Pharmacodyn

amics
 Protein Receptors
Receptors for endogenous regulatory
ligands – hormones, growth factors,
neurotransmit-ters;
Enzymes of crucial metabolic or
regulatory pathways –
Acetylcholinesterase,
Enzymes in transport processes –
Na/K pump;
Structural proteins – Tubulin;
Drug – Receptor Interactions
 Receptor – specific macromolecule
( Proteins – 90% - membrane, cytoplasmic
or extracellular enzyme, nucleic acid;
Lipids; Carbohydrates) which is the site of
action of most drugs: Only around 10% of
drug actions & effects are NOT mediated
thru receptors.
 For most drugs, the magnitude of the
pharmacological response increases as the
dose (drug concentration) increases
 Only one drug molecule occupies each
receptor site, & binding is reversible
Drug – Receptor Interactions
 Combination or binding of drug to receptor
causes some event which leads to the
response
 Response to a drug is graded or dose-
dependent
 Interactions follow simple mass-action
relationships
 For a given drug, the magnitude of the
response is directly proportional to the
number of receptor sites occupied by the
drug molecules
 The number of drug molecules is assumed
 Definitions
 Affinity – a measure of the propensity of
the drug to bind with a given receptor
(specificity)
 Potency: A potent drug induces the same
response at a lower concentration. A
potent drug has a lower EC50 value.
 Efficacy: The biologic response resulting
from the binding of a drug to its receptor.
An efficacious drug has a higher Emax
value – maximum desirable effect
 Quality – bioavailability of the drug
 The Dissociation Constant
The Dissociation Constant – KD –
drug concentration at which half
maximal binding occurs: the smaller
the KD, the greater the affinity of the
drug to the receptor; the smaller the
KD for a reaction, the lower the
concentration of drug required in
order to produce half maximal
binding
Log dose – Response curve
characteristics:
 Maximal effect (plateau)
 Potency – the location of the drug
response curve along the horizontal axis:
drug effect with respect to dose (vs.
Efficacy – maximal ceiling effect)
 Slope
 Standing curve – minute changes in dose result
in large effects
 Inclining curve – large changes in dose needed
for an effect
 Variability – the curve is different from
drug to drug, from patient to patient, &
from time to time in the same patient. So
if you want to fix the pharmacologic
Log dose – Response Curve

Maximal
effect
intensity of effect

variability

slope

potency

Log dose
 Dose – Response
Relationship
 No drug can create a new effect: a drug
only modulates a pre-existing function
 Drug-receptor interaction leads to
enhancement, inhibition, or blockade of
molecular signals, which is then amplified
thru biochemical & physiologic events to
produce the pharmacological (clinical)
effect
 The magnitude of a response is graded,
i.e. increases continuously as the
concentration of unbound drug increases
at the receptor site
 Definitions
 GRADED-RESPONSE CURVE: A plot of
efficacy (some measured value, such as
blood pressure) -vs- drug concentration.
 EC50 = drug concentration at which 50%
efficacy is attained. The lower the EC50, the
more potent the drug.
 Emax = the maximum attained biological
response out of the drug.
 QUANTAL DOSE-RESPONSE CURVE: A
graph of discrete (yes-or-no) values,
plotting the number of subjects attaining
the condition (such as death, or cure from
disease) -vs- drug concentration.
 ED50: dosage at which 50% of the population
attains the desired effect
 LD50: dose at which 50% of the population is
 Agonists & Antagonists
 Agonists – drugs that interact with &
activate receptors
 Full agonists – maximal efficacy (Emax)
 Partial agonists – less than maximal efficacy -
At low concentrations, it increases the overall
biological response from the receptor. At high
concentrations, as all receptors are occupied, it
acts as a competitive inhibitor and
decreases the overall biological response from
the receptor.
 Antagonists – drugs that prevent the
agonists from having an effect by binding
to the receptor or to part of the effector
mechanism; have no effect themselves
 AGONIST ANTAGONIST
Agonist has affinity Antagonist has
plus intrinsic activity affinity but NO
intrinsic activity
Partial agonist has Competitive
affinity & (less) antagonists may be
intrinsic activity overcome
Agonists tend to (surmountable)
Antagonists tend to
desensitize receptors up-regulate receptors
 Inhibition
 COMPETITIVE INHIBITORS: They bind to
the same site as the endogenous
molecule, preventing the endogenous
molecule from binding.
 The Dose-Response Curve SHIFTS TO THE
RIGHT in the presence of a competitive
inhibitor. EC50 is increased: more of a drug
would be required to achieve same effect.
Emax does not change: maximum efficacy is
the same, as long as you have enough of the
endogenous molecules around.
 The effect of a competitive inhibitor is
REVERSIBLE and can be overcome by a higher
dose of the endogenous substance.
 The intrinsic activity of a competitive
inhibitor is 0. It has no activity in itself, but
 Inhibition
 NON-COMPETITIVE INHIBITORS: They
either (1) bind to a different (allosteric)
site, or (2) they bind irreversibly to the
primary site.
 The Dose Response Curve SHIFTS DOWN in the
presence of a non-competitive inhibitor. EC50
is increased: more of a drug would be required
for same effect. Emax decreases: The non-
competitive inhibitor permanently occupies
some of the receptors. The maximal attainable
response is therefore less.
 The intrinsic activity of the non-competitive
inhibitor is actually a negative number, as
the number of functional receptors, and
therefore the maximum attainable biological
response, is decreased.
 Properties of a Drug
 Safety:
Therapeutic Index (TI) = LD50 / ED50
 The ratio of median lethal dose to median
effective dose.
 The higher the therapeutic index, the better.
That means that a higher dose is required for
lethality, compared to the dose required to be
effective.
 minimum dose that produces toxicity over the
minimum dose that produces an effective
therapeutic response; TI < 4 =relatively
greater potential for toxicity
Margin of Safety = LD1 / ED99
 The ratio of the dosage required to kill 1% of
population, compared to the dosage that is
effective in 99% of population.
 Drug interactions
 Synergism/Potentiation – concomitant
administration of another drug will
increase the clinical effect e.g. multi-
regimen TB treatment
 Addition – effects of two drugs
administered at the same time will be
added to each other e.g. DOLCET
 Inhibition – simultaneous administration of
another drug will decrease the effects of
the first e.g. Warfarin & vitamin K
 Pharmacokinetic interaction – giving of
another drug will affect the first’s
absorption, distribution, metabolism, &/or
excretion
 Adverse Effects & Drug
Interactions
 Side effect - part of the pharmacologic
action of the drug but not the effect the
drug is being used for; may be undesirable
(adverse) e.g. gastric irritation from
NSAIDS
 Hypersensitivity reactions / Drug
Allergy: An exaggerated, immune-
mediated response to a drug.
 TYPE-I: Immediate IgE-mediated anaphylaxis.
e.g.Penicillin anaphylaxis.

 Immunologic Reactions
 TYPE-II: Antibody-Dependent Cellular Cytotoxicity
(ADCC). IgG or IgM mediated attack against a
specific cell type, usually blood cells
(e.g.Hemolytic anemia: induced by Penicillin or
Methyldopa; Thrombocytopenia: induced by
Quinidine; Drug-induced SLE caused by
Hydralazine or Procainamide.
 TYPE-III: Immune-complex drug reaction Serum
Sickness: Urticaria, arthralgia,
lymphadenopathy, fever. Steven-Johnson
Syndrome: Form of immune vasculitis induced
by sulfonamides. May be fatal. Symptoms:
Erythema multiforme, arthritis, nephritis, CNS
abnormalities, myocarditis.
 Drug Toxicity
 Drug Toxicity: dose-dependent adverse
response to a drug.
 Organ-Directed Toxicity: Aspirin induced GI
toxicity (due to prostaglandin blockade);
Epinephrine induced arrhythmias (due to beta-
agonist); Propanolol induced heart-block (due
to beta-antagonist); Aminoglycoside-induced
renal toxicity; Chloramphenicol-induced
aplastic anemia.
 Neonatal Toxicity: Drugs that are toxic to the
fetus or newborn. Sulfonamide-induced
kernicterus;Chloramphenicol-induced Grey-
Baby Syndrome; Tetracycline-induced teeth
 Teratogens
TERATOGENS: Drugs that adversely
affect the development of the fetus:
especially dangerous during
organogenesis (3rd to 8th week)
• Thalidomide:
• Antifolates such as Methotrexate.
• Phenytoin: Malformation of fingers, cleft
palate.
• Warfarin: Hypoplastic nasal structures.
• Diethylstilbestrol: Oral contraceptive is no
longer used because it causes reproductive
cancers in daughters born to mothers taking
the drug.
• Aminoglycosides, Chloroquine: Deafness
 Idiosyncrasy
 Drug Idiosyncrasies: An unusual
response to a drug due to genetic
polymorphisms, or for unexplained
reasons.
 Isoniazid: N-Acetylation affects the
metabolism of isoniazid
• Slow N-Acetylation: Isoniazid is more likely to
cause peripheral neuritis.
• Fast N-Acetylation: Some evidence says that
Isoniazid is more likely to cause hepatotoxicity in this
group. However, other evidence says that age
(above 35 yrs old) is the most important determinant
of hepatotoxicity.
 Drug Idiosyncrasies
 Succinylcholine can produce apnea in people with
abnormal serum cholinesterase. Their cholinesterase is
incapable of degrading the succinylcholine, thus it builds
up and depolarization blockade results.
 Primaquine, Sulfonamides induce acute hemolytic
anemia in patients with Glucose-6-Phosphate
Dehydrogenase deficiency.
• They have an inability to regenerate NADPH in RBC's ------>
all reductive processes that require NADPH are impaired.
• Note that this is Acute Hemolytic Anemia, yet it is not
classified as an allergic reaction -- it is an idiosyncrasy
when caused by sulfonamides or primaquine. Other
anemias are Type-II hypersensitivity reactions.
• G6PD deficiency is most prevalent in blacks and semitics. It
is rare in caucasians and asians.
 Barbiturates induce porphyria (urine turns dark red on
standing) in people with abnormal heme biosynthesis.
• Psychosis, peripheral neuritis, and abdominal pain may be
 Tolerance
 Pharmacokinetic Tolerance: Increase in
the enzymes responsible for metabolizing
the drug. e.g.Warfarin doses must be
increased in patients taking barbiturates or
phenytoin, because these drugs induce the
enzymes responsible for metabolizing
warfarin.
 Pharmacodynamic Tolerance: Cellular
tolerance, due to down-regulation of
receptors, or down-regulation of the
intracellular response to a drug.
 Physiologic Tolerance: Two agents yield
opposite physiologic effects.
 Tolerance
 Competitive Tolerance: Occurs when an
agonist is administered with an antagonist.
Example: Naloxone and Morphine are
chemical antagonists, and one induces
tolerance to the other.
 Tachyphylaxis (Refractoriness /
Desensitization) – progressive reduction
in drug effect due to receptor
desensitization
 Homologous – decrease in number of receptors
 Heterologous – decreased signal transduction
e.g.Tyramine can cause depletion of all NE
stores if you use it long enough, resulting in
 Habituation & Addiction
Habituation – getting used to a
drug such that one becomes
emotionally dependent on the drug
Addiction – true physical as well as
emotional dependence on a drug; will
need pharmacologic support during
withdrawal