Pharmacodynamics and ADR

PHARMACODYNAMICS & ADVERSE
DRUG REACTION
By Ganesh R. BharskarPharmacology 1

TYPES / PRINCIPLES OF DRUG ACTION
• EFFECT (Type of responses):
1. Stimulation: It is selective enhancement of the level of activity of
specialized cells. Eg; adrenaline stimulate the heart.
2. Inhibition/Depression: It is selective diminution of activity of specialized
cells. Eg: quinidine depresses heart; Alcohol, Barbiturates, General
anesthetic these drug depress the CNS system
3. Replacement: This refers to the use of natural metabolites, hormones in
deficiency states. Eg; iron in anaemia; Insulin in Diabetes mellitus.
4. Irritation: This refers a nonselective, often noxious effect and is
particularly applied to less specialized cells. Eg: counterirritants increase
blood flow to the site; Eucalyptus oil, methyl salicylates.
5. Cytotoxic action: For invading parasites or cancer cells. Eg: penicillin;
Anticancer drugs
27/02/2020 Pharmacology 2

Mechanism of Drug Action

Drug Targets Sites
Drugs can interact with the following target sites in a cell
1. Receptors
2. Ion channels which incorporate a receptor and act as target sites
3. Enzymes
4. Carrier molecules

• Based on the drug target sites, the mechanisms of
drug action can be classified broadly as,
– Receptor mediated mechanisms
– Non-receptor mediated mechanisms

1. RECEPTOR MEDIATED MECHANISM
• Receptor: It is a membrane bound or intracellular
macromolecular protein which is capable of binding the specific
functional groups of the drug or endogenous substance.
• Binding of a drug with its receptor results in the formation of drug
receptor complex (DR) which is responsible for triggering the
biological response.
D + R = (DR) → Response

• Affinity: The capacity of a drug to form the complex with its
receptor (DR complex) e.g., the key entering the hole of the lock has
got an affinity to its levers.
• Intrinsic activity (or) Efficacy: The ability of a drug to trigger the
pharmacological response after making the drug-receptor complex .
• Ligand: Any molecule which attaches selectively to particular
receptors or sites

• Agonists: Agent which activates a receptor to produce an effect similar to that of the physiologic
signal molecule
Have both high affinity as well as high intrinsic activity, therefore can trigger the
maximal biological response
• Antagonists: Agent which prevents the action of an agonist on a receptor but doesn’t have any
effect of its own.
Have only affinity but no intrinsic activity. These drugs bind to the receptor and block
the binding of an endogenous agonist.
• Partial agonists: Agent which activates a receptor to produce a sub maximal effect but
antagonizes the actions of full agonist.
Have full affinity but with low intrinsic activity and hence are only partly as effective as
agonists.
• Inverse (Negative) agonists: Agent which activates a receptor to produce an effect in the opposite
direction to that of the agonist
Have full affinity but intrinsic activity ranges between 0 to -1

Four types of binding takes place between the receptor and the drug
molecule
1. Van der Waals
forces
2. Hydrogen bonding
3. Ionic interaction
4. Covalent bonding

Types of Receptors and
Signal transduction mechanisms
Type I: Ionotropic receptors (Ligand gated ion channels)
Type II: Metabotropic receptors (G proteins coupled receptors(GPCR))
1. Adenyl cyclase: cAMP system
2. Phospholipase-C: Inositol Phosphate system
3. Ion channel regulation
Type III: Enzyme linked receptors
a. Intrinsic enzyme receptors
b. JAK-STAT-kinase binding receptors
Type IV: Receptors regulating gene expression

Type I: Ionotropic receptors
•
•
•
•
Also called as “Ligand gated ion channels”
These are cell surface receptors
Enclose ion selective channels (for Na+,K+,Ca2+or Cl-)
within their molecules.
Agonist binding opens the channel, and causes
depolarization/hyperpolarization/changes in the ionic
composition
• Examples: nicotinic cholinergic, GABA-A, glycine
(inhibitory), excitatory AA(kainate, NMDA or N-methyl
D-aspartate, quisqualate) and 5HT3 receptors

• Nicotinic cholinergic receptor

Type II: G-Protein coupled receptors
• These are a large family of cell membrane receptors linked to the effector through
GTP activated proteins (G-Proteins).
• G-Proteins: 7 helical membrane spanning hydrophobic amino acid (AA) segments
which run into 3 extracellular and 3 intracellular loops.
• Agonist binding site is located on extracellular face, while another recognition site
formed by cytosolic segments binds the coupling G-protein.
• Examples: Muscarinic, Dopamine D2,β-adrenergic, α1- adrenergic, α2-
adrenergic, GABAB, 5-HT

G-Protein coupled receptors

• There are three major effector pathways through which GPCRs function
1. Adenyl cyclase: cAMP system: Activation of AC results in intracellular accumulation of
second messenger cAMP which functions through cAMP dependant protein kinase (PKA).
The PKAphosphorylates and alters the
functions of many enzymes, ion channels, transporters
and structural proteins.
2. Phospholipase-C: IP3-DAG pathway: Activation of Phospholipase- C(PLc) hydrolises the
membrane PIP2to generate IP3and DAG. IP3
mobilizes Ca2+ and DAG enhances protein kinase C (PKc) activation by Ca2+
3. Ion channel regulation: The activated G-proteins can also open or close ionic channels
specific for Ca2+,K+or Na+, without the intervention of any second messenger like cAMP or
IP3and bring about depolarization/hyperpolarization/changes in intracellular Ca2+

Type III: Enzyme linked receptors
• This class of receptors have a subunit with enzymatic property (intrinsic) or bind a JAK
(Janus-Kinase) enzyme on activation. The agonist binding site and the catalytic site lie
respectively on the outer and inner face of the plasma membrane.
• Intrinsic enzyme receptors: The intracellular domain is either a protein kinase or
guanyl cyclase
Examples: Insulin, Epidermal growth factor (EGF), Nerve growth factor (NGF)
receptors
• JAK-STAT-kinase binding receptors: These do not have intrinsic activity, but
agonist induced dimerization increases affinity for a cytoplasmic tyrosine protein
kinase JAK.
Examples: Growth hormone, many cytokines, interferons

Enzyme linked receptor
Eg: Insulin receptor

Type IV: Receptors regulating gene expression
• These are intracellular (cytoplasmic or nuclear) soluble proteins which
respond to lipid soluble chemical messengers that penetrate the cell
• Kept inhibited till the hormone binds
• Capable of binding to specific genes and facilitates their expression so
that specific mRNA is synthesized.
• Examples: All steroid hormones, thyroxin, vit. D and
vit.A

• Protein synthesis regulating receptor

2. NON-RECEPTOR MEDIATED MECHANISMS

• By counterfeit or False incorporation mechanisms
Eg: Sulfa drugs and anti-neoplastic drugs
• By virtue of being Protoplasmic poisons
Eg: Germicides and antiseptics
• Through formation of antibodies
Eg: Vaccines, Antisera
• Through placebo action
• Targeting specific genetic changes

REGULATION OF RECEPTORS
Receptor down regulation: or Desensitization
Prolonged use of agonist
Decrease Receptor number and sensitivity
Decrease Drug effect
Ex: Chronic use of salbutamol down regulates ß2 adrenergic receptors
1. Receptor down regulation: or Desensitization
2. Receptor up regulation: or Super sensitivity

Receptor up regulation: or Super sensitivity
Prolonged use of antagonist
Receptor number and sensitivity
Drug effect
Eg:- if timolol is stopped after prolong use, produce withdrawal
symptoms. Rise iop

DRUG RECEPTOR INTERACTION:
1. Selectivity:- Degree of complimentary co relation between drug and
receptor. Ex:- Adrenaline Selectivity for α, ß Receptor
2. Affinity:- Ability of drug to get bound to the receptor.
3. Intrinsic activity (IA) or Efficacy:- Ability of drug to produce a
pharmacological response after making the drug receptor complex.
Drug(D) +Receptor Drug receptor complex Response

THEORIES OF DRUG RECEPTOR INTERACTIONS
1. Occupation theory
2. Rate Theory
3. The induced-fit theory of enzyme-substrate interaction
4. Macromolecular perturbation theory
5. Activation-aggregation theory
6. Two state model of receptor activation

1. OCCUPATION THEORY
• Drugs act on binding sites and activate them, resulting in a biological
response that is proportional to the amount of drug-receptor complex
formed. The response ceases when this complex dissociates.
• Intensity of pharmacological effect is directly proportional to number
of receptors occupied
• D + R DR RESPONSE
• Response is proportional to the fraction of occupied receptors
Maximal response occurs when all the receptors are occupied

2. RATE THEORY
• The response is proportional to the rate of drug-Receptor complex
formation.
• Activation of receptors is proportional to the total number of
encounters of a drug with its receptor.
• According to this view, the duration of Receptor occupation
determines whether a molecule is agonist, partial agonist.

3. THE INDUCED-FIT THEORY
• According to this theory, binding produces a mutual plastic molding of
both the ligand and the receptor as a dynamic process.
• The conformational change produced by the mutually induced fit in
the receptor macromolecule is then translated into the biological
effect, eliminating the rigid and obsolete “ lock and key” concept of
earlier times.
• Agonist induces conformational change – response
• Antagonist does not induce conformational change – no response
• Partial agonist induces partial conformational change-partial response

4. MACROMOLECULAR PERTURBATION THEORY
• Suggests that when a drug-receptor interaction occurs, one of two
general types of Macromolecular perturbation is possible:
• a specific conformational perturbation leads to a biological response
(Agonist),
• whereas a non specific conformational perturbation leads to no
biological response (Antagonist)

5. ACTIVATION AGGREGATION THEORY
• Receptor is always in a state of dynamic equilibrium between
activated form (Ro) and inactive form (To).

6. TWO-STATE (MULTI-STATE) RECEPTOR MODEL
• R and R* are in equilibrium (equilibrium constant L), which defines
the basal activity of the receptor.
• Full agonists bind only to R*
• Partial agonists bind preferentially to R*
• Full inverse agonists bind only to R
• Partial inverse agonists bind preferentially to R

Any response to a drug which is noxious & unintended & which occurs
at doses in man for prophylaxis, diagnosis or treatmant.

Classification of ADRs
Type of reaction: (Wills and brown)
1. Type A (Augmented)
2. Type B (Bizarre)
3. Type C (Chronic)
4. Type D (Delayed)
5. Type E (End of treatment)

Types of ADRs……..
Type Type of
effect
characteristics example
A Augmented Dose dependent
predicted from the
known pharmacology
of the drug
Hypoglycaemia-
insulin
B Bizarre Unpredictable
Dose independent
Rare,fatal
Anaphylaxis to
penicillin
C Chronic Prolong treatment Analgesic neuropathy
D Delayed After years of
treatment
Antipsycotic –turdive
dyskinesia
E End of use Withdrawal effect GC withdrawal
causes
adrenocortical

Type A (Augmented) reactions
• Reactions which can be predicted from the known pharmacology of the
drug
• Dose dependent
• Can be alleviated by a dose reduction
• common
• Skilled management reduces their incidence.
• E.g.
1. Anticoagulants : Bleeding
2. Beta blockers : Bradycardia
3. Nitrates : Headache
4. Prazosin : Postural hypotension

Type B (Bizarre) reactions
1. Predictable where the mechanism is known, otherwise unpredictable
for the individual, although the incidence may be known.
2. Dose independent, rare
3. Host dependent factors important in predisposition •
4. unwanted effects due to inherited abnormalities (idiosyncrasy) and
immunological processes(drug allergy).
5. These account for most drug fatalities.
E.g. Penicillin : Anaphylaxis
Anticonvulsant : Hypersensitivity

1. Drug allergy
• Acquired, altered reaction of the body to drug.
• Immunologically mediated reaction.
• occur even with much smaller doses
• Also called Drug hypersensitivity
• Not genetic,not occurred in all
• Occurs on reexposure
• E.g. penicillin→1st time →stimulate antibody
→Ag-Ab reaction →allergy
• Chief organ: Skin, respiratory tract,GIT,Blood &
blood vessels

2. Idiosyncrasy
• unusual response to a drug due to genetic abnormality.
• Drug interacts with some unique feature of the individual, not
found in majority subjects, and produces the uncharacteristic
reaction.
• E.g.
 Isoniazid: N-Acetylation affects the metabolism of isoniazid
• Slow N-Acetylation: Isoniazid is more likely to cause
peripheral neuritis.
• Fast N-Acetylation:cause hepatotoxicity in this group.

 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.G-6-p
deficiency is most prevalent in blacks & Semitics. It is rare in
Caucasians & Asians.

Type C ( Chronic)
• Reactions due to long time exposure.
e.g. Analgesic neuropathy Dyskinesia with levodopa

Type D (Delayed) reactions
• Occur due to prolonged exposure.
• Can be due to accumulation.
• E.g. Carcinogenesis, or short term exposure at a critical time
e.g.teratogenesis.

Type E (End of use) reactions
• Occur on withdrawal especially when drug is stopped abruptly
• E.g. Phenytoin withdrawal causing Seizures
Steroid withdrawal causing Adrenocortical insufficiency.
opioid causing the withdrawal syndrome

Tolerance –
 ↓ pharmacological effect on repeated
administration of the drug.
 Pharmacokinetic Tolerance: ↑ the enzymes
responsible for metabolizing the drug.
e.g.Phenobarbitone induces metabolism of its own by
increasing its own metabolic enzyme.
 Pharmacodynamic Tolerance: Cellular tolerance, due
to down-regulation of receptors.
 Depletion of stores e.g.Amphetamine

Tachyphylaxis
When responsiveness diminishes rapidly after administration
of a drug, the response is said to be subject to tachyphylaxis.
 Tyramine can cause depletion of all NE stores if you use it
long enough, resulting in tachyphylaxis.

Drug dependence
• Drugs capable of altering mood and feelings are liable to repetitive use to
derive euphoria, withdrawal from reality, social adjustment, etc.
• Psychological dependence: Individual believes that optimal state of well
being is achieved only through the actions of the drug.
• E.g. Opioids, Cocaine.
• Physical dependence: Altered physiological state produced by repeated
administration of a drug which necessitates the continued presence of the
drug to maintain physiological equilibrium. Discontinuation of the drug
results in a characteristic withdrawal (abstinence) syndrome.
• E.g. Opioids, Barbiturates, Alcohol, Benzodiazepines

Drug dependence….
• Drug abuse: Use of a drug by self medication in a manner and amount, that
deviates from the approved medical and social patterns in a given culture at
a given time.
Drug abuse refers to any use of an illicit drug.
• Drug addiction: Compulsive drug use characterized by overwhelming
involvement with the use of a drug.
• Drug habituation: Less intensive involvement with the drug, withdrawal
produces only mild discomfort.
• Habituation and addiction imply different degrees of psychological
dependence.

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Pharmacodynamics and ADR

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