Transcript 4a-Pharmacodynamics,ADRs (Lec.1 & 2)

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,…….
13th Edi ,Ch-2,p20-40;
Lippincott Pharmacology ,6th Edi ,Ch-2 ,p25-35;
Learning objectives
 Define terms associated with drug receptor interactions (such as
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affinity, intrinsic activity/efficacy, agonist/antagonist, partial
agonist, drug potency etc)
Describe in detail the dose-response relationship
Explain drug combinations
Describe therapeutic index of a drug
Discuss the significance of therapeutic index
Identify different types of drug actions
Explain mechanisms of drug actions
Describe the receptor theory of drug actions
Determine the different factors modifying drug action
Discuss tolerance and different kinds of receptor regulation (upand down- regulations)
Define Adverse Drug Reactions
List different types Adverse Drug Reactions
Explain Pharmacovigilance
PHARMACODYNAMICS


Study of biochemical and physiological effects of drugs and
mechanisms of actions
Dose-Response Relationships:
 Relationship between receptor occupancy and drug effect
 1:1 relationship between effect & binding if spare receptors are
not involved
Effect
Note similarity
to enzyme
kinetics
From: McGraw Hill’s AccessMedicine; Katzung; Figure 2.1
Binding
Definitions to Know

Receptor: A molecule to which a drug binds to bring about a response

Agonist: A drug that activates its receptor upon binding

Pharmacological antagonist: A drug that binds without activating its receptor and,
thus, prevents activation by an agonist

Competitive antagonist: A pharmacological antagonist that can be overcome by
increasing agonist concentration

Irreversible antagonist: A pharmacological antagonist that can not be overcome by
increasing agonist concentration

Partial agonist: A drug that binds to its receptor but produces a smaller effect at full
dosage than a full agonist

Graded dose-response curve: A graph of increasing response to increasing dose

Quantal dose-response curve: A graph of the fraction of a population that shows a
specified response at progressively increasing doses.
Dose-Response Relationships

Intensity of response is proportional to number of receptors
occupied or concentration of drug-receptor complexes (DR)

Mathematical descriptions and graphical representation of drugreceptor binding and substrate-enzyme complexes are similar

Dissociation constant (KD = k-1/k1) of drug-receptor complex is
inversely related to affinity of drug for the receptor
E =
Emax x C
C + EC50
B
=
B max x C
C + KD
Usually expressed as log-dose response (LDR) curves
Properties of LDR
Measures an increase in response in an individual
as dose or concentration is increased

Cover a wide range
of doses

Typically S-shaped
or sigmoidal

Drugs acting by
same mechanism
usually have
parallel LDR curves
 Log dose
Graded dose response and dose
binding graphs.
NBME
All-or-None (quantal) Response

NBME
Number of individuals within
group responding to a given
dose; endpoint is set and an
individual is either a responder
or a non-responder

Expressed as normal
histogram or cumulative
distribution profile;

Normal histogram is usually
bell-shaped

Median effective dose (ED50):
dose to which 50% of subjects
respond

Therapeutic index and
Margin of Safety are based on
quantal responses (see next
slide)
Graded DRC
Quantal DRC
All-or-None (quantal) Response
NBME
Measures responsiveness in a population of individuals
as dose is increased
TI = LD50/ED50
= 400/100
=4
MS = LD1/ED99
= 200/250
= 0.8
What should be ideal TI & MS (CSF) with a safe drug?
A new drug was studied in a large population of
experimental subjects. Which of the following terms
best expresses the variation in sensitivity to the drug
of the subjects within the study?
A.
B.
C.
D.
E.
Drug potency
Graded dose-response curve
Margin of safety
Quantal dose-response curve
Therapeutic index
Answer: D
Quantal dose-response curves reflect the variance
in drug responsiveness within a population
Calculate Therapeutic Index from the data below
(A)20
(B)8
(C)4
(D)2
(E)0.8
What does ‘High’ or ‘Low’ TI signifies clinically ?
•Calculate margin of safety (MS) of this drug?
(A)20
(B)8
(C)4
(D)2
(E)0.8
Which of the following facts are not true about Quantal dose
response curve

(A)Used for Calculation of ED50 , TD50 , LD50 , therapeutic index

(B)Used for Determination of dose, potency for a quantal effect

(C)Used for determining maximal efficacy of a drug

(D)Many lab animals or patients, in groups are taken for different
doses

(E)Calculation of % of responders (showing quantal effect) to each
dose
NBME
Note how each of the following
alter the log dose response
curve for agonist A:
B = competitive inhibitor
C = allosteric activator
D = allosteric inhibitor
Classical Terms Used to Describe DrugReceptor Interactions
Log-dose responses for drugs A, B & C
3 agonists

Terms
NBME
Affinity: propensity of drug to bind with a given
receptor and inversely related to KD; drug
with a KD of 10-7 M has a higher affinity for
receptor than drug with a KD of 10-6 M

Potency: comparative expression relating the dose
required to produce a particular effect of given intensity
relative to a standard reference; a drug that exerts 50%
of its maximal response (ED50) at 10-7 M is more potent
than one with ED50 of 10-6 M
A & C more potent than B

Efficacy: biological response resulting from binding of drug to its receptor (maximum
response is usually assigned a value of 100%)

Intrinsic activity: often used interchangeably with efficacy (maximum response usually
assigned value of 1.0)
A & B have greater Efficacy or Intrinsic Activity than C

Full agonist: stimulates a receptor, provoking a biological response (antonym of
antagonist)

Partial agonist: provokes a maximal response somewhat less than a full agonist
A & B = Full Agonist; C = Partial Agonist

Inverse agonist: is based on the concept that there is ongoing basal signal transduction
occurring which is reduced by the inverse agonist (this response is blocked by an
antagonist)
A Model of Drug-Receptor
Interaction
Note the log dose-response
curves for:
Full agonist
Partial agonist
Antagonist
Inverse agonist
Competitive Antagonist
Interaction of an antagonist with a receptor does not result in stimulus for
biological response; but will block the effect of agonist binding at same
receptor site
 LDR for drug A
Properties of a
Competitive Antagonist

Effects overcome by
 increasing dose of agonist
 (reversible effect)

As the concentration of the antagonist
increases, Emax of agonist does not change

Intrinsic activity = 0.0 (zero)
A fixed dose of a competitive antagonist will
cause a parallel shift of the dose response
NBME
curve for an agonist to the right
Noncompetitive (Irreversible or
Allosteric) Antagonists

Effect is not completely
overcome by increasing agonist
concentration

Number of functional receptors is
decreased

As concentration of antagonist
increases, Emax decreases
because fewer functional
receptors are available

Allosteric or irreversible
inhibitors

A fixed dose of a noncompetitive antagonist will cause a nonparallel, downward
shift of the dose-response curve for the agonist to the right.
NBME
Exercise 1 Uses of dose-response curves
Determine affinity (when both binding to same Rc), potency and
efficacy of agonists
Determine safety or toxicity (from the shape of curve)
Efficacy
A
B
Toxic effect
E
NBME
F
100
C
D
50
0
Potency
1
2
3
Log dose
4
A > potent than B
C > potent but < effective than A & B
D < potent but as effective as A & B
Therapeutic
1
2
3
Log dose
4
F > safer than E, although < potent
21
Exercise 2 Uses of dose-response curves

NBME
To determine dose, potency and efficacy of antagonists
A. Dose response curve with an agonist alone
 B. Dose response curve with same agonist in the presence of
antagonist, (competitive antagonist)
 C. Dose response curve with agonist in the presence of another
antagonist (competitive antagonist)
 D. Dose response curve with agonist in the presence of another
antagonist (noncompetitive antagonist)
Effect
A
A&B
A&C
Competitive

100
antagonists
A&D
50
C > potent
than B
Non-competitive
antagonist
0
1
2
3
Log dose
4
5
According to the figure, which of the following drugs have
Q1.Highest efficacy? Q2.Highest potency?
A)Drug A
(B)Drug B
(C)Drug C
(D)Drug D
(E)Drug E
(F)Drug F
(
A vascular smooth muscle strip attached to a tension
recording devise was bathed in an organ bath. A
dose-response change in vascular tension to
acetylcholine (ACh) was assessed. Pretreatment with
which of the following would cause a parallel shift in
the dose-response curve to ACh to the right?
A.
B.
C.
D.
E.
Atropine
Nicotine
Physostigmine
Succinylcholine
Tubocurarine
Answer: A
Atropine is a competetive antagonist
of ACh at muscarinic receptors; thus
shifts dose response curve parallel
to the right
A vascular smooth muscle strip attached to a tension recording
devise was bathed in an organ bath. A dose- response change
in vascular tension to phenylephrine was assessed. An
appropriate dose of phenoxybenzamine was added and the
dose-response to phenylephrine was repeated. Which of the
following is true with respect to the dose-response curve to
phenylephrine obtained after phenoxybenzamine compared to
that obtained before phenoxybenzamine was added to the
bath?
Answer: C
A.
B.
C.
D.
E.
is an irrevesible
The curve was higher Phenoxybenzamine
antagonist; thus, a right, downward
The curve was lower shift of the dose response curve
The curve was shifted downward and to the
right
The curve was shifted parallel to the left
The curve was shifted parallel to the right
Partial Agonist as an Antagonist
A partial agonist can act as inhibitor to a full agonist
Acebutolol is a partial agonist at the β1-adrenoreceptor
Airipiprazole is a partial agonist at the dopaminergic D2
and at the serotonergic 5-HT1A receptors
NBME
Drug X when given in absence of Drug Y produces a
submaximal response (in compare to full agonist for the
Rcs of drug X) but in the presence of drug Y, it acts as
an antagonist (on the same Rcs).Drug X is a
a.Full agonist
b.Partial agonist
c.Competitive antagonist
d.Non competitive antagonist
e.Reverse agonist
Potentiation

Effect of two drugs is greater than predicted
from individual effects
 Physostigmine (an AChEI) potentiates the
response to acetylcholine (ACh)
 Cocaine (an uptake I blocker) potentiates the
effects of norepinephrine (NE) and epinephrine
(Epi)
With drug potentiation there is a shift of the
dose response curve for the agonist to the left.
NBME
A vascular smooth muscle strip attached to a tension recording
devise was bathed in an organ bath. A dose-response change
in vascular tension to norepinephrine (NE) was assessed. An
appropriate dose of cocaine was added and the dose-response
to NE was repeated. Which of the following is true with respect
to the dose-response curve to NE obtained after cocaine
compared to that obtained before cocaine was added to the
bath?
A.
B.
C.
D.
E.
Answer: D
Cocaine potentiates NE by
blocking its re-uptake; thus a
parallel shift to the left
The curve was higher
The curve was lower
The curve was shifted downward and to the
right
The curve was shifted parallel to the left
The curve was shifted parallel to the right
Learning objectives

Understand the following concepts for signaling
mechanisms and drug action
 role of intracellular receptors that regulate gene
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
expression
role of ligand-regulated transmembrane enzymes
(protein tyrosine kinases)
role of ligand-gated channels
role of G-proteins and second messengers
mechanisms of receptor desensitization
well-established second messengers: cAMP, calcium
and phosphoinositide, cGMP
interplay among signaling mechanism
Signal Coupling Mechanisms
hours
min
min
msec
sec
Nicotine
Insulin
IL-2
Growth factors Cytokines
Steroids
Epinephrine
Ligand-Gated Channels

Signals across the membrane due to changes in
ion conductance alter electrical potential of cell;
very fast response (milliseconds); ionotropic

Nicotinic/ACh--sodium channel
Other Ligand-Gated Channels

GABA--benzodiazepine--chloride channel
 Hyperpolarization
 Inhibitory

Glutamate/AMPA – sodium channel
 Depolarization
 Excitatory

Glutamate/NMDA--calcium channel
 Depolarization
 Toxicity
 Excitotoxicity
NBME
G Protein-Coupled Receptors

There are more than 100 members in the
receptor superfamily (“serpentine” or
“seven transmembrane” receptors);
metabotropic:
 G- proteins: superfamily of diverse GTP-
binding proteins that couple to “serpentine”
receptors
 Agonists promote release of GDP, allowing
attachment of GTP to nucleotide-binding
site
 When GTP is bound, G protein capable of
regulating an enzyme or ion channel
 Signal terminated by hydrolysis of GTP to
GDP; slow hydrolysis of GTP allows signal
to persist long after ligand has dissociated
from receptor
•G Proteins: Gs stimulates adenylyl cyclase; Gi inhibits adenylyl cyclase & opens a
K+ channel; Gq stimulates phospholipase C; Go closes a Ca2+ channel
Adenylyl Cyclase System
 isoproterenol
Clonidine 
Protein Kinase A
NBME
Adenylyl Cyclase System
Stimulatory agonist
Inhibitory agonists
 2 agonists (clonidine)
 ACTH
  agonists
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
(isoproterenol)
Glucagon
FSH
PGE2
Thyrotropin
Dopamine D1 agonists
Know
 Muscarinic M2 agonists
 Dopamine D2 D3 & D4
agonists
Clinical Correlates (interference of G-protein system)

1.Pertusis toxin in the
respiratory epithelial cellsfuses all αi,ßi,γi subunits of Gprotein by ADP
Ribosylation→units fail to
separate→fails to inhibit Adenylyl
Cyclase→increase in c AMP→all
respiratory manifestations

2.Cholera toxin in GI mucosacauses ADP ribosylation of
intrinsic GTPase of α stimulatory
protein→GTP fails to convert into
GDP→increase in α stimulatory
activity→increase in c AMP in GI
mucosal cells→ severe diarrhoea
The figure on the 2 preceding slides depict a signaling
pathway for some types of drugs and hormones.
Which of the following receptor subtypes is linked via
a Gi protein?
A.
B.
C.
D.
E.
Alpha-1
Beta-1
Beta-2
Dopamine-1
Muscarinic-2
Answer: E
ACh acting on mucarinic-2
receptors signals via
Gi; thus a decrease in cAMP
or opening of potassium channels
Model of Desensitization
Beta arrestin kinase pathway
phosphorylation
dephosphorylation
Once receptor is
Phosphorylated and
binds β-arrestin it is
inactive
NBME
Polyphosphoinositide Signaling
System


Muscarinic receptors (M1,
M; ex. pilocarpine)
1-adrenoceptors
(phenylephrine)
Phospholipase C

Gq

Vasopressin receptors (V1)

Angiotensin receptors
(AT1)

Serotonin receptors (5-

Know these examples!!!!!
Protein
Kinase C
The figure on the preceding slide depicts a signaling
pathway for some type of drugs and hormones. Which
of the following agonists exerts its major
pharmacological effects via this pathway?
A.
B.
C.
D.
E.
Dobutamine
Glucagon
Isoproterenol
Pilocarpine
Thyroxine
Answer: D
Pilocarpine is a M1 & M3
muscarinic agonist; thus
signals via Gq
G-protein and second messenger
control of cellular effector system
NBME
Ligand-Regulated Transmembrane
Enzymes
(receptor tyrosine kinase)
Growth Factors
Protein Tyrosine Kinase Signaling:
Insulin; Epidermal growth factor (EGF);
Platelet derived growth factor (PDGF)
NBME
Know these examples!!!!!
Ligand-Regulated Transmembrane
Enzymes
(receptor tyrosine kinase)
Cytokines
Know these examples!!!!!
Ligand Responsive Transcription
Factors (Nuclear Receptors)
Signals via Gene Expression:
Glucocorticoids;
Mineralocorticoids;
Sex steroid hormones;
Vitamin D;
Thyroid hormone;
Retinoic acid
Know these examples!!!!!
NBME
Cytoplasmic Guanylyl Cyclase

Nitric oxide (NO, a gas) is formed in
endothelial cells and diffuses through plasma
membrane of smooth muscle cells activating
guanylyl cyclase, converting GTP to cGMP

cGMP activates protein kinase G, resulting in
vasodilation; thus nitric oxide was first called
endothelial derived relaxation factor (EDRF)

Nitric oxide: also involved in many other
physiological and cytotoxic processes (see
figure on next slide)
Cytoplasmic Guanylyl Cyclase
eNOS = endothelial
nNOS = neuronal
iNOS = inducible
Peroxynitrite
ONO2-



Protein
Kinase
G
peroxynitrite
Which of the following will cause vasodilatation via the
induction of nitric oxide synthase according to the
pathway depicted in the preceding figure?
A.
B.
C.
D.
E.
Bradykinin
Fenoldopam
Hydralazine
Isoproterenol
Sodium Nitroprusside
Answer: A
Bradykinin,
Acetycholine,
& Histamine
all act on endothealial
cells to produce
Nitric oxide
Other Intracellular Sites for Drug
Action

Enzymes
Chemotherapy

Structural proteins

DNA

RNA
NBME
Summary
Of Signaling
Cross-talk
Phosphorylation >>
Dephosphorylation
Reprinted from “Rapid Review Series:
Pharmacology,” by Pazdernik,
Kerecsen, & Shaw, Table 2-1,
p. 16, © 2003 Mosby,
with permission from Elsevier.
Which of the following most accurately describes the
immediate signal transduction mechanism of insulin
when used to treat hyperglycemia in a 15-year-old boy
with type 1 diabetes mellitus?
A.
B.
C.
D.
E.
Activation of adenylyl cyclase
Activation of gene transcription
Activation of guanylyl cyclase
Activation of phospholipase C
Activation of tyrosine kinase
Answer: E
Insulin produces its biological affects first by activation
a tyrosine kinase pathway resulting in phosphorylation
of the internal domain of the receptor
Learning objectives
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
Understand variation in drug responsiveness
idiosyncratic drug response
tachyphylactic response
hypersensitivity response
alteration in concentration of drug that reaches
the receptor (pharmacokinetic effect)
variation in concentration of an endogenous
receptor ligand
alteration in the number or function of receptors
 down-regulation
 up-regulation
 post-receptor responses
Physiological Compensations and
Altered Responses




NBME
Decreased activity: Tolerance--response diminishes with
time
Pharmacokinetic tolerance:
○
○
○
Due to the induction of drug metabolizing enzymes
Called metabolic tolerance or drug disposition tolerance
Warfarin (oral anticoagulant) dose needs to be increased in patient
taking barbiturates or phenytoin
Pharmacodynamic tolerance: develops at the cellular level;
referred to as cellular tolerance; due to changes in receptor
numbers or function; Mechanisms:
○
Desensitization: process occurs rapidly when continuous exposure to
an agonist results in conversion of a channel to an altered state that
remains closed or when a receptor-coupling element is phosphorylated to
an inactive form
○
Down-regulation: process of ligand-induced endocytosis and
degradation of receptor; caused by agonists when administered at high
doses for a prolonged period
Agonists cause receptor down-regulation
Examples of Pharmacodynamic
Tolerance

Continuous exposure to β-adrenergic
agonists, such as occurs in the treatment
of asthma with albuterol, results in a
decreased responsiveness to the drug

Tolerance to the analgesic effects of
morphine upon continued use

Decreased sedation from continuous
treatment with a benzodiazepine such as
diazepam
A 26-year-old heroin addict required 100 mg (normal
dose =10 mg) of intravenous morphine to relieve
severe pain from injuries attained in an automobile
accident. Which term best explains why this individual
required such a high dose of morphine to relieve
pain?
A.
B.
C.
D.
E.
Pharmacodynamic tolerance
Pharmacokinetic tolerance
Potentiation
Answer: A
Sensitization
Opioid tolerance is due to downregulation of receptors; thus
Tachyphylaxis
requiring a large dose to produce
an effect
Physiological Compensations and
Altered Responses


Decreased activity: Tolerance--response
diminishes with time
Physiological antagonism:
○
○
○


NBME
Two agents have opposing physiological effects
Histamine causes vasodilation and norepinephrine
causes vasoconstriction
When administered together these agents tend to
counteract each other
Competitive antagonism: receptor antagonist
administered with an agonist
○
○
○
Naloxone: blocks effects of morphine.
Atropine: blocks effects of ACh at muscarinic receptor
Propranolol: blocks effects of isoproterenol at betaadrenergic receptor
Physiological Compensations and
Altered Responses


NBME
Increased activity:
Supersensitivity or hyperactivity: enhanced response to drug may be due
to increase in number of receptors (up-regulation); during absence of ligand
or prolonged presence of antagonist, ligand-induced receptor endocytosis
and degradation decreases, and, therefore, the number of receptors per unit of
tissue increases
○
Chemically induced supersensitivity: occurs after prolonged treatment with betablockers; some individuals become supersensitive to endogenous release of
catecholamines
Antagonists cause receptor up-regulation
○

Denervation induced supersensitivity: occurs at postsynaptic receptors when
presynaptic nerve is surgically destroyed or lesioned
Deficiency in degrading enzymes: usually genetic in nature; abnormal
responses are referred to as pharmacogenetic effects
○
Patients with abnormal serum cholinesterase have increased sensitivity to
succinylcholine
○
Individuals with glucose-6-phosphate dehydrogenase deficiency develop acute
hemolytic anemia when given primaquine
Physiological Compensations and
Altered Responses


Increased activity:
Competition for binding sites: Drugs may displace one another
from plasma albumin binding sites, enhancing response to one
or both agent(s).
○

NBME
If a drug is displaced from plasma protein-binding site, response is
intensified and duration of action is shortened.
Physiological synergism: Enhanced response may occur when
two drugs produce the same or similar effects through different
receptors or mechanisms; most CNS depressants act additively or
synergistically; diazepam (Valium) plus ethanol produce severe,
prolonged CNS depression
○
Terminology describing effects:



Additive or summation: 5 + 5 = 10
Synergism: 5 + 5 = 15
Potentiation: 0 + 5 = 20
Learning objectives
Understand dose dependent toxicity
Understand drug allergies
Understand drug idiosyncrasies
Understand Benefit to Risk Ratio
Understand the concept of over extension of the
pharmacological response
 Understand organ directed toxicity
 Know the four major classes of drug allergies









Type I
Type II
Type III
Type IV
ADVERSE EFFECTS (TOXICOLOGY)

NBME
Toxicity: Dose related adverse effects of drugs:
 Benefit-to-risk ratio: This expression of adverse effects;
more useful clinically than therapeutic index
 Overextension of the pharmacological response:
Responsible for mild, annoying side effects as well as
severe side effects:
○ Atropine-induced dry mouth;
○ Propranolol-induced heart block;
○ Diazepam-induced drowsiness
 Organ-directed toxicities: toxicity associated with
particular organ or organ system:
○
○
○
○
Aspirin-induced gastrointestinal toxicity
Aminoglycoside-induced renal toxicity
Acetaminophen-induced hepatotoxicity
Doxorubicin-induced cardiac toxicity
ADVERSE EFFECTS (TOXICOLOGY)

Fetal Toxicity:
NBME
some drugs are directly toxic whereas
others are teratogenic:
 Directly toxic effects:
○ Sulfonamide-induced kernicterus
○ Chloramphenicol-induced Gray baby syndrome
○ Tetracycline-induced teeth discoloration and
retardation of bone growth
 Teratogenic effects: causes physical defects in
developing fetus; effect most pronounced during
organogenesis (day 20 of gestation to end of first
trimester in human)
Human Teratogens: Thalidomide; Antifolates; Phenytoin;
Warfarin; Isotretinoin; Lithium; Valproic acid;
Fetal alcohol syndrome
KNOW this list
ADVERSE EFFECTS (TOXICOLOGY)

Drug Allergies (Hypersensitivity): abnormal response
resulting from previous sensitizing exposure activating
immunologic mechanism; differs from drug toxicity in:
 Principle:
○ Altered reaction occurs only in fraction of population
○ Dose-response is unusual: minute amount of otherwise safe drug elicits
severe reaction
○ Manifestations of reaction are different from usual pharmacological and
toxicological effects of drug
○ Primary sensitization period before individual experiences response
○ Being small molecules, most drugs by themselves are not immunogenic; they
bind covalently to self-macromolecule or alter structure of self-macromolecule
to become immunogenic
 Types: See Table on next slide
Types of Drug-Induced Hypersensitivities
Clinical
Manifestations
Type
Target Organ
I. Anaphylactic
(immediate)
Gastrointestinal
tract
Skin
Lung
Vasculature
Gastrointestinal
allergy
Urticaria
Asthma
Anaphylactic
shock
IgE
II. Cytotoxic
(autoimmune)
Circulating
Blood
Cells
Leukopenia
Thrombocytopenia
Hemolytic anemia
Granulocytopenia
IgM, IgG
III. Arthus
(immune
complex)
Blood vessels
Skin
Joints
Kidney
Serum sickness
Vasculitis
Arthritis
Glomerular
nephritis
Ag-Ab
Complexes
IV. Cellmediated
(delayed)
Skin
Lungs
Central nervous
system
Contact nephritis
Tuberculosis
Allergic
encephalitis
Sensitized
T-cells
Know
Mechanism
NBME
Hypersensitivity Reactions

Type I: Mediated by synthesis of IgE antibody
directed towards allergen

IgE molecules bind to blood basophils and tissue mast
cells via Fc receptors for antibody

When offending drug introduced into body,
immediately binds to IgE bound to sensitized cells,
resulting in release of mediators (histamine,
leukotrienes, prostaglandins)

Mediators initiate skin and smooth muscle responses,
cause tissue injury and provoke inflammatory
response

Include anaphylaxis, urticaria and angioedema
Hypersensitivity Reactions

Type II: Cytotoxicity
 Reactions are usually mediated by IgM or IgG binding to
cells or tissue
 Resulting in the activation of complement and lysis of the
cell
 Destruction of circulating cells

Type III: Mediated by immune complexes:
 Symptoms of immune-complex induced serum sickness:
○
○
○
○

Urticarial skin eruptions
Arthralgia or arthritis
Lymphadenopathy
Fever
Stevens-Johnson syndrome, such as that induced by
sulfonamides, is a severe form of immune vasculitis
Examples of Type II & III Reactions

Type II Reactions:






Penicillin-induced hemolytic anemia;
Methyldopa-induced autoimmune hemolytic anemia
Quinidine-induced thrombocytopenia
Sulfonamide-induced granulocytopenia
Clozapine-induced granulocytopenia
Type III Immune Vasculitis:





Sulfonamides
Penicillins
Thiouracils
Anticonvulsants (especially lamotrigine)
Iodides
Hypersensitivity Reactions

Type IV: Cell-mediated or delayed
hypersensitivity



Often occurs when drugs applied topically
Mediated by sensitized T-cells
Many drugs and plants (Poison ivy) can induce a
contact dermatitis
Drug Idiosyncrasies
NBME
Abnormal response not immunologically mediated;
often caused by genetic abnormalities in
enzymes or receptors; referred to as
pharmacogenetic disorders.
Pharmacogenomics
 Classical idiosyncracies:


 Patients with abnormal serum cholinesterase develop

 "Fast" and "slow" acetylation of isoniazid:
apnea when given normal doses of succinylcholine.
○ Genetic studies identify individuals as "fast" or "slow" acetylators
with bimodal distribution in general population
○ "Slow" acetylators have low hepatic N-acetyltransferase (NAT)
activity and are homozygous for autosomal recessive gene
○ "Slow" acetylators: more prone to isoniazid-induced vitamin B6
deficiency (may produce anemia and various neuropathies)
Know
Drug Idiosyncrasies
NBME
Classical idiosyncracies (cont):


Hemolytic anemia elicited by primaquine in patients whose red cells
are deficient in glucose-6-phosphate dehydrogenase:
○
○
Hemolytic anemia in G-6-PDH Deficiency: Primaquine
Sulfonamides
Nitrofurantoin
Know

Normal erythrocytes have several mechanisms that protect against
oxidative insults such as from metabolic derivatives of primaquine
About 10% of black males in the U. S. develop acute hemolytic anemia
when given normal therapeutic doses of primaquine
Barbiturate-induced porphyria occurs in individuals with abnormal
heme biosynthesis:
○
○
○
○
May induce acute attacks of porphyria
Genetic abnormality is in the pathway of heme biosynthesis
Barbiturate acid moiety mimics part of heme structure, occupying portion of
heme site on protein that regulates production of ALA synthetase
Heme is a repressor, inhibiting production of ALA synthetase and reducing
porphyrin production
A 21-year-old woman experiences an asthmatic attack
after taking 2 aspirin for a severe headache. Which of
the following terms best describes the adverse effect
of aspirin in this patient?
Answer: B
A.
B.
C.
D.
E.
An asthmatic attack produced by
Drug allergy
NSAIDs in some people is due
Drug idiosyncrasy to a shunt of arrachidonic acid
to the lipooxygenase pathway when
Drug toxicity
cyclooxygenase is inhibited; an
Placebo response Idiosyncratic reaction
Tachyphylactic response
Learning objectives
Pharmacotherapeutics:
 Understand how the use of drugs are related
to pharmacokinetics, pharmacodynamics
and adverse effects
 Understand the placebo response
 Understand the importance of drug
interactions
 Understand special aspects of Geriatric
Pharmacology
PHARMACOTHERAPEUTICS

Application of the principles of pharmacokinetics,
pharmacodynamics and adverse effects to the treatment
of patients

Selection of therapeutic regimen:
 Accurate diagnosis
 Knowledge of pathophysiology
 Knowledge of pharmacokinetics and metabolites in normal and
diseased patients
 Transfer of knowledge to effective bedside action
 Plan to make specific measurements that will reveal efficacy and
toxicity, and determine course for continued therapy

Pharmacogenomics
 Personalized Medicine
Placebo Response

Most patients perceive any therapeutic
intervention by caring, interested and
enthusiastic health care professionals as a
positive measure; a factor in alternative
medicines and therapies
 Manifestation in patient may involve objective
physiological and biochemical changes and changes
in subjective complaints associated with disease
 Incidence of a placebo response is constant between
20 and 40% in clinical trials
PowerPoint Slides

Several of the PowerPoint slides are Copyright © 2002-04,
the American Society for Pharmacology and Experimental
Therapeutics (ASPET). All rights reserved.

Some of slides in this session are from the above mentioned format
and are free for use by members of ASPET.

Some others are from various sources like text book, recommended
books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA),
Dr. S. Kacker (co-professor , Clinical Pharmacology &
Therapeutics, MUA)

Core concepts of various USMLE High yield review series like
Kaplan ,BRS etc. are thoroughly explored & integrated whenever
necessary