MRCS Part A Pharmacology Syllabus

Where is acetylcholine the neurotransmitter in the autonomic nervous system?

Acetylcholine acts at: all preganglionic autonomic fibres (sympathetic and parasympathetic) at nicotinic ganglionic receptors; all postganglionic parasympathetic fibres at muscarinic receptors; postganglionic sympathetic fibres to sweat glands; the adrenal medulla; and the somatic neuromuscular junction (nicotinic).

Contrast the effects of muscarinic agonists (parasympathetic) at the eye, heart, and secretions.

Muscarinic stimulation causes: pupil constriction (miosis) and ciliary muscle contraction (accommodation, reduced intraocular pressure); decreased heart rate (negative chronotropy) and slowed AV conduction; and increased secretions (salivary, lacrimal, bronchial, GI) — remembered as SLUDGE effects.

What are the clinical features of organophosphate (irreversible anticholinesterase) poisoning and its antidotes?

Cholinergic crisis: salivation, lacrimation, urination, defecation, GI cramps, emesis (SLUDGE), plus bronchospasm, bradycardia, miosis, muscle fasciculations and weakness. Treatment: atropine (blocks muscarinic effects) plus pralidoxime (regenerates acetylcholinesterase if given before ageing).

Compare the actions of atropine, glycopyrrolate and hyoscine (scopolamine) as antimuscarinics.

All are muscarinic antagonists. Atropine crosses the blood-brain barrier (central effects, tachycardia, mydriasis). Glycopyrrolate is quaternary and does not cross the BBB (no CNS effects; used to dry secretions and block vagal reflexes). Hyoscine crosses the BBB and is strongly antiemetic/sedative (motion sickness), with more central antimuscarinic action.

Describe the synthesis pathway of noradrenaline (norepinephrine) and the rate-limiting step.

$$\text{Tyrosine} \to \text{DOPA} \to \text{Dopamine} \to \text{Noradrenaline} \to \text{Adrenaline}$$ Tyrosine hydroxylase converts tyrosine to DOPA and is the rate-limiting enzyme. The final conversion of noradrenaline to adrenaline (by PNMT) occurs mainly in the adrenal medulla.

Summarise the main effects of the adrenergic receptor subtypes $\alpha_1$, $\alpha_2$, $\beta_1$, $\beta_2$.

$\alpha_1$: vasoconstriction, mydriasis, bladder sphincter contraction ($G_q$). $\alpha_2$: presynaptic inhibition of noradrenaline release, reduced central sympathetic outflow ($G_i$). $\beta_1$: increased heart rate, contractility and renin release ($G_s$). $\beta_2$: bronchodilation, vasodilation, uterine relaxation, glycogenolysis ($G_s$).

How does the effect of adrenaline on blood pressure differ at low versus high doses (epinephrine reversal)?

At low doses, $\beta_2$-mediated vasodilation predominates and can lower diastolic BP; at high doses $\alpha_1$-mediated vasoconstriction dominates, raising BP. If an $\alpha$-blocker is given, adrenaline's pressor effect is reversed to a depressor effect (epinephrine reversal) because unopposed $\beta_2$ vasodilation remains.

List the major classes of antihypertensive drugs with one example each.

Diuretics (thiazides, e.g. bendroflumethiazide); ACE inhibitors (ramipril); Angiotensin receptor blockers (losartan); Calcium channel blockers (amlodipine); Beta-blockers (bisoprolol); Alpha-blockers (doxazosin); Centrally acting (methyldopa, clonidine); Direct vasodilators (hydralazine).

Explain the mechanism of ACE inhibitors and their most characteristic side effect.

ACE inhibitors block angiotensin-converting enzyme, reducing conversion of angiotensin I to angiotensin II (less vasoconstriction and aldosterone) and reducing bradykinin breakdown. The characteristic side effect is a dry cough (from bradykinin accumulation); they can also cause hyperkalaemia, first-dose hypotension and angioedema, and are contraindicated in pregnancy and bilateral renal artery stenosis.

Contrast dihydropyridine and non-dihydropyridine calcium channel blockers.

Dihydropyridines (e.g. amlodipine, nifedipine) act mainly on vascular smooth muscle causing vasodilation, with reflex tachycardia possible. Non-dihydropyridines (verapamil, diltiazem) act more on the heart, reducing heart rate and contractility (negative chronotropy/inotropy) — useful for rate control but should not be combined with beta-blockers.

What is the first-line management order for essential hypertension using the ACD/step approach (e.g. NICE)?

Under 55 or type 2 diabetic (any age, non-Black): start with an ACE inhibitor/ARB (A). Over 55 or Black African/Caribbean origin: start with a calcium channel blocker (C). Step 2: A + C. Step 3: A + C + thiazide-like diuretic (D). Step 4 (resistant): add spironolactone if $K^{+} \leq 4.5$, or alpha/beta-blocker.

How does glyceryl trinitrate (GTN) relieve angina?

GTN is metabolised to nitric oxide, which activates guanylyl cyclase to raise cGMP, causing vascular smooth muscle relaxation. Predominant venodilation reduces preload (and thus myocardial oxygen demand); it also dilates coronary arteries. Given sublingually to bypass extensive first-pass metabolism.

Name the three main drug classes used for chronic stable angina and how each reduces myocardial oxygen demand.

Nitrates — venodilation reduces preload. Beta-blockers — reduce heart rate and contractility (lower oxygen demand, prolong diastolic coronary filling). Calcium channel blockers — reduce afterload (vasodilation) and, for non-dihydropyridines, heart rate/contractility. Others: ivabradine, nicorandil, ranolazine.

Why must nitrates never be co-prescribed with phosphodiesterase-5 inhibitors such as sildenafil?

PDE-5 inhibitors block breakdown of cGMP while nitrates increase cGMP; together they cause excessive vasodilation and profound, potentially fatal hypotension.

State the Vaughan-Williams classification of antiarrhythmic drugs.

Class I — sodium channel blockers (Ia quinidine, Ib lidocaine, Ic flecainide); Class II — beta-blockers; Class III — potassium channel blockers/prolong repolarization (amiodarone, sotalol); Class IV — non-dihydropyridine calcium channel blockers (verapamil, diltiazem). Unclassified: adenosine, digoxin, magnesium.

List the key adverse effects of amiodarone.

Pulmonary fibrosis, thyroid dysfunction (hypo- and hyperthyroidism, due to iodine content), hepatotoxicity, corneal microdeposits, blue-grey skin/photosensitivity, peripheral neuropathy, and QT prolongation. It has a very long half-life (weeks to months).

How does adenosine terminate supraventricular tachycardia, and what is its half-life?

Adenosine activates $A_1$ receptors, opening potassium channels and inhibiting calcium currents in the AV node, causing transient AV block that terminates re-entrant SVT. It has an extremely short half-life (<10 seconds) so is given as a rapid IV bolus; effects are antagonised by theophylline/caffeine and potentiated by dipyridamole.

Explain the mechanism of action of digoxin and its therapeutic uses.

Digoxin inhibits the $\ce{Na+/K+}$-ATPase, raising intracellular $\ce{Na+}$, which reduces $\ce{Na+/Ca^2+}$ exchange and increases intracellular $\ce{Ca^2+}$ — giving positive inotropy. It also increases vagal tone, slowing AV conduction. Used for rate control in atrial fibrillation and in heart failure. Toxicity is worsened by hypokalaemia.

Which drug classes reduce mortality in heart failure with reduced ejection fraction (HFrEF)?

ACE inhibitors/ARBs (or ARNI, sacubitril-valsartan), beta-blockers (bisoprolol, carvedilol, nebivolol), mineralocorticoid receptor antagonists (spironolactone, eplerenone), and SGLT2 inhibitors (dapagliflozin, empagliflozin) — the 'four pillars'. Diuretics relieve symptoms but do not reduce mortality.

Compare benzodiazepines and barbiturates in their action on the GABA-A receptor.

Both enhance GABA-A chloride channel activity. Benzodiazepines increase the frequency of channel opening (require GABA to act) and have a ceiling effect, making them safer. Barbiturates increase the duration of channel opening and at high doses open the channel directly (GABA-independent), giving no ceiling effect and greater lethality in overdose.

What is the antidote for benzodiazepine overdose and how does it work?

Flumazenil, a competitive antagonist at the benzodiazepine binding site of the GABA-A receptor. Used cautiously as it can precipitate seizures, especially in chronic users or mixed overdoses.

By what mechanism do SSRIs treat depression, and name two of their notable adverse effects.

SSRIs (e.g. fluoxetine, sertraline) selectively inhibit the presynaptic serotonin (5-HT) transporter, increasing synaptic serotonin. Notable adverse effects: GI upset and initial anxiety, sexual dysfunction, hyponatraemia (SIADH), increased bleeding risk, and serotonin syndrome (especially in combination with other serotonergic drugs).

What dietary and drug interaction is dangerous with non-selective irreversible MAO inhibitors?

Tyramine-rich foods (aged cheese, cured meats, red wine) can trigger a hypertensive crisis (the 'cheese reaction') because MAO normally metabolises tyramine. Combining MAOIs with other serotonergic drugs (SSRIs, opioids like pethidine) risks serotonin syndrome; a washout period is required when switching.

Distinguish typical from atypical antipsychotics in mechanism and side-effect profile.

Typical (first-generation, e.g. haloperidol, chlorpromazine) are potent $D_2$ receptor antagonists with high risk of extrapyramidal side effects and hyperprolactinaemia. Atypical (second-generation, e.g. olanzapine, risperidone, clozapine) block $D_2$ and $5\text{-}HT_2$ receptors, with fewer extrapyramidal effects but greater metabolic side effects (weight gain, diabetes, dyslipidaemia).

What are the extrapyramidal side effects of antipsychotics and their typical time course?

Acute dystonia (hours to days), akathisia (days to weeks), parkinsonism (weeks to months), and tardive dyskinesia (months to years, often irreversible). They result from $D_2$ blockade in the nigrostriatal pathway.

What is neuroleptic malignant syndrome and how is it managed?

A rare, life-threatening reaction to dopamine antagonists (antipsychotics) presenting with hyperthermia, 'lead-pipe' muscle rigidity, altered consciousness, autonomic instability, and raised creatine kinase. Management: stop the causative drug, supportive cooling and fluids, and dantrolene or bromocriptine.

Match these antiepileptic drugs to their principal mechanisms: phenytoin/carbamazepine, valproate, ethosuximide, and benzodiazepines/barbiturates.

Phenytoin and carbamazepine block voltage-gated sodium channels (prolong inactivation). Sodium valproate has multiple actions (Na channel block, increased GABA). Ethosuximide blocks T-type calcium channels (drug of choice for absence seizures). Benzodiazepines and barbiturates enhance GABA-A activity.

Why is sodium valproate avoided in women of childbearing age?

Valproate is highly teratogenic, causing neural tube defects (spina bifida), congenital malformations and neurodevelopmental impairment. It is also hepatotoxic and can cause pancreatitis, weight gain, tremor and hair loss.

Explain the WHO analgesic ladder for pain management.

Step 1: non-opioid ± adjuvant (paracetamol, NSAIDs) for mild pain. Step 2: weak opioid (codeine, tramadol) ± non-opioid ± adjuvant for moderate pain. Step 3: strong opioid (morphine) ± non-opioid ± adjuvant for severe pain. Adjuvants include antidepressants and anticonvulsants for neuropathic pain.

Describe the mechanism of action of NSAIDs and contrast COX-1 versus COX-2 inhibition.

NSAIDs inhibit cyclo-oxygenase (COX), reducing prostaglandin synthesis (anti-inflammatory, analgesic, antipyretic). COX-1 is constitutive (protects gastric mucosa, supports platelet function and renal perfusion), so its inhibition causes GI ulceration and bleeding. COX-2 is induced at sites of inflammation; selective COX-2 inhibitors (celecoxib) spare the stomach but increase cardiovascular thrombotic risk.

How do opioids produce analgesia and what are the features of opioid toxicity?

Opioids agonise $\mu$ (and $\kappa$, $\delta$) receptors — G-protein coupled — reducing neurotransmitter release and hyperpolarising neurons, decreasing pain transmission. Toxicity: the triad of respiratory depression, pinpoint pupils (miosis) and reduced consciousness, plus constipation and hypotension. Antidote: naloxone (competitive $\mu$ antagonist).

Classify insulin preparations by onset and duration of action.

Rapid-acting (lispro, aspart): onset ~15 min, peak ~1 h, duration 3–5 h. Short-acting (regular/soluble): onset ~30 min, duration 6–8 h. Intermediate (NPH/isophane): onset 1–2 h, duration 12–18 h. Long-acting (glargine, detemir): onset 1–2 h, flat profile, duration ~24 h.

State the mechanism of action of metformin and its major serious adverse effect.

Metformin is a biguanide that decreases hepatic gluconeogenesis, increases peripheral insulin sensitivity and glucose uptake, and reduces intestinal glucose absorption; it does not cause hypoglycaemia or weight gain. Its major serious adverse effect is lactic acidosis (especially in renal impairment); it should be withheld around contrast/surgery.

Compare the mechanisms of sulfonylureas, DPP-4 inhibitors, GLP-1 agonists and SGLT2 inhibitors.

Sulfonylureas (gliclazide) close $K_{ATP}$ channels on beta-cells to stimulate insulin release (risk hypoglycaemia, weight gain). DPP-4 inhibitors (sitagliptin) block incretin breakdown, raising GLP-1. GLP-1 agonists (semaglutide) mimic incretin — increase insulin, decrease glucagon, slow gastric emptying (weight loss). SGLT2 inhibitors (empagliflozin) block renal glucose reabsorption, causing glycosuria (weight loss, cardiorenal benefit, risk of euglycaemic ketoacidosis).

Describe the synthesis and action of thyroid hormones and the role of the hypothalamic-pituitary axis.

TRH from the hypothalamus stimulates TSH from the anterior pituitary, which drives the thyroid to trap iodide, incorporate it into thyroglobulin tyrosines, and form T4 (thyroxine) and T3. T4 is converted peripherally to the more active T3, which acts on nuclear receptors to increase basal metabolic rate. T3/T4 exert negative feedback on TSH and TRH.

How do carbimazole (methimazole) and propylthiouracil treat hyperthyroidism, and what serious adverse effect must patients be warned about?

Both inhibit thyroid peroxidase, blocking iodination and coupling of tyrosines (reducing T3/T4 synthesis); propylthiouracil additionally inhibits peripheral T4-to-T3 conversion. The serious adverse effect is agranulocytosis — patients must report sore throat, fever or infection for an urgent full blood count. Propylthiouracil also carries a risk of hepatotoxicity.

How is thyroid hormone replacement (levothyroxine) monitored and dosed?

Levothyroxine (synthetic T4) is given orally once daily; dose is titrated against serum TSH (aiming to normalise it), checked ~6–8 weeks after any dose change because of the long half-life (~7 days). Over-replacement risks atrial fibrillation and osteoporosis; it should be taken on an empty stomach as calcium/iron impair absorption.