Hydrochlorothiazide and hydralazine Side Effects
Please note - some side effects for Hydrochlorothiazide and hydralazine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
Side Effects by Body System - for Healthcare Professionals
Applies to: oral capsule
Immunologic side effects including development of a lupus-like syndrome have been reported. This syndrome is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg of hydralazine per day, 40% develop a positive ANA titer, and up to 6% develop a lupus-like syndrome. Of patients who receive 400 mg or more per day, 50% develop a positive ANA titer, and up to 14% develop a lupus-like syndrome.
The lupus syndrome may present as arthralgia (most common), myalgia, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea. The lupus syndrome may also be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus.
Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.
Because up to 20% of patients who receive 400 mg or more of hydralazine per day develop a systemic lupus erythematosus syndrome, some experts recommend checking a patient's acetylator status before giving higher doses. Up to 70% of "resistant" patients are fast acetylators, in whom the dose can be relatively safely increased.
Data suggest that hydralazine lupus may represent a unique hypersensitivity reaction in which antibodies to native DNA occur. These antibodies are believed to account for the clinical similarities between hydralazine-induced lupus and systemic lupus erythematosus.
Cardiovascular side effects are related to hydralazine-induced peripheral vasodilation and HCTZ-induced decreased intravascular volume. Orthostatic hypotension, with or without reflex tachycardia, may occur resulting in syncope. This may be more likely in the elderly. Palpitations, flushing, edema, or chest pain are reported in less than 5% of patients. The use of hydralazine in patients with severe chronic heart failure is associated with ischemia, including episodes of myocardial infarction.
In patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), hydralazine may increase pulmonary artery hypertension, especially during periods of hypoxia. The use of hydralazine in these patients may, on rare occasions, result in profound hypotension, tachycardia, and even death.
Rare cases of bradycardia or cardiac tamponade (associated with hydralazine-induced lupus) have been reported. Hydralazine does not have a deleterious effect on the lipid profile. In fact, hydralazine has been shown to decrease total and LDL cholesterol.
Provocation of ischemia in patients with compromised left ventricular systolic function may be due to the inability of hydralazine to decrease preload, or left ventricular filling pressures.
The mechanism of increased pulmonary hypertension in patients with PH or COPD is a decrease of systemic vascular resistance accompanied by an increase in cardiac output without a fall in the pulmonary vascular resistance. In case reports and small series of patients with PH or COPD, the use of hydralazine resulted in palpitations, chest tightness, unchanged pulmonary vascular resistance, increased pulmonary artery pressure, decreased systemic vascular resistance, and increased heart rate and cardiac output. For this reason, many experts recommend hemodynamic monitoring during hydralazine therapy if hydralazine must be used in such patients.
Caution should be used in patients with hypercholesterolemia since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%.
Caution should also be used in diabetic patients since HCTZ may also reduce insulin secretion.
Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may occur but are usually clinically insignificant, except in malnourished patients.
Metabolic side effects are common, especially when doses greater than 50 mg per day of HCTZ are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients, and may predispose some patients to significant cardiac arrhythmias, including ventricular ectopy and complete AV heart block. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. HCTZ may increase serum cholesterol.
A 61-year-old man with hypertension developed ataxia, numbness, and lower extremity weakness approximately six months after beginning hydralazine (up to 300 mg per day) and reserpine therapy. The neuropathy partially resolved after reduction of the hydralazine dosage to 60 mg daily. A complete evaluation revealed that this man was a slow acetylator of hydralazine.
Nervous system side effects including peripheral neuropathy have been reported. Peripheral neuropathy is related to the dose hydralazine used and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. Neuropathy is probably the result of pyridoxine deficiency, perhaps because the formation of a pyridoxal-hydralazine complex inactivates the coenzyme. This neuropathy can be treated by administration of pyridoxine. Headache or dizziness are reported in approximately 5% of patients. Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.
Hypersensitivity reactions are rarely associated with either drug. Anaphylaxis associated with HCTZ has been reported. Syndromes consisting of nausea, vomiting, diarrhea, and rash, occur in less than 1% of patients. Rare cases of hepatitis, retroperitoneal fibrosis, and occupational asthma associated with hydralazine have been reported. Rare cases of acute pulmonary edema, interstitial cystitis, and interstitial nephritis associated with HCTZ have been reported.
A 44-year-old woman with hypertension and acute sinusitis developed acute renal failure, edema, and a generalized maculopapular erythematous rash during therapy with ampicillin, hydralazine, and HCTZ. A complete evaluation revealed bilateral hydronephrosis and hydroureters secondary to ureteral obstruction due to retroperitoneal fibrosis. Renal function returned to baseline after oral prednisone therapy. It is unclear whether this problem was due to one or more of her medications.
A 68-year-old man with a history of myocardial infarction (MI) developed dyspnea, chest tightness, a low grade fever, dizziness, sweating, vomiting associated with cyanosis, a mild leukocytosis, radiographic evidence of pulmonary edema, clinical evidence of hypovolemia, and respiratory acidosis. MI and infection were ruled out. The patient recovered after restoration of his intravascular volume with saline and albumin. The only precipitating factor per history was the ingestion of HCTZ, which the patient had taken without incident for two years. Rechallenge resulted in recurrent acute pulmonary edema. Other signs of hypersensitivity, such as rash and eosinophilia, were absent.
Hematologic abnormalities are associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems including hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia, agranulocytosis, aplastic anemia, and thrombocytopenia have been associated with either drug.
A 71-year-old man with hypertension developed anorexia, weight loss, petechia, and microcytic anemia during therapy with hydralazine and oxprenolol. Evaluation for iron deficiency, hemolysis, or marrow depression was negative. The patient was found to have fecal blood loss, anti-DNA antibodies, decreased complement levels, a normal upper GI series, and biopsy-proven vasculitis. The syndrome resolved within two weeks after discontinuation of hydralazine.
There are rare case reports of HCTZ-induced immune hemolytic anemia. The following illustrates a fatal case:
A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, and hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs tests were positive. The patient died suddenly; autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.
Dermatologic manifestations of the hydralazine-induced lupus-like syndrome include cutaneous vasculitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus has been associated with HCTZ. Two cases of Sweet's syndrome (neutrophilic dermatosis) have been associated with hydralazine. Erythema annular centrifugum, acute eczematous dermatitis, morbilliform and leukocytoclastic vasculitis, and phototoxic dermatitis have been associated with HCTZ.
A 65-year-old man with ischemic cardiomyopathy developed a pruritic, erythematous, generalized rash within two months after beginning hydralazine (200 mg per day) therapy. There were no clinical or laboratory signs of lupus. The rash persisted upon gradual withdrawal of the patient's other medications, but cleared only after discontinuation of hydralazine. Rechallenge resulted in a recurrent pruritic rash.
A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, and personality changes associated with a new positive ANA and anti-nRNP, and skin biopsy consistent with lupus erythematosus while taking HCTZ, levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.
In one study, rapidly progressive glomerulonephritis (RPGN) was described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily hydralazine doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.
Although HCTZ has been used to treat nephrogenic diabetes insipidus, a case report in which the drug was believed to have caused this condition has been reported.
Renal side effects are common in idiopathic systemic lupus erythematosus; however, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer. New or worsened renal insufficiency may occur due to HCTZ-induced intravascular volume depletion. Rare cases of interstitial nephritis have been reported.
A 48-year-old woman with hypertension developed dyspnea, hemoptysis, pleurisy, proteinuria, and hematuria one year after beginning hydralazine (150 mg per day), polythiazide, and atenolol therapy. Other associated findings included an elevated ESR, antinuclear factor, anti-DNA titer, a positive LE test, and radiographic findings of diffuse interstitial lung disease. Two weeks after stopping hydralazine, the signs and symptoms of lupus with pulmonary involvement disappeared.
Respiratory side effects include nasal stuffiness, seen in approximately 3% of patients who are taking hydralazine. There are approximately 30 case reports of acute noncardiogenic pulmonary edema associated with HCTZ and rare cases of "hydralazine lung," associated with hydralazine-induced lupus.
Endocrinologic problems associated with thiazide diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile. This may be important in some patients with or who are at risk for diabetes or coronary artery disease.
A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased mean fasting blood glucose level after treatment. Withdrawal of thiazide therapy for seven months in 10 of the patients resulted in average reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test value. A control group was not reported.
Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in increased risk of cholesterol gallstone formation. Reports of bowel strictures associated with thiazide ingestion have been reported in the 1960's, although these patients were on a combination HCTZ-potassium product.
Gastrointestinal side effects are unusual, and include nausea, vomiting, and diarrhea. There are rare cases of pancreatitis and acute cholecystitis associated with HCTZ.
At least two cases of male impotence associated with hydralazine have been reported. The mechanism is unclear. There was no evidence of a neuropathy in either case.
Genitourinary side effects including Impotence is a rare complaint among male patients taking hydralazine.
A 59-year-old woman with hypertension and cholecystic gallbladder disease developed abdominal pain, nausea, vomiting, painful hepatomegaly, elevated serum transaminases, direct hyperbilirubinemia, and liver biopsy findings of subacute hepatitis (with bridging necrosis) within two days after hydralazine was added to her medical regimen. The signs and symptoms of hepatitis resolved after all medications were withheld, but returned upon rechallenge with hydralazine.
Hepatic reactions are rare. Less than ten cases of hepatitis are associated with hydralazine, many of which are believed to be due to hypersensitivity. Histological findings include hepatocellular, cholestatic, mixed hepatocellular-cholestatic, and granulomatous patterns.Top
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