Key Facts

Pharmacodynamics provides the theoretical framework for understanding how drugs produce their effects. Combined with pharmacokinetics, it enables rational prescribing and prediction of drug effects, side effects, and interactions.

Receptor Theory

• Drugs produce effects by interacting with biological targets — mostly receptors, but also enzymes, ion channels, and transporters
• Affinity: ability of drug to bind to receptor
• Intrinsic activity (efficacy at receptor): ability of drug-receptor complex to produce a response
• Agonist: has affinity AND intrinsic activity
• Antagonist: has affinity but NO intrinsic activity

Dose-Response Relationships

• Graded dose-response: increasing dose → increasing response in an individual
• Quantal dose-response: percentage of population responding at each dose
• ED50: dose producing 50% maximal effect
• TD50: dose causing toxicity in 50% of population
• LD50: dose causing death in 50% (animal studies)
• Therapeutic index = TD50/ED50 (or LD50/ED50)

Signal Transduction

Four major receptor superfamilies:

1. Ligand-gated ion channels (ionotropic): fastest response (milliseconds) — e.g. nicotinic ACh receptor, GABA_A receptor
2. G-protein coupled receptors (GPCRs): seconds — e.g. beta-adrenoceptors, muscarinic receptors, opioid receptors
3. Tyrosine kinase-linked receptors: minutes to hours — e.g. insulin receptor, growth factor receptors
4. Nuclear/intracellular receptors: hours to days — e.g. steroid receptors, thyroid hormone, vitamin D

Pathophysiology of Altered PD

• Receptor up-regulation: chronic antagonism → increased receptors → rebound on withdrawal (e.g. beta-blocker withdrawal → rebound tachycardia)
• Receptor down-regulation: chronic agonism → decreased receptors → tolerance (e.g. opioid tolerance)
• Desensitisation: rapid loss of receptor response — e.g. tachyphylaxis with repeated GTN use

Clinical Application

• Understanding PD guides drug selection, predicts side effects, and explains drug interactions
• Agonist examples: salbutamol (beta-2 agonist), morphine (mu-opioid agonist), insulin (tyrosine kinase)
• Antagonist examples: propranolol (beta-blocker), naloxone (opioid antagonist), losartan (AT1 antagonist)
• Partial agonist examples: buprenorphine (mu-opioid partial agonist — ceiling effect reduces overdose risk), aripiprazole (D2 partial agonist)
• Inverse agonist: reduces constitutive receptor activity — e.g. some antihistamines at H1 receptor

Side Effects Explained by PD

• Beta-blocker → bronchospasm (beta-2 antagonism in airways)
• Atropine → dry mouth, constipation, urinary retention (muscarinic antagonism)
• SSRIs → serotonin syndrome with other serotonergic drugs (excessive 5-HT stimulation)

Red Flags

• Serotonin syndrome: agitation, clonus, hyperthermia, tachycardia — multiple serotonergic drugs
• Neuroleptic malignant syndrome: rigidity, hyperthermia, autonomic instability — dopamine antagonists
• Beta-blocker withdrawal: rebound hypertension, tachycardia, angina — receptor up-regulation
• Opioid tolerance then interruption: acute withdrawal syndrome — receptor up-regulation + loss of tolerance

Clinical Assessment

• Drug response monitoring: BP (antihypertensives), HR (beta-blockers), INR (warfarin), blood glucose (insulin)
• Therapeutic drug monitoring: for narrow TI drugs — levels help assess PK but clinical response reflects PD

Pharmacogenomics Relevant to PD

• CYP2D6 polymorphisms: affect activation of pro-drugs (codeine → morphine) — PK that impacts PD
• Beta-2 receptor polymorphisms: may affect response to beta-agonists in asthma
• Warfarin sensitivity: VKORC1 polymorphisms affect warfarin PD target sensitivity

Special Tests

• Receptor binding studies: research tools — not routine clinical practice
• Dose-response assessment: titrating drug doses clinically based on observed effect

Principles of PD-Guided Prescribing

• Select appropriate target: choose drug class based on pathophysiology
• Consider receptor selectivity: selective drugs → fewer side effects (e.g. selective beta-1 blocker bisoprolol vs non-selective propranolol)
• Titrate to response: start low, increase to therapeutic effect while monitoring for side effects
• Avoid polypharmacy with same mechanism: excessive receptor stimulation/blockade

Managing PD-Related Problems

• Tolerance: rotate drugs (opioid rotation), drug holidays (GTN-free intervals 8–12 hours)
• Rebound: taper gradually rather than abrupt withdrawal (beta-blockers, corticosteroids, benzodiazepines)
• Drug interactions (PD): avoid combining serotonergic drugs; caution with QT-prolonging drugs; avoid additive CNS depression

Clinical Applications

• Reversal agents: naloxone for opioid overdose, flumazenil for benzodiazepine overdose (caution: seizure risk), protamine for heparin
• Antidote prescribing: N-acetylcysteine for paracetamol (replenishes glutathione — enzyme target)

Referral Criteria

• Clinical pharmacology: complex drug interactions, unexpected drug responses, pharmacogenomic assessment
• Toxicology: drug overdose, poisoning management

• Understanding PD improves prescribing safety and efficacy
• Narrow therapeutic index drugs: require careful dose titration and monitoring — toxicity can be fatal
• Receptor up/down-regulation: explains withdrawal phenomena and tolerance — important for safe prescribing
• Pharmacogenomics: increasingly guides individualised therapy — improves outcomes and reduces adverse effects

Receptor Superfamilies

Key PD Terms