Description

Methyldopa is a centrally acting antihypertensive drug. It is a prodrug that is converted to an active compound in the brain, where it works to lower blood pressure. Methyldopa has been in clinical use for many years and is particularly notable for its safety profile, especially in pregnant women with hypertension.

Indications

Methyldopa is primarily indicated for the treatment of hypertension (high blood pressure). Its use has become more limited due to the development of newer, more convenient, and often more effective drugs. However, it remains an important medication in specific patient populations, particularly for:

• Hypertension in Pregnancy: It is considered one of the safest and most well-studied antihypertensives for use during pregnancy.
• Patients with chronic kidney disease where other agents may not be suitable.

Mechanism of Action

Methyldopa’s therapeutic effect is due to its conversion into a false neurotransmitter that mimics the action of a natural one, leading to reduced sympathetic nervous system activity.

1. Conversion to a “False” Neurotransmitter: After oral administration, methyldopa is transported into the central nervous system (brainstem) and is converted by the enzyme DOPA decarboxylase into alpha-methyldopamine, and then further converted by the enzyme dopamine beta-hydroxylase into alpha-methylnorepinephrine.

2. Alpha-2 Agonism: Alpha-methylnorepinephrine then acts as a potent agonist (activator) of the presynaptic alpha-2 adrenergic receptors in the brainstem.

3. Reduced Sympathetic Outflow: When these receptors are stimulated, they act as a negative feedback loop, reducing the release of the primary sympathetic neurotransmitter, norepinephrine, from nerve terminals. This decreases the overall sympathetic nervous system outflow from the central nervous system.
4. Blood Pressure and Heart Rate Reduction: The reduced sympathetic stimulation to the heart and blood vessels leads to:
   • Peripheral Vasodilation: Blood vessels relax and widen, reducing peripheral resistance.

• • Decreased Heart Rate and Cardiac Output: The heart beats more slowly, and the amount of blood it pumps per minute decreases.

The combined effect of vasodilation and reduced cardiac output results in a significant and sustained reduction in blood pressure.