Methyldopa / Hydrochlorothiazide

Pronunciation: METH-il-DOE-pa/HYE-droe-KLOR-oh-THYE-a-zide
Class: Antihypertensive combination

Trade Names

Methyldopa/Hydrochlorothiazide
- Tablets, oral Methyldopa 250 mg/Hydrochlorothiazide 15 mg
- Tablets, oral Methyldopa 250 mg/Hydrochlorothiazide 25 mg

Pharmacology

Methyldopa

Causes central alpha-adrenergic stimulation, which inhibits sympathetic cardioaccelerator and vasoconstrictor centers; reduces plasma renin activity; reduces standing and supine BP.

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Hydrochlorothiazide

Increases chloride, sodium, and water excretion by interfering with transport of sodium ions across renal tubular epithelium.

Indications and Usage

For the treatment of hypertension.

Contraindications

Active hepatic disease, such as acute hepatitis and active cirrhosis; liver disorders previously associated with methyldopa therapy; anuria; concurrent therapy with MAOIs; hypersensitivity to methyldopa, hydrochlorothiazide, or other sulfonamide derivatives.

Dosage and Administration

Adults

PO 250 mg/15 mg 2 or 3 times daily or 250 mg/25 mg twice daily (max, methyldopa 3,000 mg/hydrochlorothiazide 50 mg). Alternatively, 500 mg/30 mg or 500 mg/50 mg once daily may be used.

Elderly

Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.

Renal Function Impairment

Patients with renal impairment may respond to smaller doses.

General Advice

• Dosage must be individualized, as determined by titration of the individual components. Once the patient has been successfully titrated, methyldopa/hydrochlorothiazide combination tablets may be substituted if the previously determined titrated doses are the same as in the combination.
• Since methyldopa and hydrochlorothiazide have a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 h. This is not complicated by an overshoot of blood pressure.
• To minimize sedation associated with methyldopa, start dosage increases in the evening.
• Occasionally, tolerance to methyldopa may occur, usually between the second and third month of therapy. Additional separate doses of methyldopa or replacement of methyldopa/hydrochlorothiazide tablets with single-entity agents is necessary until the new effective dose ratio is reestablished by titration.
• May be given with other antihypertensives. When given with antihypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses and the dose of these other agents may need to be adjusted to effect a smooth transition.

Storage/Stability

Store between 68° and 77 °F. Protect from light.

Drug Interactions

Hydrochlorothiazide ACE inhibitors (eg, captopril)

The risk of renal dysfunction may be increased. Monitor renal function, especially in elderly patients and patients with renal impairment. If an adverse interaction is suspected, stop one or both agents.

Adrenocorticotropic hormones, corticosteroids

Electrolyte depletion may be intensified, particularly hypokalemia. Laboratory monitoring of serum potassium is warranted.

Alcohol, barbiturates, narcotics

Potentiation of orthostatic hypotension may occur. Monitor BP.

Antihypertensive agents

Additive or potentiation of hypotensive effects. Closely monitor BP and watch for adverse reactions or unusual manifestations of drug idiosyncrasy. (See Methyldopa/Antihypertensive Agents.)

Antineoplastic agents (eg, cyclophosphamide)

Hydrochlorothiazide may prolong antineoplastic-induced myelosuppression. If coadministration cannot be avoided, use with caution.

Cholestyramine, colestipol resins

Hydrochlorothiazide absorption may be impaired. Single doses of either cholestyramine or colestipol resins bind hydrochlorothiazide, reducing GI absorption by up to 85% and 43%, respectively. Separate the administration times by as much as possible, at least 4 h. Adjust hydrochlorothiazide dose as needed.

Diazoxide

The pharmacologic effects of both drugs may be increased. Hyperglycemia, hyperuricemia, and hypotension may occur. Closely monitor BP, blood and urine glucose, and serum uric acid. If coadministration cannot be avoided, a decreased dosage of one or both agents may be required.

Digoxin

Hydrochlorothiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias. Measure plasma concentrations of potassium and magnesium; supplement low levels. Prevent further losses with dietary management.

Dofetilide

Dofetilide plasma concentrations may be increased and/or hypokalemia may occur. Prolongation of the QT interval may occur, increasing the risk of torsades de pointes. Coadministration is contraindicated.

Hypoglycemic agents, oral (eg, sulfonylureas)

Hydrochlorothiazide may increase fasting blood glucose. The effect of oral hypoglycemic agents may be decreased. Monitor blood glucose and adjust the hypoglycemic dose as needed.

Insulin

Hydrochlorothiazide may increase fasting blood glucose and decrease insulin secretion and insulin tissue sensitivity. The effect of insulin may be decreased. Monitor blood glucose and adjust the insulin dose as needed.

Lithium

Lithium Cl may be decreased, increasing lithium concentrations and the risk of lithium toxicity. Lithium generally should not be given with hydrochlorothiazide. (See Methyldopa/Lithium.)

Loop diuretics (eg, furosemide)

Hydrochlorothiazide and furosemide have synergistic effects that may result in profound diuresis and serious electrolyte abnormalities. Monitor for dehydration and electrolyte abnormalities during combined therapy. Titrate dosage with small or intermittent doses.

Nondepolarizing muscle relaxants (eg, tubocurarine)

Possible increase responsiveness to the muscle relaxant due to diuretic-induced hypokalemia. If hypokalemia cannot be corrected, a lower dosage of nondepolarizing muscle relaxants may be needed.

NSAIDs (eg, ibuprofen, indomethacin)

The diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide may be reduced. Monitor BP and the diuretic response. If an interaction is suspected, it may be necessary to discontinue the NSAID. Rarely, coadministration may also result in deterioration of renal function, including acute renal failure. Monitor renal function.

Pressor amines (eg, norepinephrine)

Response to pressor amines may be decreased. Use with caution.

Tretinoin

The risk of phototoxicity may be increased. Avoid coadministration.

Methyldopa Anesthetics

Reduced doses of anesthetics may be required. Hypotension during anesthesia can be controlled by vasopressors because adrenergic receptors remain sensitive.

Antihypertensive agents

Additive or potentiation of hypotensive effects. Closely monitor BP and watch for adverse reactions or unusual manifestations of drug idiosyncrasy. (See Hydrochlorothiazide/Antihypertensive agents above.)

Beta-adrenergic blockers, nonselective (eg, propranolol)

Coadministration may cause a rare complication of paradoxical hypertension. Monitor BP. If an acute increase occurs, discontinuation of the beta-blocker and treatment with an alpha-adrenergic blocking agent (eg, phentolamine) may be needed.

Butyrophenones (eg, haloperidol)

May potentiate the antipsychotic effects of haloperidol or the combination may produce psychosis. If an interaction occurs, discontinue one or both drugs.

Ferrous sulfate or gluconate

May decrease methyldopa absorption when ingested with ferrous sulfate or gluconate. Coadministration is not recommended.

Levodopa

The hypotensive and therapeutic effects of levodopa and methyldopa may be increased. Monitor BP and signs of levodopa toxicity. If either occurs, adjust the dose of either drug as needed.

Lithium

May precipitate lithium toxicity. Monitor for signs of lithium toxicity. Adjust dose as needed. (See Hydrochlorothiazide/Lithium.)

MAOIs (eg, phenelzine)

May lead to excessive sympathetic stimulation. Coadministration is contraindicated.

Sympathomimetics (eg, norepinephrine, phenylpropanolamine)

May potentiate the pressor effects of sympathomimetics and lead to hypertension. Monitor BP. If hypertension occurs, discontinuation of the sympathomimetic or treatment with an alpha-adrenergic blocking agent (eg, phentolamine) may be needed.

Tizanidine

Additive hypotensive effects may occur. If coadministration cannot be avoided, closely monitor BP, especially during dosage titration.

Lab Test Interferences

May interfere with tests for urinary uric acid, serum creatinine, and AST; may give falsely high levels of urinary catecholamines.

Adverse Reactions

Cardiovascular

Aggravation of angina pectoris; bradycardia; CHF; hypotension; orthostatic hypotension; prolonged carotid sinus hypersensitivity.

CNS

Asthenia; Bell palsy; decreased mental acuity; dizziness; headache; involuntary choreoathetotic movements; light-headedness; paresthesias; parkinsonism; psychic disturbances, including nightmares and reversible mild psychoses or depression; restlessness; sedation; symptoms of cerebrovascular insufficiency; vertigo; weakness.

Dermatologic

Alopecia; erythema multiforme including Stevens-Johnson syndrome; exfoliative dermatitis, including TEN; rash.

GI

Anorexia; colitis; constipation; cramping; diarrhea; distention; dry mouth; flatus; gastric irritation; nausea; pancreatitis; sialadenitis; sore or black tongue; vomiting.

Genitourinary

Amenorrhea; breast enlargement; decreased libido; gynecomastia; impotence; interstitial nephritis; lactation; renal failure or dysfunction.

Hematologic

Agranulocytosis; aplastic anemia; bone marrow depression; granulocytopenia; hemolytic anemia; leukopenia; thrombocytopenia.

Hepatic

Liver disorders including abnormal LFTs, hepatitis, intrahepatic cholestatic jaundice, and jaundice.

Hypersensitivity

Anaphylactic reactions; drug-related fever; eosinophilia; fever; lupus-like syndrome; myocarditis; necrotizing angiitis (vasculitis and cutaneous vasculitis); pericarditis; photosensitivity; purpura; rash; respiratory distress, including pneumonitis and pulmonary edema; urticaria; vasculitis.

Lab Tests

Positive tests for antinuclear antibody, lupus erythematosus cells, and rheumatoid factor; positive Coombs test; increased BUN.

Metabolic

Electrolyte imbalance (hyperkalemia, hypokalemia, hyponatremia, hypochloremic alkalosis, hypercalcemia, hypomagnesemia); glycosuria; hyperglycemia; hyperuricemia.

Musculoskeletal

Arthralgia with or without joint swelling; muscle spasm; myalgia.

Special Senses

Transient blurred vision; xanthopsia.

Miscellaneous

Edema or weight gain; hyperprolactinemia; nasal stuffiness.

Precautions

Warnings This fixed combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static, but must be reevaluated as conditions in each patient warrant.

Monitor Perform a blood cell count (hematocrit, hemoglobin, or red blood cell) before treatment is started for a baseline or to establish whether there is anemia. Evaluate renal function and fluid status and measure serum electrolytes before starting therapy and periodically thereafter. Perform periodic blood cell counts to detect hemolytic anemia. A direct Coombs test may be useful before therapy and at 6 and 12 mo later. Perform periodic determinations of hepatic function, particularly during the first 6 to 12 wk of therapy or when an unexplained fever occurs. Monitor BP and pulse on a regular basis. Monitor blood sugar in diabetic patients when drug is started or dose is changed.

Pregnancy

Category C . Use of diuretics during normal pregnancy is inappropriate and exposes the mother and fetus to unnecessary hazard. Diuretics do not prevent the development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Hypersensitivity

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

Renal Function

Use with caution. Thiazides may precipitate azotemia in these patients, and the effects of repeated dosing may be cumulative. Hypertension has recurred occasionally after dialysis in patients taking methyldopa because the drug is removed by this procedure.

Hepatic Function

Use with caution in current or previously impaired hepatic function or progressive liver disease.

Diabetes

Hyperglycemia may occur with thiazide diuretics; latent diabetes mellitus may manifest during thiazide therapy.

Edema/Weight gain

Some patients taking methyldopa experience edema or weight gain. Discontinue if edema progresses or if signs of heart failure appear.

Electrolyte imbalance

Hyperkalemia, hypokalemia, hyponatremia, hypochloremic alkalosis, hypercalcemia, and hypomagnesemia may occur.

Hematologic effects

Reversible reduction of the WBC with a primary effect on granulocytes has occurred rarely. Rare cases of granulocytopenia have been reported. Reversible thrombocytopenia has occurred rarely.

Hepatic effects

Jaundice, with or without fever, may occur. Fever has occurred within the first 3 wk of therapy, associated in some cases with eosinophilia or abnormalities in 1 or more LFTs, such as serum alkaline phosphatase, ALT, AST, bilirubin, and prothrombin time. Fatal hepatic necrosis has been reported rarely.

Hyperuricemia

May occur or acute gout may be precipitated.

Involuntary choreoathetotic movements

Have been observed in patients with severe bilateral cerebrovascular disease. Discontinue therapy if these movements occur.

Lipid effects

Thiazides tend to raise serum levels of cholesterol and triglycerides.

Positive Coombs test/hemolytic anemia

May occur; monitor patient closely because of potentially fatal complications.

Post-sympathectomy

The antihypertensive effects of hydrochlorothiazide may be enhanced in the post-sympathectomy patient.

Systemic lupus erythematosus

Thiazides may exacerbate or cause systemic lupus erythematosus.

Overdosage

Symptoms

Bradycardia, constipation, diarrhea, distention, dizziness, flatus, hypotension, light-headedness, nausea, sedation, vomiting, weakness.

Patient Information

• Caution patients that light-headedness can occur, especially during the first few days of therapy, and that it should be reported to the prescribing health care provider. Inform patients that if syncope occurs, methyldopa/hydrochlorothiazide should be discontinued until the health care provider has been consulted.
• Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in BP, with the same consequences of light-headedness and possible syncope.
• Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing health care provider.
• Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform their health care provider of significant changes in readings.
• Caution patients to avoid unnecessary exposure to UV light (eg, sunlight, tanning booths), and to use sunscreen and wear protective clothing when exposed to UV light to avoid a photosensitivity reaction.

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