Methyldopa 250mg tablet

Indications

• Hypertension
• Pregnancy-induced hypertension

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Initially 250 mg 2 to 3 times a day, gradually increased as necessary at intervals of at least 2 days; maximum daily dose is 3 g.

Mechanism of action

Methyldopa is metabolized to alpha-methylnorepinephrine, which acts as an agonist at presynaptic alpha-2 adrenergic receptors in the brainstem. This stimulation inhibits adrenergic neuronal outflow and reduces norepinephrine release, leading to decreased sympathetic nervous system activity and lower blood pressure. Additionally, methyldopa inhibits aromatic L-amino acid decarboxylase, contributing to decreased levels of norepinephrine and other biogenic amines, although this mechanism plays a minimal role in its antihypertensive effect.

Pharmacodynamics

The antihypertensive effects of methyldopa are mainly mediated by its active metabolite, alpha-methylnorepinephrine. This metabolite decreases peripheral sympathetic tone and lowers arterial pressure. Methyldopa reduces levels of serotonin, dopamine, norepinephrine, and epinephrine, resulting in lower blood pressure without significantly affecting renal blood flow or glomerular filtration rate. It may also slow heart rate in some patients. The onset of action occurs within 12 to 24 hours, with peak effects seen in 4 to 6 hours after administration.

Pharmacokinetics

Methyldopa is administered orally and is well absorbed, with peak plasma concentrations typically occurring within 1 to 2 hours. It undergoes extensive hepatic metabolism, primarily to alpha-methylnorepinephrine. The elimination half-life is approximately 2 hours, with metabolites excreted in urine. Blood pressure effects can last for 24 to 48 hours post-discontinuation.

Contra-indications

• Severe bradyarrhythmia secondary to second- or third-degree AV block
• Acute porphyrias

Adverse effects

• Constipation
• Depression
• Breast enlargement
• Cardiac inflammation
• Dizziness
• Dry mouth
• Fatigue
• Headache
• Nausea
• Postural hypotension
• Sedation
• Cognitive impairment
• Vomiting
• Diarrhoea
• Eosinophilia
• Gynaecomastia
• Haemolytic anaemia
• Skin reactions
• Delusions
• Hallucinations
• Granulocytopenia
• Lupus-like syndrome
• Pancreatitis
• Psychiatric disorders

Interactions

• Entacapone increases exposure to methyldopa (unknown effect)

Precautions

• Cerebrovascular disease
• History of depression
• Mild to moderate heart failure
• History of hepatic impairment
• Bradyarrhythmia
• Polyneuropathy
• Raynaud’s syndrome
• Other occlusive peripheral vascular disease
• Elderly patients may experience intolerance

Pregnancy

May lower fetal heart rate. Avoid oral use unless potential benefit outweighs risk.

Breast-feeding

Use with caution; consult healthcare provider.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral tablets
• Oral suspension

Mechanism of action

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. Methyldopa 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. METHYLDOPA...HAS HYPOTENSIVE ACTION INDEPENDENT OF ITS ANTIADRENERGIC ACTIONS; THIS IS PROBABLY PARTLY CENTRAL DEPRESSANT ACTION @ VASOMOTOR CENTER & PARTLY PERIPHERAL ACTION OF UNKNOWN MECHANISM. ... Alpha-methylnorepinephrine acts in the brain to inhibit adrenergic neuronal outflow from the brainstem, and this central effect is principally responsible for its antihypertensive action. IN CONSCIOUS RENAL HYPERTENSIVE RATS ALPHA-METHYLDOPA PRODUCED A LONG-LASTING FALL IN BLOOD PRESSURE WHICH WAS PARTIALLY ATTENUATED BY PRETREATMENT WITH NALTREXONE (5 MG/KG SC). PRETREATMENT WITH ANTISERUM TO BETA-ENDORPHIN APPLIED LOCALLY, ALSO BLOCKED THE DEPRESSOR RESPONSE. THESE RESULTS SUGGEST THAT THE FALL IN BLOOD PRESSURE OBSERVED AFTER ALPHA-METHYLDOPA AND ITS ACTIVE METABOLITE ALPHA-METHYLNORADRENALINE INVOLVES A BETA-ENDORPHIN LIKE PEPTIDE; A POSSIBLE SITE OF ACTION IS THE NUCLEUS TRACTUS SOLITARII. A REVIEW ON THE MECHANISM OF ACTION.

Pharmacodynamics

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. Methyldopa 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. Methyldopa 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.