Pharmaceutical Treatment for Hypertension
Initial Treatment Selection
For most patients with hypertension, initiate treatment with a thiazide or thiazide-like diuretic (chlorthalidone 12.5-25mg daily preferred over hydrochlorothiazide), an ACE inhibitor or ARB, or a calcium channel blocker, with the specific choice guided by patient ethnicity, comorbidities, and contraindications. 1, 2, 3
First-Line Drug Classes by Patient Population
For Black patients:
- Initial therapy should include a thiazide diuretic or calcium channel blocker (CCB), either alone or in combination with a RAS blocker 1
- The combination of CCB + thiazide diuretic may be more effective than CCB + ACE inhibitor/ARB in this population 1, 4
For non-Black patients:
- ACE inhibitor or ARB is typically first-line, with CCB or thiazide diuretic as acceptable alternatives 1, 4
- The sequence is: RAS blocker → add CCB → optimize doses → add thiazide diuretic if needed 4
For patients with specific comorbidities:
- Diabetes mellitus or chronic kidney disease: ACE inhibitor or ARB preferred 1
- Heart failure with reduced ejection fraction: ACE inhibitor or ARB + beta-blocker + diuretic + aldosterone antagonist 1
- Post-myocardial infarction: Beta-blocker + ACE inhibitor or ARB 1
- Chronic stable angina: Beta-blocker (if prior MI) + ACE inhibitor or ARB + thiazide diuretic 1
- Atrial fibrillation (recurrent): ARB or ACE inhibitor 1
- Chronic kidney disease with proteinuria: ACE inhibitor or ARB + loop diuretic 1
Combination Therapy Algorithm
When blood pressure remains uncontrolled on monotherapy, add a second agent from a complementary drug class rather than maximizing the dose of the first agent. 1, 4
Two-Drug Combinations
- Preferred combinations: ACE inhibitor/ARB + CCB, ACE inhibitor/ARB + thiazide diuretic, or CCB + thiazide diuretic 1, 4
- Single-pill combinations are strongly preferred over separate pills to improve adherence 1, 4
Three-Drug Combinations
- Standard triple therapy: ACE inhibitor/ARB + CCB + thiazide diuretic 1, 4
- This combination targets three complementary mechanisms: renin-angiotensin system blockade, vasodilation, and volume reduction 4
Four-Drug Regimen for Resistant Hypertension
- Add spironolactone 25-50mg daily as the preferred fourth-line agent if blood pressure remains ≥140/90 mmHg despite optimized triple therapy 1
- Spironolactone should only be added if serum potassium is <4.5 mmol/L and eGFR is >45 ml/min/1.73m² 1
- Alternative fourth-line agents if spironolactone is contraindicated: eplerenone, amiloride, higher-dose thiazide, loop diuretic, bisoprolol, or doxazosin 1
Critical Contraindications and Drug Allergies
If the patient has documented ACE inhibitor allergy (angioedema):
- Avoid all ACE inhibitors - do not attempt rechallenge 1, 5
- Avoid ARBs - cross-reactivity and angioedema can occur with ARBs in patients who developed it with ACE inhibitors 5
- Use combination of CCB + beta-blocker + thiazide diuretic instead 5
Absolute contraindications by drug class:
- Thiazide diuretics: Gout (compelling), pregnancy 1
- Beta-blockers: Asthma, second- or third-degree AV block 1
- ACE inhibitors/ARBs: Pregnancy, bilateral renal artery stenosis, history of angioedema, hyperkalemia 1
- Non-dihydropyridine CCBs (diltiazem/verapamil): Second- or third-degree AV block, heart failure 1
- Aldosterone antagonists: Renal failure (eGFR <45), hyperkalemia (K+ >4.5 mmol/L) 1
Blood Pressure Targets
Target blood pressure is <140/90 mmHg minimum for most patients, with <130/80 mmHg preferred for higher-risk patients including those with diabetes, chronic kidney disease, or established cardiovascular disease. 1, 4
- For patients ≥65 years: SBP <130 mmHg 6
- For patients with heart failure: Consider <120/80 mmHg if ventricular dysfunction present 1
- Optimal target per 2024 ESC guidelines: 120-129 mmHg systolic if well tolerated 1, 4
Monitoring and Follow-Up
Reassess blood pressure within 2-4 weeks after initiating or modifying therapy, with the goal of achieving target blood pressure within 3 months. 4
- Check serum potassium and creatinine 2-4 weeks after starting ACE inhibitor, ARB, or diuretic 4
- Monitor for hyperkalemia when combining ACE inhibitor/ARB with aldosterone antagonist 1, 4
- Confirm medication adherence before escalating therapy - non-adherence is the most common cause of apparent treatment resistance 4
Hypertensive Emergencies
For hypertensive emergencies (SBP ≥180 mmHg with acute end-organ damage), admit to ICU and initiate continuous infusion of short-acting IV antihypertensive medication. 1, 7
Preferred IV Agents by Clinical Scenario
- Acute aortic dissection: Esmolol or labetalol (target SBP ≤120 mmHg within 20 minutes) 1
- Acute pulmonary edema: Clevidipine, nitroglycerin, or nitroprusside (beta-blockers contraindicated) 1
- Acute coronary syndrome: Esmolol, labetalol, nicardipine, or nitroglycerin 1
- Eclampsia/preeclampsia: Hydralazine, labetalol, or nicardipine (ACE inhibitors and ARBs contraindicated) 1
- Acute intracerebral hemorrhage with SBP ≥220 mmHg: Careful IV therapy to reduce SBP to <180 mmHg 1
For hypertensive urgencies (severe hypertension without acute end-organ damage), treat with oral antihypertensives as outpatient - IV therapy is not required. 7, 8
Common Pitfalls to Avoid
- Never combine two RAS blockers (ACE inhibitor + ARB) - this increases adverse events without cardiovascular benefit 1, 4
- Avoid immediate-release nifedipine for hypertensive emergencies due to unpredictable response 1, 7
- Do not add beta-blocker as third agent unless compelling indications exist (angina, post-MI, heart failure, atrial fibrillation) 1, 4
- Screen for interfering substances before diagnosing resistant hypertension: NSAIDs, decongestants, oral contraceptives, systemic corticosteroids 4, 8
- Rule out secondary hypertension if blood pressure remains severely elevated despite three-drug therapy: primary aldosteronism, renal artery stenosis, obstructive sleep apnea, pheochromocytoma 1, 8
Lifestyle Modifications
Reinforce sodium restriction to <2g/day, which provides 5-10 mmHg systolic reduction and enhances medication efficacy. 1, 4, 6