What are the potential side effects of Hydrochlorothiazide (HCTZ)?

Hydrochlorothiazide (HCTZ) Side Effects

Hydrochlorothiazide can cause numerous side effects ranging from common electrolyte disturbances to rare but serious adverse reactions including non-melanoma skin cancer, with the risk of side effects being dose-dependent. 1

Common Side Effects

Electrolyte and Metabolic Abnormalities

• Hypokalemia (low potassium) - particularly at doses of 25mg and higher 1, 2
• Hyponatremia (low sodium) 1
• Hypomagnesemia (low magnesium) 2
• Hyperuricemia (high uric acid) 1
• Hyperglycemia - can worsen glycemic control in diabetic patients 1, 3
• Hyperlipidemia - particularly increased triglycerides and decreased HDL cholesterol 2, 3

Cardiovascular Effects

• Hypotension including orthostatic hypotension (may be worsened by alcohol, barbiturates, narcotics or other antihypertensive drugs) 1
• Impaired endothelium-dependent vasorelaxation - even with mild hypokalemia 2

Gastrointestinal Effects

• Nausea, vomiting, gastric irritation 1
• Anorexia, constipation, diarrhea 1
• Pancreatitis (rare but serious) 1
• Sialadenitis (inflammation of salivary glands) 1

Neurological Effects

• Dizziness, vertigo 1
• Headache, paresthesia 1
• Restlessness 1

Serious Side Effects

Dermatologic Reactions

• Non-melanoma skin cancer - increased risk, especially squamous cell carcinoma in white patients taking large cumulative doses (approximately 1 additional case per 16,000 patients per year, and for white patients taking ≥50,000mg, 1 additional case per 6,700 patients per year) 1
• Photosensitivity reactions 1
• Severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis (rare) 1
• Rash, urticaria, purpura 1

Hematologic Effects

• Aplastic anemia, agranulocytosis (rare) 1
• Leukopenia, hemolytic anemia, thrombocytopenia 1

Renal Effects

• Renal dysfunction and renal failure 1
• Interstitial nephritis 1
• Subtle renal injury - including increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress 2

Hypersensitivity Reactions

• Anaphylactic reactions 1
• Necrotizing angiitis (vasculitis) 1
• Respiratory distress including pneumonitis and pulmonary edema 1

Other Effects

• Muscle spasm 1
• Transient blurred vision, xanthopsia (yellow vision) 1
• Impotence 1
• Edema - paradoxical effect requiring discontinuation 4

Dose-Related Considerations

• Side effects are dose-related, with adverse reactions more common at doses of 25mg and higher 1
• At doses of 12.5mg, side effects are comparable to placebo 1
• Even at low doses (12.5-25mg), HCTZ can cause significant metabolic effects in patients with type 2 diabetes 3

Management of Side Effects

• For moderate to severe side effects, reduce HCTZ dosage or withdraw therapy 1
• For edema, consider alternative antihypertensive medications such as ACE inhibitors, ARBs without HCTZ component, or calcium channel blockers 4
• For patients with diabetes experiencing metabolic side effects, consider alternative antihypertensives 3
• For patients with renal impairment, dose adjustment is necessary as renal clearance is reduced in mild (CLCR = 80 ml/min), moderate (CLCR = 50 ml/min) and severe (CLCR = 30 ml/min) renal impairment 5
• Consider chlorthalidone or indapamide as alternative thiazide-like diuretics with potentially better cardiovascular outcomes 6, 7

Monitoring Recommendations

• Monitor electrolytes shortly after initiating therapy and periodically thereafter 6
• Monitor for signs of swelling, particularly during the first few weeks of therapy 4
• In patients with diabetes, monitor blood glucose and HbA1c levels 3
• In patients on long-term therapy, consider periodic skin examinations, especially in fair-skinned individuals 1

Remember that chlorthalidone and indapamide are preferred over HCTZ by some guidelines due to their longer duration of action and potentially better cardiovascular outcomes 6, 7.