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PH4.7 | PH4.7 | Hypertension Pharmacotherapy — SDL Guide (Part 2)

First-Line Antihypertensives: Thiazides, ACEi/ARBs, and CCBs

The three first-line antihypertensive drug classes — thiazide diuretics, ACEi/ARBs, and dihydropyridine CCBs — form the backbone of evidence-based hypertension management. Each has distinct pharmacokinetic properties, mechanisms, and indication profiles.

Thiazide and thiazide-like diuretics: The ALLHAT trial (33,357 high-risk hypertensive patients) compared chlorthalidone against amlodipine and lisinopril and found chlorthalidone non-inferior or superior for most outcomes, establishing thiazides as first-line. Chlorthalidone is preferred over hydrochlorothiazide (HCTZ) in clinical practice because of its longer half-life (~50 h vs ~10 h), once-daily dosing, and better evidence base. Indapamide has vasodilatory properties and fewer metabolic effects than HCTZ, making it useful in patients with glucose intolerance.

Thiazide ADRs relevant to antihypertensive use: hypokalaemia (supplement potassium, combine with ACEi/ARB which retain K), hyponatraemia (risk in elderly women), hyperuricaemia (may precipitate gout), hyperglycaemia (impair insulin secretion via hypokalaemia; relevant in pre-diabetes), erectile dysfunction (common but under-reported), mild dyslipidaemia (dose-dependent).

Dihydropyridine CCBs (amlodipine): Amlodipine is the most widely prescribed antihypertensive globally — once-daily dosing, no food interactions, effective across all age groups and ethnicities (particularly effective in elderly patients and in those of Black African ancestry, in whom RAAS-based drugs are less effective as monotherapy). The ACCOMPLISH trial demonstrated amlodipine + benazepril (ACEi) to be superior to HCTZ + benazepril for cardiovascular outcomes — supporting the ACEi + DHP-CCB combination as a preferred first-line choice. Key ADR: peripheral oedema (40% at high doses) — dose-related, non-inflammatory (distinguish from diuretic-responsive cardiac oedema); leg elevation helps.

ACEi and ARBs as antihypertensives: Covered pharmacologically in cvs1-raas SDL. In hypertension without compelling indications, they are equivalent first-line options. ACEi (particularly ramipril, enalapril) have slightly more outcome data; ARBs (particularly losartan, telmisartan) offer better tolerability (no cough). RAAS-based drugs are less effective in Black African patients (lower renin activity) as monotherapy — use CCB or diuretic first, or combine early.

Beta-Blockers, Central Agents, and Direct Vasodilators

Beta-adrenergic blockers lower BP primarily by reducing cardiac output (↓HR and ↓contractility via β1 blockade) and by reducing renin secretion from juxtaglomerular cells. They are no longer considered first-line monotherapy for uncomplicated hypertension (ASCOT-BPLA trial showed atenolol + bendroflumethiazide inferior to amlodipine + perindopril for CV outcomes), but they are strongly indicated as antihypertensives in the context of:
- HFrEF (carvedilol, bisoprolol, metoprolol succinate — COPERNICUS, CIBIS-II, MERIT-HF trials)
- Post-MI (reduce remodelling and arrhythmias)
- Angina pectoris (reduce myocardial oxygen demand)
- Tachyarrhythmias with hypertension

Beta-blocker subclassification:
- Cardioselectivity (β1-selectivity): atenolol, bisoprolol, metoprolol, nebivolol — relatively selective for β1 at therapeutic doses; safer in asthma (less β2 blockade) and less dyslipidaemia (less β2 blockade reduces LPL suppression). Selectivity is dose-dependent — at high doses, cardioselective agents also block β2.
- Non-selective: propranolol (β1+β2), nadolol, carvedilol (β1+β2+α1), labetalol (β1+β2+α1) — avoid in asthma/COPD; propranolol also lipophilic (penetrates CNS → nightmares, depression).
- Intrinsic sympathomimetic activity (ISA): pindolol, acebutolol — partial agonists; less resting bradycardia; less useful in post-MI.
- Nebivolol: β1-selective + stimulates NO release from endothelium (additional vasodilatory mechanism).

Beta-blocker ADRs: bradycardia, AV block, cold extremities, fatigue, impotence, hypoglycaemia masking (in insulin-dependent diabetes — mask tachycardia warning sign; hypoglycaemia sweating is preserved since it is α-mediated). Contraindications: acute decompensated HF, severe asthma/COPD, second- or third-degree AV block, sick sinus syndrome.

Central α2-agonists — methyldopa: Acts on α2-adrenergic receptors in the central nervous system (nucleus tractus solitarius and brainstem) → reduces sympathetic outflow → lower BP + HR. Drug of choice for oral antihypertensive in pregnancy (longest safety record in pregnancy; no evidence of fetal harm in multiple trials). ADRs: sedation, dry mouth, positive Coombs test (autoimmune haemolytic anaemia with chronic use), hepatitis (rare). Clonidine (α2 + imidazoline-1 agonist): causes rebound hypertension on abrupt withdrawal — must be tapered; used in hypertensive urgency and opioid withdrawal.

Direct vasodilators — hydralazine: Directly relaxes arteriolar smooth muscle (exact mechanism unclear; may involve guanylyl cyclase activation). Causes reflex tachycardia and fluid retention → always combined with a beta-blocker and diuretic. IV hydralazine is used in severe PIH. Chronic high doses (>200 mg/day) cause a drug-induced lupus-like syndrome (anti-histone antibodies, arthralgia, rash) — more common in slow acetylators. Minoxidil (K-channel opener, more potent vasodilator) causes marked hypertrichosis (hair growth — exploited in topical form for alopecia) and pericardial effusion at high doses; reserved for resistant hypertension. Sodium nitroprusside (IV only): releases NO directly → balanced arterial and venous dilation; fastest-acting antihypertensive for hypertensive emergency; requires ICU monitoring; prolonged infusion releases cyanide (metabolised to thiocyanate — toxic; monitor with serum thiocyanate if infused >48h).

Clinical Decision-Making: Comorbidity-Driven Prescribing

The most effective antihypertensive prescribing strategy integrates the patient's comorbidities to select drugs that simultaneously treat hypertension and the comorbid condition — achieving 'double duty' with a single agent. The following comorbidity-specific frameworks are essential.

HTN + Diabetes mellitus: ACEi or ARB is first-line — both treat hypertension AND reduce intraglomerular pressure → slow diabetic nephropathy progression (Lewis trial for ACEi in T2DM; IRMA-2, RENAAL for ARBs). Target BP <130/80 mmHg. Add CCB (amlodipine) as second agent. Avoid thiazides at high doses (worsens hyperglycaemia) and non-selective beta-blockers (mask hypoglycaemia warning).

HTN + CKD (non-diabetic with proteinuria): ACEi or ARB — nephroprotective by reducing proteinuria. If eGFR <30: loop diuretic (not thiazide) for volume control. Monitor creatinine + potassium closely.

HTN + HFrEF: Four-drug backbone (ACEi or ARNI + beta-blocker + MRA + SGLT2i) also treats hypertension. Avoid non-DHP CCBs (verapamil, diltiazem) — negative inotropy worsens HFrEF. DHP-CCBs (amlodipine) are safe in HFrEF if additional BP control needed.

HTN + Angina pectoris: Beta-blocker first-line (reduces HR → reduces myocardial O2 demand → treats angina + hypertension). Add DHP-CCB (amlodipine) if additional control needed. Avoid short-acting nifedipine (reflex tachycardia worsens angina). Non-DHP CCBs (verapamil, diltiazem) are alternatives if beta-blockers are contraindicated.

HTN in Pregnancy:
- Oral agents safe in pregnancy: methyldopa (first-line for chronic management; longest safety record), labetalol (oral or IV), nifedipine SR (second-line), hydralazine (oral or IV for acute).
- ABSOLUTELY CONTRAINDICATED in pregnancy: ACEi, ARBs, renin inhibitors (all RAAS blockers).
- For severe PIH (BP ≥160/110): IV labetalol (20 mg bolus, then infusion) or IV hydralazine (5–10 mg bolus).
- Magnesium sulphate (MgSO₄) is used for SEIZURE PROPHYLAXIS in pre-eclampsia/eclampsia — it is NOT an antihypertensive.

Hypertensive emergency (BP ≥180/120 with target-organ damage — encephalopathy, aortic dissection, acute MI, acute pulmonary oedema, eclampsia):
- Goal: reduce BP by no more than 20–25% in the first hour (prevent cerebral hypoperfusion); further reduction to 160/100 over next 2–6 hours; avoid rapid falls.
- Agents: IV labetalol (versatile — safe in most emergencies including pregnancy); IV nicardipine (DHP-CCB IV — for most hypertensive emergencies, including post-neurosurgery); IV sodium nitroprusside (most potent; needs ICU, cyanide monitoring if >48h); IV esmolol (short-acting β-blocker — aortic dissection first-choice to reduce HR + BP).
- Aortic dissection special case: esmolol (↓HR to 60 bpm) + nicardipine/nitroprusside (↓BP) — essential to blunt the aortic wall shear stress.

Hypertensive urgency (BP ≥180/120 WITHOUT target-organ damage):
- Oral agents: oral captopril (SL or oral, onset 15–30 min), oral labetalol (200 mg), oral clonidine (loading dose); outpatient setting acceptable.
- Goal: gradual BP reduction over 24–48 hours — do not lower rapidly (risk of watershed infarction).

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Self-Assessment: Antihypertensive Selection and Contraindications

Consolidate your prescribing knowledge with the following reference summaries.

Compelling indications for specific antihypertensive classes:

Comorbidity	First-line	Avoid
Diabetes + nephropathy	ACEi or ARB	Thiazide high-dose, non-selective BB
HFrEF	ACEi/ARNI + BB (carvedilol/bisoprolol)	Non-DHP CCB (verapamil, diltiazem)
Post-MI	Beta-blocker + ACEi	—
Angina	Beta-blocker or DHP-CCB	Short-acting nifedipine
Isolated systolic HTN (elderly)	Thiazide or DHP-CCB	—
Gout	Losartan	Thiazide
Pregnancy (chronic)	Methyldopa, labetalol, nifedipine SR	ACEi, ARB (absolutely contraindicated)
Severe PIH (acute)	IV labetalol, IV hydralazine	ACEi, ARB, sodium nitroprusside (fetal cyanide)
BPH + HTN	Doxazosin (α1 blocker)	—
Asthma	DHP-CCB, ACEi, thiazide	Beta-blockers

Hypertensive emergency vs urgency — management comparison:

Feature	Emergency	Urgency
BP level	≥180/120 mmHg	≥180/120 mmHg
Target-organ damage	YES (encephalopathy, MI, pulmonary oedema, aortic dissection)	NO
Route	IV (hospital)	Oral (monitored setting)
BP reduction rate	20–25% in 1st hour, then gradual	Gradual over 24–48h
Agents	IV labetalol, IV nicardipine, IV nitroprusside, IV esmolol	Oral captopril, oral labetalol, oral clonidine