, and diuretics concurrently used with
lithium are discouraged due to lithiums reabsorption in the proximal
134
convulated tubule, causing potentially toxic levels. Therefore, it is
important to have patients on lithium to receive regular serum level tests
and monitor for kidney and thyroid function.

The side effects of lithium are best remembered with LITH:
" L: Lithium
" I: Insipidus
" T: Tremors
" H: Hypothyroidism

Lithium has the following adverse effects:
1. Tremor is the most common adverse effect; in addition ataxia.
2. Decreased thyroid function in most patients (reversible)
3. Polydipsia and polyuria are frequent but reversible ! due
interference with ADH (antidiuretic hormone) action in the kidneys
4. Edema
5. ECG abnormalities (reversible). The sinus node is susceptible to
toxic effects of lithium, with depression of its normal pacemaker
function, and therefore, lithium is contraindicated in patients with a
sick sinus syndrome.
6. Lithium is excreted in breast milk and may cause lithium toxicity in
newborns.
7. Therapeutic overdoses are more common than deliberate or
accidental overdoses and usually result from an accumulation of
lithium caused by a change in the patients physical status, such as
the use of diuretics, change in renal function or pregnancy. This
condition can be treated with hemodialysis or peritoneal dialysis
until plasma concentrations fall below the usual therapeutic range.
135
LECTURE XVI
Sedative-Hypnotic Drugs
Lecturer: Dr. Edward French, Ph.D.
Introduction
Drugs assigned to the sedative-hypnotic class are able to cause sedation,
relieve anxiety, and promote sleep. Anxiety states and sleep disorders are
very common problems worldwide, and so is the use of sedative-hypnotics.
Anxiety creates physiological and psychological consequences that when
combined result in feelings of uneasiness, apprehension and worry. In its
moderate state, anxiety (and some degree of neurosis) can be regarded as
a normal behavior that increases alertness to the dangers around us and
thereby increases the chance of survival in a threatening environment.
When excessive, however, anxiety can interfere with normal daily
activities and becomes classified 0as an anxiety disorder. Physical effects,
such as increased heart rate, nausea, chest pain, and shortness of breath,
stomach pain, sweating, and headaches, can also accompany anxiety.
Physically, the body is preparing to deal with a threat. Because of anxiety
parents are protective of their childrens safety, which results in the
survival of the children. Anxiety can also be a motivator to succeed, as the
fear of failure produces anxiousness. There are many types of anxiety
disorders that include panic disorder, obsessive-compulsive disorder, post-
traumatic stress disorder, social anxiety disorder, specific phobias, and
generalized anxiety disorder.

As is the case for many of the functions of the central nervous system,
normal equilibrium is determined by a balance between excitatory and
inhibitory influences, and each individual has a different behavioral
steady-state or threshold. Therefore, different normal people become
anxious or panicked at different levels of stimuli. Clearly, the normal
population includes people who are normally anxious and others who are
relatively laid back. The therapeutic target population includes those on
the anxious side of the normal distribution, as well as those characterized
as suffering from an anxiety disorder.

Most of the excitation in the CNS is produced by the action of the
neurotransmitter glutamate on a variety of excitatory amino acid
receptors, whereas the synaptic inhibition that keeps excitation in balance
is mediated by the action of the neurotransmitter GABA on several of its
receptors. The GABA receptor that mediates most of the inhibition in the
brain is the ionotropic GABA-A receptor, which when activated opens a
chloride channel allowing the negative chloride to enter the cell, making its
potential more negative (hyperpolarization) and decreasing the
136
probability of that cell reaching a potential that would trigger an action
potential (Figure 1).

Figure 1: Schematic of the GABA-chloride ionophore and site of action for
barbiturates and benzodiazepines.

The GABA-A receptor is assembled from 5 subunits. The 2 binding sites for
GABA are located between adjacent !-1 and "-1 subunits, and the binding
pocket for benzodiazepines is between an !-1 and #-2 subunit. Zolpidem
(Ambien) (and other z-drugs) interact only with GABA-A receptor
isoforms that contain !-1 subunits.
Pharmacology
An effective sedative/anxiolytic medication should reduce ones level of
anxiety and produce a calming effect. This should occur at a dose that does
not produce a large degree of CNS depression. A hypnotic drug should
produce drowsiness and facilitate the onset and maintenance of sleep.
Figure 2 shows the hypothetical dose-response of two different drugs. One
can see that the response profile of drug B is more desirable.

The benzodiazepines fit with the actions of drug B. There are several
chemical versions of benzodiazepines, differing in their pharmacokinetic
properties (i.e. short- to long-acting). Drugs that would be included in the
drug A response are barbiturates (eg. thiopental and pentobarbital which
are used in some states for lethal injection in death penalty cases) and a
few non-barbiturate sedative-hypnotics.
137

Sedative-hypnotics are used for: relief of anxiety, insomnia, sedation and
amnesia before and during medical and surgical procedures, treatment of
epilepsy and seizure states, control of ethanol or other sedative-hypnotic
withdrawal states, muscle relaxation in specific neuromuscular disorders,
diagnostic aids for treatment in psychiatry.

Figure 2. Above are dose-response curves for two hypothetical sedative
hypnotics. Drug B would be preferred over Drug A because of its larger
safety margin.

Below are several barbiturate-related sedative/hypnotics. The
benzodiazepines are newer structures with a somewhat different
mechanism of action. What sets one benzodiazepine apart from another is
basically its pharmacokinetic properties (onset of action, duration of
action).

The Z-sedative hypnotics (eg. zolpidem (Ambien), zaleplon (Sonata), and
eszopiclone (Lunesta) are newer sedative/hypnotics with novel chemical
structures. Although structurally different from the benzodiazepine class
of agents they do share a similar mechanism of action, i.e. augmentation of
GABAs effect on the GABA-A receptor ionophore.

138


Figure 3. Chemical structures of barbiturates, benzodiazepines, and Z-
drugs.

There are also a number of other CNS acting drugs that have sedative
properties, including some antipsychotics, antidepressants and
antihistamines (best known one is Benadryl).

The British committee for review of medicines found that:

all benzodiazepines are efficacious in the short-term treatment of
symptoms of anxietyand insomnia. There is no evidence, which can justify
the particular use of any particular benzodiazepine in either anxiety or
139
insomnia. The usual division of benzodiazepines into rigid treatment
categories of antianxiety agents and hypnotics does not appear to be based
on the known pharmacological or clinical properties of this group of
compounds.

Although this is apparently true for anxiety and insomnia, it is important
to understand that different benzodiazepines have additional actions (as
muscle relaxants, anticonvulsants, and anesthetics, amnestics, for
example), and different half-lives. Differences among compounds in their
clinical properties are apparently due to actions at two different sites of
the GABA-A receptor. Furthermore, differences among benzodiazepines in
their elimination half-lives means that elderly patients with impaired
hepatic metabolism (the liver being the primary site for their metabolism)
can be given short-acting drugs for insomnia and agitation that do not
significantly impair them the next day
Drugs useful in the treatment of anxiety disorders
Generic Name Trade Name Half-Life (hrs) Dosage (mg/day)
L
o
n
g
-
A
c
t
i
n
g

B
e
n
z
o
d
i
a
z
e
p
i
n
e
s

(
C
F
C

D
r
u
g
s
)

Diazepam Valium 20-80 2-60
Chlordiazepoxide Librium 24-48 15-100
Clorazepate Tranxene 100 7.5-60
Estazolam ProSom 10-24 0.5-2.0
Prazepam Centrax 100 20-60
Quazepam Doral 30-100 7.5-15
Halazepam Paxipam 15-100 20-160
Clonazepam
*

Klonopin 34 1.5-20
Flurazepam
+
Dalmane 100 15-30
S
h
o
r
t
-
A
c
t
i
n
g

B
e
n
z
o
d
i
a
z
e
p
i
n
e
s

(
L
A
T
E

I
n
t
e
r
m
e
d
i
a
t
e
;

T
O
M

S
h
o
r
t
)

Oxazepam Serax 8 30-120
Lorazepam Ativan 15 2-6
Alprazolam Xanax 12 0.5-6
Temazepam
+
Restoril 11 15-30
Triazolam
+
Halcion 2 0.125-0.5
Midazolam
#
Versed 2 2-4
N
o
n
-
B
e
n
z
o
d
i
a
z
e
p
i
n
e

S
e
d
a
t
i
v
e
/
H
y
p
n
o
t
i
c
s

Buspirone BuSpar Serotonin 1a partial agonist
Zolpidem Ambien Potentiates GABA by binding to GABAA receptors in the
same location as benzodiazepines
Zaleplon Sonata Agonist of GABA A $ 1 subunit
Meprobamate Miltown Affects multiple sites of central nervous system, including
thalamus and limbic system. It binds to GABAA receptors,
interrupting neuronal communication in reticular
formation and spinal cord.
Chloral hydrate Noctec Enhances GABA receptor complex, causing dependency
and withdrawal symptoms.
*
marketed as an anti-convulsant
+
marketed as a hypnotic
#
parenteral only
140
Mechanism of action of benzodiazepines
Sedative-hypnotic drugs have a variety of clinical actions including
anxiolytic, hypnotic, muscle-relaxant, anti-convulsant, and anesthetic
effects. Although it is not known exactly which brain structures cause
anxiety, it has recently become clear how benzodiazepines produce their
anti-anxiety effect. The GABA-A receptors that mediate altered membrane
permeability to chloride are pentameric structures made up of a variety of
subunits (alpha, beta, and gamma).

Figure 4. The GABA-A receptor and its ligand binding sites.
Benzodiazepines and barbiturates bind to unique sites of the receptor to
potentiate the effect of endogenous GABA.

Benzodiazepines do not activate the receptor directly. Benzodiazapines
increases the frequency of chloride channel opening produced by GABA.
Barbiturates increase the duration of chloride channel opening produced
by GABA. There is also a separate binding site for alcohol. This likely
explains how the combination of alcohol with benzos or barbs can
potentiate each other and become lethal.

Different GABA-A receptors in different brain regions have different
subunit compositions, and the expression of specific subunits can be
altered by activity. Normally, benzodiazepines (e.g. the prototype
diazepam) bind to alpha subunits to increase the chloride channel opening
initiated by GABA binding to its binding site. Recent studies indicate that
141
the anxiolytic effects of diazepam are abolished by molecular alteration of
the alpha-2 subunit, which is in high concentration in brain regions
thought to mediate emotional responses. Therefore, the mechanism by
which benzodiazepines decrease anxiety is by binding to the alpha-2
subunit of the GABA-A receptor, which increases inhibition of cells in brain
regions, that mediate anxiety. However, other actions of some
benzodiazepines are apparently mediated by actions at different subunits
of the same GABA-A receptor. For example, zolpidem, an alpha-1
preferring agonist, displays sleep- inducing effects and is used clinically as
a treatment for insomnia.

Studies indicate that the alpha-1 subunit of the GABA-A receptor mediates
the sedation, amnesia and ataxic effects of the benzodiazepines, while the
alpha-2 and -3 subunits are involved in the anxiolytic and muscle-relaxing
effects.
Properties of benzodiazepines
The prototype benzodiazepine is diazepam (Valium). It is highly lipid-
soluble. Therefore, it is absorbed orally and crosses the blood-brain barrier,
as well as the placental barrier. These highly lipid-soluble drugs are
converted by the liver to more water-soluble metabolites for excretion by
the kidney. Hepatic metabolism of several benzodiazepines (diazepam,
chlordiazepoxide, prazepam, and clorazepate) forms the same product,
desmethyldiazepam, which is itself active, with a long half-life.
Desmethyldiazepam is then converted to oxazepam (Serax), which is a
short-acting metabolite used in its own right for brief sedation.

Although benzodiazepines induce sleep, and some are used as anesthetics,
respiratory depression is not as great with benzodiazepines as with
barbiturates. This is reason behind using large doses of barbiturates
instead of benzodiazepines for lethal injections. At plasma concentrations
exceeding the anxiolytic range, benzodiazepines cause impairments of
mental and motor function, confusion and amnesia. Short acting
benzodiazepines (eg. midazolam) are given for conscious sedation
procedures (eg. colonscopy) for its amnestic properties. Fatal overdose is
uncommon, except when taken in conjunction with alcohol. The main
expected side effects of benzodiazepines include sedation, ataxia, and
dependence. Withdrawal of tolerant individuals must be gradual to avoid
hyperexcitability and possibe seizures, which occur more frequently
following the abrupt discontinuation of short-acting than long-acting
benzodiazepines. The sedative effects of benzodiazepines can be blocked by
the benzodiazepine receptor antagonist flumazenil. Flumazenil can also be
used in those situations involving ingestion of large amounts of a
benzodiazepine. However, flumazenil will precipitate withdrawal signs in
patients dependent on a benzodiazepine (anxiety, insomnia, convulsions).
142
Flumazenil does not antagonize the action of barbiturates or alcohol. You
can remember this with Ben is off with the flu. Benzodiazepine effects
are off with flumazenil.
Therapeutic indications for benzodiazepines
1. Anxiety and insomnia
2. Sedation in mania or to control drug-induced hyperexcitability (e.g.
PCP intoxication)
3. Spasticity due to cerebral palsy or tetanus toxin toxicity
4. Anesthesia
5. Alcohol detoxification
6. Seizures (clonazepam in myoclonic disorders; diazepam,
medazolam, and lorazepam in status epilepticus)
7. Anesthesia
Important practical points about benzodiazepine use
One central principle of benzodiazepine use is to use the lowest effective
dose for the shortest possible time. This minimizes the potential for
dependence and withdrawal. Second, discontinuance withdrawal is most
common with short-acting benzodiazepines because cessation of use of the
long-acting drugs produces a tapering effect due to a long elimination half-
life. However, patients require weeks to months to be weaned from these
compounds. Fortunately, serious withdrawal signs, such as hallucinations
and seizures, are rare. Despite these caveats, benzodiazepines generally
produce few medical complications, and do not interact adversely with
most other medications.
Newer sedative/hypnotics
Although benzodiazepines are the current drugs of choice for anxiety and
insomnia, they produce undesirable daytime sedation and drowsiness, CNS
depression in combination with alcohol, and a potential for dependence.
Several new compounds that do not act on GABA-A receptors, or more
selective drugs that may interact only with specific GABA-A receptor
subunits have become available.
Buspirone (BuSpar)
Buspirone relieves anxiety without producing sedation, and unlike
diazepam, is not a muscle relaxant or anti-convulsant. Also, it does not
cause withdrawal signs upon abrupt withdrawal. Buspirone does not
interact with the GABA-A receptor, and may produce its desired effects as
a partial agonist at the serotonin 1a receptor, suggesting a role for
serotonin in anxiety. Also unlike the benzodiazepines, buspirone does not
act immediately; it takes a week to become effective. Therefore, buspirone
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is used for chronic anxiety states. It also produces less memory loss, less
sedation and less impairment of motor skills in addition to exhibiting
minimal addictive potential. Unlike benzodiazepines it lacks hypnotic,
anticonvulsant and muscle relaxant properties.
Buspirone is rapidly absorbed orally and undergoes a rapid first-pass
effect. Its elimination half-life is 2-4hr and it is largely metabolized by the
liver.
Zolpidem (Ambien)
Zolpidem is structurally unrelated to benzodiazepines but produces its
sedative properties by binding to one of the sites on the GABA-A receptors
that also bind benzodiazepines. Consistent with this observation is the fact
that zolpidems effects are blocked by the benzodiazepine receptor
antagonist flumazenil. However, unlike benzodiazepines, zolpidem has
minimal muscle relaxing and anticonvulsant effects. Zolpidem also
appears to have less potential for dependence and withdrawal. Its
elimination half-life is 1.5-3.5 hours and it is largely metabolized by the
liver.
Learning Objectives
Identify the therapeutic uses of benzodiazepines.
Sedative-hypnotics are used for:
" Relief of anxiety
" Insomnia
" Sedation
" Amnesia before and during medical and surgical procedures
" Treatment of epilepsy and seizure states
" Control of ethanol or other sedative-hypnotic withdrawal states
" Muscle relaxation in specific neuromuscular disorders
" Diagnostic aids for treatment in psychiatry

Benzodiazepines have the following therapeutic indications
" Anxiety and insomnia
" Sedation in mania or to control drug-induced hyperexcitability (e.g.
PCP intoxication)
" Spasticity due to cerebral palsy or tetanus toxin toxicity
" Anesthesia
" Alcohol detoxification
" Seizures (clonazepam in myoclonic disorders; diazepam, midazolam,
and lorazepam in status epilepticus)
" Anesthesia
Identify the mechanism of action of benzodiazepine anti-anxiety drugs.
Benzodiazepines do not activate the receptor directly. Benzodiazapines
increases the frequency of chloride channel opening produced by GABA.
144
Barbiturates increase the duration of chloride channel opening produced
by GABA. There is also a separate binding site for alcohol. This likely
explains how the combination of alcohol with benzos or barbs can
potentiate each other and become lethal.

Different GABA-A receptors in different brain regions have different
subunit compositions, and the expression of specific subunits can be
altered by activity. Normally, benzodiazepines (e.g. the prototype
diazepam) bind to alpha subunits to increase the chloride channel opening
initiated by GABA binding to its binding site. Recent studies indicate that
the anxiolytic effects of diazepam are abolished by molecular alteration of
the alpha-2 subunit, which is in high concentration in brain regions
thought to mediate emotional responses. Therefore, the mechanism by
which benzodiazepines decrease anxiety is by binding to the alpha-2
subunit of the GABA-A receptor, which increases inhibition of cells in brain
regions that mediate anxiety. However, other actions of some
benzodiazepines are apparently mediated by actions at different subunits
of the same GABA-A receptor. For example, zolpidem, an alpha-1
preferring agonist, displays sleep- inducing effects and is used clinically as
a treatment for insomnia.
Identify the adverse effects of anti-anxiety drugs.
Although benzodiazepines induce sleep, and some are used as anesthetics,
respiratory depression is not as great with benzodiazepines as with
barbiturates. This is reason behind using large doses of barbiturates
instead of benzodiazepines for lethal injections. At plasma concentrations
exceeding the anxiolytic range, benzodiazepines cause impairments of
mental and motor function, confusion and amnesia. Short acting
benzodiazepines (eg. midazolam) are given for conscious sedation
procedures (eg. colonscopy) for its amnestic properties. Fatal overdose is
uncommon, except when taken in conjunction with alcohol. The main
expected side effects of benzodiazepines include sedation, ataxia, and
dependence. Withdrawal of tolerant individuals must be gradual to avoid
hyperexcitability and possibe seizures, which occur more frequently
following the abrupt discontinuation of short-acting than long-acting
benzodiazepines.

Identify the agent that can reverse the effects of benzodiazepines.
The sedative effects of benzodiazepines can be blocked by the
benzodiazepine receptor antagonist flumazenil. Flumazenil can also be
used in those situations involving ingestion of large amounts of a
benzodiazepine. However, flumazenil will precipitate withdrawal signs in
patients dependent on a benzodiazepine (anxiety, insomnia, convulsions).
Flumazenil does not antagonize the action of barbiturates or alcohol.