Antiarrhythmic and antianginal drugs
Antianginal, Heart Failure and Antiarrhythmic Drugs: FCPS Part 1 Pharmacology
Nitrates, ivabradine, heart failure drugs, digoxin and the Vaughan Williams antiarrhythmic classes for FCPS Part 1. Explains which heart failure drugs reduce mortality, digoxin toxicity and Fab, amiodarone effects, adenosine, and why verapamil and β-blockers clash.
One of the most tested topics in past papers
Antianginal drugs: lowering oxygen demand
Angina occurs when myocardial oxygen demand (heart rate, contractility, wall tension from preload and afterload) exceeds supply. Every antianginal drug lowers demand; nitrates and calcium channel blockers also relieve coronary spasm.
| Drug | Mechanism | Notes |
|---|---|---|
| Nitrates (GTN, isosorbide mononitrate) | Prodrugs that release nitric oxide, activating guanylyl cyclase and raising cGMP; mainly venodilators (lower preload), arterial and coronary dilatation at higher doses | Headache, flushing, hypotension, reflex tachycardia; tolerance; never with PDE5 inhibitors |
| β-blockers | Lower rate and contractility | First line in stable angina |
| Calcium channel blockers | Vasodilatation, with or without rate slowing | Amlodipine combines safely with a β-blocker; verapamil does not |
| Ivabradine | Blocks the If (funny) current of the SA node | Slows rate without lowering BP; needs sinus rhythm; phosphenes |
| Nicorandil | K-ATP opener plus nitrate | Oral, anal and GI ulcers |
| Ranolazine | Late Na+ current block | QT prolongation |
- Sublingual GTN acts within 1–2 minutes because the oral mucosa drains into the systemic veins, bypassing first-pass liver metabolism, which destroys most swallowed GTN.
- Tolerance develops with continuous exposure, so long-acting nitrates need a nitrate-free period (asymmetric dosing). Workers in nitroglycerin factories become tolerant during the week; over the weekend the tolerance wears off and they get headache on the first working day ("Monday disease"), and withdrawal coronary spasm can occur at weekends.
- Chest pain lasting hours and not relieved by nitrates suggests infarction: do an ECG and troponin.
- Cocaine chest pain: avoid β-blockers at first, because unopposed α stimulation worsens vasospasm; use benzodiazepines and nitrates.
Heart failure with reduced ejection fraction
Falling cardiac output activates the sympathetic system, the renin–angiotensin–aldosterone system and vasopressin. These responses cause fluid retention, vasoconstriction and myocardial remodelling. Drugs that block these neurohormones prolong life; drugs that only move fluid or push contractility do not.
| Drug | Mortality effect | Notes |
|---|---|---|
| ACE inhibitor, ARB, or sacubitril–valsartan | Reduces | Sacubitril inhibits neprilysin, the enzyme that breaks down natriuretic peptides (and bradykinin), so ANP and BNP effects rise |
| β-blocker (bisoprolol, carvedilol, metoprolol succinate) | Reduces | Start when euvolaemic, titrate slowly |
| Mineralocorticoid antagonist (spironolactone, eplerenone) | Reduces | Blocks aldosterone-driven fibrosis and sodium retention; added when still symptomatic; eplerenone if gynaecomastia |
| SGLT2 inhibitor (dapagliflozin, empagliflozin) | Reduces | With or without diabetes |
| Hydralazine with isosorbide dinitrate | Reduces | Patients of African origin or ACE inhibitor-intolerant |
| Loop diuretics | None | Symptom relief of congestion only |
| Digoxin | None | Fewer hospital admissions; AF rate control |
| Ivabradine | Fewer admissions | Sinus rate 75 or more despite β-blocker |
- Acute pulmonary oedema: sit up, oxygen, IV furosemide (early benefit from venodilatation), nitrates, CPAP. Dobutamine (β1) for low-output cardiogenic shock.
- Mannitol is contraindicated because it first expands the circulating volume.
- Drugs causing heart failure: doxorubicin (dose-dependent, often permanent dilated cardiomyopathy from free radical injury; risk reduced by limiting cumulative dose and by dexrazoxane, an iron chelator), trastuzumab (usually reversible), NSAIDs, pioglitazone, non-dihydropyridine calcium channel blockers.
Digoxin
- Inhibits myocardial Na+/K+-ATPase. Intracellular Na+ rises, so the Na+/Ca2+ exchanger removes less Ca2+; more calcium is stored and released: positive inotropy. It also raises vagal tone, slowing AV conduction.
- Most suitable for AF with heart failure or in sedentary patients.
- Half-life about 36 hours; renally excreted; narrow therapeutic index.
- ECG at therapeutic levels: sagging (reverse tick) ST depression, flattened or inverted T waves, short QT. These show digoxin effect, not toxicity.
- Toxicity: anorexia, nausea, vomiting, confusion, yellow-green vision (xanthopsia) and other colour vision changes; any arrhythmia, classically ventricular ectopics, bigeminy, atrial tachycardia with block, heart block, VT.
- Precipitants: hypokalaemia (K+ competes with digoxin at the pump, so low K+ increases binding), hypomagnesaemia, hypercalcaemia, hypothyroidism, renal impairment, and amiodarone, verapamil, quinidine, macrolides.
- Acute massive overdose poisons the pump in all cells, so potassium cannot enter cells and hyperkalaemia develops; it marks severe toxicity. Treatment: digoxin-specific antibody (Fab) fragments; avoid calcium.
Exam trap Hypokalaemia precipitates chronic digoxin toxicity; hyperkalaemia signals a severe acute overdose.
Vaughan Williams classification
| Class | Mechanism | Drugs | Notes |
|---|---|---|---|
| Ia | Na+ block, prolongs action potential | Quinidine, procainamide, disopyramide | Long QT; procainamide lupus; quinidine cinchonism |
| Ib | Na+ block, shortens AP; binds ischaemic tissue | Lidocaine, mexiletine | Ventricular arrhythmias after MI |
| Ic | Strong Na+ block | Flecainide, propafenone | AF in structurally normal hearts; avoid after MI or structural disease (raised mortality) |
| II | β-blockers | Metoprolol, bisoprolol, esmolol | Slow SA and AV nodes |
| III | K+ channel block: prolongs repolarisation and refractory period | Amiodarone, sotalol, dronedarone | Long QT, torsades |
| IV | Non-dihydropyridine Ca2+ channel block | Verapamil, diltiazem | SVT, AF rate; never in VT or pre-excited AF |
| Others | Adenosine, digoxin, atropine, magnesium |
- Verapamil plus a β-blocker: both depress the SA and AV nodes and contractility, so IV verapamil in a β-blocked patient causes severe bradycardia, heart block, asystole and hypotension. Diltiazem needs similar caution.
- Adenosine acts on A1 receptors in the AV node (Gi-coupled; opens K+ channels and hyperpolarises nodal cells), causing transient AV block that terminates AV nodal re-entrant tachycardia and unmasks flutter waves. Half-life under 10 seconds: rapid bolus 6, 12, 12 mg. Chest tightness, flushing, sense of doom; avoid in asthma (use verapamil); dipyridamole potentiates, theophylline blocks.
Amiodarone
- Class III with additional I, II and IV actions; huge volume of distribution; half-life weeks to months; needs loading.
- Uses: VT and VF (300 mg IV after the third shock in arrest), AF in structural heart disease.
- Adverse effects: hypo- or hyperthyroidism (iodine), pulmonary fibrosis, hepatitis, corneal microdeposits, optic neuropathy, photosensitivity and slate-grey skin, neuropathy, bradycardia, long QT.
- Raises digoxin and warfarin levels (halve doses).
- Corneal deposits are also caused by chloroquine and chlorpromazine.
QT prolongation and torsades
Class Ia and III drugs, macrolides, quinolones, haloperidol, citalopram, TCAs, methadone, ondansetron, quinine, domperidone, especially with hypokalaemia, hypomagnesaemia or hypocalcaemia. Treat torsades with IV magnesium sulphate.
Antihypertensive and diuretic facts tested with this chapter
| Problem | Key fact |
|---|---|
| Tinnitus and deafness on IV furosemide with gentamicin | Loop diuretics block NKCC2 (and the cochlear isoform): ototoxicity |
| ENaC blocker that spares potassium | Amiloride |
| Confusion with Na+ 122 after starting bendroflumethiazide | Thiazide-induced hyponatraemia |
| Thiazide failing at eGFR 18 | Thiazides lose effect at low GFR |
| Metolazone added to furosemide | Blocks compensatory distal sodium uptake |
| Collapse after first ramipril dose on high-dose furosemide | BP had become angiotensin-dependent |
| Creatinine up 20% on ramipril, K+ normal | Continue and recheck |
| Lip and tongue swelling on lisinopril | Bradykinin |
| Pregnant on lisinopril | Stop; switch to labetalol or nifedipine; methyldopa has the longest safety record |
| Antihypertensive that lowers urate | Losartan |
| Hair growth on resistant-hypertension drug | Minoxidil (K-ATP opener; topical for alopecia) |
| Confusion and lactic acidosis after days of nitroprusside | Cyanide toxicity |
| Hypertensive emergency | Lower about 25% in the first hour |
| Type B dissection | β-blocker before nitroprusside to prevent a reflex rise in aortic wall stress |
| Raynaud phenomenon | Nifedipine |
| Diabetic with hypothyroidism, BP 200/100 | Propranolol least appropriate |
Remember Neurohormone blockers save lives; diuretics and digoxin save admissions.
How FCPS asks about this
- Class III mechanism: potassium channel block prolonging repolarisation.
- Sacubitril: inhibits neprilysin, raising natriuretic peptides.
- Digoxin in heart failure in sinus rhythm: fewer admissions, no survival benefit.
- Digoxin overdose with hyperkalaemia and heart block: digoxin-specific Fab fragments.
- IV verapamil in a β-blocked patient: both depress SA and AV nodes, risking asystole.
- Nitrate factory worker with Monday headache: loss of tolerance over the weekend.
- Cardiomyopathy after breast cancer chemotherapy: doxorubicin; dexrazoxane reduces risk.
Test yourself on this topic
5 of the 106 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with chronic kidney disease (eGFR 18 mL/min/1.73 m²) has worsening ankle oedema and BP 168/96 mmHg despite bendroflumethiazide 2.5 mg daily. Which of the following explains the poor response?
Answer: Thiazides lose effect at low GFR
Thiazides block the Na⁺/Cl⁻ co-transporter in the distal convoluted tubule, which normally reabsorbs only about 5% of filtered sodium. When GFR is very low, little sodium is filtered and reaches this site, and thiazides, which must be secreted into the tubule by organic anion transporters, compete with accumulated organic acids. Their effect is therefore weak below an eGFR of about 30. A loop diuretic, often at higher dose, is used instead; metolazone retains some activity.
Diuretics in CKD
- Thiazides: weak below eGFR ~30
- Low filtered Na⁺ reaching DCT
- Secretion competes with organic acids
- Use a loop diuretic instead
Remember Poor kidneys need loop diuretics.
Exam trap Loop diuretics in CKD often need higher doses because less drug reaches the tubule.
Why the other options are wrong
- Thiazides are inactivated by uraemic toxins Uraemic acids compete for secretion, but the drug is not inactivated.
- The dose of a thiazide must be doubled Higher doses of bendroflumethiazide add little and raise side effects.
- Thiazides act only on the loop of Henle They act on the distal convoluted tubule, not the loop.
- Thiazides increase renin too much Renin rise is not the main reason here.
After 3 days of high-dose sodium nitroprusside infusion for hypertensive emergency, a patient becomes confused with metabolic acidosis and a high lactate. What is the likely cause?
Answer: Cyanide toxicity
Sodium nitroprusside releases nitric oxide (vasodilation) and cyanide ions. Cyanide is normally converted to thiocyanate in the liver using thiosulfate. With high doses, prolonged infusion or liver impairment, cyanide accumulates, blocking cytochrome oxidase and causing lactic acidosis, confusion and arrhythmias. It is treated by stopping the infusion and giving sodium thiosulfate or hydroxocobalamin. Thiocyanate itself can accumulate in renal failure.
Nitroprusside toxicity
- Releases NO and cyanide
- Cyanide → lactic acidosis
- Treat: thiosulfate or hydroxocobalamin
- Thiocyanate builds up in renal failure
Remember Long nitroprusside: think cyanide.
Exam trap Protect the infusion from light.
Why the other options are wrong
- Thiocyanate deficiency Thiocyanate accumulates, not deficient.
- Methaemoglobin reduction Methaemoglobin can form; not reduced.
- Hypokalaemia Not the cause of this picture.
- Rebound hypertension Not with ongoing infusion.
A woman has Raynaud phenomenon causing painful attacks several times a day despite keeping warm and stopping smoking. Which drug is first-line?
Answer: Nifedipine
Raynaud phenomenon is episodic vasospasm of digital arteries triggered by cold or stress. Conservative measures (warmth, gloves, stopping smoking, avoiding vasoconstrictors) come first. If attacks remain frequent or severe, a dihydropyridine calcium channel blocker such as modified-release nifedipine is first-line. Beta-blockers, triptans, ergots and decongestants can worsen vasospasm.
Raynaud treatment
- Keep warm, stop smoking
- First drug: nifedipine
- Avoid beta-blockers, ergots, triptans
- Secondary Raynaud: look for scleroderma
Remember Raynaud: warm hands, then nifedipine.
Exam trap Digital ulcers suggest secondary Raynaud and need specialist care.
Why the other options are wrong
- Propranolol Can worsen vasospasm.
- Sumatriptan Vasoconstrictor.
- Ergotamine Vasoconstrictor.
- Pseudoephedrine Vasoconstrictor.
A man on regular isosorbide mononitrate finds it less effective after a few weeks. How is this tolerance prevented?
Answer: Nitrate-free interval
Continuous nitrate exposure causes tolerance, probably through depletion of sulfhydryl groups needed to release nitric oxide, neurohormonal activation and oxidative stress. A daily nitrate-free period (usually overnight, e.g. isosorbide mononitrate at 8 a.m. and 2 p.m., or removing patches at night) restores sensitivity. Tachyphylaxis is very rapid tolerance after repeated doses (e.g. ephedrine depleting noradrenaline). Sildenafil with nitrates causes dangerous hypotension.
Nitrate tolerance
- Continuous exposure → tolerance
- Prevent: nitrate-free interval (8–12 h)
- Never with PDE-5 inhibitors (sildenafil)
- Tachyphylaxis: rapid tolerance (ephedrine)
Remember Give nitrates a night off.
Why the other options are wrong
- Double the dose weekly Worsens tolerance.
- Dose 6-hourly round the clock Continuous exposure causes tolerance.
- Add sildenafil Dangerous hypotension.
- Wear a patch continuously Continuous patches cause tolerance.
A 66-year-old man with heart failure with reduced ejection fraction developed potassium of 6.4 mmol/L and a sharp rise in creatinine on both an ACE inhibitor and an ARB, so neither can be used. Which combination can be given to reduce afterload and preload instead?
Answer: Hydralazine with isosorbide dinitrate
Hydralazine is an arteriolar dilator that lowers afterload, and isosorbide dinitrate is mainly a venodilator that lowers preload. Together they improve symptoms and survival in HFrEF and are used when ACE inhibitors, ARBs and sacubitril–valsartan are not tolerated or contraindicated, for example because of hyperkalaemia or renal failure. Hydralazine also reduces nitrate tolerance through an antioxidant effect. The combination has particular evidence in patients of African descent.
Hydralazine–nitrate
- Hydralazine: arteriolar dilator, afterload
- Isosorbide dinitrate: venous dilator, preload
- Use when ACEi/ARB/ARNI not tolerated
- Hydralazine reduces nitrate tolerance
Remember No RAAS blocker possible: hydralazine plus nitrate.
Exam trap Hydralazine alone causes reflex tachycardia and fluid retention, and can cause drug-induced lupus.
Why the other options are wrong
- Amlodipine with low-dose indapamide No survival benefit in heart failure.
- Verapamil with low-dose digoxin Verapamil is a negative inotrope and harmful in HFrEF.
- Doxazosin with spironolactone Doxazosin does not improve outcomes, and spironolactone would worsen hyperkalaemia.
- Clonidine with modified-release nifedipine Neither improves outcomes; nifedipine may worsen heart failure.
Where this sits in the CPSP syllabus
- Paper 1: Cardiovascular and blood drugs, Antianginal, heart failure and antiarrhythmic drugs
- Medicine & Allied, Paper 2: Systemic drugs, Antihypertensives, antianginals, heart failure and antiarrhythmic drugs
Read next
Drug dose pages
Doses, cautions and practical tips for drugs in this chapter.