Pharmacodynamics and therapeutic index
Pharmacodynamics: agonists, antagonists, potency, efficacy and therapeutic index
Receptor types and second messengers, partial and inverse agonists, types of antagonism, potency versus efficacy and therapeutic index. Worked examples show how each concept turns into an exam answer.
Core definitions
- Affinity: how tightly a drug binds its receptor.
- Intrinsic activity: how well the bound drug activates the receptor (1 for a full agonist, 0 for an antagonist).
- Potency: the dose needed for a given effect (EC50), read from the position of the dose–response curve; further left means more potent.
- Efficacy (Emax): the maximum response possible, read from the height of the curve. Efficacy matters more clinically: loop diuretics are more efficacious than thiazides whatever the dose.
Receptor families and second messengers
| Receptor family | Speed | Examples |
|---|---|---|
| Ligand-gated ion channel | Milliseconds | Nicotinic ACh, GABA-A, NMDA, 5-HT3 |
| G protein-coupled | Seconds | Adrenergic, muscarinic, dopamine, opioid, histamine |
| Enzyme-linked | Minutes | Insulin (tyrosine kinase), cytokines (JAK–STAT), ANP (guanylate cyclase) |
| Nuclear (intracellular) | Hours | Steroids, thyroid hormone, vitamin D, retinoids |
| G protein | Pathway | Receptors |
| Gq | Phospholipase C, IP3 (releases calcium) and DAG (activates protein kinase C) | Alpha-1, M1, M3, H1, V1, AT1 |
| Gs | Adenylate cyclase, more cAMP | Beta-1, beta-2, beta-3, D1, H2, V2 |
| Gi | Less cAMP | Alpha-2, M2, D2, opioid |
- cGMP is the second messenger of nitric oxide (soluble guanylate cyclase) and ANP (membrane guanylate cyclase). Penile erection is parasympathetic: NO raises cGMP, relaxing smooth muscle (sildenafil blocks its breakdown by PDE5).
Agonists
| Type | Intrinsic activity | Examples |
|---|---|---|
| Full agonist | 1 | Morphine (mu), salbutamol (beta-2), adrenaline |
| Partial agonist | Between 0 and 1; antagonises a full agonist when both are present | Buprenorphine (mu), pindolol (beta), varenicline (nicotinic), aripiprazole (D2), buspirone (5-HT1A) |
| Inverse agonist | Negative; switches off a constitutively active receptor | Some H1 antihistamines, beta-carbolines at the benzodiazepine site |
- Buspirone is a 5-HT1A partial agonist anxiolytic: no sedation, dependence or muscle relaxation, but it takes 1–2 weeks to work.
- Bromocriptine and cabergoline are dopamine D2 agonists. Dopamine tonically inhibits prolactin, so they shrink prolactinomas and lower prolactin.
- Salbutamol (beta-2 agonist) stimulates Na+/K+ ATPase, driving potassium into cells: repeated nebulisation causes hypokalaemia, plus tremor and tachycardia. The same effect is used to treat hyperkalaemia.
- Mirabegron is a beta-3 agonist that relaxes the detrusor in overactive bladder without the cognitive burden of antimuscarinics in the elderly.
- Alprostadil (prostaglandin E1) keeps the ductus arteriosus open in duct-dependent heart disease such as transposition of the great arteries; watch for apnoea.
Antagonists
| Type | Mechanism | Agonist curve | Examples |
|---|---|---|---|
| Competitive reversible | Same site; overcome by more agonist | Parallel shift right, Emax unchanged | Atropine, oxybutynin and dicyclomine (muscarinic), naloxone, propranolol |
| Irreversible | Covalent or very tight binding | Emax falls | Phenoxybenzamine (alpha), aspirin on COX |
| Non-competitive (allosteric) | Binds a different site | Emax falls | Ketamine on NMDA |
| Physiological | Opposite effect through different receptors | Not applicable | Adrenaline reverses histamine in anaphylaxis; glucagon versus insulin |
| Chemical | Binds the drug itself | Not applicable | Protamine with heparin, chelators, digoxin Fab, sugammadex |
- Oxybutynin blocks M3 receptors on the detrusor, treating urge incontinence from detrusor overactivity; dry mouth and confusion are typical side effects.
- Allosteric modulators bind a separate site and change how the receptor responds to its own ligand. Benzodiazepines are positive allosteric modulators of GABA-A: they raise the frequency of chloride channel opening only when GABA is present, which gives a ceiling effect. Barbiturates prolong opening and can open the channel directly, so they are more dangerous; alcohol removes the benzodiazepine safety margin.
Enzyme inhibition by drugs
- Competitive inhibitors resemble the substrate and bind the active site; enough substrate overcomes them (Km rises, Vmax unchanged). Methotrexate mimics folate and binds dihydrofolate reductase. Leucovorin (folinic acid) rescue works because it is already reduced and bypasses the blocked step; folic acid cannot, as it still needs DHFR.
- Non-competitive inhibitors lower Vmax; irreversible inhibitors (aspirin, organophosphates, omeprazole) last until new enzyme is made.
Dose–response and therapeutic index
- Graded curves describe the size of effect in one person; quantal curves describe the fraction of a population responding (ED50, TD50, LD50). Spare receptors allow a full response with only some receptors occupied.
- Therapeutic index = TD50 ÷ ED50 (LD50 ÷ ED50 in animals). With TD50 400 mg/kg and ED50 20 mg/kg, TI = 20. Higher is safer.
- Narrow therapeutic index: warfarin, digoxin, lithium, theophylline, aminoglycosides, phenytoin, ciclosporin; these need level monitoring.
- Therapeutic window: the concentration range between minimum effective and minimum toxic levels.
Changes in response
- Tachyphylaxis: rapid loss of effect after a few doses, from depleted transmitter stores (ephedrine, tyramine, amphetamine) or nitrates.
- Tolerance: gradual loss over time (opioids, benzodiazepines, alcohol, nitrates needing a nitrate-free period).
- Down-regulation with chronic agonists (beta-2); up-regulation with antagonists, so stopping a beta-blocker abruptly causes rebound tachycardia and angina.
- Synergism: greater than additive. Potentiation is when one drug has no effect alone but boosts another (carbidopa with levodopa, clavulanic acid with amoxicillin).
- Idiosyncrasy: genetically determined abnormal response.
Drug development
- Phase I: healthy volunteers, safety and kinetics. Phase II: patients, efficacy and dose. Phase III: large randomised controlled trials against standard care. Phase IV: post-marketing surveillance for rare adverse effects (yellow card reports).
Remember Potency is where the curve sits; efficacy is how high it goes.
Exam trap A competitive antagonist shifts the curve right without lowering the maximum; an irreversible one lowers the maximum.
Exam trap A partial agonist given with a full agonist behaves as an antagonist (buprenorphine can precipitate withdrawal).
How FCPS asks about this
- Therapeutic index with TD50 400 and ED50 20 mg/kg: 20.
- Second messenger of alpha-1 receptors: Gq, phospholipase C, IP3 and DAG; cGMP is used by nitric oxide and ANP.
- How benzodiazepines act: positive allosteric modulators of GABA-A.
- Methotrexate's inhibition type: competitive, at the DHFR active site; folinic acid bypasses it.
- Non-sedating anxiolytic taking two weeks: buspirone, a 5-HT1A partial agonist.
- Drugs for overactive bladder: oxybutynin (M3 antagonist) or mirabegron (beta-3 agonist); bromocriptine is a D2 agonist.
- Electrolyte change with repeated salbutamol: hypokalaemia; alprostadil keeps the duct open in transposition.
Test yourself on this topic
5 of the 84 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
How does an irreversible (non-competitive) antagonist such as phenoxybenzamine change the agonist dose-response curve?
Answer: Lowers the maximum response
A competitive (reversible) antagonist binds the same site as the agonist; raising agonist concentration overcomes it, so the curve shifts right (EC50 rises) with the same maximum (e.g. propranolol, atropine, naloxone). An irreversible or non-competitive antagonist inactivates receptors (covalent binding, as with phenoxybenzamine, or allosteric binding), so the maximal response falls and cannot be restored by more agonist; if spare receptors exist, a right shift may occur first. Phenoxybenzamine is used for phaeochromocytoma before surgery.
Antagonists
- Competitive: right shift, same max (surmountable)
- Irreversible/non-competitive: lower max (insurmountable)
- Example: phenoxybenzamine (phaeochromocytoma)
Remember Competitive moves the curve; irreversible flattens it.
Why the other options are wrong
- Right shift, same maximum That is a competitive antagonist.
- Shifts the curve left That would be a sensitiser.
- Raises the maximum response Not possible for an antagonist.
- No effect on the curve It reduces the response.
A newborn with transposition of the great arteries becomes more cyanosed as the ductus arteriosus starts to close. Which drug keeps the duct open?
Answer: Alprostadil (PGE1)
The ductus arteriosus is kept open in fetal life by low oxygen and prostaglandin E2 from the placenta. After birth, rising oxygen and falling prostaglandins close it within days. In duct-dependent lesions (transposition, pulmonary atresia, critical coarctation), a prostaglandin E1 infusion keeps it open; apnoea is the main side effect. NSAIDs and paracetamol close it in preterm babies with PDA.
Ductus arteriosus
- From left sixth arch
- Open: low O₂, prostaglandins
- Keep open: PGE1 (alprostadil)
- Close: indomethacin, ibuprofen
Remember Prostaglandins open; NSAIDs shut.
Exam trap Watch for apnoea when starting prostaglandin E1.
Why the other options are wrong
- IV indomethacin Closes the duct.
- Oral ibuprofen Closes the duct.
- IV paracetamol Can close the duct.
- IV digoxin Not for the duct.
Natural GnRH is a decapeptide with a plasma half-life of only a few minutes, whereas leuprorelin and goserelin act for hours to weeks. Which structural change underlies the longer action of these agonists?
Answer: D-amino acid substitution at position 6
In native GnRH the bond between positions 6 (glycine) and 7 is the main site cleaved by peptidases. Agonists replace glycine-6 with a bulky D-amino acid and often modify the C-terminal position 10 (ethylamide). This resists enzymatic breakdown and stabilises the active shape, raising receptor affinity and prolonging half-life. Depot formulations (implants, microspheres) then release the drug steadily, producing the continuous stimulation that down-regulates the receptor.
GnRH agonist design
- Native GnRH: decapeptide, minutes
- Position 6: D-amino acid
- Position 10: ethylamide
- Result: resistant to peptidases
Remember Change position 6 and the peptide lasts.
Exam trap Long action plus depot release gives continuous exposure, which is why agonists suppress.
Why the other options are wrong
- Addition of a steroid side chain GnRH analogues are peptides, not steroids.
- Conversion to a cyclic glycoprotein They remain small linear peptides.
- Removal of the pyroglutamate end The pyroglutamate end is kept.
- Coupling to an albumin carrier Not how standard agonists are made.
A woman with heart disease in preterm labour at 30 weeks cannot take nifedipine or beta-agonists because of their cardiovascular effects. She is given an intravenous peptide tocolytic with few maternal side effects. How does it act?
Answer: Oxytocin receptor antagonist
Atosiban is a peptide analogue of oxytocin that competitively blocks oxytocin (and vasopressin V1a) receptors on the myometrium. It reduces IP3-mediated calcium release and the frequency of contractions. Because oxytocin receptors are concentrated in the uterus, it has few cardiovascular side effects, unlike nifedipine (hypotension, tachycardia) or beta-agonists (tachycardia, pulmonary oedema). It is used to delay delivery long enough for corticosteroids.
Tocolytics
- Atosiban: oxytocin antagonist
- Nifedipine: calcium channel blocker
- Terbutaline: beta-2 agonist
- Indomethacin: COX inhibitor
Remember Atosiban blocks oxytocin at its receptor.
Exam trap Tocolytics buy time for steroids; they do not improve outcome by themselves.
Why the other options are wrong
- Calcium channel blocker That is nifedipine.
- Beta-2 receptor agonist That is terbutaline or ritodrine.
- Cyclooxygenase inhibitor That is indomethacin.
- Nitric oxide donor That is glyceryl trinitrate.
A woman with a poor urinary stream and high residual volume has urodynamic evidence of bladder neck obstruction with normal detrusor contractions. She improves on tamsulosin. On which receptors does this drug act?
Answer: Alpha-1 receptors at the bladder neck
The bladder neck and proximal urethra contain smooth muscle rich in alpha-1 (mainly alpha-1A) adrenoceptors. Sympathetic fibres from T11–L2 contract this muscle during bladder filling to help continence. Tamsulosin blocks these receptors, relaxing the bladder neck and lowering outflow resistance. Alpha agonists, such as decongestants, can do the opposite and precipitate retention.
Bladder outlet receptors
- Bladder neck: alpha-1A
- Sympathetic T11–L2
- Tamsulosin relaxes the outlet
- Alpha agonists can cause retention
Remember Alpha-1 tone keeps the bladder neck closed.
Exam trap Tamsulosin commonly causes postural hypotension, especially with the first dose.
Why the other options are wrong
- Muscarinic M3 receptors on the detrusor Blocking M3 would weaken voiding.
- Beta-3 receptors on the detrusor Beta-3 agonists relax the detrusor during storage.
- Nicotinic receptors on the sphincter The external sphincter is striated muscle with nicotinic receptors; tamsulosin does not act there.
- Dopamine receptors in the urethra Not the target.
Where this sits in the CPSP syllabus
- Paper 1: General pharmacology, Pharmacodynamics: receptors, agonists, antagonists, potency, efficacy, therapeutic index
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