Methyldopate

Uses

Methyldopate is used for Hypertension

Methyldopate is also used to associated treatment for these conditions: High Blood Pressure (Hypertension), Hypertensive crisis

How Methyldopate works

The exact mechanism of methyldopa is not fully elucidated; however, the main mechanisms of methyldopa involve its actions on alpha-adrenergic receptor and the aromatic L-amino acid decarboxylase enzyme, to a lesser extent. The sympathetic outflow is regulated by alpha (α)-2 adrenergic receptors and imidazoline receptors expressed on adrenergic neurons within the rostral ventrolateral medulla. Methyldopate is metabolized to α‐methylnorepinephrine via dopamine beta-hydroxylase activity and, consequently, alpha-methylepinephrine via phenylethanolamine-N-methyltransferase activity. Mediating the therapeutic effects of methyldopa, α‐methylnorepinephrine and α-methylepinephrine active metabolites are agonists at presynaptic alpha-2 adrenergic receptors in the brainstem. Stimulating alpha-2 adrenergic receptors results in the inhibition of adrenergic neuronal outflow and attenuation of norepinephrine release in the brainstem. Consequently, the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system is reduced, leading to a reduction in blood pressure.

The L-isomer of alpha-methyldopa also reduces blood pressure by inhibiting aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase, which is an enzyme responsible for the syntheses of dopamine and serotonin. Inhibiting this enzyme leads to depletion of biogenic amines such as norepinephrine. However, inhibition of aromatic L-amino acid decarboxylase plays a minimal role in the blood-pressure‐lowering effect of methyldopa.

Dosage

Methyldopate dosage

Adult Use-

Initiation of Therapy: The usual starting dosage of Methyldopate is 250 mg two or three times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than two days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. When Methyldopate is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When Methyldopate is given with antihypertensives other than thiazides, the initial dosage of Methyldopate should be limited to 500 mg daily in divided doses; when Methyldopate is added to a thiazide, the dosage of thiazide need not to be changed.

Maintenance Therapy: The usual daily dosage of Methyldopate is 500 mg to 2 g in two to four doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 gm. Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of Methyldopate frequently will restore effective control of blood pressure. A thiazide may be added at any time during Methyldopate therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 gm of Methyldopate daily. Methyldopate is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.

Pediatric Use-

Initial dosage is based on 10 mg/kg of body weight daily in two to four doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3 gm daily, whichever is less.

Side Effects

Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. The following systemic side effects may rarely occurs with the use of Methyldopate - angina pectoris, congestive heart failure, orthostatic hypotension, edema or weight gain, bradycardia, pancreatitis, colitis, vomiting, diarrhea, nausea, constipation, dryness of mouth, hyperprolactinemia, bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; rheumatoid factor, hepatitis, jaundice, myocarditis, pericarditis, vasculitis, eosinophilia, parkinsonism, bell's palsy, nightmares and reversible mild psychoses or depression, dizziness, lightheadedness, paresthesias, arthralgia, myalgia, nasal stuffiness, rash, amenorrhea, gynecomastia, lactation, impotence. However, significant adverse effects due to Methyldopate have been infrequent and this agent usually is well tolerated.

Toxicity

The lowest published toxic dose via oral route is 44 gm/kg/3Y (intermittent) in a female. Oral LD₅₀ is 5000 mg/kg in rats and 5300 mg/kg in mice. Intraperitoneal LD₅₀ is 300 mg/kg in rats and 150 mg/kg in mice.

Acute overdosage is characterized by acute hypotension and other presentations attributed to the brain and gastrointestinal dysfunction, such as excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distention, flatus, diarrhea, nausea, and vomiting. Symptomatic and supportive measures should be initiated in the event of methyldopa overdose. Overdosage following recent oral ingestion can be managed by gastric lavage or emesis, as well as infusions to limit further drug absorption. Cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity should be closely monitored. The use of sympathomimetic drugs such as levarterenol, epinephrine, and metaraminol bitartrate, or dialysis may be considered.

Precaution

Patient with history of haemolytic anaemia, liver disease or depression; parkinsonism, hepatic porphyria. Not intended for the treatment of phaeochromocytoma. Renal or hepatic impairment. Childn, elderly. Pregnancy and lactation.

Interaction

When Methyldopate is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients may require reduced doses of anesthetics when on Methyldopate. When Methyldopate and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Coadministration of Methyldopate with ferrous sulfate or ferrous gluconate is not recommended.

Food Interaction

• Take with or without food. Drug pharmacokinetics is unaffected.

Methyldopate multivitamins interaction

[Moderate] ADJUST DOSING INTERVAL: The oral bioavailability and pharmacologic effects of methyldopa may be decreased during concurrent administration with iron-containing products.

The proposed mechanism is chelation of methyldopa by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract.

In one study, five hypertensive patients receiving chronic methyldopa therapy (250 mg to 1500 mg daily) all had elevated blood pressure following the addition of ferrous sulfate 325 mg three times daily for 2 weeks.

The systolic pressure had increased by more than 15 mmHg in three of the patients and the diastolic pressure increased by more than 10 mmHg in two.

Blood pressure returned to baseline within 7 days of discontinuing the iron.

In 12 normal subjects, administration of methyldopa 500 mg with ferrous sulfate 325 mg or ferrous gluconate 600 mg resulted in an 88% and 79% reduction, respectively, in the renal excretion of unmetabolized, free methyldopa compared to administration of methyldopa alone.

In another study, administration of ferrous sulfate simultaneously with methyldopa reduced the bioavailability of methyldopa by 83%, while administration one hour or two hours before methyldopa reduced its bioavailability by 55% and 42%, respectively.br>
Until more information is available, patients receiving methyldopa in combination with iron-containing products should be advised to separate the times of administration by as much as possible.

Patients should be monitored closely for altered hypertensive effect and methyldopa dosage increased as necessary.

Selection of an alternative antihypertensive therapy may be necessary.

Methyldopate Drug Interaction

Moderate: multivitamin, prenatalUnknown: aspirin, aspirin, amoxicillin / clavulanate, diphenhydramine, calcium / vitamin d, omega-3 polyunsaturated fatty acids, furosemide, atorvastatin, acetaminophen, montelukast, levothyroxine, acetaminophen, valproic acid, thiamine, cyanocobalamin, pyridoxine, ascorbic acid, cholecalciferol, cetirizine

Methyldopate Disease Interaction

Major: liver diseaseModerate: cerebrovascular disease, dialysis, hemolytic anemia, leukopenia, peripheral edema, pheochromocytomaMinor: psychoses

Volume of Distribution

The apparent volume of distribution ranges between 0.19 and 0.32L/kg and the total volume of distribution ranges from 0.41 to 0.72L/kg. Since methyldopa is lipid-soluble , it crosses the placental barrier, appears in cord blood, and appears in breast milk.

Elimination Route

Methyldopate is incompletely absorbed from the gastrointestinal tract following oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The mean bioavailability of methyldopa is 25%, ranging from eight to 62%. Following oral administration, about 50% of the dose is absorbed and T_max is about three to six hours.

Half Life

The plasma half-life of methyldopa is 105 minutes. Following intravenous injection, the plasma half-life of methyldopa ranges from 90 to 127 minutes.

Clearance

The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency.

Elimination Route

Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products. Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine.

Unabsorbed drug is excreted in feces as the unchanged parent compound. After oral doses, excretion is essentially complete in 36 hours.

Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, possibly leading to more profound and prolonged hypotensive effects in these patients.

Pregnancy & Breastfeeding use

Pregnancy Category B. Methyldopate appears in breast milk. Therefore, caution should be exercised when Methyldopate is given to a nursing woman.

Contraindication

Methyldopate is contraindicated in patients with:

• active hepatic disease, such as acute hepatitis and active cirrhosis.
• liver disorders previously associated with Methyldopate therapy.
• hypersensitivity to any component of these products.
• On therapy with monoamine oxidase (MAO) inhibitors.

Special Warning

Pediatric Use: There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients.

Acute Overdose

Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting). In the event of overdosage, symptomatic and supportive measures should be employed. When ingestion is recent, gastric lavage or emesis may reduce absorption. When ingestion has been earlier, infusions may be helpful to promote urinary excretion.

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