Q1 LONG ANSWER 10M ★ High-yield

Describe the mechanisms of drug action. Classify receptors and describe their signal transduction mechanisms.

Pharmacology · 2nd Professional — Para-Clinical

Definition

Pharmacodynamics is the study of what the drug does to the body — the biochemical and physiological effects of drugs and their mechanisms of action.

Mechanisms of Drug Action

Mechanism	Explanation	Examples
Through receptors	Binding to a specific macromolecule that transduces a signal — the commonest mechanism	Adrenaline, morphine, salbutamol, atropine
Enzyme inhibition	Competitive, non-competitive or irreversible	Aspirin on cyclo-oxygenase (irreversible); ACE inhibitors; statins on HMG-CoA reductase; neostigmine on cholinesterase; allopurinol on xanthine oxidase
Ion channels	Blockade or modulation of voltage-gated channels	Calcium channel blockers; local anaesthetics on sodium channels; sulphonylureas on ATP-sensitive potassium channels; phenytoin
Transporters and pumps	Inhibition of carrier-mediated transport	Digoxin on Na+/K+ ATPase; proton pump inhibitors on H+/K+ ATPase; SSRIs on the serotonin transporter; frusemide on the Na-K-2Cl cotransporter
Antimetabolites	Structural analogues incorporated in place of a natural substrate	Methotrexate (folate analogue), 5-fluorouracil, sulphonamides (PABA analogue), 6-mercaptopurine
Physical action	Bulk, adsorption, osmosis, radioactivity	Bulk laxatives, activated charcoal, mannitol, radioiodine, liquid paraffin
Chemical action	Direct chemical reaction	Antacids neutralise acid; chelating agents (desferrioxamine, EDTA, penicillamine); protamine neutralises heparin
Altering cell membranes	Physicochemical disruption	Amphotericin B binds ergosterol; polymyxins; general anaesthetics

Receptors — Definition and Terminology

A receptor is a specific macromolecule, usually a protein, with which a drug or endogenous ligand interacts to produce a characteristic response.

Term	Meaning
Affinity	The ability of a drug to bind to the receptor
Intrinsic activity (efficacy)	The ability of the bound drug to activate the receptor and produce a response
Agonist	Affinity plus full intrinsic activity (IA = 1)
Partial agonist	Affinity with submaximal intrinsic activity (0 < IA < 1)
Antagonist	Affinity but NO intrinsic activity (IA = 0)
Inverse agonist	Affinity with negative intrinsic activity (IA = −1); produces the opposite effect by stabilising the inactive form of a constitutively active receptor
Spare receptors	Receptors surplus to those needed for a maximal response; explains why a maximal effect can occur with only partial occupancy

CLINICAL PEARL

Affinity and intrinsic activity are independent properties, and every class of ligand is defined by their combination. An antagonist binds beautifully and does nothing — high affinity, zero intrinsic activity. That is precisely why it blocks: it occupies the site without activating it. Setting out the two properties first makes the whole classification derivable rather than memorised.

Types of Receptor

Type	Structure	Transduction	Time scale	Examples
1. Ligand-gated ion channels (ionotropic)	Multi-subunit protein forming a central pore	Direct opening of the channel; ion flux	Milliseconds — the fastest	Nicotinic acetylcholine receptor, GABAA, NMDA and AMPA glutamate, glycine, 5-HT3
2. G-protein coupled (metabotropic)	Seven transmembrane domains; the largest family, and the target of about a third of all drugs	G protein activation → second messengers	Seconds	Muscarinic, adrenergic, dopamine, opioid, histamine, serotonin (except 5-HT3), prostaglandin
3. Enzyme-linked (kinase-linked)	Single transmembrane span with an intracellular catalytic domain	Receptor dimerises and autophosphorylates; phosphorylation cascade	Minutes to hours	Insulin receptor and growth factor receptors (tyrosine kinase); cytokine receptors (JAK-STAT); atrial natriuretic peptide (guanylyl cyclase)
4. Nuclear / intracellular	Cytoplasmic or nuclear; a DNA-binding and a ligand-binding domain	Altered gene transcription and protein synthesis	Hours to days — the slowest, with a long-lasting effect	Steroids (glucocorticoid, mineralocorticoid, sex hormones), thyroid hormone, vitamin D, retinoids

The time scale follows directly from the mechanism — opening a pore is instantaneous, a second messenger cascade takes seconds, phosphorylation takes minutes, and making new protein takes hours. This is why an intravenous corticosteroid does not relieve acute bronchospasm, and why adrenaline does

G Proteins and Second Messengers

G protein	Effector	Second messenger	Receptors
Gs (stimulatory)	Adenylyl cyclase activated	CAMP increased → protein kinase A	Beta1, beta2, D1, H2, glucagon
Gi (inhibitory)	Adenylyl cyclase inhibited	CAMP decreased	Alpha2, M2, D2, opioid, GABAB
Gq	Phospholipase C activated	IP3 and DAG → intracellular calcium release and protein kinase C	Alpha1, M1, M3, H1, 5-HT2, vasopressin V1

Other messengers — cGMP (nitric oxide and atrial natriuretic peptide; the target of sildenafil, which inhibits its breakdown by phosphodiesterase-5), and calcium–calmodulin
Toxins acting on G proteins — cholera toxin locks Gs ON (persistent cAMP rise and massive intestinal secretion); pertussis toxin locks Gi off

Non-receptor Targets in Detail

Target	Drug and effect
Na+/K+ ATPase	Digoxin inhibits it → intracellular sodium rises → the Na+/Ca2+ exchanger works less → intracellular calcium rises → increased contractility
H+/K+ ATPase	Omeprazole binds irreversibly to the gastric proton pump; acid secretion resumes only when new pump protein is made, which is why a once-daily dose suppresses acid all day despite a short half-life
Cyclo-oxygenase	Aspirin acetylates it irreversibly; other NSAIDs inhibit it reversibly — hence aspirin alone gives lasting antiplatelet action
Dihydrofolate reductase	Methotrexate in man; trimethoprim selectively in bacteria — selectivity comes from a many-thousandfold difference in affinity for the bacterial enzyme
Voltage-gated sodium channels	Local anaesthetics block conduction; phenytoin stabilises neuronal membranes
ATP-sensitive potassium channels	Sulphonylureas close them → depolarisation → calcium entry → insulin release
Reuptake transporters	SSRIs, tricyclic antidepressants, cocaine and amphetamine all act on monoamine transporters
Bacterial ribosome and cell wall	Structures absent in man — the basis of selective toxicity for aminoglycosides, macrolides and penicillins

Selective toxicity is the central principle of chemotherapy — exploiting a target the pathogen has and the host does not, or one that differs enough in structure to allow discrimination

Regulation of Receptors and Applied Aspects

Down-regulation — prolonged exposure to an agonist reduces receptor number or sensitivity; the basis of tolerance to opioids and of tachyphylaxis to beta-agonists
UP-regulation — prolonged blockade increases receptor number; this is why abrupt withdrawal of a beta-blocker causes rebound angina, tachycardia and infarction, and why clonidine withdrawal causes a hypertensive crisis. These drugs must be tapered
Receptor selectivity is relative, not absolute — salbutamol is beta2-selective but causes tremor and tachycardia at higher doses, because selectivity is lost as the dose rises
Drug design targets receptor subtypes to improve selectivity — beta1-selective blockers for asthmatic patients with heart disease, H2 blockers for acid without the sedation of H1 blockade
Steroids take hours to act because they work through gene transcription — so in acute asthma or anaphylaxis they are started early but adrenaline or a bronchodilator provides the immediate effect
Constitutive receptor activity explains inverse agonists, and matters clinically for antihistamines and some beta-blockers, which are inverse agonists rather than pure antagonists
Selective toxicity has limits — antifungals and antivirals are more toxic than antibacterials because fungi are eukaryotes and viruses use host machinery, leaving fewer targets the host does not share

All questions in General Pharmacology: Pharmacodynamics

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