Dopamet Tablet

Dopamet Tablet 250 mg, or α-methyldopa, is a centrally acting sympatholytic agent and an antihypertensive agent. It is an analog of DOPA (3,4‐hydroxyphenylanine), and it is a prodrug, meaning that the drug requires biotransformation to an active metabolite for therapeutic effects. Dopamet Tablet 250 mg works by binding to alpha(α)-2 adrenergic receptors as an agonist, leading to the inhibition of adrenergic neuronal outflow and reduction of vasoconstrictor adrenergic signals. Dopamet Tablet 250 mg exists in two isomers D-α-methyldopa and L-α-methyldopa, which is the active form.

First introduced in 1960 as an antihypertensive agent, methyldopa was considered to be useful in certain patient populations, such as pregnant women and patients with renal insufficiency. Since then, methyldopa was largely replaced by newer, better-tolerated antihypertensive agents; however, it is still used as monotherapy or in combination with hydrochlorothiazide. Dopamet Tablet 250 mg is also available as intravenous injection, which is used to manage hypertension when oral therapy is unfeasible and to treat hypertensive crisis.

Dopamet Tablet 250 mg is a centrally-acting alpha-2 adrenergic agonist used to manage hypertension alone or in combination with hydrochlorothiazide, and to treat hypertensive crises.

Dopamet Tablet 250 mg is indicated for the management of hypertension as monotherapy or in combination with hydrochlorothiazide. Dopamet Tablet 250 mg injection is used to manage hypertensive crises.

• High Blood Pressure (Hypertension)
• Hypertensive crisis

Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors. Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure. Dopamet Tablet 250 mg causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine. Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension. Dopamet Tablet 250 mg also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur.

Following oral administration, blood-pressure-lowering effects are observed within 12 to 24 hours in most patients, and a maximum reduction in blood pressure occurs in 4 to 6 hours. Blood pressure returns to pre-treatment levels within 24 to 48 hours following drug discontinuation. Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 10 to 16 hours.

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. Dopamet Tablet 250 mg 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.

Dopamet Tablet 250 mg 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.

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.

Dopamet Tablet 250 mg is less than 15% bound to plasma proteins and its primary metabolite, O-sulfate metabolite, is about 50% protein bound. Following intravenous administration, approximately 17% of the dose in normal subjects were circulating in the plasma as free methyldopa.

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.

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

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

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.

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

• Initiation of Therapy: The usual starting dosage of Dopamet Tablet 250 mg 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 Dopamet Tablet 250 mg is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When Dopamet Tablet 250 mg is given with antihypertensives other than thiazides, the initial dosage of Dopamet Tablet 250 mg should be limited to 500 mg daily in divided doses; when Dopamet Tablet 250 mg is added to a thiazide, the dosage of thiazide need not to be changed.
• Maintenance Therapy: The usual daily dosage of Dopamet Tablet 250 mg 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 Dopamet Tablet 250 mg frequently will restore effective control of blood pressure. A thiazide may be added at any time during Dopamet Tablet 250 mg 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 Dopamet Tablet 250 mg daily. Dopamet Tablet 250 mg 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.