Antihypertensive Drugs

Antihypertensive drugs lower blood pressure by reducing cardiac output, systemic vascular resistance or circulating volume. Treatment aims to prevent stroke, heart failure, coronary disease, kidney failure and dementia. Most patients need combination therapy.

Definition and grading. Hypertension is a clinic blood pressure of 140/90 mmHg or more on repeated measurement, confirmed by home or ambulatory readings of 135/85 mmHg or more. Grade 1 is 140 to 159 or 90 to 99 mmHg, grade 2 is 160 to 179 or 100 to 109 mmHg, and grade 3 is 180 or 110 mmHg or more.

Epidemiology. Hypertension affects over a billion adults worldwide, and prevalence in sub-Saharan Africa is high and rising. In Kenya roughly one in four adults is affected, with low rates of awareness, treatment and control.

Drug classes. Thiazide and thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, alpha blockers, mineralocorticoid receptor antagonists, central sympatholytics, direct vasodilators and direct renin inhibitors.

Mechanism. Diuretics reduce plasma volume and later peripheral resistance. Renin-angiotensin blockers reduce angiotensin II vasoconstriction and aldosterone-driven sodium retention. Calcium channel blockers relax arteriolar smooth muscle. Beta blockers reduce cardiac output and renin. Vasodilators and alpha blockers reduce vascular tone. Central agents lower sympathetic outflow.

Response by ancestry and age. Low renin states are more common in older adults and people of African ancestry, so calcium channel blockers and thiazide-like diuretics lower blood pressure more than ACE inhibitors, angiotensin receptor blockers or beta blockers used alone.

• Thiazide-like diuretics: indapamide 1.5 mg modified release or 2.5 mg daily; chlortalidone 12.5 to 25 mg daily. Hydrochlorothiazide 12.5 to 25 mg daily is weaker in outcomes.
• ACE inhibitors: ramipril 2.5 to 10 mg daily, lisinopril 10 to 40 mg daily, perindopril 4 to 8 mg daily, enalapril 5 to 40 mg daily.
• Angiotensin receptor blockers: losartan 50 to 100 mg daily, candesartan 8 to 32 mg daily, telmisartan 40 to 80 mg daily, valsartan 80 to 320 mg daily.
• Calcium channel blockers: amlodipine 5 to 10 mg daily; nifedipine modified release 30 to 90 mg daily; lercanidipine 10 to 20 mg daily.
• Mineralocorticoid receptor antagonist: spironolactone 25 to 50 mg daily as the fourth-line choice.
• Beta blockers: bisoprolol 5 to 10 mg daily, only with a compelling indication.
• Alpha blockers: doxazosin 1 to 16 mg daily as add-on.
• Central agents: methyldopa 250 mg 2 to 3 times daily in pregnancy; clonidine as a late option.

• When to treat: start drug therapy at a confirmed 140/90 mmHg or more when there is diabetes, chronic kidney disease, target organ damage, established cardiovascular disease or a 10-year cardiovascular risk of 10% or more. Treat all with grade 2 or grade 3 hypertension. In patients over 80 years, treat from 150/90 mmHg.
• Targets: under 140/90 mmHg in all, under 130/80 mmHg where tolerated and in diabetes or chronic kidney disease. In patients over 80 years, aim for under 150/90 mmHg.
• Step 1: an ACE inhibitor or angiotensin receptor blocker for patients under 55 years who are not of African ancestry. A calcium channel blocker for patients of African ancestry or aged 55 years or over. Dual therapy in a single tablet is preferred from the start in grade 2 disease.
• Step 2: ACE inhibitor or angiotensin receptor blocker plus calcium channel blocker, or plus a thiazide-like diuretic. In patients of African ancestry, a calcium channel blocker with a thiazide-like diuretic or an angiotensin receptor blocker.
• Step 3: all three of ACE inhibitor or angiotensin receptor blocker, calcium channel blocker and thiazide-like diuretic.
• Resistant hypertension: uncontrolled on three drugs at full dose including a diuretic. Confirm adherence, exclude white coat effect with ambulatory readings, and look for secondary causes. Add spironolactone 25 to 50 mg daily if potassium is 4.5 mmol/L or under, otherwise an alpha or beta blocker.
• Compelling indications: ACE inhibitor or angiotensin receptor blocker with albuminuric kidney disease or diabetes. Beta blocker and ACE inhibitor in heart failure with reduced ejection fraction. ACE inhibitor with indapamide after stroke.
• Pregnancy: treat from 140/90 mmHg with labetalol, nifedipine or methyldopa. Avoid ACE inhibitors, angiotensin receptor blockers and direct renin inhibitors.
• Lifestyle: salt under 5 g daily, weight reduction, regular exercise, alcohol limits and cessation of tobacco.

Contraindications. Pregnancy for renin-angiotensin blockers, bilateral renal artery stenosis, angioedema history with ACE inhibitors, and the class-specific contraindications of each member.

Adverse effects. Hypotension, dizziness and falls, electrolyte disturbance (hypokalaemia with diuretics, hyperkalaemia with renin-angiotensin blockers and spironolactone), acute kidney injury, ankle oedema with calcium channel blockers, cough with ACE inhibitors, and erectile dysfunction with several classes.

Interactions. NSAIDs raise blood pressure and, with an ACE inhibitor or angiotensin receptor blocker plus a diuretic, cause acute kidney injury. Potassium supplements, trimethoprim and spironolactone raise potassium. Lithium levels rise with ACE inhibitors, angiotensin receptor blockers and thiazides.

Monitoring. Blood pressure at 4 weeks after each change until controlled, then every 6 to 12 months. Potassium, creatinine and sodium 1 to 2 weeks after starting or increasing a renin-angiotensin blocker or diuretic, then annually. Urine albumin-to-creatinine ratio yearly in diabetes and kidney disease.

Referral and escalation. Blood pressure of 180/120 mmHg or more with chest pain, neurological signs, papilloedema, retinal haemorrhage or acute kidney injury is a hypertensive emergency and needs admission. Suspect secondary hypertension in patients under 40 years, with resistant hypertension, hypokalaemia, abrupt onset or worsening, or an abdominal bruit.

Special groups. Older adults: start low and avoid postural hypotension. Black patients: lower response to monotherapy with a renin-angiotensin blocker or beta blocker, and higher angioedema risk with ACE inhibitors. Diabetes: avoid beta blocker and thiazide combinations where other options exist. Kidney disease: a loop diuretic is usually needed for volume control when eGFR is under 30 mL/min/1.73 m2.