Pharmacology chapters
Pharmacodynamics and receptors
What a drug does to the body: the four receptor families and their speed, agonists, partial agonists, inverse agonists and antagonists, dose-response curves, potency versus efficacy, therapeutic index, and tolerance, tachyphylaxis and receptor up- and down-regulation.
- Pharmacodynamics is what the drug does to the body; most drugs act on receptors (also enzymes, ion channels and transporters). The four receptor families, fastest to slowest: ligand-gated ion channels (milliseconds: nicotinic, GABA-A), G protein-coupled receptors (seconds: Gs ↑cAMP, Gi ↓cAMP, Gq → IP3/DAG/Ca²⁺), enzyme-linked receptors (minutes: insulin, growth factors) and intracellular receptors (hours: steroids, thyroid hormone, vitamin D).
- An agonist has affinity and efficacy; a partial agonist has lower maximal effect and can act as an antagonist in the presence of a full agonist (buprenorphine); a competitive antagonist shifts the dose-response curve to the right without lowering the maximum (surmountable), whereas an irreversible or non-competitive antagonist lowers the maximum.
- Potency is the dose needed (EC50: curve position); efficacy is the maximal effect (curve height) and matters more clinically; therapeutic index = TD50 ÷ ED50 (or LD50 ÷ ED50 in animals).
On this page
Overview
Pharmacodynamics describes what a drug does to the body: its biochemical and physiological effects and their mechanisms. Most drugs act by binding to receptors, but drugs also act on:
- Enzymes (aspirin on COX, ACE inhibitors, neostigmine on cholinesterase).
- Ion channels (local anaesthetics block sodium channels; calcium channel blockers).
- Transporters (SSRIs on serotonin reuptake; digoxin on Na⁺/K⁺-ATPase; proton pump inhibitors).
- Physical or chemical means (antacids neutralise acid; osmotic diuretics; chelating agents).
Receptor families
| Family | Speed | Mechanism | Examples |
|---|---|---|---|
| Ligand-gated ion channels | Milliseconds | Binding opens an ion channel | Nicotinic ACh (Na⁺), GABA-A (Cl⁻: benzodiazepines, barbiturates), NMDA glutamate, 5-HT3 |
| G protein-coupled receptors (7 transmembrane) | Seconds | G protein → second messengers | Muscarinic, adrenergic, dopamine, histamine, opioid, most hormone receptors |
| Enzyme-linked receptors (tyrosine kinase) | Minutes | Receptor has or activates kinase activity | Insulin, growth factors (EGF, PDGF); cytokine receptors (JAK-STAT: erythropoietin, interferons, growth hormone) |
| Intracellular (nuclear) receptors | Hours to days | Drug enters the cell, receptor binds DNA → gene transcription | Steroids (glucocorticoids, sex hormones), thyroid hormone, vitamin D, retinoids |
G proteins and second messengers
| G protein | Effect | Receptors |
|---|---|---|
| Gs | Activates adenylyl cyclase → ↑ cAMP | β1, β2, D1, H2, V2, glucagon |
| Gi | Inhibits adenylyl cyclase → ↓ cAMP | α2, M2, D2, opioid |
| Gq | Activates phospholipase C → IP3 (releases Ca²⁺) and DAG (protein kinase C) | α1, M1, M3, H1, V1 |
"Qiss and Qiq till you're siq of sqs" lists the G-protein type for α1, α2, β1, β2, M1, M2, M3, D1, D2, H1, H2, V1, V2 in order: q, i, s, s, q, i, q, s, i, q, s, q, s.
Agonists and antagonists
- Affinity: how strongly a drug binds the receptor.
- Efficacy (intrinsic activity): ability to activate the receptor once bound.
| Drug type | Affinity | Efficacy | Example |
|---|---|---|---|
| Full agonist | Yes | Full (intrinsic activity 1) | Morphine at μ receptors, adrenaline |
| Partial agonist | Yes | Partial (between 0 and 1) | Buprenorphine (μ opioid), pindolol (β, intrinsic sympathomimetic activity), aripiprazole |
| Antagonist | Yes | None (0) | Naloxone, atropine, propranolol |
| Inverse agonist | Yes | Negative: opposite effect to agonist on receptors with baseline activity | Some antihistamines; β-carbolines at benzodiazepine sites |
A partial agonist given with a full agonist acts as an antagonist: buprenorphine can cause withdrawal in a person dependent on heroin or methadone.
Types of antagonism
| Type | Mechanism | Effect on dose-response curve | Example |
|---|---|---|---|
| Competitive (reversible) | Competes for the same site; overcome by more agonist | Parallel shift to the right; Emax unchanged; potency of agonist falls | Atropine vs ACh, naloxone vs morphine, propranolol vs adrenaline |
| Irreversible | Binds covalently | Lowers Emax (not surmountable) | Phenoxybenzamine (α), aspirin on platelet COX, organophosphates on cholinesterase |
| Non-competitive (allosteric) | Binds a different site | Lowers Emax | Ketamine on NMDA channel |
| Physiological (functional) | Two agonists act on different receptors with opposite effects | (n/a) | Adrenaline vs histamine in anaphylaxis; glucagon vs insulin |
| Chemical | Drug binds the other drug directly | (n/a) | Protamine neutralises heparin; chelating agents (dimercaprol) bind metals |
| Pharmacokinetic | One drug changes the other's absorption, metabolism or excretion | (n/a) | Rifampicin lowers warfarin levels |
Competitive = right shift, same maximum. Irreversible / non-competitive = lower maximum.
Dose-response relationships
Graded dose-response curve
Plots effect against log dose, giving an S-shaped (sigmoid) curve in one subject or tissue.
- EC50 / ED50: dose giving 50% of the maximal effect.
- Emax: maximal effect.
- Potency: the amount of drug needed for a given effect. A more potent drug has a lower EC50; its curve lies further left.
- Efficacy: the maximal effect a drug can produce (curve height).
Potency = position on the x-axis; efficacy = height. Efficacy matters more clinically: a loop diuretic (furosemide) has higher efficacy than a thiazide, though thiazides are more potent per milligram.
Quantal dose-response curve and therapeutic index
A quantal curve plots the percentage of a population showing a defined all-or-none effect against dose.
- ED50: dose effective in 50% of the population.
- TD50: dose toxic in 50%; LD50: lethal in 50% (animals).
- Therapeutic index (TI) = TD50 ÷ ED50 (or LD50 ÷ ED50 in animal studies).
TI = TD50 ÷ ED50
Drug A: ED50 = 10 mg, TD50 = 400 mg → TI = 400 ÷ 10 = 40 (wide, safe)
Drug B: ED50 = 0.25 mg, TD50 = 0.5 mg → TI = 0.5 ÷ 0.25 = 2 (narrow)
Drug B needs blood level monitoring (like digoxin or lithium).
Drug B is the more POTENT drug (lower ED50) but the LESS SAFE one.
Drugs with a narrow therapeutic index: digoxin, lithium, warfarin, phenytoin, theophylline, aminoglycosides.
Spare receptors
A maximal response can occur when only a fraction of receptors are occupied (for example insulin receptors, cardiac β receptors). An irreversible antagonist first shifts the curve right before it lowers the maximum.
Changes in drug response
- Tolerance: reduced response after repeated use, so higher doses are needed (opioids, nitrates, alcohol, benzodiazepines).
- Tachyphylaxis: rapid tolerance after a few doses; usually from depletion of stores or receptor desensitisation (ephedrine, amphetamine, tyramine: release noradrenaline until stores run out; nitrates).
- Desensitisation and down-regulation: continued agonist exposure reduces receptor number or response (β2 agonists in asthma).
- Up-regulation (supersensitivity): long-term blockade increases receptors; sudden stopping causes rebound (stopping β-blockers abruptly → tachycardia, angina; clonidine withdrawal → hypertension).
- Idiosyncrasy: abnormal, genetically determined response (G6PD deficiency and primaquine haemolysis; succinylcholine apnoea with pseudocholinesterase deficiency; malignant hyperthermia).
Expect: the four receptor families and their speed, G-protein types for common receptors, second messengers (cAMP, IP3, DAG), affinity vs efficacy, partial agonist (buprenorphine) and inverse agonist, competitive vs irreversible antagonists and their effects on curves, physiological and chemical antagonism (adrenaline vs histamine, protamine vs heparin), potency vs efficacy, therapeutic index, tolerance vs tachyphylaxis, and rebound on stopping β-blockers.
Quick revision
- Speed: ion channel (ms) > GPCR (s) > enzyme-linked (min) > nuclear (h).
- Gs ↑cAMP (β1, β2); Gi ↓cAMP (α2, M2); Gq IP3/DAG (α1, M1, M3, H1).
- Partial agonist: lower maximal effect; antagonises full agonists (buprenorphine).
- Competitive antagonist: right shift, same Emax. Irreversible: lower Emax.
- Physiological antagonism: adrenaline vs histamine. Chemical: protamine vs heparin.
- Potency = EC50 (position); efficacy = Emax (height).
- TI = TD50 ÷ ED50; narrow TI needs monitoring.
- Tachyphylaxis: ephedrine, nitrates. Rebound: stopping β-blockers.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
How does a competitive antagonist affect the dose-response curve?
It shifts the agonist's curve to the right in parallel without lowering the maximum, because more agonist can overcome the block.
What is the difference between potency and efficacy?
Potency is how much drug is needed to produce an effect (lower dose = more potent); efficacy is the maximum effect the drug can produce.
What is a partial agonist?
A drug that binds the receptor but produces less than the maximal response even at full occupancy; it can block a full agonist given at the same time.
What is the therapeutic index?
The ratio of the dose that is toxic in 50% of people to the dose that is effective in 50% (TD50 ÷ ED50); a small value means a narrow margin of safety.