Hydrochlorothiazide and timolol Side Effects
Please note - some side effects for Hydrochlorothiazide and timolol 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 tablet
Timolol-hydrochlorothiazide (HCTZ) is generally well tolerated. Most side effects are mild and transient.
Cardiovascular side effects have included sinus bradycardia and hypotension. Sinus bradycardia is reported in 1.2% of the patients, but is reported in up to 9% of patients who are taking timolol alone. Hypotension is reported in 1.6% of patients, and can result in syncope, particularly in the elderly. Atrioventricular conduction disturbances or exacerbation of congestive heart failure are reported in less than 1% of patients. Rarely, HCTZ-induced hypokalemia can predispose some patients to significant cardiac arrhythmias, including ventricular ectopy and complete AV heart block.
Metabolic side effects associated with HCTZ are more common when daily doses exceed 50 mg. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. Timolol-HCTZ may increase serum cholesterol and decrease HDL lipoprotein cholesterol.
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, timolol-HCTZ should be used with caution in diabetic patients and in those with hypercholesterolemia. Timolol, like some other beta-blockers, may also have an unfavorable effect on the lipid profile.
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.
Respiratory problems associated with timolol-HCTZ, as with other drugs that contain beta-antagonists, include bronchial constriction in susceptible patients. Dyspnea is reported in 1% to 6% of patients. There are approximately 30 case reports of acute noncardiogenic pulmonary edema associated with HCTZ. The mechanism is not known, but may be due to hypersensitivity to the drug.
Alternative therapy should be considered in patients with reactive airways disease. Case reports of fatal respiratory arrests have been reported in patients with asthma who were given timolol, even after topical ophthalmic administration.
A case of refractory rhinitis has been reported, thought to be due to timolol-induced vasomotor rhinitis.
Hypersensitivity reactions occur in less than 1% of patients. They may present as nausea, vomiting, diarrhea, or rash. Case reports of acute pulmonary edema, interstitial cystitis, interstitial nephritis, and anaphylaxis have been reported.
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 and eosinophilia, were absent.
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.
Dermatologic reactions are usually due to the HCTZ component. Thiazides may induce phototoxic dermatitis, erythema annular centrifugum, acute eczematous dermatitis, and morbilliform or leukocytoclastic 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. Rare cases of generalized psoriasis and hyperpigmented nailbeds have been associated with timolol.
A case of amaurosis fugax has been associated with timolol, but the patient had underlying cerebrovascular disease, autonomic dysfunction, and an arrhythmia.
Nervous system side effects include fatigue in 2% to 6%, headache in 4%, and dizziness in 6% of patients. Rare cases of worsened myasthenia gravis, visual hallucinations, insomnia, and depression have been associated with timolol, and rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.
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.
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.
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 value. A control group was not reported.
Endocrinologic side effects associated with timolol, as with other non-selective beta-blockers, include masking the signs and symptoms and blunting the normal physiologic response to hypoglycemia. Both timolol and HCTZ may cause an increase in serum triglycerides, LDL, and VLDL cholesterol, and a decrease in HDL cholesterol. Thiazide diuretics may induce glucose intolerance. Some of these side effects may be important in patients with or who are at risk for diabetes or coronary artery disease.
Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in an 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 complaints of general abdominal pain, nausea, constipation, or diarrhea have been reported in less than 1% of patients. There have been rare reports of pancreatitis and acute cholecystitis associated with HCTZ.
Psychiatric side effects, such as confusion, depression (including acute suicidal ideation), vivid and frightening dreams, or visual hallucinations have been associated with timolol.
Musculoskeletal pains are reported in less than 1% of patients.
Genitourinary complaints of impotence and decreased libido are rare.
An 86-year-old man with glaucoma who was taking timolol 0.5% eyedrops developed fever, malaise, pleurisy, and recurrent sterile pleural effusions associated with antinuclear and histone antibodies. The syndrome resolved completely after discontinuation of timolol.
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, hemoglobinuria, and elevated serum lactate dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg/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.
Immunologic reactions are extremely rare. A single case of reversible systemic lupus erythematosus has been associated with ophthalmic timolol solution and rare cases of allergic vasculitis have been associated with HCTZ.
Hematologic side effects have not been reported during therapy with the combination product. Cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.Top
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