Pharmacology chapters
Antihypertensives and heart failure drugs
The drug classes that lower blood pressure (ACE inhibitors, ARBs, calcium channel blockers, diuretics, beta blockers and others) with their mechanisms, adverse effects and best uses; drugs in pregnancy and hypertensive emergencies; and the drugs that treat heart failure, including digoxin and its toxicity.
- ACE inhibitors (enalapril, lisinopril, ramipril) block angiotensin II formation and bradykinin breakdown → dry cough, angioedema, hyperkalaemia, first-dose hypotension and renal impairment in bilateral renal artery stenosis; contraindicated in pregnancy; ARBs (losartan) work similarly without the cough. Calcium channel blockers: dihydropyridines (amlodipine, nifedipine) dilate arteries (ankle oedema, flushing, reflex tachycardia); verapamil and diltiazem slow the heart (avoid with β blockers; verapamil causes constipation). Thiazides cause hypokalaemia, hyponatraemia, hyperuricaemia (gout), hyperglycaemia, hypercalcaemia; loop diuretics cause hypokalaemia, hypocalcaemia and ototoxicity; spironolactone causes hyperkalaemia and gynaecomastia.
- In pregnancy: labetalol, methyldopa, nifedipine, hydralazine; avoid ACE inhibitors and ARBs.
- Heart failure with reduced ejection fraction: drugs that improve survival are ACE inhibitor/ARB or sacubitril-valsartan, β blocker (bisoprolol, carvedilol), mineralocorticoid antagonist (spironolactone) and SGLT2 inhibitor; loop diuretics relieve congestion but do not prolong life; digoxin (inhibits Na⁺/K⁺-ATPase) controls rate and symptoms; its toxicity (nausea, xanthopsia, arrhythmias) is worsened by hypokalaemia; antidote digoxin-specific antibody fragments.
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Overview
Blood pressure = cardiac output × peripheral resistance. Drugs lower it by reducing blood volume (diuretics), cardiac output (β blockers, some calcium channel blockers), vascular resistance (vasodilators, ACE inhibitors, ARBs, α blockers) or sympathetic outflow (central α2 agonists).
Common first-line classes: ACE inhibitors or ARBs, calcium channel blockers and thiazide-like diuretics; choice depends on age, ethnicity and other conditions. Follow current national guidelines for the step order.
Drugs acting on the renin-angiotensin system
ACE inhibitors
Captopril, enalapril, lisinopril, ramipril, perindopril.
Mechanism: block angiotensin-converting enzyme → less angiotensin II (less vasoconstriction and aldosterone) and less breakdown of bradykinin (more vasodilation).
Uses: hypertension, heart failure, after myocardial infarction, diabetic nephropathy and proteinuric kidney disease (reduce glomerular pressure).
Adverse effects:
- Dry cough (bradykinin) in a significant minority: switch to an ARB.
- Angioedema (bradykinin): rare but dangerous.
- Hyperkalaemia (less aldosterone).
- First-dose hypotension (especially with diuretics or dehydration).
- Renal impairment, especially in bilateral renal artery stenosis (angiotensin II maintains glomerular filtration there).
- Rash, taste disturbance (captopril).
- Teratogenic (fetal kidney damage).
Contraindications: pregnancy, bilateral renal artery stenosis, history of angioedema, hyperkalaemia.
Angiotensin receptor blockers (ARBs)
Losartan, valsartan, telmisartan, candesartan. Block the AT1 receptor. Same uses and most adverse effects as ACE inhibitors (hyperkalaemia, renal impairment, teratogenic), but no cough (no effect on bradykinin). Losartan also lowers uric acid.
Do not combine an ACE inhibitor with an ARB routinely (hyperkalaemia, kidney injury).
Calcium channel blockers
| Group | Drugs | Main action | Adverse effects |
|---|---|---|---|
| Dihydropyridines | Amlodipine, nifedipine | Arterial vasodilation | Ankle oedema, flushing, headache, reflex tachycardia (short-acting nifedipine), gum hyperplasia |
| Non-dihydropyridines | Verapamil (heart > vessels), diltiazem | Slow the heart (SA and AV nodes), reduce contractility | Bradycardia, heart block, constipation (verapamil), worsened heart failure |
Uses: hypertension, angina, arrhythmias (verapamil for SVT and rate control), Raynaud's (nifedipine), preterm labour (nifedipine), subarachnoid haemorrhage (nimodipine).
Verapamil + β blocker (especially IV) can cause severe bradycardia, heart block and asystole.
Diuretics
| Class | Site and mechanism | Uses | Adverse effects |
|---|---|---|---|
| Loop (furosemide, bumetanide) | Block Na⁺-K⁺-2Cl⁻ co-transporter in the thick ascending limb of loop of Henle; most powerful | Oedema (heart failure, acute pulmonary oedema, nephrotic syndrome, cirrhosis), hypercalcaemia | Hypokalaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia, metabolic alkalosis, ototoxicity (with aminoglycosides), hyperuricaemia, dehydration |
| Thiazides (hydrochlorothiazide, chlorthalidone, indapamide) | Block Na⁺-Cl⁻ co-transporter in the distal convoluted tubule | Hypertension, mild oedema, nephrogenic diabetes insipidus, calcium kidney stones (less urinary calcium) | Hypokalaemia, hyponatraemia, hyperuricaemia (gout), hyperglycaemia, hypercalcaemia, hyperlipidaemia, erectile dysfunction |
| Potassium-sparing: aldosterone antagonists (spironolactone, eplerenone) | Block aldosterone receptors in the collecting duct | Heart failure, primary hyperaldosteronism, ascites in cirrhosis, resistant hypertension | Hyperkalaemia, gynaecomastia (spironolactone; anti-androgen), menstrual upset |
| Potassium-sparing: ENaC blockers (amiloride, triamterene) | Block epithelial sodium channels in the collecting duct | With thiazides or loops to prevent hypokalaemia; lithium-induced DI (amiloride) | Hyperkalaemia |
| Carbonic anhydrase inhibitor (acetazolamide) | Proximal tubule | Glaucoma, altitude sickness, idiopathic intracranial hypertension | Metabolic acidosis, hypokalaemia, kidney stones |
| Osmotic (mannitol) | Proximal tubule and loop (osmotic) | Raised intracranial pressure, acute glaucoma | Fluid overload and pulmonary oedema initially |
Loops lose calcium ("loops lose"); thiazides retain calcium. Both cause hypokalaemia; spironolactone and amiloride cause hyperkalaemia.
Other antihypertensives
- β blockers: not first-line for uncomplicated hypertension in many guidelines, but used with angina, after MI, in heart failure, arrhythmias and pregnancy (labetalol). See adrenergic drugs.
- α1 blockers (doxazosin, prazosin): useful with prostatic enlargement; first-dose hypotension.
- Central α2 agonists: methyldopa (pregnancy; haemolytic anaemia, positive Coombs test, hepatitis, sedation), clonidine (rebound hypertension on stopping).
- Direct vasodilators: hydralazine (arterioles; reflex tachycardia, drug-induced lupus in slow acetylators; with nitrates in heart failure), minoxidil (potassium channel opener; hirsutism, fluid retention; topical for hair loss).
- Sodium nitroprusside: IV, very short-acting; dilates arteries and veins (releases NO); hypertensive emergencies; risk of cyanide (and thiocyanate) toxicity with prolonged use (treated with sodium thiosulphate, hydroxocobalamin).
Hypertension in pregnancy
Safe choices: labetalol (often first-line), methyldopa, nifedipine (modified-release), hydralazine (IV in severe cases). Avoid: ACE inhibitors, ARBs (fetal kidney damage), and generally diuretics. Magnesium sulphate prevents and treats eclamptic seizures.
Hypertensive emergency
Very high BP with acute organ damage (encephalopathy, acute heart failure, aortic dissection, acute kidney injury, eclampsia). Lower BP gradually (usually by no more than about a quarter in the first hour, except aortic dissection) with IV labetalol, nitroprusside, glyceryl trinitrate, nicardipine or hydralazine. Too rapid a fall can cause stroke or MI.
Heart failure
Chronic heart failure with reduced ejection fraction
| Drug group | Effect |
|---|---|
| ACE inhibitor (or ARB, or sacubitril-valsartan: a neprilysin inhibitor plus ARB) | Reduces mortality; less afterload and preload, less remodelling |
| β blocker (bisoprolol, carvedilol, metoprolol succinate) | Reduces mortality; start low, increase slowly once stable |
| Mineralocorticoid antagonist (spironolactone, eplerenone) | Reduces mortality; watch potassium |
| SGLT2 inhibitor (dapagliflozin, empagliflozin) | Reduces mortality and hospital admission, with or without diabetes |
| Loop diuretic (furosemide) | Symptom relief (congestion, oedema); no mortality benefit |
| Digoxin | Symptom control and fewer admissions; rate control in AF; no mortality benefit |
| Hydralazine + isosorbide dinitrate | Option when ACE inhibitors and ARBs cannot be used |
| Ivabradine | Slows sinus rate (If channel) when heart rate stays high |
In heart failure with reduced ejection fraction, ACE inhibitor/ARB/ARNI, β blocker, MRA and SGLT2 inhibitor prolong life; diuretics and digoxin only improve symptoms.
Acute pulmonary oedema: sit upright, oxygen if hypoxic, IV furosemide, nitrates if BP allows; non-invasive ventilation; inotropes (dobutamine) if in shock.
Digoxin
Mechanism: inhibits Na⁺/K⁺-ATPase in heart muscle → more intracellular sodium → less calcium removed by the Na⁺/Ca²⁺ exchanger → more intracellular calcium → stronger contraction (positive inotrope). Also increases vagal tone → slows the SA node and AV conduction (rate control in AF).
Pharmacokinetics: long half-life (about 36–40 hours); renal excretion (reduce dose in kidney impairment and the elderly); large Vd; narrow therapeutic index.
Toxicity:
- Gut: anorexia, nausea, vomiting, diarrhoea (often the first signs).
- Eyes: blurred vision, yellow-green vision (xanthopsia).
- CNS: confusion, fatigue.
- Heart: almost any arrhythmia: ventricular ectopics (bigeminy), AV block, atrial tachycardia with block, ventricular tachycardia. ECG at therapeutic levels shows "reverse tick" ST depression (a drug effect, not toxicity).
Factors that increase toxicity: hypokalaemia (potassium competes with digoxin at the pump; diuretics are a common cause), hypercalcaemia, hypomagnesaemia, renal impairment, hypothyroidism, old age; drugs that raise digoxin levels: amiodarone, verapamil, quinidine, clarithromycin.
Treatment of toxicity: stop digoxin, correct potassium (cautiously), treat arrhythmias (atropine for bradycardia); for severe toxicity give digoxin-specific antibody fragments (Fab).
In digoxin toxicity, hypokalaemia makes it worse, but severe acute overdose itself causes hyperkalaemia (pump blocked), which is a sign of severity.
Expect: ACE inhibitor mechanism, cough, angioedema, hyperkalaemia and contraindications, ARB differences, dihydropyridine vs non-dihydropyridine calcium channel blockers (ankle oedema, constipation, verapamil with β blockers), sites and adverse effects of diuretics (thiazides and gout, loops and ototoxicity, spironolactone and gynaecomastia), drugs in pregnancy, nitroprusside and cyanide, hydralazine lupus, mortality-reducing drugs in heart failure, digoxin mechanism, toxicity and factors that worsen it.
Quick revision
- ACE inhibitors: cough, angioedema (bradykinin), hyperkalaemia; avoid in pregnancy and bilateral RAS.
- ARBs: same benefits, no cough.
- Amlodipine: ankle oedema. Verapamil: constipation, heart block with β blockers.
- Loops: ↓K⁺, ↓Ca²⁺, ototoxic. Thiazides: ↓K⁺, ↓Na⁺, ↑urate, ↑glucose, ↑Ca²⁺.
- Spironolactone: hyperkalaemia, gynaecomastia.
- Pregnancy: labetalol, methyldopa, nifedipine.
- Heart failure survival: ACEi/ARB/ARNI, β blocker, MRA, SGLT2 inhibitor.
- Digoxin: Na⁺/K⁺-ATPase; toxicity ↑ with hypokalaemia; xanthopsia; Fab antidote.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
Why do ACE inhibitors cause a dry cough?
They block the breakdown of bradykinin, which builds up in the airways.
Which antihypertensives are used in pregnancy?
Labetalol, methyldopa, nifedipine and hydralazine; ACE inhibitors and ARBs are avoided.
Which drugs reduce mortality in heart failure?
ACE inhibitors (or ARBs or sacubitril-valsartan), beta blockers, mineralocorticoid antagonists and SGLT2 inhibitors.
What makes digoxin toxicity more likely?
Hypokalaemia, hypercalcaemia, hypomagnesaemia, kidney impairment, old age and drugs such as amiodarone and verapamil.