Methyldopa

Methyldopa or alpha-methyldopa (brand names Aldomet®, Apo-Methyldopa®, Dopamet®, Novomedopa®) is a centrally-acting adrenergic antihypertensive medication. It 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.

Mechanism of action

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.

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

All drugs in this class can cause "rebound" hypertension due to an up-regulation of alpha-2 receptors while under the influence of the drug. If the drug is abruptly withdrawn, the "original" as well as "new" receptors become available and cause a severe reaction to the "normal" SNS activity (which is usually in excess). In other words, the SNS typically releases more norepinephrine (NE) than is needed to activate receptors (leading to a sustained response), and extra receptors leads to an over-response (in this case mediated by alpha-2 receptors leading to vascular smooth muscle constriction = 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:

  • 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 thrombocytopaenia (low platelets) or leucopaenia (low white blood cells)
  • Hypersensitivity reactions including lupus erythematosus-like syndrome, myocarditis (heart muscle inflammation), pericarditis and rashes
  • Ejaculatory failure, Impotence, decreased libido, gynaecomastia (breast enlargement in men), hyperprolactinaemia and amenorrhoea

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