Chlorthalidone / reserpine Side Effects
Some side effects of chlorthalidone / reserpine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
For the Consumer
Applies to chlorthalidone / reserpine: oral tablet
If you experience any of the following serious side effects, stop taking chlorthalidone and reserpine and seek emergency medical attention:
an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
a very irregular heartbeat;
heart failure (shortness of breath, swelling of ankles or legs, sudden weight gain of 5 pounds or more);
abnormal bleeding or bruising;
yellow skin or eyes;
uncontrollable hand, arm, or leg movements; or
little or no urine.
Other, less serious side effects are more likely to occur. Continue to take chlorthalidone and reserpine and talk to your doctor if you experience
fatigue or drowsiness;
dizziness (avoid standing up too quickly and use caution when performing hazardous activities);
anxiety, depression, or nightmares;
diarrhea, nausea, vomiting, or acid stomach (take chlorthalidone and reserpine with food or milk if it upsets your stomach);
stuffy nose or a dry mouth (sucking on ice chips or sugarless hard candy may relieve a dry mouth);
tingling or numbness in your arms, legs, hands, or feet;
muscle weakness or cramps;
increased hunger or thirst;
sensitivity to sunlight; or
impotence or difficulty ejaculating.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
For Healthcare Professionals
Applies to chlorthalidone / reserpine: oral tablet
The metabolic side effects of chlorthalidone, as with other thiazide diuretics, may require electrolyte monitoring and/or potassium supplementation. Approximately 14% of patients develop hypokalemia during therapy. The risk of hypokalemia, hypomagnesemia, hyponatremia, and hypochloremia appears to be dose-related. Hypercalcemia and an increased serum bicarbonate may result from chlorthalidone diuresis.
In a prospective study of 83 patients who were taking daily doses of chlorthalidone 200 mg, 23 (28%) developed a decrease in their serum potassium concentration by at least 0.6 mEq/L. Keeping the serum potassium replenished during chlorthalidone therapy decreases the risk of arrhythmias, myopathy, hyponatremia and hyperglycemia.
Rare reports of reserpine-induced bronchospasm are believed to be due to inactivation of beta-adrenergic receptors. This can result in a marked potentiation of the bronchoconstrictive effect of histamine.
The respiratory system is affected by reserpine, with 8% of patients complaining of nasal congestion. A single case of bronchospasm has been associated with reserpine.
Cardiovascular side effects are related to decreased sympathetic tone associated with reserpine and decreased intravascular volume and hypokalemia associated with chlorthalidone. Hypotension has been reported in approximately 8% of patients; orthostatic hypotension complicated by syncope has been reported in rare cases. Hypokalemia may induce or provoke arrhythmias in some patients. A rare case of paroxysmal atrial tachycardia with block associated with reserpine in a patient who was not taking a digitalis preparation has been reported.
The initial report from the Multiple Risk Factor Intervention Trial (MRFIT) raised the possibility that an earlier analysis suggesting increased coronary heart disease (CHD) mortality observed in a subset of men with hypertension who were taking diuretics may be misleading. Subsequent analysis of the data revealed no consistent relationship of CHD mortality to the dose of chlorthalidone, to the most recent serum potassium concentration, or to the presence of premature ventricular depolarizations (PVDs). It is probable that these men had left ventricular hypertrophy, which is associated with a greater incidence of PVDs, even in the absence of diuretic therapy.
Chlorthalidone-induced hypokalemia can rarely cause serious arrhythmias in otherwise healthy patients, but should not cause arrhythmias while keeping the serum potassium concentration within normal limits in patients who are predisposed to arrhythmias.
A woman with paroxysmal atrial tachycardia developed sinus pauses during reserpine therapy which were reproducible by carotid massage, except when isoproterenol was given. Reserpine is known to increase vagal tone and to deplete cardiac catecholamines.
One patient, in a series of 231, had emergent hypertension, stroke, and thyrotoxic crisis. Reserpine 1 mg intramuscularly resulted in a blood pressure drop from 180/100 to an unmeasurable level. The patient recovered after isoproterenol therapy.
Hypersensitivity reactions to thiazide diuretics usually involve the skin. Thiazides and the chemically related drug, chlorthalidone, have been implicated as the cause of necrotizing vasculitis, psoriasiform eruptions, and pseudoporphyria (bullous photosensitive lesions) in rare cases.
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.
Common nervous system side effects include sedation, lethargy (different from the psychiatric syndrome of depression), drowsiness, weakness, vertigo, insomnia, or headache in approximately 1% to 5% of patients. 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. Sleep disturbances have been reported in 18% of patients who are taking chlorthalidone. These may be made worse with a sodium-restricted diet. Headache or fatigue has been reported in approximately 7% of patients.
New or worsened renal insufficiency may develop if patients become too dehydrated. Chlorthalidone has been associated with mild decreases in urine concentrating ability and renal plasma flow, suggestive of interference with renal tubular function.
Genitourinary problems include decreased sexual libido, erections, or orgasm in 5% (reserpine) to 42% (chlorthalidone) of male patients. Decreased sexual arousal and orgasm are rarely reported among female patients.
The etiology of sexual dysfunction associated with chlorthalidone is not known. One study of 19 middle-aged hypertensive men showed no significant decrease in serum zinc or testosterone levels relative to a control group of 31 unmedicated middle-aged normotensive men. While sexual dysfunction was reported in 42% of treated men (compared to 16% in the control group), serum testosterone and zinc levels were actually higher in the treated group, and were highest in the men on the highest dose of chlorthalidone.
One study revealed that sexual dysfunction associated with chlorthalidone may be worsened by a low sodium diet and ameliorated by a diet designed to help lose weight. The influence of diet alone or the associated nutritional counseling and sense of well-being on sexual function was not measured.
Endocrinologic abnormalities related to chlorthalidone, as with other thiazide diuretics, include decreased glucose tolerance and an adverse effect on the lipid profile. This may be important in some patients with a history of diabetes or coronary artery disease. Reserpine-induced hyperprolactinemia can result in gynecomastia in men or breast engorgement or pseudolactation in women.
Chlorthalidone is associated with increases in total serum cholesterol, triglycerides, and LDL cholesterol.
At least one case of severe glucose intolerance, resulting in hyperosmolar hyperglycemic nonketotic coma, has been associated with chlorthalidone. The patient did not have diabetes, had a normal fasting blood glucose prior to chlorthalidone therapy, and did well on no antidiabetic medications after resolution of the acute episode of hyperglycemia. Infection and myocardial infarction were ruled out.
Due to unopposed parasympathetic activity produced by catecholamine depletion, reserpine increases gastrointestinal motility and secretory activity. Because of this, new diarrhea or worsening of existing diarrhea or increased salivation has been reported in 2% of patients. Increased appetite, abdominal pain, or vomiting have rarely been reported. Approximately 5% to 10% of patients who are taking chlorthalidone complain of nausea, vomiting, abdominal cramping, diarrhea, or constipation. A case of acute bacterial pancreatitis and rare cases of intrahepatic cholestasis have been associated with chlorthalidone.
The depressive syndrome 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 develops during reserpine therapy.
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.
Cases of progressive generalized paralysis associated with chlorthalidone-induced hypokalemia have been reported. In some of these cases, muscle histology is remarkable for vacuolar degeneration.
Musculoskeletal weakness or cramps have been reported in approximately 7% of patients. Chlorthalidone-induced hypokalemia has resulted in hypokalemic myopathy in rare cases.
A 63-year-old man with hypertension, ischemic heart disease, chronic bronchitis, and type II diabetes mellitus was stable on multiple medications until chlorthalidone was substituted for hydrochlorothiazide. Within three weeks after beginning chlorthalidone, the patient developed a diffuse upper extremity pruritic rash, fever, dyspnea, malaise, and fatigue associated with a peripheral leukocyte count of 2,000/mm3. Bone marrow aspiration revealed hypocellularity of the myeloid line only. Within nine days after stopping chlorthalidone, the patient's leukocyte count returned to normal. No other cause of neutropenia was discovered; an antineutrophil antibody was investigated, but not proven.
Rare hematologic side effects have been associated with chlorthalidone, including neutropenia, agranulocytosis, thrombocytopenia, and aplastic anemia.
A rare ocular side effect, transient myopia, has been associated with chlorthalidone.
The mechanism of myopia is unknown. There is evidence of an allergic reaction, where the ciliary body may become edematous, and of a direct disturbance by chlorthalidone of the normal salinity of the lens. Either may alter the refractive index. In some cases, ultrasonography of affected eyes has shown a difference both in the anterior chamber depth and in the lens thickness during chlorthalidone therapy.
A 79-year-old woman with hypertension, taking reserpine, potassium, HCTZ, and ibuprofen, developed fatigue, anorexia, fever, night sweats, and weight loss. Associated laboratory findings showed anemia, lymphocytosis, thrombocytopenia, IgA kappa paraproteinemia, positive ANA, and a positive Coombs' test. Bone marrow biopsy, lymphangiography, and lymph node biopsy showed bone marrow lymphocytosis, enlarged foamy abdominal lymph nodes with irregular filling, and angioimmunoblastic lymphadenopathy. Within four days after discontinuation of reserpine (her other medications were continued), the paraprotein level normalized and the platelet count rose. After an additional nine months of prednisone therapy, all signs and symptoms resolved.
Immunologic side effects are rare. A single case of angioimmunoblastic lymphadenopathy has been associated with reserpine. In a study of 231 patients, only 1 case of a lupus-like syndrome was observed (the patient had previously received hydralazine).
Oncologic concerns were raised after a large drug surveillance center in Boston reported an association between reserpine, a stimulator of prolactin, and breast cancer, which was partially, but not completely, confirmed in two similar centers in Europe. A critical review of these studies elucidated several design flaws. Subsequent, controlled studies have failed to show an association between reserpine and an increased incidence of breast carcinoma.
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