Tri-Hydroserpine Side Effects
Generic name: hydralazine / hydrochlorothiazide / reserpine
Medically reviewed by Drugs.com. Last updated on Feb 14, 2023.
Note: This document contains side effect information about hydralazine / hydrochlorothiazide / reserpine. Some dosage forms listed on this page may not apply to the brand name Tri-Hydroserpine.
Applies to hydralazine / hydrochlorothiazide / reserpine: oral tablet.
Immunologic
Because up to 20% of patients who receive 400 mg of hydralazine per day or more 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.[Ref]
Immunologic side effects including a lupus-like syndrome have been reported. The lupus 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 or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome.
The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea. It 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.
Immunologic side effects associated with reserpine are rare. A single case of angioimmunoblastic lymphadenopathy has been associated with reserpine. In one study of 231 patients, only one case of a lupus-like syndrome was recorded. The patient had previously received hydralazine.[Ref]
Metabolic
Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, VLDL lipoprotein cholesterol levels by 50%, and may reduce insulin secretion, it should be used with caution in diabetic patients and in those with hypercholesterolemia.
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.[Ref]
Metabolic side effects are commonly associated with HCTZ, especially when doses greater than 50 mg per day are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50%, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. HCTZ may increase serum cholesterol.[Ref]
Nervous system
Nervous system side effects commonly associated with reserpine have included sedation, lethargy (different from the psychiatric syndrome of depression), drowsiness, weakness, vertigo, insomnia, or headache in approximately 1% to 5% of patients. Peripheral neuropathy has been associated with hydralazine. This problem is dose-related and is more common in slow acetylators. Headache or dizziness is reported in approximately 5% of patients who are taking hydralazine alone. Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.[Ref]
Hydralazine-associated peripheral neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine.
While reserpine is used to treat tardive dyskinesia, extrapyramidal movements may worsen upon withdrawal of therapy. A case of CNS hypertension, believed to be due to cerebral edema, has been associated with reserpine. Increased parkinsonian movements upon reserpine withdrawal (as with neuroleptics) may be due to supersensitivity to dopamine as a result of increased dopamine receptors that developed during reserpine therapy.[Ref]
Hypersensitivity
Hypersensitivity reactions to HCTZ, manifest as nausea, vomiting, diarrhea, and rash, are reported in less than 1% of patients. Cases of acute pulmonary edema, interstitial cystitis, interstitial nephritis, and anaphylaxis have been associated with HCTZ or other thiazide diuretics. Hypersensitivity reactions to hydralazine are rare, presenting as hepatitis, retroperitoneal fibrosis, or occupational asthma.[Ref]
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, HCTZ, and hydralazine. 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, and 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 or eosinophilia, were absent.[Ref]
Cardiovascular
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. Thus, in heart failure patients, hydralazine is often administered with a venous vasodilator such a nitrate.
The mechanism of increased pulmonary hypertension (PH) associated with hydralazine 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. Hydralazine-induced ventilation/perfusion mismatching with associated hypoxemia may also contribute to increased PH.
In case reports and small series of patients, the use of hydralazine in such patients 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, if hydralazine must be used, many experts recommend hemodynamic monitoring during hydralazine therapy in such patients.
Rare cases of sinus pauses and profound hypotension during reserpine therapy have been reported. Reserpine is known to increase vagal tone and to deplete cardiac catecholamines.[Ref]
Cardiovascular side effects can occur as a result of all three drugs in this combination product, which makes it a poor choice for the treatment of hypertension in the elderly or in patients with angina pectoris. By causing peripheral vasodilation and reflex tachycardia, palpitations, flushing, edema, or chest pain have been reported in up to 5% of patients who are taking hydralazine alone. The risk of hypotension or orthostatic changes is increased with the addition of reserpine and HCTZ. Reflexive tachycardia may be blunted by reserpine, which can cause bradycardia (and rare cases of syncope with bradycardia) in 3% of patients. The use of hydralazine in patients with severe chronic heart failure has rarely been 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 have been associated with hydralazine-induced lupus.
Cardiac arrhythmias, including ventricular ectopy and complete AV heart block, have been associated with HCTZ-induced hypokalemia and hyponatremia.[Ref]
Psychiatric
The depressive syndrome associated with reserpine usually consists of melancholy, loss of self confidence, early morning awakening, loss of libido, and reduced appetite.
A case of reserpine withdrawal psychosis has been reported. This uncommon condition may be due to dopamine receptor supersensitivity, which may develop during reserpine therapy.[Ref]
Psychiatric problems related to reserpine therapy can be serious. Depression occurs in 2% to 28% of patients, is more likely when daily doses exceed 0.5 mg, and can present at any time during therapy. Suicidal ideation has been reported. Reserpine-induced depression is quickly reversible if therapy is withdrawn as soon as the syndrome is recognized, but can persist for several months after drug discontinuation if the syndrome fully develops. Reserpine withdrawal psychosis has been reported.[Ref]
Dermatologic
Dermatologic reactions to HCTZ are rare, and include erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus has been associated with HCTZ. The hydralazine-induced lupus-like syndrome can include cutaneous vasculitis. A generalized, pruritic rash without evidence of lupus has also been associated with hydralazine. Two cases of Sweet's syndrome (neutrophilic dermatosis) have been associated with hydralazine.[Ref]
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, personality changes, and positive ANA and anti-nRNP titers while taking HCTZ, levothyroxine, and amitriptyline. A skin biopsy was consistent with lupus erythematosus. Her rash 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.[Ref]
Respiratory
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.
Rare reports of reserpine-induced bronchospasm are believed to be due to inactivation of beta-adrenergic receptors, which can result in a marked potentiation of the bronchoconstrictive effect of histamine.[Ref]
Respiratory system side effect have included nasal congestion, occurring in 3% to 8% of patients who are taking either reserpine or hydralazine. Rare cases of bronchospasm (reserpine), "hydralazine lung" (hydralazine-induced lupus), and acute noncardiogenic pulmonary edema (HCTZ) have been reported.[Ref]
Gastrointestinal
Gastrointestinal side effects due to unopposed parasympathetic activity produced by catecholamine depletion may result in increased gastrointestinal motility and secretory activity. Because of this, new diarrhea or worsening of existing diarrhea or increased salivation have been reported in 2% of patients who were taking reserpine alone. Rare gastrointestinal complaints include increased appetite, abdominal pain, or vomiting. Rare cases of acute pancreatitis and acute cholecystitis have been associated with thiazide diuretics.[Ref]
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.[Ref]
Renal
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 have been 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 in which the drug was believed to have caused this condition has been reported.[Ref]
Renal side effects including new or worsened renal insufficiency may occur due to HCTZ-induced intravascular volume depletion. Rare cases of interstitial nephritis have been associated with HCTZ. While renal side effects are common in idiopathic systemic lupus erythematosus, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome have often been accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.[Ref]
Hematologic
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 left ventricular hypertrophy and mild coronary atherosclerosis, but no obvious cause of death.
A 71-year-old man with hypertension developed anorexia, weight loss, petechiae, and a 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.[Ref]
Hematologic abnormalities have been associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems: hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia and agranulocytosis have been associated with hydralazine, and rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.[Ref]
Genitourinary
Genitourinary complaints have been limited to impotence, reported in approximately 5% of male patients.[Ref]
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.[Ref]
Endocrine
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 7 months in 10 of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test values. A control group was not reported.[Ref]
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. Reserpine can cause elevation of serum prolactin levels. This can result in gynecomastia in men or breast engorgement or pseudolactation in women.[Ref]
Hepatic
A 59-year-old woman with hypertension and cholecystic gallbladder disease developed abdominal pain, nausea, vomiting, and painful hepatomegaly associated with 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.[Ref]
Hepatic reactions are rare. Less than ten cases of hepatitis have been associated with hydralazine, many of which are believed to be due to hypersensitivity. Histologic findings include hepatocellular, cholestatic, mixed hepatocellular-cholestatic, and granulomatous patterns.[Ref]
Musculoskeletal
Musculoskeletal cramps have occasionally been reported during HCTZ-induced diuresis.[Ref]
Oncologic
Oncologic concerns were raised after a large drug surveillance center in Boston reported an association between reserpine, a stimulator of prolactin, and breast cancer in 1974. These data were partially, but not completely, confirmed in two similar centers in Europe. A critical review of the these studies elucidated several design flaws. Subsequent, controlled studies failed to show an association between reserpine and an increased incidence of breast carcinoma.[Ref]
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References
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