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Chlorothiazide / methyldopa Side Effects

Applies to chlorothiazide/methyldopa: oral tablet.


The mechanism of methyldopa hepatotoxicity is believed to be delayed hypersensitivity, although some speculate an accumulation of metabolites which are directly hepatotoxic in late-onset cases.

A 78-year-old woman with hypertension and diabetes developed acute renal failure and a clinical picture of sepsis while taking methyldopa. Autopsy revealed disseminated non-necrotizing granulomas throughout her liver, spleen, lung, lymph nodes, and bone marrow, as well as findings of myocarditis. There was no evidence of infection, including tuberculosis.

A 75-year-old man with hypertension developed severe cholestatic liver disease six years after beginning methyldopa 250 mg per day. There was no evidence of viral or obstructive disease.[Ref]

Hepatic toxicity may be highly significant. Transient elevations of liver function tests are seen in 5% of patients who are taking methyldopa. Symptomatic hepatitis--usually resembling viral hepatitis--is uncommon. Usually beginning within the first four weeks of therapy, the syndrome typically presents as a fever, followed by icterus, weakness, nausea, and abdominal pain. It usually resolves within three weeks after drug withdrawal, but rare cases of chronic hepatitis and late onset hepatitis have been reported. Serious hepatotoxicity is rare, occurring in approximately 0.1% of patients. Rare cases of granulomatous hepatitis and fatal submassive hepatic necrosis, postnecrotic cirrhosis, and chronic hepatitis have been associated with methyldopa. Alternative therapy is recommended in patients with liver cirrhosis or acute hepatitis due to the risk of additional hepatotoxicity associated with methyldopa.[Ref]


Hematologic abnormalities include hemolytic anemia due to a methyldopa-provoked autoantibody with associated positive direct Coombs test in 10% to 20% of patients who take the drug chronically. Rare cases of neutropenia, pure red blood cell aplasia, thrombocytopenia, positive LE cells, and rheumatoid factor have been associated with methyldopa, and rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with thiazide diuretics.[Ref]

In one case of methyldopa-associated neutropenia, a methyldopa-dependent antibody against granulocytes was isolated.

A 75-year-old man with hypertension developed pure red blood cell aplasia within three months after starting methyldopa therapy. The Coombs test and immunoglobulin levels were normal; bone marrow biopsy revealed an absence of erythroid precursors. There was no evidence of hemolysis or infection. Erythroblastosis was observed within five days after drug withdrawal.

A 70-year-old woman with diabetes and hypertension developed thrombocytopenia and an elevated ANA titer associated with methyldopa. Unfortunately, the thrombocytopenia was complicated by a thrombotic stroke. Her platelet count and elevated ANA titer resolved upon substitution with nifedipine. In some cases of methyldopa-associated thrombocytopenia an antiplatelet IgG antibody has been isolated.[Ref]


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.

Rare cases of hypercalcemia, milk-alkali syndrome (hypercalcemia, metabolic alkalosis, and renal insufficiency) have been associated with chlorothiazide.

Chlorothiazide-induced hypercalcemia appears to depend on circulating parathyroid hormone.[Ref]

Metabolic changes associated with chlorothiazide, as with other thiazide diuretics, are relatively common, especially when daily doses greater than 500 mg are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% and may predispose patients to cardiac arrhythmias. Mild metabolic alkalosis, hyponatremia, hypomagnesemia, hypophosphatemia, hypercalcemia, hyperglycemia, hypercholesterolemia, and hyperuricemia are also relatively common. The electrolyte and intravascular fluid shifts that may occur during chlorothiazide diuresis can provoke hepatic encephalopathy in patients with hepatic cirrhosis.[Ref]


A 58-year-old man with hypertension and coronary artery disease experienced asystole during carotid massage during methyldopa therapy, which resolved upon discontinuation of the drug and was reproducible on rechallenge.

A 75-year-old man with chronic obstructive pulmonary disease and hypertension developed signs and symptoms of congestive heart failure associated with complete AV heart block while taking methyldopa. Six days after stopping the drug, normal sinus rhythm returned. Rechallenge resulted in recurrent complete AV heart block.[Ref]

Cardiovascular problems associated with methyldopa include hypotension in up to 10% and sinus and AV nodal conduction disturbances in 0.2% of patients. Orthostatic hypotension may be more likely due to the added risk of chlorothiazide-induced intravascular volume depletion. This, and rare cases of methyldopa-induced carotid hypersensitivity, can result in syncope in some patients. New AV nodal block, including Mobitz types I and II and complete AV heart block, have been associated with methyldopa. Rare case reports of paradoxical hypertension have been associated with methyldopa, and rare cases of cerebrovascular insufficiency have been associated with thiazide-induced diuresis. Myocarditis has rarely been associated with methyldopa-induced hepatitis or pneumonitis.[Ref]


Immunologic side effects include the development of a positive antinuclear antibody (ANA) titer and rare cases of a lupus syndrome associated with methyldopa. Retroperitoneal fibrosis and lymphadenopathy have rarely been associated with methyldopa.[Ref]

A 55-year-old man with hypertension developed hemolytic anemia, arthritis, and photosensitivity associated with an ANA against class H1 histones 13 months after beginning methyldopa. The syndrome and laboratory abnormalities resolved after drug discontinuation and steroid therapy.[Ref]

Nervous system

Nervous system complaints include dizziness in up to 19%, insomnia in less than 5%, general fatigue in 1% to 10%, and headache in 2% of patients who are taking methyldopa. New choreoathetotic movements and exacerbations of parkinsonian symptoms have rarely been associated with methyldopa.[Ref]


Hypersensitivity reactions to methyldopa are described under "Hepatic" and "Cardiovascular" side effects (hepatitis and myocarditis). Rare cases of vasculitis, rash, drug fever, and anaphylactoid-like reactions have also been associated with the drug. Hypersensitivity reactions to chlorothiazide usually involve the skin (cutaneous vasculitis, urticaria, rash, purpura), but may involve the gastrointestinal system (nausea, vomiting, or diarrhea), the genitourinary system (interstitial nephritis), and the respiratory system (acute noncardiogenic pulmonary edema, pneumonitis). Thiazide diuretics may induce phototoxic dermatitis.[Ref]

Two case reports of hypotension, fever, chills, and diarrhea associated with a leukocytosis and negative blood cultures have been reported after the use of methyldopa in elderly patients. In each case rechallenges were positive.

Thiazides may induce allergic reactions in patients who are allergic to sulfonamides.[Ref]


A retrospective case-control drug surveillance study has revealed the relative risk of acute cholecystitis associated with the use of a thiazide diuretic is 2.0. The suspected explanation for this association is the potentially deleterious effect thiazides have on the serum lipid profile. Chlorothiazide-induced hypercholesterolemia or hypertriglyceridemia may enhance the formation of some types of gallstones.

A 68-year-old man with hypertension developed diabetic ketoacidosis (DKA) four weeks after beginning methyldopa 1,000 mg per day. Naive rechallenge of the drug 10 months later resulted in recurrent DKA associated with ultrasonographic evidence of pancreatitis. The patient later showed signs of chronic pancreatitis, including weight loss, steatorrhea, and pancreatic calcification.[Ref]

Gastrointestinal side effects include diarrhea, nausea, vomiting, constipation, or abdominal pain in 1% to 5% of patients. Rare cases of pancreatitis or colitis have been associated with methyldopa, and rare cases of pancreatitis or acute cholecystitis have been associated with thiazide diuretics. A single case of "black tongue" has been associated with methyldopa.[Ref]


Dermatologic reactions may indicate hypersensitivity to chlorothiazide. Erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis (including toxic epidermal necrolysis), or alopecia have been associated with the drug on rare occasions. Dermatologic reactions to methyldopa include case reports of sun-exposed rashes, hyperpigmentation, nodular rashes, or lichenoid eruptions.[Ref]


Renal side effects including new or worsened renal insufficiency associated with chlorothiazide therapy is a probable sign of intravascular volume depletion, and serves as a signal to reduce or withhold therapy. Rare cases of allergic interstitial nephritis have been associated with chlorothiazide.[Ref]


An 81-year-old man with hypertension developed hyponatremia associated with a urine to serum osmolality ratio of 1.5. A standard water test with and without methyldopa revealed less free water excretion with the drug than without. Interestingly, the patient's bone marrow revealed noncaseating granulomas; there was no evidence of thyroid, adrenal, pulmonary, cardiac, CNS disease, or tuberculous infection. The patient's hyponatremia, abnormal liver function tests, and abnormal bone marrow findings normalized upon withdrawal of methyldopa.

Limited data show transient reductions in HDL lipoprotein cholesterol of approximately 10% associated with the use of methyldopa in middle-aged men with hypertension. Over time, however, this reduction tended to revert to baseline values.[Ref]

Endocrinologic changes associated with chlorothiazide, as with other thiazide diuretic agents, include decreased glucose tolerance 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. Amenorrhea or galactorrhea, resulting from methyldopa-induced hyperprolactinemia, has been reported. A single case of inappropriate secretion of antidiuretic hormone has been associated with methyldopa.[Ref]


A 62-year-old man developed mania within 4 weeks after switching from methyldopa to nifedipine antihypertensive therapy.

In one study of 41 elderly patients, ages 75 to 85, without pretreatment dementia, who were treated with methyldopa, decreased ability to perform object assembly tasks were noted, but depression was no more likely than with placebo.[Ref]

Psychiatric side effects are unusual, are probably related to methyldopa, and include depression in 2% of patients. Rare cases of paranoia and forgetfulness have also been associated with the drug.[Ref]


In one study of 258 men, 16% reported impotence. In one study of 27 males with hypertension, 7 complained of decreased libido, inability to sustain erections, and difficulty in ejaculation.[Ref]

Genitourinary complaints are rare. Impotence among male patients has been rarely associated with either drug, but may be under-diagnosed. Limited data suggest that methyldopa may precipitate in urine in some patients, providing the nidus for calcium phosphate calculi.[Ref]


Respiratory system problems are rare. Nasal congestion is reported in less than 5% of patients who are taking methyldopa. A rare case of bronchospasm has been reported in a chemist who manufactured methyldopa.[Ref]

A 27-year-old chemist who manufactured methyldopa developed nasal congestion, sneezing, and exertional wheezing associated with a demonstrable fall in FEV1 by 30%. Her signs and symptoms resolved when the environmental exposure to methyldopa was removed. No antibodies to methyldopa were found.[Ref]


Musculoskeletal cramping or spasms are occasionally reported during chlorothiazide diuresis.[Ref]


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Further information

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Some side effects may not be reported. You may report them to the FDA.