Pharmacodynamics

What is pharmacodynamics

Effect of drug on body

Pharmacodynamics : 4 Mechanisms of drug action and 2 examples (besides point 4 has 1 example)

1. Bind to specific receptors (most drugs)

• Cell memb receptors = Adrenoreceptors, cholinoreceptors, histamine receptors

• Intracellular receptors = Steroid receptors

2. Direct chemical interaction

• Antacids neutralize gastric HCL

• Chelating agents bind to (certain) metals

3. Physical or physiochem properties (osmotic properties)

• MgSO₄ acts as osmotic laxative

• Mannitol acts as osmotic diuretic

4. Struct analogs of normal (endogenous) subst in body & incorporated into cellular components altering their functions.

• eg: 5-flurouracil (anticancer) acts as struct analog of uracil & incorporated into messenger RNA instead of uracil.

Transmembrane signaling mechanisms: (Def) & types

Def of Transmembrane signalling mech: Molecular process transduce extracellular signals into intracellular msgs that control cell functions

1. Ionotropic receptors (Ion chained linked)

Description/Action

• Receptors linked directly to Ligand Gated ion channels (ion selective channels in plasma memb)

• Confined to excitable tissues & involved mainly in fast synaptic transmission

• Neurotransmitter acts on nerve/muscle cell postsynaptic memb → transiently ↑ its permeability to particular ions

Onset

• Action of transmitter reaches peak in fraction of millisecond

• Fastest onset

Example

1. Nicotinic cholinergic (/acetylcholine) receptors

2. 5HT3 receptor (serotonin)

3. GABAa receptors

4. glutamate receptors

Function example:

• Removing hand from hot water

Ionotropic receptors /Ion chained linked (Description/Action and onset)

Description/Action

Structure : Extracellular receptor linked directly to Ligand Gated ion channels (ion selective channel in plasma memb)

Action: Neurotransmitter acts on nerve/muscle cell postsynaptic memb → transiently ↑ its permeability to particular ions

Location: Confined to excitable tissues & involved mainly in fast synaptic transmission

Onset

• Fastest onset as transmitter action peak in fraction of millisecond and ends in millisecond.

Ionotropic receptors /Ion chained linked (examples, functional example)

Examples:

1. Nicotinic cholinergic (/acetylcholine) receptors

2. 5HT3 receptor (serotonin)

3. GABAa receptors

4. glutamate receptors

Function example: Removing hand from hot water

G-Protein-Coupled Receptors (Mech, Role, Families, Onset)

(G protein = guanine nucleotide binding protein)

Description/ action

• Mech : Drug binds with extracellular (surface) receptor → activates G- protein in cytoplasm → regulates certain enzymes activity (adenylcyclase, phospholipases) or ion channels

• Role: changing conc of 2nd messenger (cAMP, IP3…)

• Families: Gs stimulate adenylcylase and Gi inhibits it

Onset

• 2nd fastest onset as stimulated within milliseconds remains active for about 10 secs

G protein coupled receptor examples and function example

Examples

1. Muscarinic cholinergic receptors

2. Adrenergic receptors

3. Dopaminergic receptors

4. 5HT (1,2,4) receptors

5. Opiate receptors

Functional examples: Airway smooth muscle relaxation

Tyrosine kinase linked receptors (2 domains, mech, and time for effect)

Description/ action

Transmembrane receptors have 2 domains:

1. Extracellular domain for drug binding

2. cytoplasmic domain with tyrosine kinase activity

Mech: Binding of drug to extracellular domain → stimulates tyrosine kinase activity of cytoplasmic domain → Phosphorylation of target proteins on tyrosine residues

Tyrosine kinase linked receptors (time for effect , example and functional example)

Time for effect : Mins

Example: Insuline

Functional example: Glucose uptake in cells

Intracellular receptors ( Description and example + functional example)

Description/action

• Mech: Lipid soluble drugs cross cell memb & bind to specific receptor protein in cell. → regulation of gene expression → protein synthesis level changed of various target tissues

• Example : Steroid receptor, Thyroid hormone, Vit D

• Functional example : Cellular proliferation

Time (Onset , time for effect) (incl clinical example for onset)

Time:

• Onset from 30 mins - several hrs (till new protein synthesised) so glucocorticoids not immediate relieve acute bronchial asthma symptoms.

• Time for effect: Hrs - days

Agonist vs Antagonist

Agonist : Drug mimic endogenous regulatory substances

Antagonist: Drug inhibit endogenous regulatory substances action

Affinity and Intrinsic activity (incl for agonist vs antagonist)

Affinity: degree drug binds to receptor

Intrinsic activity =efficacy: Drug ability to activate receptor and produce max effect

• Agonist = need Affinity to receptor and intrinsic activity to produce effect

• Antagonist = need affinity to receptor but lack intrinsic activity so not produce effect

Partial agonist (def, when act as agonist or antagonist , example)

Def:

Drug with adequate affinity to receptor but low intrinsic activity.

Fail to produce max response (receptor full occupancy) due to low intrinsic activity (not low affinity)

When partial agonist act as agonist : Low conc , Full agonist absent

When partial agonist act as antagonist: High conc , Full agonist present

Example of partial agonist: pentazocine

Inverse agonist / (-) antagonist (Def, Example)

Def:

Drug block agonist effect & produce opposite effect

(High affinity & opposite intrinsic activity)

Example:

B carbolines inverse agonist to benzodiazepines

blocks the benzodiazepines effect (sedation, anti convulsive) and produces opposite effect as anxiety and convulsions (drug has some intrinsic activity)

Drug antagonism (Def, types)

Def: ↓ effect of drug when combined with other drug

Types

1. Pharmacological antagonism ( pharmacokinetics & pharmacodynamic/receptor antagonism)

2. Chem antagonism

3. Physical antagonism

4. Physiological antagonism

Types of pharmacodynamic antagonism (Physiological antagonism)

1. Competitive antagonism (surmountable)

2. Non-competitive (irreversible) antagonism

Competitive antagonism (Key features, 2 examples)

Features:

• Location: Binds to same site on receptor as agonist

• Key features: Agonist give max effect but at higher conc as competitive antagonist than if agonist was alone.

• Reversible:Inhibition surmountable (overcome) by ↑agonist conc

• Graph interpretation: Agonist conc curve shift right in competitive antagonist presence. Means agonist can still produce max effect but at higher doses. Still parellelism of curve.

Examples:

• Propanolol competes with B - agonist for B-adrenergic receptors

• Naxolone competes with morphine at opiod receptors

Irreversible or non- competitive antagonism (What causes it, graph interpretation, what is it dependent on, example)

Antagonist bind to receptor irreversibly may be due to

1. Very high affinity of agonist to receptors

2. Antagonist form covalent bond with receptors

• Agonist bind only to remaining receptor & max response not reached (not even at high agonist conc)

• Agonist conc curve shift down & loss of parallelism

• If antagonist occupy all receptor the agonist not give any response and give response only when new receptors synthesise.

Action duration of irreversible antagonist not depend on rate of elimination but on synthesis of new receptor

Example:

Phenoxybenzamine irreversible antagonist to a-receptors

Pharmacokinetic antagonism (Pharmacological antagonism)

Drug -Drug interactions which cause ↓ drug effect incl absorption, biotransformation, excretion

Physiological/functional antagonism ,

Def:

• 1 drug produce physiological action opposite to another drug

(2 receptor 2 drug opposite reactions)

Example:

• Epinephrine physiological antagonist to histamine

Epinephrine = Bronchodilation, Vasoconstriction, ↑BP

Histamine = Bronchochonstriction, Vasodilation, ↓BP

Chemical antagonism and Physical antagonism examples

Chemical antagonism

Chem interaction between 2 drugs → Neutralisation

Eg1: protamine (+) neutralises heparin (-) ,

Eg 2: antacids (alkaline) neutralises gastric HCL (acid)

Physical antagonism

Eg: Activated charcoal cause adsorption of strychnine, theophylline →↓ their absorption

2 types of Variations in response to drugs and 2 cause.

a. Qualitative variations like allergy or idiosyncrasy

b. Quantitative variation hypoactive or hyperactive patients

(not Hypo/hypersensitive as they indicatesallergic reaction only)

Variations may occur in same person

Causes are drug tolerance (development) and idiosyncrasy

Development of drug tolerance: Define tolerance (incl response curve and examples) and how can we ↓ tolerance

Tolerance:

↓ intensity of drug response after repeated administration

Dose-response curve to shift right as higher dose needed to produce previous response.

Tolerance develop rapid to certain effect and slowly to other effect

• Rapid: Morphine Euphoria tolerance

• Slower: GIT effect (constipation) effect

↓ tolerance = Stopping drug administration for short period (1-2 wks) then give previous dose (no ↑)

Development of drug tolerance: Define tachyplaxis (acute tolerance), cross tolerance and example

Tachypylaxis (acute tolerance)

Def: Rapid development of tolerance after 1 dose or few doses

Eg: ephedrine

Cross tolerance

Def:

• Tolerance occur between drugs chem or pharmacologically related

• Important in medical treatment of person dependent on any drug

Eg: Morphine and heroid and alcohol and barbiturates

Types of tolerance

a. Pharmacodynamic

Mech:

• Body cell adaptation to drug presence due to change in receptor, enzyme or membrane drug action

• (Adaptation = cellular tolerance = Functional)

Common: More common

Eg:

• Most common type occur with addicting drugs such as morphine, amphetamine, barbiturates

• Can occur with organic nitrates

b. Pharmacokinetic

Mech:

• Change in distribution & metabolism of drug after repeated administration → ↓drug conc in blood → ↓ effect of drug

• (Metabolic tolerance, dispositional tolerance)

Common: Less common

Eg:

• can occur with barbiturates which induce liver microsomal enzyme → ↑its own metabolism → ↓conc

• Can occur with alcohol as ↓absorption on repeated administration

Idiosyncrasy (Def, Cause, 4 Examples )

Def: Abnormal reaction the chem subst. Reaction in very small dose or extremely insensitive to high dose.

Cause : genetic deficiency of enzyme or genetic alteration in receptor function.

Match the genetic enzyme deficiency or abnormality with its drug reaction:

1. G6PD deficiency

2. Cholinesterase deficiency

3. Vitamin K epoxide reductase mutation

4. Malignant hyperthermia with…

Examples

1. Deficiency of G-6-P dehydrogenase enzyme → severe haemolytic anemia with antimalarial drugs (eg.primaquine) , a methyl dopa, certain foods (eg: beans)

2. Deficiency of Cholinestrase enzyme (hydrolyse succinylcholine) → Severe apnea with succinylcholine

3. Genetic abnormality in Vit k epoxide reductase enzyme → Resistant to warfarin (oral anticoagulant) action

4. Malignant hyperpyrexia syndrome with halothane