PHARMACOLOGY
Pharmacotherapeutics I
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.
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.
pH = pKa + log
x
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
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)
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.
Deamination Amphetamine
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.
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.
t 1/2 = ln 0.5/ ke
t 1/2 = (0.693)/ β
t 1/2 = (0.693) Vd/ ClB
ClB = • Vd
ClB = ke• Vd
ClB = 0.693/t1/2 (Vd)
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.
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
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
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