💡 ABCT 102 — Essay answer cards

State A = Absorption, D = Distribution, M = Metabolism, E = Excretion up front, then close the paragraph with the course mantra: what goes in, MUST come out. Absorption: route determines speed and completeness. Oral is most convenient but slow and subject to first-pass; IV is the fastest and is the 100% bioavailability reference against which every other route is compared.

Vd = dose / plasma concentration. Only the unbound (free) fraction is pharmacologically active and available for distribution, metabolism and excretion; protein binding acts as a reservoir but limits immediate action. High-perfusion organs receive drug first - liver 26.5%, kidney 22%. Distribution sets three things: onset, intensity, duration of action.

Peripheral capillaries are fenestrated, so most drugs pass. CNS capillaries have tight junctions with no gaps, so entry depends on lipophilicity and ionisation state: only small, lipophilic, unionised molecules cross. The placental barrier follows the same rule, which is why thalidomide crossed it.

CYP450 in the liver. Phase I oxidises, reduces or hydrolyses to expose a polar group; Phase II conjugates to make the molecule water-soluble. First-pass metabolism reaches ~90% for some drugs, which is why sublingual nitroglycerin works. State explicitly that the liver is the MAJOR site, not the only site, and that metabolites can be more active or more toxic than the parent.

MW below ~300 Da goes to urine; above ~500 Da goes to bile; 300-500 Da uses both. Three renal processes: glomerular filtration (free, low MW, water-soluble, low Vd), active tubular secretion (ATP-requiring, saturable, non-specific carriers), and tubular reabsorption. Protein-bound drug behaves as a macromolecule and is not filtered.

Ion trapping: normal urine is about pH 5.3, so alkalinising with NaHCO3 traps weak acids (aspirin, barbiturates) and acidifying with NH4Cl traps weak bases (amphetamine). Tubular competition: probenecid prolongs penicillin (beneficial) but reduces nitrofurantoin efficacy in UTI (antagonising). Special populations: neonates have more total body water and the elderly have fewer functional nephrons - both need dose reduction.

Write [X] + [R] <-> [XR] -> E in the first three lines and name the terms: X is drug concentration at the receptor, R is free receptor, XR is the drug-receptor complex, E is the pharmacological effect. The Law of Mass Action (rate proportional to the product of reactant concentrations) is the kinetic basis of occupancy, and occupancy driving response.

Four receptor types ordered by speed: ligand-gated ion channel (nicotinic, GABA-A; milliseconds), GPCR (muscarinic, adrenergic; seconds), kinase-linked (insulin, growth factors; minutes to hours), nuclear (steroid, thyroid; hours, via gene transcription). Then the two properties: affinity is the probability of occupying a receptor; intrinsic efficacy is the ability to activate once bound. An agonist has both; an antagonist has affinity and no efficacy.

On a linear concentration axis the curve is a hyperbola; on a log axis it is the symmetric sigmoid used in practice. ED50 measures potency (position on the x-axis, lower = more potent); Emax measures efficacy (height of the curve); Kd measures binding affinity. State explicitly that Kd is NOT ED50 - binding is not response.

A full agonist reaches maximal response at only 5-10% occupancy because of spare receptors (the receptor reserve). A partial agonist needs 100% occupancy for a submaximal response, and behaves as an antagonist when a full agonist is present. An antagonist binds but produces no conformational change and therefore no activation. Spare receptors also buffer against competitive antagonists - the reserve must be eaten into before Emax falls.

Competitive antagonism: parallel shift to the right, Emax unchanged, surmountable. Non-competitive or allosteric: right shift plus a lower ceiling. Separately distinguish physiological antagonism (two agonists on different receptors with opposing effects, e.g. noradrenaline versus acetylcholine on blood pressure), pharmacological antagonism (same pathway), and chemical antagonism (direct chemical reaction, no receptor involved). Binding strength predicts reversibility, and reversibility predicts curve shape.

Therapeutic Index = TD50 / ED50. A larger TI means a safer drug; a narrow TI demands therapeutic monitoring. Close by restating that potency and efficacy are independent axes, and that potency is a comparative term only meaningful between agonists acting at the same receptor - the lecture example being drug A at about 0.3 nM being roughly 1000 times more potent than drug D at 300 nM.

Sympathetic = fight-or-flight, noradrenaline onto adrenoceptors. Parasympathetic = rest-and-digest, acetylcholine onto muscarinic and nicotinic receptors. Enteric = the GI tract, which can function with or without CNS input. Add the classic trap: acetylcholine is also the transmitter at the ganglia of BOTH arms and at the somatic neuromuscular junction.

alpha1: smooth muscle, Gq / IP3, vasoconstriction, blocked by prazosin. alpha2: presynaptic, Gi / reduced cAMP, reduces noradrenaline release, agonist clonidine, antagonist yohimbine. beta1: heart, Gs / cAMP, raises rate and contractility, blocked by atenolol and metoprolol. beta2: bronchi and vessels, Gs, bronchodilation, agonist salbutamol. beta3: adipose, lipolysis, mirabegron for bladder. Muscarinic M1, M3, M5 are Gq / IP3; M2 and M4 are Gi. Nicotinic receptors are ion channels and therefore fast; atropine blocks muscarinic, curare or tubocurarine blocks nicotinic.

Adrenaline is non-selective alpha plus beta and dose-dependent: at very low doses beta2 dominates (bronchodilation, vasodilation, widened pulse pressure); at higher doses alpha effects dominate (renal and skin vasoconstriction, raised systemic vascular resistance). Noradrenaline is primarily alpha, giving intense vasoconstriction usually with reflex bradycardia. Dopamine stimulates alpha, beta and D1/D2 in a dose-dependent way. Isoprenaline is beta only; dobutamine is mainly beta1 with no dopamine-receptor effect.

Direct agonists act on the receptor (catecholamines, phenylephrine). Indirect agents raise endogenous catecholamine levels: amphetamine promotes release, cocaine and tricyclic antidepressants block reuptake, MAO inhibitors prevent metabolism. Mixed agents do both (dopamine, ephedrine). Then make the design point: non-catechol structures such as phenylephrine and ephedrine escape COMT and MAO, giving longer half-life and oral viability.

alpha-blockers: phentolamine is competitive and non-selective; phenoxybenzamine binds irreversibly by covalent bonding so effects last several days and it is used in pheochromocytoma; prazosin, doxazosin and terazosin are alpha1-selective, lowering blood pressure but also reducing cardiac output, heart rate, renal blood flow and GFR. beta-blockers are all competitive antagonists. Non-selective agents include propranolol (lipid-soluble, crosses the BBB), carvedilol (also alpha1) and labetalol (mixed, used in pregnancy-induced hypertension and pre-eclampsia). Cardioselective beta1 agents include atenolol, metoprolol, bisoprolol and esmolol (ultrashort, onset about 2 minutes, duration about 10 minutes). Blocking beta2 causes bronchospasm and worsens peripheral vascular disease.

alpha2 is presynaptic negative feedback, so blocking it increases noradrenaline release and blunts the vasodilation you wanted. Close with MAO-A handling noradrenaline and 5-HT while MAO-B handles dopamine, which is exactly why an MAO inhibitor plus tyramine-rich food such as cheese or red meat produces a hypertensive crisis.

BP = CO x PVR, and CO = HR x SV. MAP = DBP + one third of (SBP - DBP). Give both staging systems: the 2017 ACC/AHA thresholds (stage 1 = 130-139 / 80-89, stage 2 at or above 140 / 90) and the older WHO grades, which sit higher (grade 1 = 140-159 / 90-99). Diagnosis requires three separate measurements at one-month intervals, not a single reading.

About 90-95% of hypertension is primary or essential, meaning the cause is unknown; the remainder is secondary to a known cause. Uncontrolled pressure hits five targets: brain (stroke), vessels (aneurysm and rupture), heart (myocardial infarction and failure), kidneys (renal failure) and eyes (vision loss).

A: ACE inhibitors and ARBs (lisinopril, losartan) reduce angiotensin II through the RAAS; the signature side effects are dry cough and hyperkalaemia. B: beta-blockers (atenolol, metoprolol) blunt sympathetic drive at beta1, lowering rate and contractility. C: calcium channel blockers (amlodipine, nifedipine) reduce calcium influx and cause vasodilation. D: diuretics.

Loop diuretics (frusemide, bumetanide) inhibit the Na-K-Cl cotransporter in the thick ascending limb and handle about 25% of the sodium load. Thiazides (hydrochlorothiazide, indapamide) inhibit the Na-Cl transporter in the distal tubule, about 5%. Potassium-sparing agents (spironolactone as an aldosterone antagonist, amiloride) act at the distal tubule and collecting duct.

Loop and thiazide diuretics cause hypokalaemia, which predisposes to arrhythmias, so plasma potassium must be monitored. Potassium-sparing agents avoid this. Also watch for dehydration and general electrolyte disturbance from diuresis.

Vaughan Williams classification: class I are sodium blockers (IA quinidine, IB lignocaine, IC flecainide), class II are beta-blockers, class III are potassium blockers (amiodarone, which raises the effective refractory period and prolongs QT), class IV are calcium blockers (verapamil, diltiazem); use-dependent block means higher affinity for open or inactivated channels. In heart failure, digoxin inhibits Na/K-ATPase, raising intracellular calcium and acting as a positive inotrope, while beta-blockers paradoxically improve survival - but only if started low and titrated slowly, with benefit appearing at around three months.

Asthma is chronic inflammation of the bronchioles that makes the airways hypersensitive - reversible bronchial hyperresponsiveness. COPD is chronic bronchitis plus emphysema, driven mainly by smoking, and the damage is structural, so it is not fully reversible. Say the word reversible for asthma and not-fully-reversible for COPD in the first paragraph; every drug choice later follows from it.

Reliever versus controller. Relievers are bronchodilators used as needed; controllers are anti-inflammatory drugs taken regularly to prevent attacks. The single most common exam error is calling an inhaled corticosteroid a reliever - it prevents, it does not rescue.

Beta-2 agonists act directly on bronchial beta-2 receptors: salbutamol and levalbuterol are SABA (short-acting, rescue), salmeterol, formoterol and indacaterol are LABA (long-acting, regular control, added when a steroid alone fails). Muscarinic antagonists occupy M3, so acetylcholine released by parasympathetic fibres can no longer make the smooth muscle contract — the airway stays relaxed: ipratropium and tiotropium, and note they lean COPD rather than asthma, because cholinergic tone is a larger share of the reversible obstruction there. Methylxanthines: theophylline is anti-inflammatory and bronchoprotective at low dose but needs a higher dose for bronchodilation, which brings toxicity - a narrow therapeutic window.

Inhaled corticosteroids (beclomethasone, fluticasone, mometasone) inhibit phospholipase A2, so arachidonic acid is not released. Leukotriene modifiers: montelukast and zafirlukast block the receptor, zileuton blocks synthesis by inhibiting 5-lipoxygenase. Mast cell stabilisers (cromolyn, nedocromil) block calcium channels so degranulation never happens. Roflumilast is a selective PDE4 inhibitor that raises cAMP - severe COPD only, and it is NOT a bronchodilator.

Antihistamines block H1: first-generation agents (diphenhydramine, promethazine, chlorpheniramine) cross the blood-brain barrier, so they sedate - and that same CNS penetration is why they double as anti-emetics for motion sickness; second-generation loratadine is non-sedating. Decongestants are alpha-agonists (pseudoephedrine, phenylephrine, oxymetazoline) causing vasoconstriction - they shrink swollen tissue only, they do not stop a runny nose or sneezing. Anti-tussives (codeine, pholcodine, dextromethorphan) act on the brainstem cough centre; codeine carries addiction risk via morphine metabolism. Expectorants (guaifenesin) raise the water content of secretions - they make cough productive, they do not suppress it. Mucolytics: acetylcysteine thins mucus.

Inhalation acts locally on lung tissue at a much smaller dose than oral, so systemic side effects are fewer, and combination products (LABA plus glucocorticoid) are standard. Then add the commercial point the lecture makes: when the molecule is generic, the device - dry powder versus metered dose - is the differentiator and the patent moat. Lung surfactants (Curosurf, porcine; Survanta, bovine) are the cultural-sensitivity example used in neonatal care.

Asthma: SABA as needed, then inhaled corticosteroid, then ICS plus LABA, then add a leukotriene modifier or theophylline. COPD: long-acting bronchodilators (LAMA and/or LABA) with or without ICS, roflumilast for severe disease to reduce exacerbations, and smoking cessation plus pulmonary rehabilitation upstream of all of it. Finishing on the ladder shows you can sequence therapy, which is what a long-answer mark scheme rewards.

The BBB is a selective semi-permeable membrane that preserves CNS homeostasis. Only lipid-soluble drugs of roughly 400-600 Da cross by passive diffusion. Then state the trade-off honestly: raising lipophilicity improves entry but can reduce biological activity and causes retention in non-target tissue such as fat. This is why CNS discovery is hard and why brain-targeted delivery is an active development field.

Open the classification with the lecture's own top-level division. Most classes are depressants; the stimulant group is amphetamine, methamphetamine, caffeine and the anorexiants such as phentermine. Naming the split first shows you have the map rather than a list.

Opioids bind the mu receptor (morphine, codeine, fentanyl at roughly 100 times morphine's potency). NSAIDs and salicylates block COX-1 and COX-2, reducing prostaglandins: aspirin is acetylsalicylic acid and celecoxib is the COX-2-selective example. Paracetamol is a weak prostaglandin-synthesis inhibitor. Anti-migraine: ergotamine as an alpha-adrenergic vasoconstrictor and sumatriptan.

GABA deficiency lets nerves fire excessively, producing seizures. Drugs either enhance GABA (barbiturates prolong chloride channel opening and hyperpolarise the membrane; benzodiazepines potentiate GABA-A, with the alpha1 subtype giving sedation, amnesia and anticonvulsant effect and alpha2 giving anxiolysis; GABA analogues such as gabapentin and pregabalin; reuptake inhibitors such as tiagabine) or dampen the excitatory drive (perampanel as a non-competitive AMPA glutamate antagonist, sodium and calcium channel blockers, ezogabine opening Kv7 potassium channels).

Parkinson disease is dopamine deficiency in the basal ganglia, and normal movement requires acetylcholine and dopamine to be balanced. The anticholinergic arm cuts excess acetylcholine (benztropine, trihexyphenidyl, procyclidine). The dopaminergic arm raises dopamine: levodopa with carbidopa, where carbidopa blocks peripheral dopa-decarboxylase so levodopa reaches the brain; selegiline as an MAO-B inhibitor; bromocriptine as a dopamine-receptor agonist.

The vomiting centre sits in the medulla and is triggered by the chemoreceptor trigger zone, vestibular nuclei, cerebral cortex and GI tract. 5-HT3 antagonists (ondansetron, granisetron) for chemo, radiation and post-operative nausea; NK1 antagonists (aprepitant, blocking substance P) for acute and delayed nausea; anticholinergics such as scopolamine for motion sickness; phenothiazines blocking D2, M and H1 (prochlorperazine) for severe cases.

Anxiolysis is not synonymous with benzodiazepines: SSRIs, SNRIs and tricyclics are preferred long-term because they act more slowly but rarely cause dependence. And cholinesterase inhibitors for Alzheimer disease (donepezil, rivastigmine, galantamine) are symptomatic only - they do not modify the disease.

Route choice depends on the physical properties of the drug, the condition of the patient and the type of disease. Bioavailability is measured against the IV reference at 100%. Mention first-pass where oral administration is relevant.

Vd, the free versus bound fraction, protein binding as a reservoir, and the barriers (BBB, placenta).

Phase I and Phase II, CYP450 induction and inhibition, the possibility of active or toxic metabolites, then renal elimination with the molecular-weight cut-offs and ion trapping.

Receptor type, affinity, efficacy, spare receptors and the second messenger involved.

ED50, Emax, potency versus efficacy, and antagonism if the question touches on drug combinations.

TI = TD50 / ED50, therapeutic monitoring for narrow-TI drugs, adverse drug reactions, and dose reduction in neonates, the elderly and renal impairment.

Examiners reward a single coherent worked example far more than six shallow ones. The best carriers in this course are salbutamol (beta2 selectivity, inhaled route, asthma), propranolol (non-selective beta blockade, so bronchospasm is the trade-off), or levodopa with carbidopa (peripheral enzyme blockade, then BBB crossing, then dopamine restoration). Pick one and run steps 1 to 6 on it.