Chapter 14: Antihypertensive drugs and treatment

The five principal first-line classes are ACE inhibitors, angiotensin-receptor blockers (ARBs), calcium-channel blockers (CCBs), thiazide or thiazide-like diuretics, and beta-blockers. Their selection is based on the ability to lower pressure alone, randomised evidence for reducing morbidity and mortality, and acceptable tolerability and safety. Renin–angiotensin-system (RAS) blockade is a common component of combinations when not contraindicated; beta-blockers are especially useful when there is a specific cardiac indication.

Randomised trials and meta-analyses show that all five classes lower systolic and diastolic pressure, reduce hypertension-related outcomes compared with placebo and generally have similar effects on the combined risk of major cardiovascular events and death when used as initial treatment. Differences are more apparent for individual outcomes: beta-blockers may prevent stroke less effectively, CCBs may prevent heart failure less effectively, and thiazide diuretics may prevent heart failure more effectively. Much of the outcome benefit comes from the pressure reduction itself, so having several classes allows treatment to be matched to the patient.

Blood-pressure effects extend to home and ambulatory readings. Adverse effects are often dose-related, and differences between classes are reduced when lower doses are combined. Alpha-blockers, centrally acting drugs and mineralocorticoid-receptor antagonists have a secondary role because outcome trials are fewer or adverse effects are more frequent, but they can be valuable in selected patients or resistant hypertension. SGLT2 inhibitors and non-steroidal MRAs have modest pressure effects but strong outcome evidence in selected diabetes and CKD populations.

Practical contraindications and cautions

Class	Important contraindications	Cautions
ACE inhibitor or ARB	Pregnancy or planned pregnancy, previous angio-oedema, severe hyperkalaemia, bilateral renal-artery stenosis or stenosis in a solitary functioning kidney	Potential pregnancy without reliable contraception; monitor creatinine and potassium
Beta-blocker	Severe asthma, high-grade sinoatrial or atrioventricular block, marked bradycardia	Asthma, impaired glucose tolerance, athletes and physically active people
Dihydropyridine CCB	Marked tachyarrhythmia, severe oedema and selected severe HFrEF situations	Peripheral oedema
Non-dihydropyridine CCB	High-grade conduction block, severe heart failure with EF<40%, bradycardia and important P-glycoprotein/CYP3A4 interactions	Constipation, drug interactions and reduced contractility
Thiazide or thiazide-like diuretic	Severe hyponatraemia, selected obstructive kidney disease and relevant sulfonamide hypersensitivity	Gout, impaired glucose tolerance, pregnancy, hypercalcaemia, hypokalaemia and bone malignancy
MRA	Severe hyperkalaemia or severe renal impairment	Potassium, kidney function and P-glycoprotein/CYP3A4 interactions

Renin–angiotensin-system blockers

ACE inhibitors

ACE inhibitors are among the most widely used antihypertensive drugs. Their early availability produced a large randomised evidence base, particularly in heart failure, coronary disease and high cardiovascular risk, where substantial benefits have been demonstrated.

Rare angio-oedema is more frequent in Black people. Cough affects approximately 5–10% of treated patients, with estimates ranging from 1.5% to 11%, and is more common in women and people of Asian ancestry. In a study of about half a million people, discontinuation was lower with ACE inhibitors than with beta-blockers, CCBs or diuretics and only slightly higher than with ARBs.

ARBs

ARBs have similar antihypertensive and protective efficacy to ACE inhibitors through a different form of RAS inhibition and with a smaller randomised evidence base. Their main advantage is tolerability: adverse effects are close to placebo and discontinuation is among the lowest of all antihypertensive treatments. ACE inhibitors and ARBs are broadly homogeneous classes with several available compounds.

Renin inhibitors and dual RAS blockade

Aliskiren is a potent, long-acting drug alone or with a diuretic or CCB. Several outcome trials were stopped early because of adverse effects, particularly when aliskiren was combined with another RAS blocker, and it is now rarely used in Europe.

ACE inhibitors, ARBs and aliskiren should not be combined. Dual RAS blockade does not improve cardiovascular outcomes and increases adverse effects, including kidney failure by about 40%, hyperkalaemia by about 44% and hypotension by about 42% in high-risk or type 2 diabetes populations.

Calcium-channel blockers

CCBs are a heterogeneous class divided into vascular-selective dihydropyridines and non-dihydropyridines. They are effective in hypertension, particularly in older people and many Black populations.

Dihydropyridines, especially amlodipine, were used in most outcome trials. They can be used when pressure must be controlled in HFrEF if necessary, but care is required because of modest negative inotropy and fluid-related oedema. Drug interactions are limited compared with non-dihydropyridines.

Diltiazem and verapamil also lower pressure but slow atrioventricular conduction and heart rate and are class IV antiarrhythmics. They can be useful for rate control but should be avoided in high-grade block, marked bradycardia, severe systolic heart failure and relevant P-glycoprotein or CYP3A4 interactions. Constipation is particularly associated with verapamil.

Diuretics

Thiazide and thiazide-like diuretics

Thiazides and thiazide-like drugs remain effective antihypertensives. They are especially useful in salt-sensitive hypertension and in combination with RAS blockade or a CCB. Their metabolic effects include hypokalaemia, hyponatraemia, hyperuricaemia, impaired glucose tolerance and, in some people, hypercalcaemia. These effects are dose-related and should be monitored.

Indapamide and chlorthalidone have longer action than hydrochlorothiazide. In PATHWAY-3, combining low-dose amiloride with hydrochlorothiazide lowered home systolic pressure more than higher-dose hydrochlorothiazide alone without the same adverse glucose effect. Diuretic choice should account for eGFR, sodium, potassium, gout, pregnancy and volume status.

Loop diuretics

Loop diuretics are particularly useful when eGFR is substantially reduced, with oedema or volume overload, and in heart failure. Torsemide has a longer half-life than furosemide and may permit less frequent dosing. They are not usually the first choice for uncomplicated hypertension without a volume indication.

Potassium-sparing diuretics and MRAs

Amiloride blocks the epithelial sodium channel and can be used for oedema, potassium preservation or resistant hypertension. PATHWAY-3 found similar home systolic reduction with amiloride 10–20 mg and hydrochlorothiazide 25–50 mg over 24 weeks, while low-dose combination therapy produced greater reduction than high-dose hydrochlorothiazide. PATHWAY-2 follow-up found office pressure reductions of 20.4 mmHg with amiloride and 18.3 mmHg with spironolactone, without serious adverse effects, but potassium increased with amiloride.

Triamterene is another epithelial-sodium-channel blocker with limited independent evidence but additional pressure reduction when combined with hydrochlorothiazide. Spironolactone and eplerenone are established in HFrEF, but dedicated hypertension outcome trials are lacking. Hyperkalaemia and endocrine adverse effects limit routine use except in primary aldosteronism and resistant hypertension.

A meta-analysis of 12 randomised trials involving 1,655 people confirmed that spironolactone substantially lowers pressure in resistant hypertension and supports PATHWAY-2. Finerenone, a non-steroidal MRA, produces a modest pressure reduction and reduces kidney and cardiovascular outcomes in diabetic kidney disease. In FIDELIO-DKD, systolic pressure fell by about 2.7 mmHg when finerenone was added to RAS blockade; only a small proportion of treatment effect was mediated by the pressure change, and hyperkalaemia led to discontinuation in about 1.7%.

Beta-blockers

Propranolol, atenolol and metoprolol reduce stroke, heart failure and major cardiovascular events compared with placebo. Compared with other antihypertensives, beta-blockers are broadly similar for major cardiovascular events but may prevent stroke less effectively. This may reflect small differences in achieved pressure, including central systolic pressure.

Beta-blockers can increase new diabetes in people at risk, especially with metabolic syndrome, and have less favourable tolerability than RAS blockers in real-world studies. They are particularly indicated in heart failure, angina, after myocardial infarction, atrial fibrillation and some younger women who may become pregnant. The class is heterogeneous; beta-1 selectivity and direct vasodilation matter.

Nebivolol and carvedilol are vasodilating third-generation beta-blockers. Nebivolol, and to some extent bisoprolol, may increase nitric oxide and have more favourable sexual and metabolic effects. Carvedilol, bisoprolol, metoprolol and nebivolol improve outcomes in HFrEF. Dedicated hypertension outcome trials for vasodilating beta-blockers are limited and real-world comparisons are inconsistent.

Beta-blockers have useful indications in many cardiac, vascular and non-cardiac conditions. Concerns about depression should not prevent appropriate use; systematic evidence has not shown a clinically important increase in depression or most psychiatric adverse events. Resting heart rate above 80/min is common in hypertension and is associated with higher risk of atrial fibrillation, heart failure and death. This phenotype may support beta-blocker use when clinically appropriate.

Other agents

Alpha-1 blocker doxazosin was as effective as chlorthalidone for the primary coronary endpoint in ALLHAT but was associated with more heart failure and its study arm was stopped early. Alpha-blockers may still help selected patients, especially when benign prostatic symptoms coexist, but they can cause orthostatic hypotension and fluid retention.

Centrally acting drugs such as clonidine and methyldopa can lower pressure but often cause sedation, dry mouth, bradycardia or rebound hypertension when stopped abruptly. Direct vasodilators such as hydralazine and minoxidil are generally reserved for difficult resistant cases and require attention to tachycardia and fluid retention.

ARNI therapy, particularly sacubitril/valsartan, has strong outcome indications in heart failure. Its role as a routine hypertension drug is less established than its role in HFrEF; blood pressure, kidney function and potassium must be monitored.

Drug combinations

Most people need more than one drug. Combining complementary mechanisms improves efficacy at lower doses, reduces dose-related adverse effects and may improve adherence. The preferred core combinations are a RAS blocker with a CCB or thiazide-like diuretic. ACE inhibitor plus ARB or aliskiren should not be used.

Initial two-drug treatment is appropriate for many people with grade 2 or higher hypertension or pressure substantially above target. A single-pill combination simplifies the regimen and can improve persistence. If two drugs are insufficient, add the third core class. Resistant hypertension is usually defined after confirmed uncontrolled pressure despite an appropriate three-drug regimen including a RAS blocker, CCB and diuretic.

Spironolactone is usually the preferred fourth drug when kidney function and potassium permit. PATHWAY-2 supports its efficacy, but CKD, hyperkalaemia and drug interactions require caution. Amiloride, beta-blockers, alpha-blockers or centrally acting drugs may be alternatives in selected patients.

Prescribing, monitoring and deprescribing

Correct prescribing is one of the most important clinical actions for maintaining adherence and persistence. Review the indication, dose, timing, interactions, pregnancy potential, kidney function, electrolytes, orthostatic symptoms, oedema, heart rate and home or ambulatory readings. Reassess after acute illness, dehydration, changes in diet, cancer treatment or a change in adherence.

Routine discontinuation of effective antihypertensive treatment is not recommended. Stopping for months has been associated with more coronary disease, stroke and heart-failure admissions. Deprescribing may be considered in severe orthostatic hypotension, very low pressure, frailty, falls, acute kidney injury or limited goals of care, but should be gradual and monitored because rebound hypertension and events can occur.

Cardiovascular risk reduction beyond pressure

Antihypertensive treatment is only one part of risk reduction. In eligible people, LDL-cholesterol lowering with statins and antiplatelet treatment for established cardiovascular disease should follow the relevant prevention or secondary-prevention guideline. Antiplatelet drugs are not routinely prescribed solely for uncomplicated hypertension because bleeding risk may outweigh benefit.

Evidence mentioned

• PATHWAY-2 supports spironolactone as an effective add-on in resistant hypertension.
• PATHWAY-3 examined diuretic strategies and metabolic effects.
• ALLHAT informs comparisons of thiazide and alpha-blocker strategies.
• ACE inhibitors and ARBs should not be combined routinely.
• Meta-analyses generally show that benefit is driven by achieved pressure and patient context rather than a universally superior class.