What antihypertensive medication has the least reported side effects in a general adult population with hypertension and no significant comorbidities?

Which Antihypertensive Has the Least Side Effects?

Thiazide or thiazide-like diuretics, ACE inhibitors, ARBs, and long-acting calcium channel blockers all have comparable and favorable side effect profiles as first-line agents, with ARBs (like losartan) demonstrating the lowest discontinuation rates due to adverse effects in head-to-head comparisons. 1, 2

Side Effect Profile Comparison

ARBs (Angiotensin Receptor Blockers)

• ARBs have the most favorable tolerability profile among first-line agents, with discontinuation rates for adverse events of only 2.3% compared to 3.7% for placebo in large clinical trials 3
• The most common side effects occurring in ≥2% of patients on losartan include: dizziness (3%), upper respiratory infection (8%), nasal congestion (2%), and back pain (2%) 3
• Critically, ARBs do not cause the persistent dry cough that affects ACE inhibitors - studies show cough incidence with losartan (17-29%) is similar to placebo (25-35%), versus 62-69% with lisinopril 3

ACE Inhibitors

• Well-tolerated overall with few serious adverse effects 4, 5
• The major limitation is persistent dry cough occurring in a few percent of patients, which can necessitate discontinuation 3
• Do not cause hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia 5
• Rare but serious: angioedema (though less common than previously thought) 3

Thiazide Diuretics

• Generally well-tolerated, particularly chlorthalidone which shows superior cardiovascular outcomes 1, 2
• Metabolic side effects can occur: hypokalemia, hyperglycemia, hyperuricemia, hypercholesterolemia 5
• These metabolic effects are clinically manageable and can be mitigated when combined with ACE inhibitors or ARBs 1

Calcium Channel Blockers

• Well-tolerated with predictable side effects related to vasodilation 1, 2
• Common effects include peripheral edema and headache (mechanism-related, not idiosyncratic)
• No significant metabolic disturbances 2

Agents to Avoid as First-Line

Beta-Blockers

• Significantly less effective than diuretics for stroke prevention and cardiovascular events 1
• Should not be first-line unless ischemic heart disease or heart failure is present 6

Alpha-Blockers and Central Alpha-Agonists

• Highlighted as likely to produce more adverse effects, particularly in older adults 1
• Not recommended as first-line therapy 6

Clinical Decision Algorithm

For patients prioritizing minimal side effects:

1. Start with an ARB (e.g., losartan 50mg daily) if no specific comorbidity dictates otherwise - lowest discontinuation rate and no cough 3, 2

2. ACE inhibitor as alternative if cost is a concern (generally less expensive than ARBs) - accept 3-5% risk of cough requiring switch 3, 5

3. Thiazide diuretic (chlorthalidone preferred) for patients who can tolerate monitoring of electrolytes and metabolic parameters 1, 2

4. Calcium channel blocker for patients who cannot tolerate RAAS inhibitors - predictable vasodilatory effects 2

Important Caveats

• All four first-line classes (thiazides, ACE inhibitors, ARBs, CCBs) are endorsed equally by major guidelines with strong recommendations based on cardiovascular outcome data 1, 2
• The WHO provides strong recommendation (high-quality evidence) that any of these four classes can be used as initial treatment 2
• Most patients require 2+ medications for adequate control, so side effect profiles of combinations matter - typical effective combination is diuretic + ACE inhibitor or ARB + calcium channel blocker 2
• Never combine ACE inhibitors with ARBs - this increases adverse effects without additional benefit 6