What are the potential side effects of antihypertensive medications such as thiazide-like diuretics, Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), and calcium channel blockers in a patient with hypertension?

Side Effects of Antihypertensive Medications

All first-line antihypertensive medications—thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers—have distinct side effect profiles that require monitoring, but none demonstrates a clearly superior overall safety profile compared to the others. 1

Thiazide and Thiazide-Like Diuretics

Electrolyte and Metabolic Disturbances

• Hypokalemia is the most common electrolyte abnormality, developing especially with brisk diuresis, severe cirrhosis, or concomitant corticosteroid/ACTH use 2
• Hyponatremia may occur in edematous patients, particularly in hot weather; elderly patients face heightened risk 1, 2
• Hypomagnesemia can develop due to increased urinary magnesium excretion 1
• Hyperuricemia or frank gout may be precipitated in susceptible patients 2
• Hyperglycemia and new-onset diabetes occur more frequently with thiazides, though this does not reduce their cardiovascular efficacy 3

Cardiovascular and Renal Effects

• Thiazide-induced hypokalemia is associated with increased blood glucose, and treating the hypokalemia may reverse glucose intolerance 4
• Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially affecting myocardial activity 2
• Hypercalcemia can occur as calcium excretion decreases; pathological parathyroid changes with hypercalcemia and hypophosphatemia have been observed in rare cases 2

Other Side Effects

• Most thiazide-related adverse effects are dose-related, involving electrolyte and metabolic abnormalities 5
• Symptomatic adverse effects occur in approximately 8-10% of patients when used as initial monotherapy 6
• Impotence has been reported, though this is not universally accepted as a diuretic-related side effect 4

Monitoring Requirements

• Serum creatinine/eGFR and potassium levels should be monitored at least annually in patients on diuretics 1
• Periodic determination of serum electrolytes should be performed at appropriate intervals 2

ACE Inhibitors

Serious Adverse Events

• Acute kidney injury (AKI) can occur, particularly in patients with reduced glomerular filtration 1
• Hyperkalemia is a significant risk, especially when combined with other RAS blockers or in patients with CKD 1
• Angioedema is a compelling contraindication to continued use 1

Contraindications and Precautions

• Absolutely contraindicated in pregnancy 1
• Contraindicated in bilateral renal artery stenosis 1
• The combination of ACE inhibitors with ARBs should be avoided due to increased risks of hyperkalemia and AKI without added cardiovascular benefit 1

Monitoring Requirements

• Serum creatinine/eGFR and potassium should be monitored at least annually 1
• More frequent monitoring is needed in patients with reduced glomerular filtration who are at increased risk 1

Tolerability

• ACE inhibitors show little or no dose-dependent increase in side effects 1
• Withdrawals due to adverse effects are lower compared to beta-blockers (ARR 1.0%) 7

Angiotensin Receptor Blockers (ARBs)

Adverse Events Profile

• Hyperkalemia risk is similar to ACE inhibitors, particularly when combined with other RAS blockers 1
• Acute kidney injury can occur, especially in high-risk patients 1
• Aliskiren (direct renin inhibitor) may cause acute renal failure in patients with severe bilateral renal artery stenosis 1

Contraindications

• Pregnancy is an absolute contraindication 1
• Bilateral renal artery stenosis 1
• Avoid combination with ACE inhibitors or renin inhibitors due to increased cardiovascular and renal risk 1

Monitoring Requirements

• Serum creatinine/eGFR and potassium levels should be monitored at least annually 1
• Detection and management of AKI and hyperkalemia is critical as each increases risks of cardiovascular events and death 1

Tolerability

• ARBs show little or no dose-dependent increase in side effects 1
• Generally well-tolerated with symptomatic adverse effects in approximately 8-10% of patients 6

Calcium Channel Blockers

Dihydropyridine CCBs (e.g., Amlodipine)

• Peripheral edema is common and dose-related 1
• Tachyarrhythmias are a possible contraindication for dihydropyridine CCBs 1
• In ALLHAT, amlodipine showed a 38% higher rate of heart failure compared to chlorthalidone 1

Non-Dihydropyridine CCBs (Verapamil, Diltiazem)

• AV block (grade 2 or 3) is a compelling contraindication 1
• Heart failure is a possible contraindication 1
• Can be safely combined with dihydropyridine CCBs 1

General Tolerability

• Symptomatic adverse effects occur in approximately 8-10% of patients when used as initial monotherapy 6
• Side effects are dose-related 1

Important Drug Interactions and Combinations to Avoid

Harmful Combinations

• Simultaneous use of ACE inhibitor, ARB, and/or renin inhibitor is potentially harmful and not recommended, increasing risks of hyperkalemia, syncope, and AKI 1
• Combining mineralocorticoid receptor antagonists with ACE inhibitors or ARBs increases hyperkalemia risk, requiring regular monitoring 1

Drug Interactions

• NSAIDs blunt thiazide effects 4
• Thiazides combined with beta-blockers may increase fatigue, lethargy, and glucose levels 4
• Thiazides may increase responsiveness to tubocurarine and decrease arterial responsiveness to norepinephrine 2
• Insulin requirements in diabetic patients may change (increase, decrease, or remain unchanged) with thiazide use 2

Common Pitfalls to Avoid

• Do not automatically discontinue thiazide diuretics when eGFR decreases to <30 mL/min/1.73 m²; assess risks and benefits individually 1
• Avoid using two or more drugs from the same class except for diuretics with different mechanisms of action 1
• Address barriers to medication adherence (cost, side effects) before diagnosing resistant hypertension 1
• Beta-blockers should not be preferred in patients with metabolic syndrome, abdominal obesity, impaired fasting glucose, or glucose intolerance due to dysmetabolic effects 1