Stages of Drug Development and Role of Post-Marketing Surveillance
Standard Answer:
(2023 Main; also “Briefly describe the process of drug development” — 2021 Resit) Stages of drug development 1. Drug discovery – identification of a lead compound through target identification, high-throughput screening, natural product isolation, or rational/computer-aided drug design. 2. Preclinical testing – in-vitro and animal studies to assess pharmacodynamics, pharmacokinetics (ADME), and toxicology (acute, sub-acute, chronic toxicity, carcinogenicity, teratogenicity). Determines the No Observed Adverse Effect Level (NOAEL) and a starting human dose. 3. Filing of an Investigational New Drug (IND) application with the regulatory authority (e.g., FDA/NAFDAC) before human trials begin. 4. Clinical trials (human testing) ◦ Phase I – small number (20–100) of healthy volunteers; establishes safety, tolerability, pharmacokinetics, and dose range. ◦ Phase II – few hundred patients with the target disease; establishes efficacy and further safety, determines optimal dosing (sometimes split IIa/IIb). ◦ Phase III – large-scale randomized controlled trials (hundreds to thousands of patients); confirms efficacy, monitors adverse effects, compares with standard treatment. Data from this phase supports the New Drug Application (NDA)/ marketing authorization. 5. Regulatory review and approval – the regulatory body reviews all preclinical and clinical data before granting a license for marketing. 6. Phase IV – Post-marketing surveillance (pharmacovigilance) – conducted after the drug is approved and in general use. Role of post-marketing surveillance • Detects rare adverse effects (incidence <1/1000) that Phase III trials, limited in size and duration, cannot reliably detect. • Identifies adverse effects that occur only after long-term use, in special populations (pregnant women, children, the elderly, patients with comorbidities) excluded from pre-approval trials. • Detects drug interactions that emerge only with widespread, real-world polypharmacy. • Assesses long-term efficacy and effectiveness outside the controlled trial setting. • Relies on spontaneous reporting systems (e.g., the Yellow Card Scheme in the UK, MedWatch in the US, NAFDAC pharmacovigilance in Nigeria), cohort and case-control studies, and prescription-event monitoring. Examples • Thalidomide – teratogenicity (phocomelia) was detected only after widespread marketing, leading to the strengthening of pharmacovigilance systems globally. • Rofecoxib (Vioxx) – increased risk of myocardial infarction and stroke detected through post-marketing surveillance (VIGOR trial follow-up), leading to voluntary withdrawal in 2004. • Cerivastatin – withdrawn after post-marketing reports of fatal rhabdomyolysis, particularly in combination with gemfibrozil. • Troglitazone – withdrawn after reports of severe hepatotoxicity emerged post-marketing.
Advantages and Disadvantages of Oral vs Intravenous Routes
Standard Answer:
(2023 Main; “Classify routes of administration; merits/demerits of oral and parenteral” — 2022 Main; 2018) Feature Oral Route Intravenous Route Onset of action Slow (subject to absorption, Immediate/rapid — ideal for emergencies first-pass metabolism) Convenience Self-administered, painless, Requires trained personnel, aseptic convenient technique Bioavailability Variable, reduced by first-pass 100% (bypasses absorption entirely) metabolism Dose control/ Difficult to titrate precisely Easy to titrate; can stop infusion titration immediately if toxicity occurs Cost Cheap More expensive (equipment, personnel, sterile preparation) Suitability Suitable for most chronic/ Suitable for emergencies, unconscious/ maintenance therapy vomiting patients, irritant drugs Drug Subject to gastric acid, Avoids gut and hepatic first-pass destruction enzymatic degradation, food destruction interactions Reversibility Can be limited by gastric Cannot easily “retrieve” drug once given lavage/activated charcoal if — risk of irreversible toxicity/anaphylaxis recent Large volumes Not applicable Can administer large fluid volumes and sustain constant plasma levels via infusion Risks Nausea, GI irritation, Infection, thrombophlebitis, embolism, unpredictable absorption in requires strict asepsis, fluid overload disease states Patient Better for outpatients/self-care Requires hospital/clinical setting, poor for compliance long-term outpatient use Classification of routes of drug administration (for the broader 2022 question): Broadly divided into: • Enteral – oral, sublingual/buccal, rectal • Parenteral – intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intra-arterial • Topical/local – transdermal, inhalational, ophthalmic, intranasal, vaginal 3 & Related. Indirect-Acting Cholinomimetics (Anticholinesterases) (Recurs extensively: 2023 Main, 2022 Main, 2021 Main, 2021 Resit, 2018/19, 2015, 2014, 2013, 2011, 2010) Classification (by duration/reversibility of enzyme inhibition): • Reversible (short-acting) – Edrophonium • Reversible (medium-duration, carbamylating) – Physostigmine, Neostigmine, Pyridostigmine, Rivastigmine • Irreversible (organophosphates) – Echothiophate, Malathion, Parathion, Dichlorvos, Sarin, Tabun (nerve agents) Mechanism of action Anticholinesterases inhibit acetylcholinesterase (AChE), the enzyme that hydrolyses acetylcholine (ACh) at the synaptic cleft, thereby increasing the concentration and duration of action of endogenous ACh at both muscarinic and nicotinic receptors. • Reversible agents bind the esteratic/anionic site of AChE, forming a carbamylated enzyme complex that hydrolyses slowly (minutes to hours), temporarily inactivating the enzyme. • Organophosphates phosphorylate the serine hydroxyl at the active site, forming a highly stable bond. With time, the phosphorylated enzyme undergoes “aging” (loss of an alkyl group), after which the inhibition becomes permanent and irreversible — recovery requires synthesis of new enzyme. • Edrophonium binds by electrostatic/hydrogen bonding at the anionic site only (no covalent bond), giving a very short duration of action (~10 minutes) — used diagnostically. Pharmacological/clinical effects Increased ACh leads to: miosis, increased salivation/sweating/lacrimation, increased GI motility and secretions, bronchoconstriction, bradycardia, increased neuromuscular transmission (skeletal muscle contraction). Clinical uses • Myasthenia gravis – Pyridostigmine, Neostigmine (increase ACh at neuromuscular junction to improve muscle strength) • Diagnosis of myasthenia gravis – Edrophonium (Tensilon test) • Reversal of non-depolarizing neuromuscular blockade post-surgery – Neostigmine (with atropine/glycopyrrolate to prevent muscarinic side effects) • Glaucoma – Physostigmine, Echothiophate (topical miotics, reduce intraocular pressure) • Paralytic ileus and urinary retention (atony) – Neostigmine, Bethanechol (indirect action) • Alzheimer’s disease – Rivastigmine, Donepezil, Galantamine (CNS-penetrant, improve central cholinergic transmission) • Antidote to antimuscarinic (atropine) poisoning – Physostigmine (crosses blood-brain barrier) Organophosphate (nerve agent/insecticide) toxicity — symptoms, signs, treatment (2021 Main, “Highlight the symptoms, signs and drug treatment of organophosphate poisoning”) • Muscarinic effects (DUMBELS mnemonic): Diarrhoea, Urination, Miosis, Bradycardia/ Bronchorrhoea/Bronchospasm, Emesis, Lacrimation, Salivation. • Nicotinic effects: muscle fasciculations, weakness, paralysis, tachycardia, hypertension. • CNS effects: anxiety, confusion, seizures, coma, respiratory center depression. • Cause of death: respiratory failure from a combination of bronchospasm/ bronchorrhoea, neuromuscular (respiratory muscle) paralysis, and central respiratory depression. Treatment 1. Decontamination – remove clothing, wash skin. 2. Atropine – competitively blocks muscarinic receptors; given in large, repeated doses titrated to drying of secretions (not pupil size). 3. Pralidoxime (2-PAM) – reactivates AChE by removing the phosphate group from the enzyme, but only effective before “aging” occurs; regenerates functional enzyme, reversing both muscarinic and nicotinic effects (especially neuromuscular). 4. Diazepam – for seizure control. 5. Supportive care: airway management, ventilation.
Drugs Influencing Cholinergic Neurohumoral Transmission
Standard Answer:
(2021 Resit, 2021 Main [via termination], 2015) Steps in cholinergic transmission and how drugs act at each: 1. Synthesis – Choline + Acetyl-CoA → ACh, by choline acetyltransferase (ChAT). Hemicholinium blocks choline reuptake into the nerve terminal, reducing synthesis (research tool only). 2. Storage – ACh stored in synaptic vesicles. Vesamicol blocks vesicular ACh transporter (research tool). 3. Release – Ca²⁺-dependent exocytosis upon depolarization. Botulinum toxin blocks release (used therapeutically for dystonia, spasticity, cosmetic use); Black widow spider venom causes massive release. 4. Receptor interaction – ◦ Muscarinic receptor agonists (e.g., bethanechol, pilocarpine, carbachol) and antagonists (atropine, hyoscine, ipratropium). ◦ Nicotinic receptor agonists (nicotine, succinylcholine) and antagonists (tubocurarine, atracurium — competitive; succinylcholine at the depolarizing phase). 5. Termination – ACh is hydrolysed by acetylcholinesterase in the synaptic cleft into choline and acetate. Anticholinesterases (as above) prolong action by inhibiting this step.
Classification of Drugs Blocking Cholinergic Receptors
Standard Answer:
(Antimuscarinics/Antinicotinics) (2021 Resit, 2018/19, 2010) A. Antimuscarinic agents (muscarinic receptor antagonists) • Naturally occurring: Atropine, Hyoscine (scopolamine) • Semi-synthetic/synthetic — quaternary (poor CNS penetration): Ipratropium, Tiotropium, Glycopyrrolate, Propantheline • Synthetic — tertiary (CNS-penetrant): Benztropine, Trihexyphenidyl (used in Parkinsonism), Oxybutynin, Tolterodine, Tropicamide, Cyclopentolate One use each of four antimuscarinic agents: 1. Atropine – pre-anaesthetic medication to reduce secretions and prevent vagal bradycardia; also as antidote in organophosphate/cholinergic poisoning. 2. Ipratropium bromide – bronchodilator in COPD and asthma (inhaled, minimal systemic absorption). 3. Tropicamide/Cyclopentolate – mydriasis and cycloplegia for ophthalmic examination. 4. Oxybutynin/Tolterodine – overactive bladder (urge incontinence). 5. Benztropine/Trihexyphenidyl – Parkinsonism and drug-induced extrapyramidal symptoms. 6. Hyoscine (scopolamine) – motion sickness, pre-anaesthetic sedation. B. Ganglion blockers (nicotinic Nₙ antagonists) – Trimethaphan, Hexamethonium (largely historical, used in hypertensive emergencies/controlled hypotension). C. Neuromuscular blockers (nicotinic Nₘ antagonists) — see Q6 below.
Neuromuscular Blockers — Classification and Succinylcholine Mechanism
Standard Answer:
(2022 Main, 2021 Main, 2013 — recurs heavily) Classification • Non-depolarizing (competitive) blockers ◦ Long-acting: Tubocurarine, Pancuronium ◦ Intermediate-acting: Vecuronium, Rocuronium, Atracurium, Cisatracurium ◦ Short-acting: Mivacurium • Depolarizing blockers ◦ Succinylcholine (suxamethonium) — the only clinically used agent in this class. Mechanism of non-depolarizing agents: Competitively block ACh at the nicotinic (Nₘ) receptor on the motor end-plate without activating it, preventing depolarization and muscle contraction. Reversible with anticholinesterases (neostigmine), which increase ACh to out-compete the blocker. Mechanism of succinylcholine (depolarizing): • Structurally resembles two ACh molecules joined together; binds and activates nicotinic receptors, causing sustained depolarization of the motor end-plate. • Phase I (depolarizing) block – sustained depolarization → initial transient fasciculations, then flaccid paralysis because the end-plate cannot repolarize and respond to further ACh release (receptor remains open/inactivated). • Unlike ACh, succinylcholine is not rapidly hydrolysed by acetylcholinesterase at the synapse; it is instead slowly hydrolysed by plasma pseudocholinesterase (butyrylcholinesterase), so depolarization is prolonged. • With prolonged exposure, a Phase II (desensitizing) block may develop, resembling a non-depolarizing block, which is not reversed (and may be worsened) by anticholinesterases. • Clinical use: rapid-sequence intubation (rapid onset ~30–60 sec, short duration ~5–10 min) due to rapid hydrolysis by pseudocholinesterase. • Adverse effects: hyperkalemia (dangerous in burns, spinal cord injury, neuromuscular disease), malignant hyperthermia (with volatile anaesthetics), prolonged apnoea in patients with atypical/deficient pseudocholinesterase, postoperative muscle pain (from initial fasciculations), bradycardia. Pancuronium (asked specifically, 2010): long-acting non-depolarizing blocker; competitive antagonist at Nₘ receptors; vagolytic effect causes tachycardia; excreted mostly unchanged renally.
Termination of Adrenergic Action — Modulation for Clinical Use
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(Recurs across nearly every year: 2023 Resit, 2022 Main, 2021 Main, 2021 Resit, 2017, 2013, 2012, 2011, 2010) Major means of termination of adrenergic (noradrenergic) neurotransmission: 1. Reuptake-1 (neuronal uptake) – via Norepinephrine Transporter (NET) back into the presynaptic terminal — the major mechanism (~90% of released NE). 2. Reuptake-2 (extraneuronal uptake) – into postsynaptic/glial/other cells (minor pathway). 3. Enzymatic degradation: ◦ Monoamine oxidase (MAO) – located intraneuronally (mitochondria); metabolizes NE that re-enters the neuron. ◦ Catechol-O-methyltransferase (COMT) – located extraneuronally (e.g., liver); metabolizes circulating catecholamines. 4. Diffusion away from the synapse (minor contribution). Clinical modulation of each step and its therapeutic application: Mechanism Drug(s) Effect Clinical use modulated Block NET Tricyclic antidepressants ↑ synaptic NE Depression (TCAs); (reuptake-1) (imipramine), Cocaine, ADHD (atomoxetine) Atomoxetine Inhibit MAO Phenelzine, ↑ intraneuronal Depression, Parkinson’s Tranylcypromine (non- NE/monoamines disease (selegiline) selective); Selegiline (MAO-B selective) Inhibit COMT Entacapone, Tolcapone ↑ availability of Adjunct in Parkinson’s levodopa/ disease dopamine peripherally Deplete NE Reserpine (blocks VMAT, ↓ NE release Historically hypertension stores prevents vesicular (largely obsolete due to storage) depression side effect) Prevent NE Guanethidine (displaces ↓ sympathetic Historical antihypertensive release NE, blocks release) outflow Adverse effects of this modulation: TCAs and MAO inhibitors can cause hypertensive crisis (especially MAO inhibitors with tyramine-containing foods — “cheese reaction”), postural hypotension, sedation, anticholinergic effects (TCAs). This is the same underlying concept tested repeatedly as “termination of adrenergic action” — the answer above applies to all repeated instances of this question across years.
Adrenergic Agents — Classification, Receptor Sites
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(2013 — “Classification of Adrenergic agents”; “Sites, agonists and antagonists of adrenergic receptors”) Classification of adrenergic agents: • Direct-acting agonists – act directly on adrenoreceptors: Norepinephrine, Epinephrine, Isoproterenol (non-selective); Phenylephrine (α1); Clonidine (α2); Dobutamine (β1); Salbutamol/Terbutaline (β2) • Indirect-acting agonists – cause release of endogenous NE: Amphetamine, Tyramine • Mixed-acting agonists – both direct action and NE release: Ephedrine, Metaraminol • Antagonists (blockers): ◦ α-blockers: Prazosin (α1-selective), Phentolamine (non-selective, reversible), Phenoxybenzamine (non-selective, irreversible) ◦ β-blockers: Propranolol (non-selective), Atenolol/Metoprolol (β1-selective, cardioselective), Labetalol/Carvedilol (mixed α/β) Receptor sites and effects: • α1 – vascular smooth muscle (vasoconstriction), radial muscle of iris (mydriasis), bladder trigone/sphincter (contraction) • α2 – presynaptic nerve terminals (inhibits further NE release, negative feedback); also some postsynaptic CNS sites (sympatholytic, e.g., clonidine) • β1 – heart (↑ rate, ↑ contractility, ↑ conduction velocity); juxtaglomerular cells (↑ renin release) • β2 – bronchial, vascular, and uterine smooth muscle (relaxation/bronchodilation, vasodilation, tocolysis); skeletal muscle (glycogenolysis, tremor) • β3 – adipose tissue (lipolysis), detrusor muscle (relaxation) Uses of α-adrenoreceptor blocking agents (2012): • Prazosin, Terazosin, Doxazosin – hypertension; benign prostatic hyperplasia (relax prostatic/bladder neck smooth muscle) • Phentolamine – pheochromocytoma (pre-operative and crisis management), hypertensive emergencies from catecholamine excess (e.g., cocaine toxicity, MAOI-tyramine interaction), reversal of local anaesthetic-induced vasoconstriction • Phenoxybenzamine – long-term preoperative preparation for pheochromocytoma • Tamsulosin – benign prostatic hyperplasia (uroselective, minimal cardiovascular effect) Cardioselective (β1-selective) blockers (2013): Atenolol, Metoprolol, Bisoprolol, Esmolol — preferentially block β1 receptors in the heart at lower doses, reducing risk of bronchospasm compared to non-selective agents, making them preferred in patients with COPD/asthma who require β-blockade (e.g., post-MI, heart failure, hypertension).
Prazosin — Effects and Adverse Effects
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(2018/2019) Effects: α1-selective antagonist → vasodilation (arterial and venous) → ↓ peripheral vascular resistance and ↓ blood pressure; relaxes prostatic and bladder neck smooth muscle (used in BPH); improves lipid profile modestly (↓ LDL, ↑ HDL) compared to other antihypertensives. Adverse effects: • First-dose phenomenon – profound orthostatic hypotension and syncope after the first dose (mitigated by starting at a low bedtime dose) • Dizziness, headache, palpitations (reflex tachycardia, though less than with non-selective vasodilators) • Nasal congestion • Fluid retention/oedema with chronic use • Priapism (rare)
Tachyphylaxis and Tolerance
Standard Answer:
(2018/2019) • Tachyphylaxis – rapid development of diminished response to a drug after repeated doses given over a short period (minutes to hours), often due to receptor desensitization, depletion of mediator stores, or receptor internalization. Example: repeated doses of indirect sympathomimetics like ephedrine cause tachyphylaxis due to depletion of releasable NE stores. • Tolerance – a gradual decrease in response to a drug developing over days to weeks of continued use, requiring escalating doses to achieve the same effect. Mechanisms include pharmacokinetic (enzyme induction, e.g., barbiturates), pharmacodynamic (receptor downregulation/desensitization, e.g., opioids, nitrates), and behavioral tolerance. Example: tolerance to opioid analgesia and to nitrate-induced vasodilation.
Pyridostigmine — Mechanism
Standard Answer:
(2018/2019) Reversible anticholinesterase; carbamylates the esteratic site of acetylcholinesterase, temporarily inactivating the enzyme and increasing ACh availability at the neuromuscular junction. Used in myasthenia gravis to improve muscle strength; has a longer duration of action than neostigmine and better oral bioavailability, making it preferred for chronic maintenance therapy.
Depolarizing Neuromuscular Blockers, Sequential Inhibition, Antibiotic Selection, Advantages of Combination Therapy
Standard Answer:
(2018/2019 — “write notes on”) a. Depolarizing neuromuscular blockers: See succinylcholine mechanism above (Q6). Key features: initial fasciculations followed by flaccid paralysis; not reversed (may be worsened) by anticholinesterases; metabolized by plasma pseudocholinesterase; risk of hyperkalemia and malignant hyperthermia. b. Sequential inhibition (sequential blockade): A form of synergism in antimicrobial chemotherapy where two drugs inhibit sequential steps of the same metabolic pathway, producing a bactericidal/more potent effect than either drug alone, and reducing the emergence of resistance. Classic example: Trimethoprim–sulfamethoxazole (cotrimoxazole) — sulfamethoxazole inhibits dihydropteroate synthase (blocking incorporation of PABA into folic acid), while trimethoprim inhibits dihydrofolate reductase (blocking conversion of dihydrofolate to tetrahydrofolate) — sequential blockade of folate synthesis, resulting in bactericidal synergy. c. Antibiotic selection (selection of antimicrobial therapy): Rational choice of an antibiotic depends on: identification of the causative organism (culture and sensitivity), site of infection (tissue penetration, e.g., CNS requires agents crossing the blood-brain barrier), host factors (renal/hepatic function, pregnancy, age, allergy, immune status), pharmacokinetic profile of the drug, spectrum of activity (narrow vs broad), cost, and local resistance patterns. d. Advantages of combination antimicrobial therapy: • Broadens the spectrum of coverage for mixed/unidentified infections (empirical therapy) • Prevents or delays the emergence of resistance (e.g., in TB treatment) • Achieves synergistic or additive bactericidal effect (e.g., sequential blockade, β-lactam + aminoglycoside) • Allows dose reduction of individual toxic drugs • Treats polymicrobial infections effectively
General Mechanisms of Drug Action, Bioavailability, First-Pass Effect, Volume of Distribution
Standard Answer:
(2018) a. General mechanisms of drug action: 1. Action on receptors – agonists, antagonists, partial agonists (most drugs) 2. Action on enzymes – inhibition (e.g., ACE inhibitors, statins) or activation 3. Action on ion channels – direct blockade (local anaesthetics on Na⁺ channels) or modulation via receptors 4. Action on transport systems/carriers – e.g., SSRIs block serotonin reuptake transporter 5. Non-receptor mediated (physicochemical) mechanisms – e.g., antacids neutralizing gastric acid, osmotic diuretics, chelating agents b. Bioavailability, first-pass effect, factors affecting absorption: • Bioavailability (F) – the fraction of an administered dose that reaches the systemic circulation unchanged. IV bioavailability = 100% (reference standard). • First-pass effect – metabolism of a drug (by gut wall and/or liver) after oral absorption and before it reaches systemic circulation, reducing the amount of active drug available systemically. Drugs with high first-pass metabolism (e.g., propranolol, lidocaine, nitroglycerin, morphine) show markedly reduced oral bioavailability. • Factors affecting absorption: drug formulation (tablet, solution, enteric coating), lipid solubility and degree of ionization (pH-partition), particle size, GI motility and transit time, presence of food, GI blood flow, first-pass metabolism, P-glycoprotein efflux at the gut wall, and drug interactions (chelation, e.g., tetracyclines with calcium). Measures to circumvent first-pass metabolism (2010): • Sublingual or buccal administration (drains into systemic circulation via lingual/facial veins, bypassing portal circulation) — e.g., sublingual nitroglycerin • Rectal administration (partial bypass — lower rectal veins drain to inferior vena cava) • Parenteral routes (IV, IM, SC) • Transdermal administration • Inhalation c. Volume of distribution (Vd) and half-life: • Vd – the theoretical volume into which a drug appears to distribute, relating the amount of drug in the body to plasma concentration: Vd = Dose / C₀. • A high Vd implies extensive tissue distribution (e.g., lipophilic drugs, drugs bound to tissue proteins) — plasma concentration is low relative to total body drug. • A low Vd implies the drug is confined mainly to plasma/extracellular fluid (e.g., highly protein-bound or large hydrophilic drugs). • Relationship to half-life: t½ = 0.693 × Vd / Clearance. For a constant clearance, an increase in Vd prolongs the half-life (more drug is “hidden” in tissues, so it takes longer to clear from plasma). Conversely, an increase in clearance shortens half-life for a constant Vd.
Drug Development / Dean Isaiah Ibeh HIV “cure” and Deconcotion X Cases
Standard Answer:
(2013 — UNIBEN/NAFDAC scandal questions) These questions ask students to apply the scientific protocol for drug discovery, development, testing, and approval (see Q1 above) to critique an unverified therapeutic claim. Key points to discuss: • Any claimed cure must pass through preclinical validation (mechanism of action, animal toxicology and efficacy studies) before human use. • Human testing must follow Phase I–III clinical trials, with appropriate ethical approval, informed consent, and independent oversight (Institutional Review Boards/Ethics Committees). • Claims of efficacy require peer-reviewed publication and reproducibility by independent investigators. • Regulatory bodies (NAFDAC in Nigeria, FDA elsewhere) must review data and grant approval before a product can be marketed as a “cure.” • Bypassing these steps — as alleged in the “Deconcotion X”/Bioclean II case — violates scientific and ethical protocol, risking patient harm, false hope, and public health consequences, and is why regulatory bodies publicly dissociate from unverified claims.
Basic Pharmacological Terms
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(Recurs across nearly every year: 2017, 2016, 2014, 2013, 2011, 2010) • Agonist – a drug that binds a receptor and produces a biological response, having both affinity and efficacy (intrinsic activity = 1). • Partial agonist – binds the receptor and produces a submaximal response even at full receptor occupancy (intrinsic activity between 0 and 1); can act as an antagonist in the presence of a full agonist by competing for the receptor while producing less effect (e.g., buprenorphine, pindolol). • Antagonist – binds a receptor without producing a response (intrinsic activity = 0), blocking the action of agonists. • Inverse agonist – binds the same receptor as an agonist but produces the opposite effect, reducing constitutive receptor activity below baseline. • Affinity – the strength of binding of a drug to its receptor. • Intrinsic activity/efficacy – the ability of a drug-receptor complex to produce a maximal functional response. • Potency – the amount (dose/concentration) of drug required to produce a given effect; reflected by the position of the dose-response curve on the dose axis (EC50/ED50); more potent drugs produce the desired effect at lower doses. • Efficacy – the maximum effect (Emax) a drug can produce, regardless of dose; reflected by the height of the dose-response curve. • Bioavailability – fraction of administered dose reaching systemic circulation unchanged. • Tolerance – see Q10. • Therapeutic Index (TI) – ratio of the toxic dose to the effective dose (TD50/ED50 in animals, or LD50/ED50); larger TI = wider margin of safety. • Therapeutic window – the range of plasma concentrations between the minimum effective concentration and the minimum toxic concentration, within which the drug produces its desired effect without unacceptable toxicity. • Clearance – the volume of plasma from which a drug is completely removed per unit time. • Therapeutic equivalence – two formulations of a drug producing the same clinical effect when administered in the same dose. • Chemical equivalence – two formulations containing the same amount of the same active chemical substance, meeting the same standards. • Half-life (t½) – time taken for plasma drug concentration (or amount in the body) to fall by 50%. • First-order kinetics – rate of elimination is proportional to drug concentration (constant fraction eliminated per unit time); most drugs follow this. • Zero-order kinetics – rate of elimination is constant regardless of concentration (enzyme systems are saturated); e.g., ethanol, phenytoin (at high doses), aspirin (in overdose). • Side effect – an effect other than the intended therapeutic effect, occurring at normal therapeutic doses, may be predictable from the drug’s pharmacology (e.g., dry mouth with antimuscarinics). • Adverse effect – any undesirable/harmful effect of a drug, encompassing side effects and more serious reactions. • Toxic effect – a harmful effect resulting from excessive dose or accumulation, often an exaggeration of the pharmacological action (e.g., digoxin toxicity causing arrhythmias). • LD50 – the dose of a substance that is lethal to 50% of a test animal population; used to estimate acute toxicity and (with ED50) the therapeutic index. • Synergism – combined effect of two drugs is greater than the sum of their individual effects. • Addition (summation) – combined effect of two drugs equals the sum of their individual effects. • Potentiation – one drug (with little or no effect of its own on a particular action) enhances the effect of another drug. • Ion trapping – phenomenon where a weak acid or base becomes ionized (and thus “trapped,” unable to diffuse back across a membrane) in a compartment of pH that favors its ionized state; exploited therapeutically, e.g., alkalinizing urine (with sodium bicarbonate) to trap and enhance excretion of weak acids like aspirin or phenobarbital in overdose. • Receptor down-regulation – decrease in receptor number/density following prolonged exposure to an agonist, contributing to tolerance/desensitization. • Pharmacogenetics – study of genetically determined variation in drug response (e.g., slow vs fast acetylators affecting isoniazid metabolism; G6PD deficiency affecting risk of hemolysis with oxidant drugs).
Determining LD50 of a Substance
Standard Answer:
(2013, 2012, 2011) Definition: the dose that produces death in 50% of a test animal population under standard conditions. Method: groups of animals (e.g., rodents) are given a range of graded doses of the test substance; the percentage mortality at each dose is recorded and plotted (log dose vs. probit or percentage mortality), generating a sigmoid dose-response curve; the dose corresponding to 50% mortality is read off as the LD50. Arithmetic method of Kärber (2011): an alternative graphical/arithmetic method to estimate LD50 without full probit analysis, using the formula: LD50 = LD100 − [Σ(a × b) / n] where a = the interval between two successive doses, b = the mean number of dead animals at two successive doses, and n = the number of animals per group. This method requires fewer animals and computation than probit analysis. Used together with the ED50 (effective dose in 50%) to calculate the Therapeutic Index (TI = LD50/ED50).
Dose-Response Curve — Potency, Efficacy, Antagonism
Standard Answer:
(2021 Main, 2013, 2013 — recurs heavily) The dose-response curve plots the pharmacological effect (y-axis) against the log of drug dose/concentration (x-axis), typically producing a sigmoid curve. • Potency vs Efficacy: Potency is read from the position of the curve along the x-axis (a more potent drug’s curve lies to the left, reaching the same effect at a lower dose). Efficacy is read from the maximum height (Emax) of the curve — a drug with greater efficacy reaches a higher maximal effect regardless of dose required. • Competitive vs Non-competitive antagonism: ◦ Competitive (surmountable) antagonism – the antagonist binds reversibly to the same receptor site as the agonist; increasing agonist concentration can displace the antagonist and restore the maximal response. On the dose-response curve, this produces a parallel rightward shift of the curve with no change in Emax. ◦ Non-competitive (insurmountable) antagonism – the antagonist binds irreversibly, or at an allosteric site distinct from the agonist site, preventing receptor activation even at high agonist concentrations. This produces a downward shift in Emax, with the curve becoming flatter, and the shift is not reversed by increasing agonist dose. • Partial agonists vs Potentiation: A partial agonist has intrinsic activity between 0 and 1, producing a submaximal effect at full receptor occupancy — it may reduce a full agonist’s effect if given together (behaving as a competitive antagonist for the “extra” effect) while still producing some agonism itself. Potentiation, by contrast, describes one substance enhancing the effect of another substance beyond what either could achieve alone, without necessarily acting at the same receptor. • Efficacy and Potentiation (distinguishing intrinsic activity vs potentiation, 2013): Efficacy is an intrinsic property of a drug-receptor interaction (maximal effect achievable). Potentiation is an interaction between two different agents where one enhances the effect of the other — e.g., clavulanic acid potentiates amoxicillin by inhibiting β-lactamase, without having significant antibacterial activity of its own.
Concept of Drug Antagonism
Standard Answer:
(2014, 2013, 2011) Types of antagonism: 1. Pharmacological (receptor) antagonism – competitive or non-competitive, as above (e.g., naloxone vs morphine at opioid receptors). 2. Chemical antagonism – the two substances combine chemically, neutralizing the active drug (e.g., protamine sulfate neutralizing heparin; chelating agents like dimercaprol binding heavy metals). 3. Physiological (functional) antagonism – two agonists act at different receptors/ systems but produce opposite physiological effects, cancelling each other out (e.g., histamine causing bronchoconstriction and hypotension opposed by epinephrine’s bronchodilation and vasoconstriction via different receptors). 4. Pharmacokinetic antagonism – one drug alters the absorption, distribution, metabolism, or excretion of another, reducing its effect (e.g., enzyme inducers like rifampin reducing plasma levels of other drugs).
Phases and Factors Affecting Drug Metabolism
Standard Answer:
(2021 Resit, 2023 Resit) Phases of drug metabolism (biotransformation): • Phase I reactions – convert the drug into a more polar metabolite by introducing or exposing a functional group; mainly catalyzed by the cytochrome P450 (CYP450) system in the liver (and gut, lung, kidney). ◦ Oxidation – hydroxylation, dealkylation (most common; CYP450-mediated) ◦ Reduction – e.g., azo/nitro reduction ◦ Hydrolysis – e.g., ester and amide hydrolysis (esterases) ◦ Products may be active, inactive, or (rarely) more toxic than the parent drug. • Phase II reactions (conjugation) – the drug or its Phase I metabolite is conjugated with an endogenous substrate to form a highly polar, usually inactive compound suitable for excretion. ◦ Glucuronidation (most common — UDP-glucuronosyltransferases) ◦ Sulfation ◦ Acetylation (N-acetyltransferase — genetically variable, “fast” vs “slow” acetylators, relevant to isoniazid) ◦ Glutathione conjugation (important in detoxifying reactive metabolites, e.g., of paracetamol) ◦ Methylation Factors affecting drug metabolism: • Genetic factors (pharmacogenetics) – e.g., CYP2D6 polymorphisms (poor/ultra-rapid metabolizers), NAT2 acetylator status. • Age – neonates have immature hepatic enzyme systems; elderly have reduced hepatic blood flow and enzyme activity. • Liver disease – reduced hepatic metabolic capacity, portosystemic shunting. • Enzyme induction – e.g., rifampin, phenytoin, carbamazepine, chronic alcohol use — increase CYP450 synthesis, accelerating metabolism of co-administered drugs (and sometimes of itself, “auto-induction”). • Enzyme inhibition – e.g., cimetidine, ketoconazole, erythromycin, grapefruit juice — decrease metabolism, raising plasma levels of co-administered drugs. • Nutritional status – malnutrition (protein deficiency) impairs enzyme synthesis. • Route and other drugs (drug interactions). • Disease states – renal failure can reduce hepatic metabolism of some drugs; hyperthyroidism can increase metabolic rate. • Sex – some CYP isoforms show sex-based differences in activity. • Species/genetic differences in experimental context.
Chemistry of a Drug and Its Pharmacokinetic Profile
Standard Answer:
(2022 Main, 2012) Physicochemical properties of a drug determine its pharmacokinetic behaviour: • Lipid solubility – lipophilic drugs cross membranes more readily (better oral absorption, CNS penetration), while hydrophilic drugs require transporters or remain confined to extracellular compartments. • Molecular size – smaller molecules diffuse more readily across membranes and capillary pores. • Degree of ionization (pKa) and pH-partition hypothesis – only the un-ionized form of a weak acid/base crosses lipid membranes efficiently; the extent of ionization depends on the drug’s pKa relative to the pH of the environment (e.g., weak acids like aspirin are largely un-ionized and well absorbed in the acidic stomach; weak bases are better absorbed in the alkaline small intestine). • Protein binding – highly protein-bound drugs (e.g., warfarin) have restricted distribution to tissues and a smaller free (active) fraction; displacement interactions can transiently increase free drug and toxicity. • Chemical stability – susceptibility to gastric acid or enzymatic degradation (e.g., insulin, penicillin G are acid-labile and must be given parenterally or with special formulation). • Presence of specific functional groups – determine sites of metabolism (e.g., ester groups hydrolysed by esterases) and routes of excretion. These properties collectively determine a drug’s absorption, volume of distribution, rate/ route of metabolism, and route of excretion.
Ion Trapping, Therapeutic Window, Therapeutic Index, Receptor Theory
Standard Answer:
(2016, 2013 — “write short notes”) • Ion trapping – see Q15. • Therapeutic window/index – see Q15. • Receptor theory, receptor and non-receptor mediated drug actions: ◦ Receptor theory – drugs act by binding to specific macromolecular targets (receptors), producing a conformational change that triggers a biological effect; described by the occupation theory (effect proportional to receptors occupied) as modified by concepts of efficacy/intrinsic activity and spare receptors. ◦ Receptor-mediated actions – most drugs act via specific receptors (GPCRs, ligand-gated ion channels, enzyme-linked receptors, nuclear receptors) — e.g., β-agonists, opioids, steroid hormones. ◦ Non-receptor mediated actions – drugs acting through simple physical or chemical mechanisms without a specific receptor — e.g., antacids neutralizing gastric acid, osmotic laxatives/diuretics drawing water by osmotic gradient, chelating agents binding heavy metals, general anaesthetics (older theory: physical effect on neuronal membrane lipid bilayer).