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Hydrochlorothiazide / methyldopa Side Effects

Commonly reported side effects of hydrochlorothiazide/methyldopa include positive direct coombs test. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to hydrochlorothiazide / methyldopa: oral tablet

In addition to its needed effects, some unwanted effects may be caused by hydrochlorothiazide / methyldopa. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking hydrochlorothiazide / methyldopa:

  • Unexplained fever shortly after starting to take this medicine

If any of the following side effects occur while taking hydrochlorothiazide / methyldopa, check with your doctor or nurse as soon as possible:

Signs and symptoms of too much potassium loss
  • Dry mouth
  • increased thirst
  • irregular heartbeats
  • muscle cramps or pain
  • nausea or vomiting
  • unusual tiredness or weakness
  • weak pulse
Less common
  • Mental depression or anxiety
  • nightmares or unusually vivid dreams
  • Cough or hoarseness
  • dark or amber urine
  • diarrhea or stomach cramps (severe or continuing)
  • fever, chills, troubled breathing, and fast heartbeat
  • general feeling of discomfort or illness or weakness
  • joint pain
  • lower back or side pain
  • painful or difficult urination
  • pale stools
  • skin rash, hives, or itching
  • stomach pain (severe) with nausea and vomiting
  • tiredness or weakness after having taken this medicine for several weeks (continuing)
  • yellow eyes or skin

Some of the side effects that can occur with hydrochlorothiazide / methyldopa may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Dizziness or light-headedness when getting up from a lying or sitting position
  • drowsiness
  • dryness of mouth
  • headache
Less common
  • Decreased sexual ability or interest in sex
  • diarrhea
  • increased sensitivity of skin to sunlight (skin rash, itching, redness or other discoloration of skin or severe sunburn after exposure to sunlight)
  • loss of appetite
  • numbness, tingling, pain, or weakness in hands or feet
  • slow heartbeat
  • stuffy nose
  • swelling of breasts or unusual milk production

For Healthcare Professionals

Applies to hydrochlorothiazide / 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 nonnecrotizing 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 have been reported. Granulomatous hepatitis is a rare manifestation of methyldopa hepatotoxicity. 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 on chronic therapy. Cases of neutropenia, pure red blood cell aplasia, thrombocytopenia, positive LE cells, and elevated rheumatoid factor have been reported. Rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with hydrochlorothiazide (HCTZ).[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 ANA titer resolved upon substitution with nifedipine. In some cases of methyldopa-associated thrombocytopenia an antiplatelet lgG antibody has been isolated.

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 no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.[Ref]


Cardiovascular problems include hypotension in up to 10% and sinus and AV nodal conduction disturbances in 0.2% of patients. HCTZ-induced hypokalemia can predispose some patients to develop significant arrhythmias, including ventricular ectopy and complete AV heart block. Hypotension and methyldopa-induced carotid sinus hypersensitivity can result in syncope in some patients. Rare cases of paradoxical hypertension or myocarditis (in association with hepatitis or pneumonitis) have been associated with methyldopa.[Ref]

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

A 75-year-old man with chronic obstructive pulmonary disease and hypertension developed new signs and symptoms of congestive heart failure associated with new 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]


Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, VLDL lipoprotein cholesterol 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% of patients, and may predispose some to develop arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, hypercholesterolemia, and elevated serum uric acid levels are also relatively common problems during HCTZ therapy.[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]

Immunologic changes have been associated with methyldopa. The drug can induce the development of a positive antinuclear antibody (ANA) titer. Rare cases of a lupus syndrome, retroperitoneal fibrosis and lymphadenopathy have been reported.[Ref]


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

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 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.[Ref]

Hypersensitivity reactions to either drug are rare, but may be severe. A syndrome consisting of nausea, vomiting, diarrhea, and rash has been reported in less than 1% of patients who are taking HCTZ. There have also been rare cases of acute pulmonary edema, interstitial cystitis or nephritis, and anaphylaxis associated with HCTZ and rare cases of vasculitis, rash, drug fever, and anaphylactoid-like reactions associated with methyldopa.[Ref]

Nervous system

Nervous system complaints are probably due to methyldopa, and include dizziness in up to 19%, general fatigue in 1% to 10%, insomnia in less than 5%, and headache in 2% of patients. New choreoathetotic movements and exacerbations of parkinsonian symptoms have rarely been associated with the drug. Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.[Ref]


Dermatologic reactions associated with HCTZ include erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Reports of hyperpigmentation, nodular rashes, and lichenoid eruptions have been associated with methyldopa. Either drug 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.[Ref]

A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, 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.[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.[Ref]

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.[Ref]


A 68-year-old man with hypertension developed diabetic ketoacidosis (DKA) four weeks after beginning methyldopa 1000 mg per day. Naive rechallenge of the drug ten 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.

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]

Gastrointestinal side effects include diarrhea or nausea in 1% to 5% of patients who are taking methyldopa. A case of "black tongue" has been associated with methyldopa, and rare cases of acute cholecystitis, pancreatitis, or colitis have been associated with either drug.[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, or CNS disease, and no evidence of tuberculosis 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% in middle-aged men with hypertension who were taking methyldopa. Over time, however, this reduction tended to revert to baseline values.

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.[Ref]

Endocrinologic problems, such as amenorrhea or galactorrhea, resulting from methyldopa-induced hyperprolactinemia have been reported. 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. A case of inappropriate secretion of antidiuretic hormone has been associated with methyldopa.[Ref]


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

Respiratory system problems are rare. Nasal congestion has been reported in less than 5% of patients who are taking methyldopa. A rare case of bronchospasm is reported in a chemist involved in the manufacture of methyldopa. There have been approximately 30 case reports of acute noncardiogenic pulmonary edema associated with HCTZ.[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. Depression occurs in 2% of patients who are taking methyldopa. There have also been rare cases of paranoia and forgetfulness associated with methyldopa, particularly in the elderly.[Ref]


Genitourinary complaints of impotence among male patients who are taking methyldopa is rarely reported, but may be underdiagnosed. Limited data suggest that methyldopa may precipitate in urine in some patients, providing the nidus for calcium phosphate calculi.[Ref]

In one study of 258 men who were taking methyldopa, 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]


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108. Ramsay L, Wakefield VA, Harris E "Methyldopa-induced chronic pancreatitis." Practitioner 226 (1982): 1166, 1169

109. Dietz MW "Iatrogenic jejunal ulcer." Am J Roentgenol Radium Ther Nucl Med 99 (1967): 136-8

110. Reinus FZ, Weinberger HA, Fischer WW "Medication-induced ulceration of the small bowel." Am J Surg 112 (1966): 97-101

111. Holland GW "Stenosing ulcers of the small bowel associated with thiazide and potassium therapy." N Z Med J 64 (1965): 383-5

112. Balizet L "Recurrent parathyroid adenoma. Association with prolonged thiazide administration." JAMA 225 (1973): 1238-9

113. Arze RS, Ramos JM, Rashid HU, Kerr DN "Amenorrhoea, galactorrhoea, and hyperprolactinaemia induced by methyldopa." Br Med J (Clin Res Ed) 283 (1981): 194

114. Leon AS, Agre J, McNally C, et al "Blood lipid effects of antihypertensive therapy: a double-blind comparison of the effects of methyldopa and propranolol." J Clin Pharmacol 24 (1984): 209-17

115. Tchen P, Luchins DJ, Rose RP "Possibility of depression as a side effect of methyldopa." Am J Psychiatry 147 (1990): 128

116. Labbate LA, Holzgang AJ "Manic syndrome after discontinuation of methyldopa." Am J Psychiatry 146 (1989): 1075-6

117. Endo M, Hirai KO, Ohara M "Paranoid-hallucinatory state induced in a depressive patient by methyldopa: a case report." Psychoneuroendocrinology 3 (1978): 211-5

118. Wurzelmann J, Frishman WH, Aronson M, et al "Neuropsychological effects of antihypertensive drugs." Cardiol Clin 5 (1987): 689-701

119. Ghosh SK "Methyldopa and forgetfulness." Lancet Jan (1976): 202-3

120. Murphy KJ "Bilateral renal calculi in patients receiving methyldopa." Med J Aust July (1976): 20-1

121. Newman RJ, Salerno HR "Sexual dysfunction due to methyldopa." Br Med J Oct (1974): 106

122. Taylor RG, Hoffbrand BI, Crisp AJ, et al "Plasma sex hormone concentrations in men with hypertension treated with methyldopa and/or propranolol." Postgrad Med J 57 (1981): 425-6

Not all side effects for hydrochlorothiazide / methyldopa may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

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