Methyldopa

Methyldopa or alpha-methyldopa (brand names Aldomet, Apo-Methyldopa, Dopamet, Novomedopa) is a centrally-acting adrenergic antihypertensive medication. Its use is now deprecated following introduction of alternative safer classes of agents. However it continues to have a role in otherwise difficult to treat hypertension and pregnancy-induced hypertension.

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Pharmacokinetics

Methyldopa has variable absorption from the gut of approximately 50%. It is metabolized in the intestines and liver; its metabolite alpha-methylnorepineprine acts in the brain to stimulate alpha-adrenergic receptors decreasing total peripheral resistance. It is excreted in urine.

Mechanism of action

Methyldopa, in its active metabolite form, leads to increased alpha-2 receptor-mediated inhibition of sympathetic nervous system (SNS) (centrally and peripherally), allowing peripheral sympathetic nervous system (PSNS) tone to decrease. Such activity leads to a decrease in total peripheral resistance (TPR) and cardiac output.

Rebound effect

If methyldopa is abruptly withdrawn, rebound hypertension happens. This results because the long term use of methyldopa lowers the sensitivity of presynaptic alpha 2 receptors: the release of norepinephrine (NE) from sympathetic nerve endings is modulated by NE itself acting on the presynaptic alpha 2 autoreceptors thus inhibiting its own release. The discontinuation of methyldopa removes the inhibition on NE release leading to excessive NE release from the SNS and the rebound hypertension.

History

When introduced it was a mainstay of antihypertensive therapy, but its use has declined, with increased use of other safer classes of agents. One of its important present-day uses is in the management of pregnancy-induced hypertension, as it is relatively safe in pregnancy compared to other antihypertensive drugs.

Side effects

There are many possible reported side-effects with some, whilst rare, being serious. Side effects are usually fewer if the dose is less than 1 g per day:^[1]

• Gastro-intestinal disturbances
• Dry mouth
• Bradycardia (slow pulse rate)
• Worsening of angina
• Orthostatic hypotension (Postural hypotension)
• Sedation, headaches, dizziness
• Myalgia (muscle pain), arthralgia (joint pain) or paraesthesia (numbness)
• Nightmares, mild psychosis, depression
• Parkinsonism
• Bell's palsy
• Abnormal liver functions tests and hepatitis
• Pancreatitis
• Haemolytic anaemia
• Bone marrow suppresion leading to thrombocytopenia (low platelets) or leucopenia (low white blood cells)
• Hypersensitivity reactions including lupus erythematosus-like syndrome, myocarditis (heart muscle inflammation), pericarditis and rashes
• Ejaculatory failure, Impotence, decreased libido, gynecomastia (breast enlargement in men), hyperprolactinaemia and amenorrhoea
• Note that if used in pregnant women, it may cause a positive Coombs test