Chlorthalidone / clonidine Side Effects
Some side effects of chlorthalidone / clonidine 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 / clonidine: oral tablet
Get emergency medical help if you have any of these signs of an allergic reaction while taking chlorthalidone / clonidine: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have a serious side effect such as:
dry mouth, increased thirst, drowsiness, restless feeling, nausea, vomiting, increased urination, muscle pain or weakness, fast heart rate, feeling light-headed, fainting, or seizure (convulsions);
easy bruising or bleeding, unusual weakness;
red or purple spots on your skin;
urinating more or less than usual, or not at all;
feeling short of breath, even with mild exertion;
swelling, rapid weight gain;
numbness or tingly feeling; or
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).
Less serious side effects of chlorthalidone / clonidine may include:
dry mouth, loss of appetite;
diarrhea, constipation, upset stomach;
feeling restless or nervous;
sleep problems (insomnia);
nightmares or unusual dreams;
breast swelling or tenderness;
mild itching or skin rash; or
impotence or loss of interest in sex.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.
For Healthcare Professionals
Applies to chlorthalidone / clonidine: oral tablet
The most common side effects are related to the alpha-adrenergic receptor blocking effects of clonidine. These side effects are dose-related, typically decrease over time, and mostly affect the nervous system, cardiovascular system, and the gastrointestinal system.
Nervous system side effects associated with clonidine include drowsiness in 28% and dizziness in 9% of patients. Sleep disturbances occur in 18% and headache or fatigue in 7% of patients who are taking chlorthalidone. Patients with decreased autoregulation of cerebral blood flow, such as the elderly, appear to be at increased risk for cerebral hypoperfusion if their blood pressure is lowered too much or too quickly by clonidine.
A study of 13 patients who had pre- and post-clonidine cerebral blood flow (CBF) measured by nuclear scanning revealed that patients with an initially high pretreatment CBF tended to demonstrate decreased CBF after clonidine therapy.
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 clonidine-chlorthalidone therapy decreases the risk of arrhythmias, myopathy, hyponatremia and abnormal glucose metabolism.
Cardiovascular side effects include hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients on clonidine alone, and this can be made worse with chlorthalidone-induced intravascular volume depletion. Rare cases of syncope have been associated with orthostatic hypotension. Rebound hypertension (which may be worse than pretreatment values and result in a hypertensive emergency) can present as irritability, tremors, headache, increased salivation, nausea, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction.
Other cardiovascular side effects include sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Chlorthalidone-induced hypokalemia may predispose some patients to cardiac arrhythmias.
A case of sinus arrest associated with clonidine has been reported. A 65-year-old man with diabetes, hypertension and unexplained syncope developed more frequent syncope and dizziness associated with documented episodes of sinus arrest during the first week of clonidine therapy. The patient had no hypoglycemia or orthostatic changes. The syncope and dizziness resolved upon discontinuation of clonidine; continuous electrocardiographic monitoring revealed gradual and complete disappearance of sinus pauses. Junctional bradycardia and AV heart block have also been reported.
Ventricular tachycardia (VT) relatively refractory to lidocaine, but responsive to intravenous phentolamine, has been associated with clonidine withdrawal (one case report). The authors believe that the VT was probably produced by humoral or neural stimulation of unregulated myocardial alpha-adrenergic receptors.
Data from the Multiple Risk Factor Intervention Trial (MRFIT) showed no consistent relationship between the incidence of cardiovascular mortality and the use of diuretics in patients with hypertension. There was no consistent relationship of cardiovascular mortality and the dose of chlorthalidone, the most recent serum potassium concentration, or the presence of premature ventricular depolarizations (PVDs). It is probable that the hypertensive patients in the study 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, and only rarely causes arrhythmias when the serum potassium concentration is within normal limits in patients who are predisposed to arrhythmias.
Genitourinary side effects including impotence has been reported with both clonidine (24% of male patients) and chlorthalidone (42% of male patients). Impotence may present as decreased sexual libido, decreased erections, or retrograde or delayed ejaculation. Decreased sexual arousal and orgasm have rarely been reported among female patients.
The etiology of sexual dysfunction associated with chlorthalidone is not known. One study of 19 middle-aged men showed no significant decrease in serum zinc or testosterone 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.
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.
Gastrointestinal system complaints include dry mouth in 30% and constipation in 15% of patients. Approximately 5% to 10% of patients 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.
Renal side effects including new or worsened renal insufficiency may develop if patients become too dehydrated. Chlorthalidone is associated with mild decreases in urine concentrating ability and renal plasma flow, suggestive of interference with renal tubular function.
Chlorthalidone, like other thiazides, has been 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.
A single case of new-onset nephrotic syndrome has been associated with clonidine. A 68-year-old black man with hypertension, status post unilateral nephrectomy, was incidentally found to have 4+ proteinuria, 1+ glycosuria, new elevated blood glucose levels, and between 1.8 and 5.4 grams of protein per 24-hour urine collection within six weeks after starting clonidine. The signs and symptoms of diabetes and the nephrotic syndrome disappeared within five months after discontinuation of clonidine. Because of his solitary kidney, a renal biopsy was not performed.
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. Rare cases of gynecomastia or hyperglycemia have been associated with clonidine.
Cases of progressive generalized paralysis associated with chlorthalidone-induced hypokalemia have been reported. In some of these cases, muscle histology has been remarkable for vacuolar degeneration.
Musculoskeletal weakness or cramps are 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.
Hematologic side effects associated with chlorthalidone include rare reports of neutropenia, agranulocytosis, thrombocytopenia, and aplastic anemia.
Psychiatric side effects including depression is rarely reported, but is the most common psychiatric reaction to clonidine. Rare cases of frank psychoses and delirium have been associated with clonidine withdrawal.
A 66-year-old woman with a history of psoriasis in remission developed erythematous, scaly plaques on the extensor surfaces of her forearms within three days after beginning clonidine therapy for control of flushing. The author of this case report suspects that clonidine may cause a fall in intracellular cAMP, leading to epidermal cell proliferation, and, in some cases, a psoriasiform eruption.
Dermatologic reactions have been associated with hypersensitivity reactions to chlorthalidone. A case of exacerbation of psoriasis has been associated with clonidine.
Immunologic reactions are rare. A case of immune-complex disease associated with clonidine has been reported.
A 46-year-old woman developed forearm edema, mild thenar atrophy, and skin hypopigmentation within three months after beginning clonidine for perimenopausal flushing. Electromyelography was consistent with carpal tunnel syndrome. At surgical decompression, a skin biopsy revealed changed consistent with immune-complex disease. The patient's signs and symptoms abated after physical therapy and discontinuation of clonidine.
A 9-year-old boy with asthma developed a severe asthma attack after an oral clonidine stimulation test. The authors of this case report suspect that clonidine stimulates alpha-adrenergic receptors in the pulmonary arteries, which results in decreased pulmonary blood flow, producing relative pulmonary hypoxemia, setting off an asthma attack.
Respiratory system reactions to clonidine are extremely rare. A case of severe bronchospasm associated with clonidine has been reported in the pediatric literature.
Ocular side effects associated with chlorthalidone have included rare reports of transient myopia.
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.
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