Although it is a centrally acting sympathomimetic, it does not block reuptake or transporters. It may reduce the dopaminergic and serotonergic transmission in the peripheral nervous system and it indirectly affects norepinephrine (noradrenaline) synthesis. Methyldopa acts on alpha-2 adrenergic receptors, which are found on the pre synaptic nerve terminal. This inhibits the synthesis of norepinephrine by inhibiting tyrosine hydroxylase. The S-enantiomer of methyldopa is a competitive inhibitor of the enzyme aromatic L-amino acid decarboxylase (LAAD), which converts L-DOPA into dopamine. L-DOPA can cross the blood brain barrier and thus methyldopa may have similar effects. LAAD converts it into alpha-methyldopamine, a false prescursor to norepinephrine, which in turn reduces synthesis of norepinephrine in the vesicles. Dopamine beta hydroxylase (DBH) converts alpha-methyldopamine into alpha-methylnorepinephrine, which is an agonist of the presynaptic α2-adrenergic receptor causing inhibition of neurotransmitter release. Pharmacokinetics
Maximum decrease in blood pressure occurs 4-6 hours after oral dosage. The half-life of methyldopa is 105 minutes. Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine. History
When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.
As elucidated by Alfred Sommer, even mild, subclinical deficiency can also be a problem, as it may increase childrens risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness.VAD is estimated to affect about one-third of children under the age of five around the world. It is estimated to claim the lives of 670,000 children under five annually. Around 250,000–500,000 children in developing countries become blind each year owing to VAD, with the highest prevalence in Southeast Asia and Africa. According to the World Health Organization (WHO), VAD is under control in the United States, but in developing countries, VAD is a significant concern. Globally, 65% of all children aged 6 to 59 months received two doses of vitamin A in 2013, fully protecting them against VAD (80% in the least developed countries). Signs and symptoms
The most common cause of blindness in developing countries is Vitamin A deficiency. The WHO estimated in 1995 that 13.8 million children had some degree of visual loss related to VAD. Night blindness and its worsened condition, xerophthalmia, are markers of Vitamin A deficiency, collections of keratin in the conjunctiva, known as Bitots spots, and ulceration and necrosis of cornea keratomalacia can be seen. Conjunctival epithelial defects occur around lateral aspect of the limbus in the subclinical stage of VAD. These conjunctival epithelial defects are not visible on a biomicroscope, but they take up black stain and become readily visible after instillation of kajal (surma); this is called "Imtiazs sign".