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VETERINARY

PHARMACOLOGY
Pharmacotherapeutics I

ANECITO G. JUAN, DVM, DipVSt, MS


LECTURE I
INTRODUCTION TO VETERINARY PHARMACOLOGY
Introduction
Pharmacological Terms:
 Drug - any chemical agent other than nutrient or essential
dietary ingredient, when administered interacts with living
processes and modify existing function (e.g. therapeutic
agents, poisons and substances use for research).
 Medicine - medical intervention with an intention of
producing a therapeutic effect (e.g. acupuncture or drugs).
 Materia Medica - study of the physical and chemical
characteristics of materials used as medicines.
 Pharmacology – “pharmaco” greek for drug or medicine;
broadly deals with drug disposition, action and effects at
both the molecular (MOA) and whole organism level
(therapeutic & adverse effects).
Pharmacological Terms:
 Pharmacokinetics – refers to “what the body does to the drug”; time
course of drug concentrations in the body is governed by
absorption, distribution, metabolism and excretion processes
(ADME); when sufficient concentration of the drug is present at the
site of action for a specific period of time, pharmacologic effect
occur. It determines the routes of administration, dose, onset of
action, time of peak action, duration of action and frequency of
administration.
 Pharmacodynamics - deals with “what the drug does to the body”;
include mechanism of drug action, biologicaland physiological
effect of drug on the body, dose-response relationship, drug
interaction, drug safety and factors modifying drug action.
 Pharmacotherapeutics - deals with the application of drugs for use
in diagnosis, prevention, treatment of diseases and purposeful
alteration of physiological functions (e.g. anesthesia and estrus
synchronization).
Pharmacological Terms:
 Toxicology - deals with the harmful effects of drugs, mechanism of
action, conditions under which harmful effects occur, symptoms,
diagnosis and treatment of poisonings.
 Paracelsus (grandfather of pharmacology) stated that “all substances are
potential poisons, there is none which is not a poison. The right dose differentiates
a poison from a remedy”. A poison can be a remedy (e.g. warfarin).

 Clinical pharmacology - deals with drug’s rational development,


effective use, safe use and proper evaluation in the diagnosis,
prevention and treatment against human and animal diseases.
 Molecular pharmacology - deals with the basic mechanisms of drug
action relating drug biologic activity with structure of drug
molecules.
 Pharmacy - is the art and science of preparing, compounding and
dispensing of drugs, it include studies on the source, dosage
(posology) and weights and measures (metrology) of drugs.
Drug Sources

 Minerals
– e.g. sulfur, iron, electrolytes
 Botanicals (plants, molds, bacteria)
– e.g. digitalis, antibiotics, anticancer
 Animal
– e.g. hormones: insulin, thyroid hormone; lanolin
 Synthetic (manmade, engineered: most drugs are synthetic,
have > purity than naturally derived drugs)
– e.g. aspirin, steroids, procaine
History
 Pen Tsao – 2700 BC earliest compilation of drugs in the reign of
Chinese emperor Shennung
 Kahun papyrus – Egypt 2000 BC, lists of prescriptions for uterine
diseases in women and veterinary medicine
 Ebers papyrus – Egypt 1500 BC, earliest known formulary, a
collection of folklore composed of 800 Rx for specific diseases.
 500 BC – Greek philosopher & physicians advance the idea that
disease is not cause by gods or demons, rather cause by
imbalance of body humors affected by temperature, humidity,
acidity & sweetness.
 Hippocrates – Greek, 460-370 BC, father of medicine, began the
practice of medicine from an art to a systematic clinical science
using systematic observations, believer of the healing power of
nature.
 Galenical preparation - 131-201 AD, most authoritative
materiamedica for the next 1400 years
 Dioscorides- 77 AD, compiled the first materiamedica,
composed of therapeutic substances
 Paracelsus –TheoprastusBombastus von Hohenheim, Swiss
physician 1492-1541, renaissance; introduce the use of specific
drugs e.g. opium, for directed purpose: ‘All substances are
poisons, there is none which is not a poison. The proper dosage
separates a poison from a remedy’.Grandfather of
pharmacology.
 ValeriusCordus –1547,Europe,first to publish a Pharmacopoeia
entitled Dispenatoriumin Nuremberg Germany.
 EdinnburghPharmacopoeia ,1689, London
 US Pharmacopoeia – USP-0,1820; most recent USP-30
 British Pharmacopoeia – 1864 until today
 Sir Christopher Wren – 1656, first IV injection of opium
 Jesuits, South America – brought bark of cinchona tree from
South Africa for malaria cure
 William Withering – 1783, English physician, reported the use of
foxglove plant to cure dropsy, edema caused by CHF
 Magendie– 1800, French physiologist & pharmacologist, first to
prove that that substances can be absorbed in blood and
exert systemic effect; study IV injections of ipecac, morphine,
strychnine, etc.
 Orfila– 1813, published a book Toxicology GeneralClaude
Bernard – mid 1800, demonstrated digitalis (foxglove) action
on the heart
 Dale – 1692, London, applied the term pharmacology to
the study of MateriaMedica
 Rudolph Bucheim–1847, biochemist, established 1st
Experimental Pharmacology Laboratory, Baltic City,
Estonia (evidence based pharmacology); argued
pharmacology is a separate discipline from
MateriaMedica, pharmacy & chemistry.
 Oswald Schmiedeberg – 1872, successfully separated
pharmacology from Materia Medica based on
experimental methodology, founded the first
pharmacology journal. Father of modern pharmacology.
 Dr.John Abel - first full time professor in pharmacology,
University of Michigan, father of American
pharmacology
Veterinary Pharmacology History
 5000 BC – evidence of Indian military hospital for horses and
elephants, extensive medical education at Hindu University in Takasila
 Publius Vegetius - 5th century, veterinary compilation of substances for
farm animals.
 1700 – an epidemic wiped out most cattle population in Western
Europe.
 1760-90 – formal establishment of veterinary colleges and hospitals in
France, Austria, Germany, England, Scotland& Netherlands
 1791- Royal College of Veterinary Surgeon, London
 1823 – Royal (Dick) School of Veterinary Studies, Edinburgh
 1852 -first US Veterinary Colleges in Philadelphia; 1854 in Boston, later
in Iowa, Ohio, Ontario, Pennsylvania and New York.
These colleges were adjuncts to schools of medicine, the
curriculum that included materia medica, paving way to new
fields of pharmacology and later veterinary pharmacology.

Veterinary pharmacology provide rational basis for the use of


drugs in different animal species. It apply similar principle with
human pharmacology except for species differences on
anatomy and physiology (comparative drug action &
disposition) including emphasis on antiparasitic drugs, drug
residues for food safety and drugs for avian, exotic and
aquatic medicine.
Drugs are endogenous or exogenous chemical agent that
interacts with living processes e.g. simple inorganic salt
(sodium bicarbonate), complicated molecule
(progesterone), natural animal or plants products (insulin,
morphine), semi-synthetic (aspirin), synthetic
(phenobarbital) and endogenous substances (adrenaline,
hormones).
Drugs do not have unique actions it only serve to increase or
decrease existing physiological or biochemical functions
(quantitative not qualitative in their effects). Actions are
expressed relative to existing body condition at the time of
administration e.g. temperature, blood pressure, glucose,
etc.
Drugs are classified under three name categories: chemical
name, official/approved/non-proprietary/generic name
and brand/trade or proprietary name.
chemical name - (7-chloro-1,3-dihydro-1-methyl-5-phenyl-
2H-1,4-benzodiazepin-2-one) gives its precise chemical
components;
official name - (diazepam) is given when it is marketed and
adopted throughout different countries and;
brand name - (valium, sedapam) arises when it is marketed
by more than one company in different countries.
Drug Regulation
FDA (Food & Drug Administration) – government regulatory body
that establish standards, guidelines and enforce to food & drug
manufacturers the safety, purity or effectiveness of their
products. It prohibit sale and use of food and drug that would
cause serious health problems.
It protect consumers, health professionals and animals by
maximizing the benefit of drugs while minimizing their dangers.
Manufacturers must demonstrate that the drug is safe as
claimed by the label.
They must provide reliable analytical method to detect
drug residues in animal foodstuffs and an acceptable
withdrawal period in food animals.
 Prescription (Rx)drugs – FDA approved, limited to use under the
supervision of a licensed veterinarian or physician because of their
potential danger, toxicity or administration difficulty (e.g. antibiotics).
Patient need to be seen by the practitioner.
Veterinarian/client/patient relationship (VCPR) must exist, it is
obtained only through a veterinarian/physician or via Rx e.g.
antibiotics, CNS drugs.
 OTC - over the counter drug may be purchased by the client without
Rx, it does not have significant potential for toxicity (e.g. aspirin,
paracetamol).
 Extra-label – use of a drug in a manner not specifically described on
the FDA approved label, if use must be accompanied with the order
of a licensed practitioner (e.g. ivermectin in dog). It must not result in
drug residues in food animals.
 Controlled substances – drugs considered dangerous because of
their potential for drug abuse or misuse (illicit use of an illegal drug or
the improper use of a legal Rx drug), it is regulated by DEA (Drug
Enforcement Administration). Controlled drugs are classified into 5
schedules, the higher the schedule the lower the risk of abuse
potential.
 S1 – high potential for abuse and has no current accepted
medical use e.g. marijuana, heroin, LSD
 S2- high potential for abuse but has current accepted medical use
e.g. cocaine, morphine, amphetamine, pentobarbital, etorphine,
fentanyl
 S3- has potential for abuse but less than s1 and s2 and has
accepted medical use e.g. acetaminophem+codeine, ketamine,
thiamylal, thiopental, hydrocodone
 S4- low potential for abuse relative to s3 and has accepted
medical use e.g. diazepam, phenobarbital, butorphanol
 S5- low potential for abuse relative to s4 and has accepted
medical use e.g. codeine cough syrups, buprenorphine,
diphenoxylate.

To prescribe controlled substances one must register annually


with DEA.
LECTURE II
DRUG ABSORPTION AND ROUTES OF DRUG ADMINISTRATION
DRUG ABSORPTION AND DISPOSITION
A. REACHING THE SITE OF ACTION
Drug absorption is the movement of drug from the site of administration
into the systemic blood circulation that will carry it to the target sites.

 Patient factors
 Drug factors:
 pH of the environment
 Pka
 gastric motility
 molecular size
 first-pass-effect
 pH
 presence of food
 route of administration
 blood flow
 dosage form  surface area age
 health status
 genetic factors
 metabolic rate
 sex
 Bioavailability is the percent of drug administered that actually
enters the systemic circulation.

Drug Transport
 Lipid diffusion – drug must be non-ionized (lipid soluble) to dissolve
through the lipid bi-layer, primary pathway for drug transport (also true
for elimination organs).
a. Phospholipid bilayer - act as a barrier to drug transfer across the
membrane.
-has polar and ionic hydrophilic end on the surfaces and a
hydrophobic end on the inner layer of the membrane.
-non-ionized drugs cross membranes based on their ability to
dissolve in the lipid portion of the membrane.
-bilayer is embedded with proteins, changes in lipid fluidity alter
protein conformation a primary mechanism for gaseous anesthetics. –
-integral proteins in the membrane form aqueous channels for
drug filtration, enzymes for active or facilitated transport.
b. Simple diffusion - is a passive process governed by Ficks
law.
-rate of diffusion of a substance is directly proportional
to its concentration gradient across the membrane,
thickness of membrane, lipid/water partition coefficient
(lipid & water solubility) and diffusion coefficient (molecular
size, conformation, solubility, degree of ionization).
-drug absorption is faster from organs with large
surface area e.g. small intestine than from organs with
small surface area e.g. stomach;
-faster from organs with thin membrane barriers e.g.
lung alveoli than from those with thick barriers e.g. the skin.

Rate = (C1- C2) x x Area


c. Weak acids and weak bases
1) Majority of drugs are either weak acids or weak bases.
The degree to which these drugs are lipid soluble (non-
ionized) is determined by their pKa and the pH of the
medium containing the drug:
pKa (-log of acidic dissociation constant/ ratio of ionization at a given pH) - pH
where 50% of the drug is ionized and 50% is non-ionized.
The proportion of ionized and non-ionized forms of drugs
having pKa = pH of the medium will be the same.

a) In monogastric animals with a low stomach pH, weak acids


such as aspirin (pKa 3.5) tend to be better absorbed from the
stomach than weak bases because of the acidic
conditions.
b) Weak bases are poorly absorbed from the acidic
environment of the stomach because they exist
mostly in the ionized state (low lipid solubility).
Weak bases are better absorbed from the small
intestine where the environmental pH is more
alkaline.
Strong bases e.g. quaternary ammonium
compounds (d-tubocurarine) with very high pKa (12)
are completely ionized at all physiological pH,
poorly absorbed and mainly extracellularly
distributed.
x

2) Henderson-Hasselbalch equation – used to


calculate the percent of a drug that exists in ionized
form or to determine the concentration of a drug
across a biologic membrane; needs to know
whether a drug is an acid or a base.

a) Weak acids: the unprotonated, dissociated forms are


ionized and are less lipid soluble while the protonated,
undissociated forms are non-ionized and are more lipid
soluble.

pH = pKa + log
x

b) Weak bases: the unprotonated, dissociated forms


are non-ionized and are more lipid soluble while the
protonated, undissociated forms are ionized and are
less lipid soluble.

pH = pKa + log
Example. The Henderson-Hasselbalch equation
can be used to determine the concentration
ratio (plasma/gastric fluid) of non-ionized aspirin,
a weak acid (pKa 3.5), following achievement of
equilibrium.
Biologic membrane

Plasma (pH 7.4) Gastric fluid (pH 1.5)

HA (1) non-ionized
non-ionized HA (1)


H+ + A- (0.01) Ionized
Ionized H+ + A- (10,000)
1.01 units of the drug on this side of the membrane at
 equilibrium
unprotonated (U)
10,001 units of the drug on this side of the membrane at pH = pKa + log
equilibrium U protonated(P)
1.5 = 3.5 + log P
unprotonated (U)
pH = pKa + log U
U
protonated(P) -2 = log
P
7.4 = 3.5 + log P
U
Take the antilog of both sides
3.9 = log U
P 0.01 =
P
Take the antilog of both sides
If U = 0.01, then P = 1 (1:100)
U
10,000 =
P
If U = 10,000 then P = 1 (10,000:1)

Plasma concentration (10,001)


=9,900
Gastric fluid (1.01)
Therefore:
i. Low pH in the stomach would render much of aspirin non-
ionized and readily absorbed.
ii. High pH in the blood would render much of aspirin ionized
(trapped) in the plasma.
iii. Transmembrane concentration gradient= 10000/1.01, the total
drug concentration on both sides that are different. Which
favors transport of aspirin from stomach into plasma, this is also
true for other WA e.g. pcn, phenylbutazone, etc., but WB will
be trapped in this environment e.g. morphine, ketamine &
phenothiazine.
iv. At equilibrium the concentration of unionized aspirin is the
same on both sides of the membrane.
v. Summary: pH partitioning phenomenon means WA are readily
absorbed in an acid environment and trapped in alkaline
environment, while WB are readily absorbed in an alkaline
environment and trapped in acid environment.
Drug Transport

 Aqueous diffusion or filtration – passive process dictated by


molecular size and electrostatic charge; most capillaries are porous
or fenestrated that allow large molecules exchange between
blood and tissue, except brain, CSF having additional membranes
e.g. glial cells
a. low molecular weight chemicals e.g. water and urea cross
membranes better than predicted by their lipid solubility, it
suggests that plasma membranes possess water filled protein
pores that allow drugs to cross by aqueous diffusion or filtration.
b. A simple diffusion governed by Ficks law.
c. Filtration is limited to small drug molecules capable of passing
thru channels in the membrane whose diameter is 10x larger in
capillary endothelium than intestinal epithelium.
d) Small water-filled pores in most capillaries permit
aqueous diffusion of molecules up to the size of small
proteins between the blood and extravascular space.
e) Most drugs have a molecular weight between 100 and
1000.
f) Glomerular filtration typically manifest the existence of
membranes pores, it permit the transport of large
molecular weight substances but small enough to retain
albumin (mol.wt.= 60,000).
 Facilitated diffusion - specialized selective transport
a. Require a specific carrier, it is capacity limited (TM)
and is not governed by Ficks law.
b. Cell membrane lipid bilayer contains protein
carriers.
c. Cellular energy is not required as it does not
operate against a concentration gradient.
d. Carriers can be selectively inhibited e.g.
probenecid
e. Not a major mechanism for drug transport e.g. re-
absorption of glucose by the kidney.
 Active transport – specialized selective transport
a. Active transport require energy, specific carrier and
operates against a concentration gradient.
b. The chemical structure of the drug is important in
attaching to the carrier molecule. For example, the
anticancer drug 5-fluorouracil is absorbed from the
intestine by the same carrier system used to absorb
uracil (co-transport).
c. Not governed by Ficks law and transport capacity is
limited (TM).
 Pinocytosis (cell drinking) and phagocytosis (cell eating)
- are specialized vesicular transport; minor methods for
drug absorption; it requires energy characterized by
membrane in-folding and subsequent vesicle
internalization and release of the drug into the
cytoplasm. Important in the absorption of large
molecules (e.g. polypeptides, bacterial toxins,
antigens, and food proteins by the gut).
Routes of Administration
 Alimentary Routes
a. Oral – drug must get into solution in GIT fluids prior to absorption.
Forms: solutions, suspension, pills, tablets, bolus, capsules, pellets,
etc.
1) Advantages - safest route, approximate 75% bioavailability,
most convenient, cheap, painless, assistance not required
and drugs need not be sterile.
Small intestine is the primary site for most drug(WA, pKa>3;
WB pKa<7.8) absorption: Lined by simple columnar
epithelium, extensive surface area (villi & microvilli, folds),
alkaline pH, high blood flow, extensive capillary and
lymphatic network.
Stomach absorption only for unionized and small molecules
e.g. ethanol.
Pharmaceutical factors affecting GIT absorption:
- disintegration
- dissolution
- barrier diffusion

Enterohepatic recycling - renders a conjugated drug from


systemic circulation excreted in the bile into the small intestine.
Drug is then unconjugated by resident intestinal bacterial flora
and if unionized the drug is reabsorbed from the small intestine
back in the blood, prolonging the drug activity. Emulsifying
property of bile also renders fatty substances to solubilize in
aqueous environment, forming large surface area micelles that
are delivered to the intestinal brush border for diffusion into the
cell.
2) Disadvantages
a) Some drugs may have low bioavailability e.g. propranolol
are extensively subjected to first pass effect, loss of drug on
passage thru the GIT and the liver (biotransformation)
before they reach the systemic circulation. This can be
avoided by buccal and rectal routes (drug absorbed distal
to the mouth and proximal to the rectum by-passes the
hepatic portal vein).
b) Some drugs may irritate the gastrointestinal mucosa.
c) Cornified epithelium, surface mucus, digestive juices (acid)
and enzymes of the stomach are harsh barriers against
drug (pcn, insulin) absorption. In ruminants, the bacterial
enzymes may inactivate the drug, or the digestive process
may be altered by the drug e.g. as occurs with
antimicrobials.
d) The presence of food may significantly decrease absorption,
slower and less complete. Specie dependent e.g.
continuous foraging in ruminants and horses, has relatively
stable gastric pH vs dogs, cats & pigs. Food component in
milk e.g. divalent cations (Ca2+, Ms2+) may chelate
tetracyclines.
e) Forestomach of ruminants is a major obstacle for absorption
of oral dosage form. Rumen is a large fermentation vat
(cattle > 50L; sheep > 5L), lined with stratified epithelium, pH6,
extensive saliva, designed for VFA absorption. Extensive
dilution of drug and decrease rate of absorption.
f) Slower action - not suited for emergencies. Formulation
factors influence disintegration and dissolution e.g. tablets,
particle size, homogeneity of excipients.
g) Unpalatable drugs are difficult to administer.
h) May cause vomiting.
i) Not useful for uncooperative and vomiting patients.
j) Polar drugs are not absorb e.g. streptomycin

1) Other considerations
a) Antimuscarinic and narcotic drugs may delay gastric
emptying; slow the rate of drug absorption and prolong the
drug onset time.
b) A hyperactive gut e.g. diarrhea may shorten the transit time
and lessen the drug-gut contact time, leading to reduced
absorption.
c) Enteric-coated tablets may protect the drug from destruction
by stomach acid; it enhance absorption.
b. Rectal/suppository - partial avoidance of first-pass-
effect; useful for drugs with unpleasant taste; can
accommodate larger volume of drugs; useful for
feverish, constipated and unconscious or vomiting
animals.

c. Buccal (pouch between gums and cheek)and


sublingual (under the tongue) – this routes by-passes
hepatic portal vein (first-pass-effect) and thus
eliminates the potential for first pass hepatic
biotransformation.
 Parenteral Routes - by-passes the gastrointestinal tract
a. Types
1) Intravenous – 100% bioavailability; instantaneous
complete absorption but potentially more
dangerous if administration is very rapid.
2) Intramuscular – often much faster absorption and
higher bioavailability than oral route.
3) Subcutaneous – slower absorption than IM
4) Intraperitoneal
5) Intrathecal
6) Intra-arterial - 100% bioavailability
b. Advantages
a) Rapid onset (the IV route is faster than the IM route; which
is faster than the SC route)
b) useful in an unconscious or vomiting animal
c) absorption is more uniform and predictable

Because absorption from IM and SC routes is determined in


part by the amount of blood flow to that site, the
absorption of local anesthetics is often purposely slowed
by co-administration with epinephrine, which decreases
the blood flow to the injection site.
b. Disadvantages
a) Asepsis is necessary.
b) Parenteral administration may cause pain, and there is
a risk of penetrating a blood vessel during intramuscular
injection.
c) If the speed of onset is so rapid (IV) adverse
cardiovascular responses may occur.
d) In food animals, staining of the meat (iron dextran) or
abscess formation (irritating drugs) may occur with
intramuscular injection, which may devalue the
carcass.
 Topical administration – applied to the skin or mucous membranes of
the eye, nose, throat, airway or vagina for local effect.
For systemic effect, absorption is slow but first pass effect is
avoided.
Epidermis is covered with sebum, multi-layered (stratum
corneum/stratified dead keratinocytes embedded in lipids but the
cells are hydrophilic; stratum germinativum keratinocytes differentiate
to replace dead cells at the surface; stratum granulosum synthesize
lipids) of varying thickness is an efficient absorption barrier
(impermeable to aqueous solutions and most ions) thus the rate of
absorption is slower and dependent on the lipid solubility of the drug
and the area of application.
Abraded or sun burnt skin may absorb more drug than intact skin.
Pathways for absorption are intercellular (unionized), transcellular,
intrafollicular and via sweat glands (small, polar molecules).
 Transdermal –Dermis is highly vascular and provide ready
access for absorption once epidermal barrier is passed.
Vasoconstriction retard absorption while vasodilation
enhance. Appendages e.g. sweat glands, hair and
sebaceous glands extend thru the epidermis with regional and
specie variability.

 Inhalation - used for volatile/gaseous anesthetics and nasal


spray for respiratory diseases. Response is rapid because of
the large surface area of the lungs and the large blood flow to
the lungs.
LECTURE III
DRUG DISTRIBUTION
Drug Distribution
 the reversible transfer of a drug from systemic circulation to
the tissues. The junctions between the capillary endothelial
cells are not tight, thereby permitting free drug (drug not
bound to plasma proteins) to rapidly reach equilibrium on
both sides of the vessel wall.
 Factors affecting drug distribution:
 protein binding
 tissue perfusion
 membrane permeability
 volume of distribution
Protein Binding
 Only the unbound drug is able to cross cell membranes freely.
 Albumin is the principal protein in the systemic circulation,
produced by the liver.
 Proteins are large molecules and cannot leave the capillaries,
thus drug-protein complexes are trapped in the blood.
 Only the free drugs are able to leave the capillaries.
 The drug-protein binding reaction is reversible and obeys the
laws of mass action:

drug + protein  drug-protein


(free) (bound)
a. Acidic drugs are bound primarily to albumin, and basic
drugs are bound primarily to α1-acid glycoprotein.
b. Binding does not prevent a drug from reaching its site of
action, but it slows the rate at which a drug reaches a
concentration sufficient to produce a pharmacologic
effect.
c. Binding of a drug to blood or tissue proteins will increase
drug concentration in vascular or tissue fluid, it restricts
drug diffusion out of the compartment.
d. Liver disease and protein-losing diseases will result in
more free drugs available to target tissue and risk of
potential side effects from high levels of the drug
increases.
e. Effect on drug elimination:
1) Drug-protein binding limits glomerular filtration
because bound drugs cannot be filtered.
2) Binding does not typically limit the elimination of
drugs that are actively secreted by the kidney or
metabolized by the liver, because the fraction of the
drug that is free is transported and metabolized. As
the free drug concentration is lowered, there is rapid
dissociation of the drug-protein complex to maintain
the amount of drug in the free state.
3) Sulfa drugs with a high affinity for binding to protein
are eliminated more slowly in urine than those sulfa
drugs with a lower binding affinity for plasma
proteins.
f. Drug interactions may occur when two drugs
that are simultaneously used bind at the same
site on the plasma proteins. Competition for the
same site increases the percent of drug in the
free form, thereby increasing the
pharmacologic toxicologic response to the
displaced drug.
Tissue Perfusion
 Is the relative amount of blood supply to an area or body system,
varies among body systems and animal species.
 Distribution is rapid in well perfuse tissues (brain) than poorly perfuse
tissues (fat)
 e.g. higly lipophilic anesthetic thiopental given IV is initially rapidly
distributed to the brain and slowly distributed to the fats, it
continued to be redistributed from brain (concentration drop) to
the blood and to the fat thus consciousness is regained.
 Redistribution of a drug from its site of action to other tissues lowers
its concentration at its site of action, thereby terminating the drug
response.
 Tissue perfusion is also affected by alterations of blood flow rates
caused by disease (heart failure) and drug treatments
(epinephrine).
Membrane Permeability
1. CNS distribution - most blood capillaries except in the CNS
have only one cell layer thickness and have small holes
between cells to allow small drug molecules (polar and non-
polar) to move in and out of the capillaries. However,
distribution of drugs into the CNS and CSF is restricted. These
are processes that contribute in keeping drug concentrations
low in the CNS:
a. Blood-brain barrier. Most of the CNS capillary walls (except
area postrema, pineal body, posterior lobe of
hypothalamus) have no holes and the endothelial junctions
are tight and glial cells surround the capillaries creating
extra barrier. These features will not allow filtration and will
only allow the most lipophilic drug to diffuse across
undamaged CNS cell membranes and enter the CSF.
b. Active transport mechanisms exist for organic acids and
bases in the choroids plexus, allowing transport of drugs
from the cerebrospinal fluid into the blood e.g. CNS
concentrations of penicillin, a weak acid are kept low by
this active transport system.
c. CSF produced within the ventricles circulates through
the ventricles and over the surface of the brain and
spinal cord to flow directly into the venous drainage
system of the brain. This process continuously dilutes the
drug’s concentration in the CSF.
2. Transplacental distribution – many drugs can pass thru
the placenta; sink effect.
a. Drug transfer across the placenta occurs primarily by
simple diffusion, most easily if the drugs are lipid-
soluble. Even if drugs with low lipid solubility are
given to the mother, the fetus is exposed to some
extent.
b. Drugs that affect the maternal CNS e.g., anesthetics,
analgesics, sedatives, tranquilizers have the physical-
chemical characteristics to freely cross the placenta
and affect the fetus.
3. Other distribution barriers - joints,prostate, testicles, and
globe of the eye contain barriers that prevent drug
penetration, thus limiting drug concentration in these
tissues.
Volume of Distribution
 Drugs distribute into several compartments (ICF, ECF: plasma,
interstitium, transcellular, digestive)
 Drugs bind to lipids, proteins or nucleic acids
 Apparent Volume of Distribution (Vd: hypothetical) is the volume
into which drug distributes.
 5% of drugs having very large molecular weight and extensively
bound to plasma proteins will distribute (trapped) only in the
plasma.
 20% of drugs that are hydrophilic with low molecular weight will
distribute into the plasma and interstitium.
 60% of drugs that are hydrophobic with low molecular weight can
move into the ECF and intracellular fluid thus distributing to the total
body water
Vd relates the amount of drug in the body to the
concentration in the plasma. It assumes that the drug
concentration in the blood is equal to the drug
concentration dispersed throughout the rest of the
body.
If a drug has a large Vd, the fraction of drug present in the
blood will be lower after distribution e.g. dog with
ascites. If Vd is abnormally large, drug concentration in
the blood will be out of therapeutic range, this needs
modification of drug dosage to achieve the desired
therapeutic response.
VD = D/C
C = plasma concentration of drug
D = total amount of drug in the body

An exceptionally large Vd e.g. drug sequestration in the


fetus, fat, bone, thyroid and abdominal fluid reduces the
fraction of drug present in the blood and also reduces
the delivery of drug to excretory organs (kidney, liver),
this can lead to an increase in half-life and extend the
duration of drug action.
LECTURE IV
DRUG METABOLISM
Drug Metabolism (Biotransformation)
 Drug action is terminated upon removal of the drug from the site of
action.
 The main mechanisms are:
 biotransformation
 re-distribution
 excretion
 The rate at which a reversibly bound active drug ceased to act
depends on the rate of the main process for their elimination
 e.g. procaine is primarily hydrolyzed in the plasma, thiopental is
redistributed to fats, penicillin is actively secreted in the kidney
 Most drugs are reversibly bound to receptors and are
slowly eliminated by a combination of biotransformation
and excretion.
 Covalently or irreversibly bound drugs
(organophosphates) may require the re-synthesis of such
bounded constituents before drug action ceases.
 Biotransformation is the conversion of unionized drugs
into more polar, hydrophilic compounds in order to
facilitate their excretion.
 The liver is the most important organ for
biotransformation, but the lung, kidney, and
gastrointestinal epithelium also play a role.
 On GIT absorption, drugs are delivered via portal
circulation to the liver prior to their systemic circulation,
losing some of the drugs due to rapid hepatic
inactivation called “first pass effect”.
 If first pass effect is extensive little active drug will reach
the circulation after oral absorption.
 Extensive hepatic inactivation may be circumvented by
giving large oral doses or by using other routes that by-
passes the liver.
e.g. intravenous, buccal, sublingual and rectal
administration.
 Kinetics of Metabolism:
a) 1st order kinetics – metabolic transformation of drugs is
catalyzed by enzymes, it obeys Michaelis Menten
kinetics.

Rate of drug metabolism =Vmax (C)/ Km + (C)

But in most cases the concentration of the drug is much less


than the Michaelis constant, Km, thus the equation is reduce
to:

Rate of drug metabolism =Vmax (C)/ Km

Rate of drug metabolism is directly proportional to the


concentration of free drug, a constant fraction of the drug is
metabolized per unit time.
b) Zero order kinetics – few drugs the doses are very
large (aspirin, ethanol, phenytoin), so the
concentration is much greater than the Km.

Rate of drug metabolism =Vmax (C)/ (C) = Vmax

The enzyme is saturated by a high free drug concentration


and the rate of metabolism remains constant over time
(non-linear kinetics), a constant amount of drug is
metabolized per unit time.
Function of Biotransformation
 Following filtration at the renal glomerulus, most lipid-
soluble drugs are reabsorbed from the filtrate.
Biotransformation of drugs to more water-soluble (polar)
chemicals reduces their ability to be reabsorbed, thus
enhancing their excretion and reducing their volume of
distribution.
 Although drug biotransformation frequently reduces the
biological activity of the xenobiotic, it is not synonymous
with drug inactivation because the parent chemical may
be transformed to a chemical with greater or significant
biologic activity.
Phases of Enzymatic Reaction
a. Phase I also referred to as microsomal enzymes, they are found in
the hepatic SER.
1) Oxidation is the addition of oxygen or the removal of hydrogen
from the drug.
i. Microsomal oxidation - carried out by the cytochrome P-
450 family of isozymes. The enzyme system is a mixed
function oxidase; one atom of oxygen is incorporated in
the drug molecule and the other atom of oxygen
combines with hydrogen to form water. NADPH provides
the reducing equivalents (table 1.1).
Newborn, cachectic, patients with liver disease and
hypothermic animals have decreased microsomal
metabolism, thus drugs may have prolonged effect in these
animals.Greyhounds are deficient with oxidative enzymes,
thus slowly metabolized thiobarbiturates.
Table 1-1. Microsomal Oxidation Reactions

Oxidation Reaction Substrate


Side chain and aromatic Pentobarbital, phenytoin,
hydroxylation phenylbutazone

N- or O-dealkylation Morphine, codeine, diazepam

N-oxidation Acetaminophen, nicotine

S-oxidation Phenothiazines (e.g., chlorpromazine)

Deamination Amphetamine

Desulfuration Thiopental, parathion


ii. Non-microsomaloxidation - few chemicals are
oxidized by enzymes found in the cytosol or
mitochondria.
• Alcohol dehydrogenase and aldehyde
dehydrogenase oxidize ethanol and
acetaldehyde.
• Monoamine oxidase (MAO) oxidizes epinephrine,
norepinephrine, dopamine, and serotonin.

2) Reduction Reactions - involve the addition of hydrogen


to the drug molecule, occur less frequently than oxidation
reactions. Enzymes are located in both microsomal and
non-microsomal fractions. Examples of chemicals
biotransformed by reduction include chloramphenicol,
prontosil, and naloxone.
3) Hydrolysis - chemicals with either ester or amine
linkages undergo hydrolysis.
a) Esterases occur primarily in non-microsomal
systems and are found in the plasma, liver, and
other tissues. Examples of drugs hydrolyzed by
esterases include acetylcholine, succinylcholine,
and procaine.
b) Amidases are non-microsomal enzymes found
primarily in the liver. Examples of drugs hydrolyzed
by amidases include procainamide and
indomethacin.
b. Phase II (conjugation) - a phase I metabolite or a
parent chemical (containing OH, COOH, NH2, SH)
may undergo phase II biotransformation. This process
involves the coupling of an endogenous chemical to
the drug metabolite (Table 1-2).
1) Enzyme systems are present in the microsomes,
cytosol, and mitochondria.
2) Products of phase II biotransformation have >water
solubility and are more readily excreted via the
kidney.
Table 1-2. Phase II Biotransformation

Conjugation Reaction Substrate

Glucuronidation Morphine, acetaminophen,


sulfathiazole, digitoxin
Acetylation Sulfonamides, clonazepam
Glutathione conjugation Ethacrynic acid
Glycine conjugation Salicylic acid, nicotinic acid
Sulfate conjugation Catecholamines, acetaminophen
Methylation Catecholamines, histamine
Factors Affecting Drug Metabolism
a. Concurrent drug use. Certain drugs and chemicals (e.g.,
Phenobarbital, pentobarbital, phenylbutazone,
organochlorine pesticides, polycyclic hydrocarbons)
increase the synthesis of liver cytochrome P-450
enzymes, increasing the rate of drug biotransformation
and reducing the magnitude and duration of the dose-
response curve. Enzyme induction may explain some
types of drug tolerance.
b. Age. The ability to metabolize drugs is reduced in fetal,
newborn, and aged animals.
c. Sex. Male rats metabolize some drugs more rapidly than
female rats. The extent to which this phenomenon
occurs in other animals is unclear.
d. Disease. Liver pathology or dysfunction reduces the
biotransformation ability of the liver. Other diseases
(e.g., CHF, renal disease) may alter drug distribution,
thereby influencing drug metabolism. Chemical inhibitor
such as SKF-525 reduces drug metabolism.
e. Species differences
1) Aquatic amphibian and fish have low concentrations
of drug metabolizing enzymes, cytochrome P-450
system is primarily developed in terrestrial animals.
2) Cats have reduced glucuronyltransferase
(glucuronidation) activity and slowly metabolize
aspirin and paracetamol.
3) Dogs lack the ability to acetylate (acetylation)
aromatic amino groups such as those present in
sulfonamides.
4) Ruminants have low plasma pseudocholinesterase
levels; thusdrugs such as succinylcholine have a
longer duration of action in ruminants than in horses,
dogs, or cats.
5) Horse, cattle, goats and certain strains of
rabbits(herbivores) have high level of atropinase in
the liver than carnivores and are quite resistant to
belladonna leaves poisoning.
6) Pigs are deficient in sulfation activity, slowly
metabolize paracetamol.
LECTURE V
DRUG EXCRETION
Drug Excretion
 Refers to the processes by which a drug or drug metabolite is
eliminated from the body.
 Any fluid eliminated from any route in the body may excrete
drugs.
 e.g. urine, bile, feces, expired air, saliva, milk, sweat and
tears
 Drugs which are to a large extent, excreted unchanged owe
their duration of action to their excretion rate, irrespective of
the route.
 e.g. rapid exhalation of inhalant anesthetics with low lipid
solubility and renal excretion of polar drugs e.g.
aminoglycoside antibiotics
Urine
 The kidney is the most important drug excretory organ.
Filtered and actively transported active and inactive drugs in
tubular filtrate with low lipid solubility (ionized) are eliminated
in the urine. However tubular re-absorption will allow
unionized drugs to re-enter the circulation. Any combination
of these processes determines the final urinary drug
composition.
a. Glomerular filtration rate (GFR). Free molecules <66,000 Daltons
that are not bound to plasma proteins are readily filtered in the
glomerulus. High plasma protein binding to some drugs will
retard GFR (renal clearance). GFR is dependent on the
concentration of free drug in the plasma.
b. Active tubular secretion. Drug clearance by tubular secretion is
not limited by protein binding since in the proximal tubule,
active transport carriers exist for both free and protein bound
acid and base drugs.
Tubular secretion rate is an active saturable process, the
carriers can be blocked (competition) by metabolic inhibitors
and it is not influenced by protein binding but rather to the total
drug concentration.
As free drug is removed by the tubular cells, bound drug
very rapidly dissociates to maintain equilibrium and availability
of free drug.
Competition between drugs for the same carrier system
can lead to adverse drug reactions or can be used to
therapeutic advantage (e.g. probenecid inhibits the transport
of penicillin, thereby reducing the tubular secretory rate and
enhancing the plasma concentration of penicillin).
Actively Secreted Drugs
Weak Acid Drugs Weak Base Drugs
Penicillin Histamine
Ampicillin Serotonin
Chlorothiazide Procainamide
Ethacrynic acid Neostigmine
Furosemide Trimethoprim
Probenecid Atropine
Salicylate
Phenylbutazone
Cephalosporins
c. Passive tubular re-absorption. Only lipid-soluble drugs are
reabsorbed in this manner. Because most drugs are weak
acids or weak bases, the pKa, of the drug and the pH of the
tubular filtrate affect how much of the drug is unionized (re-
absorbable).
Excretion of weak electrolytes can be influenced by
imposing appropriate changes in urinary pH since the same
principles involved in drug absorption also apply to
excretion, namely the more lipid soluble the drug the less
readily will it be excreted.
Thus urinary acidification will retard the excretion of
weak acids (phenobarbital) while weak bases
(amphetamine) will be enhanced. Urinary alkalization will
have opposite effects.
d. However the extent to which urinary pH influences drug
renal clearance depends to a large extent on its pKa,
since this value determines the ratio of ionized to
unionized drug at a given pH.
Only acids which have a pKabetween 3-8 and bases
whose pKa between 6-11 will have renal clearance which
are very sensitive to changes in urinary pH.
Outside these values renal clearance will be insensitive
to pH changes since within the physiological urinary pH
range acids with a pKa of <3 and bases with a pKa of >11
are likely to be completely ionized and rapidly cleared,
while at the other extreme acids with a pKa of >8 and
bases of pKa of <6 will be unionized and have low renal
clearance.
1) Diet influences the urinary pH for both carnivores and
herbivores.
i. In carnivores, the urinary pH ranges from 5.5-7.0
ii. In herbivores, the urinary pH ranges from 7.0-8.0
2) Excretion can be enhanced for drugs eliminated
primarily by the kidney by altering the pH of the urine.
For practical purposes, this principle applies only to
weak acidic or weak basic drugs with a pKa of 5-8.
Sodium bicarbonate raises urinary pH which tends to
promote the excretion of weak acids (parent and
metabolites) with pKa ranges of 3-8.
3) Quaternary drugs (R4-N+) are polar at all urine pHs.
They are eliminated rapidly because they cannot be
reabsorbed.
e. Increasing the rate of urine flow by administering
diuretics (mannitol) will increase rate of renal
clearance and the opposite will occur when urine flow
is retarded by reduced renal perfusion or renal disease.
f. In kidney disease (main excretory organ), renal blood
flow, tubular secretory powers and glomerular filtration
rate are reduced thereby reducing all renal drug
elimination processes.
If the rate of drug renal clearance falls drastically, a
drug which depends solely on renal excretion for its
elimination will rapidly accumulate and, especially for
drugs with low TI (digoxin, tetracycline,
aminoglycosides), toxicity is likely unless drug dosage is
reduced to correspond to the elimination rate.
Bile and Feces
 Drugs excreted in the feces are derived from polar
unabsorbed orally ingested drugs (aminoglycosides, antacids,
purgatives) and those excreted by the liver into the bile.
Parent drug or the conjugated form that is polar and having a
molecular weight <300 that are not reabsorbed in the
enterohepatic circulation will be eliminated via the bile and
voided in the feces.
a. Passive and active transport processes exist in the hepatocytes
for transporting acidic, basic, and neutral drugs into the bile
and ultimately into the doudenum. Because these drugs may
eventually be reabsorbed from the gut lumen, biliary
elimination processes tend to be less effective than renal
excretion processes for eliminating a drug from the body.
b. A drug secreted by the liver into the bile either unchanged or
after conjugation passes into the intestine to be eliminated in
the feces.
However if the drug is lipid soluble or its glucuronic acid
conjugate is hydrolysed in the intestine by bacterial
glucuronidases, the liberated active drug may be reabsorbed
instead of being eliminated.
Enterohepatic cycles will often prolong the half-life of drugs
that are primarily excreted in the bile and will continue until the
drug is finally eliminated by fecal excretion of glucuronide that
escapes hydrolysis or by renal excretion.
Enterohepatic circulation can significantly increase a drug’s
sojourn in the body.
Breast Milk
 Drugs that are unionized move to the milk by passive
diffusion.
a. Although this is not a significant route for drug excretion, it
is important because drugs given to the mother can
affect the newborn via the milk. For example,
antimicrobial drugs given to the mother can affect the
microflora of the newborn’s gastrointestinal tract.
b. Drugs that are bases are generally found in higher
concentrations in milk than in plasma. Milk is acidic
relative to plasma. Therefore, weak organic bases diffuse
from the plasma into the milk, where they become more
ionized, preventing passage back to the plasma (ion
trapping).
Saliva
 Unionized drugs enter the saliva by passive diffusion from
the blood.
 Saliva is generally swallowed and the drugs re-circulate,
in conditions of excess salivation drugs may be expelled.
 Saliva is a minor route for drug excretion, but it is
important in herbivores receiving parenteral
antimicrobials, because swallowing antimicrobial drug-
laden saliva may upset the digestive process in the
rumen.
Expired Air
This route of elimination is most important for
volatile drugs e.g. inhaled anesthetics.

Tears and Sweat


Unionized drugs passively diffused into the tears
and sweat which are minor routes of excretion.
LECTURE VI
PHARMACOKINETICS
Pharmacokinetics
 Is the study of the time course of drug concentrations in
the body, it depends on the processes of ADME.
 It is the basis for establishing withdrawal times for meats
and milk when drugs are administered to food-
producing animals.
 Permits the calculation of dose and dosing interval.
Plasma Concentration-Time Profile

 The processes of drug distribution and elimination are best


understood by monitoring the plasma drug concentration
over time following an intravenous injection.
a. Drug distribution and elimination. The plasma
concentration rapidly decreases as a result of both
distribution out of the vascular compartment and
elimination.
1. Immediately after injection, the rapid decrease in the blood
concentration for most drugs is primarily the result of distribution
2. Eventually, the plasma and tissue concentrations reach an
equilibrium and the rate of decrease in the plasma from this
point on is governed primarily by elimination processes.
3. If the drug distribution and elimination processes have
significantly different rates, then the plasma drug concentration-
time profile can be used to analyze these two processes.
b. Mathematically, the concentration-time curve can be
depicted as composed of two straight lines.
1. During the distribution phase, the drug is transferred from the
plasma. The line representing the distribution phase has an
intercept (A) and a slope (α).
2. During the elimination phase, the drug leaves the body. The line
representing the elimination phase has an intercept (B) and a
slope () ke. Most drugs are eliminated by a first-
order(exponential) process, a constant fraction of the drug is
eliminated per unit of time.
Rate of drug exit from the body increases proportionately as
the plasma concentration increases and at every point in time is
proportional to the plasma concentration of the drug.
Since most drug concentrations are usually too low to
saturate the pharmacokinetic processes, their rate is governed
by the Law of Mass Action and is proportional to drug
concentration.
3. The theoretical plasma concentration at time zero
(immediately following injection) equals A + B.
4. The area under the plasma concentration curve (AUC) is
the area under the plasma concentration-time curve from
the first time drug concentration can be measured to the
last time. The AUC can be calculated by the trapezoidal
method or estimated as follows:

A B
AUC =   
  
3. Body compartments. Pharmacokinetic analysis frequently uses
the linear compartmental approach. This method
mathematically models the body as a series of
interconnecting compartments in which drugs are distributed
and eliminated.
These compartments do not correspond to physiologic or
anatomic areas in the body; they are abstract mathematical
entities that are useful for predicting drug concentrations.

1. The distribution of drugs in the body is frequently depicted using


a one, two or three compartment model.
2. Because many drugs used in veterinary medicine can be
described by a two compartment open model, this is the only
model described here.
d. Apparent volume of distribution (Vd). The apparent volume
of distribution is a proportionality constant relating the plasma
drug concentration to the total amount of drug in the body.
It is a theoretical volume into which an injected dose of a
drug would have to disperse if it were to be present
throughout that volume in the same concentration as occurs
in plasma immediately following the injection (time zero).
The mathematical expression for the apparent volume of
distribution is:
Vd = amount of drug in the body/ plasma drug concentration

Dose
Vd =
A B
  
  
Where dose is the amount (mg or g) administered; A and α
are the intercept and slope of the distribution phase,
respectively; and B and  are the intercept and slope (ke) of the
elimination phase, respectively.
Because the apparent volume of distribution can be used to
calculate the amount of a drug needed to achieve a desired
plasma concentration, it is common to divide the apparent
volume of distribution by the animal’s weight so that the units are
ml/kg or L/kg.

Vd – volume of distribution is constant for most drugs showing 1st


order kinetics, the Css concentration is directly proportional to
the infusion rate.
ke – 1st order rate constant for drug elimination from the total body,
the Css concentration is directly proportional to the infusion
rate.
The Half-Life (t1/2)
 Refers to the time needed to reduce the drug concentration by
50%. This value is determined during the elimination phase of
the drug.
In 2 0.693

t1/2 =  

a. It primarily depends on drug volume of distribution, and


clearance (renal excretion) and to some extent by
biotransformation.
If clearance obeys 1st order kinetics then a single
figure of half-life(independent of dosage) can be
obtained.
But if clearance obeys zero order kinetics then half-life
will not be constant but proportional to concentration
increases with increasing plasma concentration).
(

t 1/2 = ln 0.5/ ke
t 1/2 = (0.693)/ β
t 1/2 = (0.693) Vd/ ClB

b. It indicates the time required to attain or lose 50% of the


steady state(Css) concentration (plasma concentration
that remains constant, rate constant of drug absorption =
the rate constant of drug elimination (ke).
c. Diseases, age and other variables alter drug clearance readily
than its Vd.

d. T ½ will not change despite decrease in clearance if Vd


decreases at the same time.

e. For drugs given intravenously, if clearance obeys 1st order


kinetics, Css is achieved in about 4 half-lives: 50%,1st t1/2; 75%,
2ndt1/2; 87.5%, 3rdt1/2; 93.75%, 4tht1/2.

f. Drugs given orally in fixed doses of fixed time interval, may be


absorbed slowly and the Css is influenced by both the rate of
absorption and the rate of elimination.
g. The half-life has limited value as an indicator of drug
elimination or distribution, it is useful guide to drug dosage
scheduling.
Drugs with very short half-life must be infused IV to
maintain steady state concentration (oxytocin,
lignocaine) while drugs with long half-life initial doses must
be reduced as therapy progresses to avoid toxic
accumulation.
Total Body Clearance (ClB)
 Volume of blood (plasma) that is effectively cleared of a
drug in a specified period of time.

ClB =  • Vd
ClB = ke• Vd
ClB = 0.693/t1/2 (Vd)

a. Clearance expresses the rate of drug removal from the


body.
b. Clearance is constant for most drugs showing 1st order
kinetics. Css is directly proportional to infusion rate, if
infusion rate is doubled, the plasma concentration at Css
is also doubled (assuming Vd remains constant).
c. At steady state (Css) of the plasma concentration, the
elimination rate = infusion rate.

Css= infusion rate/ total clearance


ClB = rate of elimination/ plasma concentration

c. Infusion rate does not change the time needed to


achieve Css.
d. Increasing the loading dose and maintaining the infusion
rate provides a transient increase in drug level but Css
remains unchanged
e. Doubling both the infusion rate and dose will lead to
4-fold increase in Css.
g. Css is inversely proportional to the clearance e.g. kidney or
liver diseases decrease drug clearance and will increase
Css concentration of an infused drug.
h. Disease and infection may alter drug distribution and
clearance but not the half-life.
In other words, the volume of distribution and
clearance can be altered, and thus the half-life will be
altered, but altering the half-life will not necessarily affect
the volume of distribution or clearance. Therefore,
clearance is a more important pharmacokinetic term than
half-life.
Bioavailability (F)
 Amount of drug reaching the systemic circulation intact.
a. The bioavailability of an intravenous dose is 100%, or 1. All other
routes of administration have a bioavailability of less than 1.
Bioavailability is calculated as follows:
F = AUC (other route)/AUC (iv)

(AUC) nIV  dose IV   nIV


F=
(AUC) IV  dose nIV   IV
Where:
AUC = the area under the plasma concentration curve (used to
calculate F); nIV = non-intravenous route of administration; IV =
intravenous route of administration; and  = slope of the
elimination phase (ke).
b. Determination of dosage
1) Knowledge of bioavailability for an oral dosage is
particularly important, because it indicates what the
extravascular dose must be multiplied by to obtain an
equivalent intravenous dose. The presence of food
may alter the bioavailability of some drugs.
2) A dose may be calculated if the drug’s bioavailability
(F), clearance (ClB), and the average steady state
concentration ( ) of the drug needed to produce the
pharmacologic response are known:

F  dose
= C p   Cl
dosing interv al B
3) Dosage Regimens – a plan for drug administration
over a period of time, results in the achievement of
therapeutic levels without exceeding the toxic
concentration.
i. Loading dose – It is used to load the Vd with a
large single dose of a drug to achieve the target
plasma level rapidly (drugs with long half-life)
followed by an infusion (maintenance dose) to
maintain the steady state.
If the dose is very large it should be given slowly
to avoid excessive high peak levels during
distribution.

Loading dose = Vd x desired plasma


concentration
ii. Maintenance dose – use to maintain the plasma
concentration within specified range over long
periods of therapy. Maintenance rate of drug
administration is equal to the rate of elimination at
steady state. Maintenance dose is a function of
clearance.

Dose rate = clearance x desired plasma


concentration
LECTURE VII
PHARMACODYNAMICS: MECHANISMS OF DRUG-RECEPTOR
INTERACTIONS
Drug action refers to where and how the effect is produced or
the initial consequence of binding between drug and
receptors e.g. cell enzymes, cell membranes or other
specialized cell components.
Drug effects are the biochemical and physiological changes the
drug causes e.g. antipyretic effect of aspirin. If homeostatic
control mechanism operate, drug action may induce reflex
effects e.g. histamine dilates blood vessels induce reflex
tachycardia, direct stimulant action of norepinephrine in the
heart is reflexly reverse by its hypertensive action.
Site of drug action is the part of the body (cell membrane,
intracellular, may not be found in effector organ) on which
drug acts to initiate the chain of events which lead to its
characteristic effect. For effective drug use, it is important to
know the site of action e.g. morphine vs atropine on mydriasis.
Receptors
 Receptors bind ligands.
 Receptor concept originated from Paul Ehrlich (1854-1915) and J.N.
Langley (1852-1915).
 Functional drug receptors are sensitive and specific macromolecules
(proteins, nucleic acids) present in cell membrane or intracellularly for
which a drug has a high degree of selectivity.
 When activated it will initiate a biochemical change within the cell or
tissue to produce specific pharmacologic response.
 Low drug concentration activate one or few receptors which may be
lost as drug concentration increases causing widespread effects.
 Drugs may also bind non-specifically to non-functional receptors both
intra and extracellularly e.g. plasma proteins and tissue proteins.
 Drug binding to receptors uses chemical bonds between
complementary (lock and key) molecules similar to those used for
enzyme-substrate interactions.
 The bonds formed in decreasing order of strength:
 Very stable, long-lasting and essentially irreversible:
i. Covalent binding – high binding energy occur when
atoms which do not differ greatly in electro-negativity
share electrons. Uncommon interaction e.g. OP,
anticancer alkylating agents, phenoxybenzamine
 Weaker electrostatic Ionic Bonds (cation & anion)
i. Ionic bond – weaker bond characterized by transfer
of electrons to another atom to forms an electrovalent
compound.
 Very Weak Bonds (Hydrogen Bonds and Van der Waals
Forces)
i. Hydrogen bond
i. hydrogen combine with the other atoms in a
molecule or a compound.
ii. very weak bond, but presence of several H-bonds
can stabilize the interaction.
ii. Van der Waals bond
i. very weak bond between dipoles or induced
dipoles and between similar atoms
ii. because of the abundance and close contact, this
bonds determines the specificity of drug-receptor
interaction.
Drugs
 Drugs have two identifiable properties: affinity for the
receptor and intrinsic activity.
1. Affinity is a proclivity to bind to a receptor.
2. Intrinsic activity is the property of the drug that permits is
to initiate postreceptor processes that lead to a response.
a. Agonists are drugs that have both affinity and intrinsic
activity. Examples include acetylcholine, xylazine,
epinephrine, histamine, angiotensin, and prostaglandin
F2α.
b. Antagonists are drugs that have an affinity for the
receptor site but lack intrinsic activity. They block
or reduce the effects of agonists.

1) Antagonists may act in a competitive or


noncompetitive manner.
2) Antagonists may be reversible or irreversible.
Antagonism
 Three types of antagonism in pharmacology: receptor,
physiologic, and chemical.
1. Receptor antagonism, two drugs, an agonist and an
antagonist, compete for the same receptor (Table
1-4).

Table 1-4. Receptor Antagonism


Agonist Antagonist
Isoproterenol Propranolol
Epinephrine Phentolamine
Histamine Chlorpheniramine
Acetylcholine Atropine
2. Physiologic antagonism, receptors in opposing
physiologic systems are activated simultaneously.
• Example, epinephrine increases heart rate while
acetylcholine (Ach) decreases heart rate.
3. Chemical antagonism, a drug forms chemical bonds
with two or more molecules.
• Example, dimercaprol (British antilewisite, BAL)
chelates mercury and p-penicillamine chelates
copper, lead, and mercury, leading to increased
excretion of the metals. This type of antagonism
often does not require a cellular receptor.
Signal Transduction
 Four mechanisms by which receptors produce a
pharmacologic response.
1. Ligand-gated ion channels regulate the flow of ions
through the cellular plasma membrane channels.
a. Once the drug (ligand) binds to the receptor, the
response occurs within milliseconds.
b. Examples of synaptic transmitters that act via ion
channels include acetylcholine (at nicotinic
receptors), γ-aminobutyric acid (GABA), glycine, and
glutamate.
2. G proteins couple the binding of the ligand on the cell
surface receptor with intracellular second messengers.
a. An agonist binds to a receptor, causing guanosine diphosphate
(GDP) to be displaced from the G protein replaced with
guanosine triphosphate (GTP).
b. The G protein-GTP complex regulates the activity of enzymes or
ion channels to produce a response.
i. Hydrolysis of the GTP to GDP halts the activity of the enzyme or ion
channels.
ii. The G protein-GTP complex may last for as long as 10 seconds,
whereas the initial agonist-receptor complex may have lasted for
only a few milliseconds. Therefore, amplification of the original
agonist-receptor signal is possible.
c. G proteins may elicit either stimulatory or inhibitory responses.
Each cell may have more than one G protein type.
3. Intracellular receptors are activated by a group of hormones
[corticosteroids, mineralocorticoids, estrogens, progesterone,
triiodothyronine (T3), thyroxine (T4), vitamin D] that are highly
lipid-soluble and thus, are able to cross the cellular plasma
membrane.
a. Glucocorticoid receptors are located in the cytoplasm.
They combine with the drug and then move to the
nucleus. Receptors for T3, T4, and the estrogens are in the
nucleus. The receptor-drug complex increases binding of
ribonucleic acid (RNA) polymerase, leading to
transcription of target genes.
b. The response time can range from minutes to hours
because new proteins must be synthesized. Similarly, the
offset time is long once drug treatment is stopped. Effects
may persist for hours to days.
4. Protein tyrosine kinases mediate the responses of insulin,
epidermal growth factor (EGF), platelet-derived growth
factor (PDGF), and other trophic hormones.
a. Receptors are proteins, found in the cell membrane,
consisting of an extracellular portion that binds the
ligand, a transmembrane portion that transmits the
signal through the cell membrane, and a cytoplasmic
portion that terminates in the cytoplasm.
b. The cytoplasmic portion of the receptor possesses
tyrosine kinase activity. The enzyme catalyzes the
phosphorylation of substrate proteins, which produces
a biologic response.
Dose-Response Relationships
 Dose is the quantity of a drug to be administered at one time to
achieve a therapeutic response.
 Dosage is the determination and regulation of the size (dose),
frequency, and number of doses.
 Drug concentration is the actual amount administered divided by the
Vd.
 Types of dose-response relationship:
 Arithmetic linear plot: Hyperbolic curve (horizontal/arithmetic dose,
vertical/response)
 Log plot: Sigmoid curve ((horizontal/log dose, vertical/response):
Advantages – detailed data on low dose range, display wide range of
doses, central portion (20-80%) of maximum is linear
 Graded dose-response
 Quantal dose-response
Graded Dose-Response Relationship

 Biologic system progressive increases in the dose


(concentration) produce a proportional magnitude
(continuous and progressive increase) in response.
Drug-Receptor interaction and response theories
 1. Occupation theory – magnitude of response of a drug is a function of receptor
occupancy and all receptors must be occupied for maximal response (classical
and not valid)to happen.
 magnitude of response is directly proportional to the proportion of receptors
occupied (affinity) and the outcome of interaction (efficacy). If two agonist
are equiactive, no conclusion can be made regarding the number of
receptors occupied since they may possess different efficacies.
 Spare receptor theory – maximal drug effect can be achieved by occupation
of only fraction of the receptors, regarded as spare or reserve receptors
 Two state theory – receptor exists in two conformational states, active and
inactive state that are in equilibrium with each other. Magnitude of response is
determined by the relative affinity of a drug for the two conformations.
 2. Rate theory – magnitude of response is a function of the rate of receptor
interaction/dissociation.
 Generally antagonists rate of dissociation from receptors is lower than
agonists
 Antagonist form more stable drug-receptor complexes
Selectivity
 Selectivity – measured by relative amount of drug required to
produce one action compared with that for another action
using dose-response curves e.g. curare is slightly more selective
to nicotinic receptors in NMJ while hexamethonium is more
selective to nicotinic receptor at autonomic ganglia.
 Selectivity of action – drug in wide range of concentrations
displays only one action. It is more desirable , it will exert only the
desired effect vs adverse actions e.g. penicillin, vitamin B12).
 Receptor selectivity – drug may interact with one specific
receptor, but if that receptor serves functions common to most
cell its effects will be widespread e.g. antibiotics and anticancer
drugs that are inhibitors of protein synthesis, local anesthetics
How to minimize variability of drug
responses in experiments?
 Biological material is by nature variable
 Standardize biological material and experimental conditions
 Randomize subjects into different experimental groups
How to do randomize? Control the biological material, plan
according to tables of random numbers
 Perform cross-over studies – each subjects acts as his own control by
receiving each of the experimental drugs sequentially after the
effects of previous treatment have ceased.
 Placebo – e.g. subjective effects (analgesia, behavior) of inert
dummy drug (lactose) given to alternative (control) treatment vs
new drug. Placebo effect result from mere act of drug administration
when the therapeutic effort alone may induce psychological
reactions which modify central and peripheral responses.
Tolerance and toxicity
 Tolerance is manifested by reduce effectiveness on repeated
administration of the same drug with progressive increases in dosage
required to maintain an effect.
 May develop equally to all actions of a drug, higher doses is required to
produce desirable actions, then toxicity is more likely to occur e.g. alcohol.
Tolerance to sedative effects develops but not to the lethal effects.
 Mechanisms:
 Pharmacodynamic – cellular adaptation occurs with < tissue
responsiveness e.g. ethanol, nicotine, opiates.
 Pharmacokinetic - > rate of drug disposition due to induction of liver
microsomal enzymes e.g. barbiturates. It may induce tolerance to itself
and other drugs .
 Depletion of endogenous mediators (NE) e.g. indirect acting drugs given
at high concentration and rapidly (tyramine, ephedrine)
 Tachyphylaxis – is a rapidly (acute) developing drug tolerance due to
depletion of active endogenous substance e.g. tyramine
Withdrawal syndrome, iatrogenic dss

 WS – unpleasant physiological and psychological disturbances


develops when regular administration of drugs which cause
physical dependence e.g. ethanol, cocaine, nicotine is
discontinued. Terminated by re-administering the addictive drug.

 ID – disorder caused by the practitioner due to many factors some


of which are out of his control e.g. genetic factors
 Prescribing unnecessary drug, administering the wrong dosage
are less excusable
Drug interaction, hypersensitivity
 DI – modification of one drug by another
 Intended, beneficial or unexpected, undesirable, harmful
 may occur at any of the biological processes (pharmacodynamic or
pharmacokinetics)
 May occur outside the body, reduces the amount of drug available e.g.
mixing acidic drugs with basic drugs.
 Inside the body; drugs may induce changes in gut motility and contents
e.g. TCN absorption is < by calcium and antacids
 Greatest significance for drugs with narrow range of effective
concentration and those with low TI (warfarin, digoxin) and those where
underdosage is detrimental (estrogen)
 Hypersensitivity – allergic sometimes severe rxn which occur at lower or
therapeutic doses e.g. asthma with aspirin, anaphylaxis with pcn
 Hypersensitivity is produce by non-protein, low molecular wt.chemicals
reacting with tissue proetins to form antigenic drug complexes
Pharmacokinetics
Kinetics of accumulation and elimination of most drugs:
 Rate obey the law of mass action, it is proportional to drug concentration - most drug concentration
are too low to saturate
 Most drugs: 1st order kinetics (exponential), a constant fraction being absorbed and eliminated per
unit time
 1st order drug elimination: plasma concentration-time plot is exponentially and linearly when log
of the plasma concentration-time is plotted
 Constant half-life, its elimination time will be a multiple of this value. 50% decline in plasma
concentration occur in 1st half-life, it will reach 7% of its initial value in 4 half-lives.
 Drugs given IV: Plateau or steady state will be achieve in 4 half-lives, during iv plasma
concentration rises exponentially at a rate equal to its elimination half-life (4 t1/2)
 In general, time required to attain plateau depends solely on drugs elimination half-life
 The shorter the t1/2 the faster the ddrug achieves its plateau concentration
 Zero order kinetics – few drugs e.g. ethanol saturate their elimination process, a constant amount
being absorbed and eliminated per unit time
 Concentration- time plot is linear
 x

 Xx
Plasma half-life
 T1/2 – time in which plasma concentration of a drug changes by 50%
 Dependent on clearance and Vd
 1st order kinetics, single t1/2 can be obtained it is independent of the
dodage (most drugs)
 Zero order kinetics, t1/2 is not constant but proportional to drug
concentration, it increases with increasing plasma concentration
 Useful guide for drug dosage scheduling
 Drug with short t1/2 , must be given IV to maintain plateau concentration
e.g. oxytocin, lidocaine
 Drug with long t1/2, it will accumulate if initial dose were not decreased as
therapy progresses e.g. digoxin
T1/2 calculation

 Noting the time taken for any concentration to fall by half


 Measuring the slope of linear plot and calculating the Ke (rate
constant for elimination and t1/2 using the formula:
T ½ = 0.693/Ke
Fluctuation of plasma drug concentration
 Dependent on the length of dosing interval relative to its half-life
 The longer the t1/2 and or the shorter the dosage interval, the least degree of
fluctuation
 Since t1/2 is constant, fluctuation can only be minimized by increasing the
frequency of administration and decreasing the dose accordingly
 To prolong duration of drug effect in most cases it is advisable to increase the
frequency of drug administration rather than the dose
 If the dose is raised a higher peak concentration is reached that may alter
the spectrum of activity, if the TI is narrow, toxic manifestations may
happen.
 Increasing the dose prolongs drugs effects for those drugs obeying 1st order
kinetics
 Duration of action increases as the log of the dose, geometric increments
in dose is required to produce linear increments in duration of action e.g.
2mg=1hr, 4mg=2hrs, 8mg=3 hrs.
Maintenance dose

 Dose given at stated constant time intervals, just establishes but does not
exceed the desired effective drug concentration
 MD = desired plasma concentration x clearance
 Clearance = Ke x Vd or 0.693/t1/2 (Vd)
 Time required for maintenance dose to approach plateau is
approximately 4 t1/2
 Not acceptable for drugs with long t1/2 e.g. cardiac glycosides,
antiarrhymic drugs
 How to overcome this latency?
Give initial high dose (loading/priming dose)
Loading dose

 Initial high dose immediately attains the therapeutic response followed by


smaller maintenance doses
 LD = desired plasma concentration x Vd
 Or LD = MD x t1/2 x 1.44

 Cumulative toxicity:
 Cumulation results when drug intake exceeds its clearance from the
body and toxicity is manifested mostly by long acting drugs e.g.
digoxin, thyroxine

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