Side Effects of Hydrochlorothiazide
Hydrochlorothiazide causes electrolyte disturbances (particularly hypokalemia and hyponatremia), metabolic abnormalities, and carries an increased risk of non-melanoma skin cancer with long-term use. 1
Electrolyte Disturbances
Hypokalemia (Low Potassium)
- Hypokalemia occurs in approximately 12.6% of hydrochlorothiazide users, equivalent to ~2.0 million US adults 2
- The mechanism involves increased urinary potassium excretion through the distal tubule 3
- Higher risk groups include:
- Hypokalemia persists even with potassium supplementation in 27.2% of monotherapy patients and 17.9% of polytherapy patients 2
- Thiazide-induced hypokalemia is associated with increased blood glucose and may contribute to glucose intolerance 4
- The risk is dose-dependent, with doses ≥25 mg showing significantly more electrolyte shifts than 12.5 mg 1, 5
Hyponatremia (Low Sodium)
- Severe hyponatremia can occur, particularly when combined with ARBs or during sodium restriction 3, 6
- The mechanism involves impaired urinary dilution in the distal convoluted tubule and enhanced proximal water reabsorption due to volume depletion 7
- Elderly patients have heightened risk and require close monitoring 8
- Hyponatremia during combined sodium restriction and hydrochlorothiazide cannot be accounted for solely by sodium balance changes 6
Metabolic Side Effects
- Hyperglycemia and glycosuria occur through mechanisms related to hypokalemia 1, 4
- Hyperuricemia results from volume contraction and competition with uric acid for renal tubular secretion 1, 4
- Chronic hypercholesterolemia may develop with long-term use 7
Cardiovascular Effects
- Orthostatic hypotension, particularly when combined with alcohol, barbiturates, narcotics, or other antihypertensives 1
- Complaints of dizziness and weakness are common, especially with concurrent sodium restriction 6
Renal Effects
- Renal function decline is dose-dependent, with higher doses causing more rapid decline in eGFR 7
- Renal failure, renal dysfunction, and interstitial nephritis can occur 1
- Increased risk of end-stage renal disease with prolonged use 7
Serious Hypersensitivity Reactions
- Acute pulmonary edema is a rare but potentially life-threatening allergic reaction 1, 9
- Anaphylactic reactions, necrotizing angiitis (vasculitis), and respiratory distress including pneumonitis 1
- Photosensitivity, urticaria, rash, and purpura 1
Dermatologic Effects
- Non-melanoma skin cancer risk is significantly increased, predominantly squamous cell carcinoma (SCC) 1
- The increased risk for SCC in white patients taking cumulative doses ≥50,000 mg is approximately 1 additional case per 6,700 patients per year 1
- Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, and alopecia 1
Hematologic Effects
- Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia 1
Gastrointestinal Effects
- Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia 1
Neurologic Effects
- Vertigo, paresthesia, dizziness, headache, and restlessness 1
- Transient blurred vision and xanthopsia (yellow vision) 1
Other Effects
- Muscle spasm 1
- Impotence 1
- Weakness and fatigue, typically caused by fluid and electrolyte imbalances 9
Critical Monitoring Requirements
Monitor electrolytes (sodium, potassium, chloride, bicarbonate) and renal function within 4 weeks of initiation or dose escalation 8, 5
- Continue monitoring every 3-6 months once stable 10
- More frequent monitoring (every 5-7 days) is required when initiating therapy or changing doses 10