Centrally acting sympatholytic drugs, once commonly used for hypertension except for clonidine, are now seldom employed. They work by decreasing sympathetic outflow from brainstem vasomotor centers while enhancing sensitivity to baroreceptor control. This approach reduces dependency on posture compared to drugs acting directly on peripheral sympathetic neurons.
Methyldopa, an L-dopa analog, is metabolized to alpha-methyldopamine and alpha-methylnorepinephrine. Although it replaces norepinephrine in nerve vesicles, its antihypertensive effect arises from stimulating central alpha-adrenoceptors. Similarly, clonidine, initially developed as a nasal decongestant, acts as a partial agonist at alpha-adrenoceptors, causing transient blood pressure elevation followed by prolonged hypotension. It primarily affects medullary alpha-adrenoceptors, enhancing baroreflex sensitivity and reducing sympathetic tone.
Both clonidine and methyldopa suggest that blood pressure regulation involves central adrenergic neurons influencing baroreceptor reflexes. While clonidine binds tightly to alpha-2 receptors and modulates norepinephrine release, methyldopa impacts heart rate and cardiac output differently, implying distinct sites of action within brainstem vasomotor centers.
Guanabenz and guanfacine, similar to clonidine in their effects on central alpha-adrenoceptors, are less frequently used and offer no significant advantages over clonidine.
Methyldopa
Methyldopa, once widely used but now primarily reserved for treating hypertension during pregnancy, lowers blood pressure mainly by reducing peripheral vascular resistance, occasionally affecting heart rate and cardiac output. Most cardiovascular reflexes remain unaffected, and its blood pressure lowering effect is not significantly influenced by posture, although postural hypotension can occur, especially in dehydrated patients. Methyldopa offers the potential benefit of lowering renal vascular resistance.
Pharmacokinetics
In terms of pharmacokinetics, methyldopa crosses the blood-brain barrier via an aromatic amino acid transporter. The usual oral dose achieves peak antihypertensive effects within 4-6 hours, lasting up to 24 hours due to accumulation of its metabolite, alpha-methylnorepinephrine, in nerve ending vesicles after the parent drug has cleared from circulation.
Toxicology
The most common adverse effect of methyldopa is sedation, particularly early in treatment, with long-term use potentially causing persistent mental fatigue and impaired concentration. Less frequent side effects include nightmares, depression, dizziness, and extrapyramidal symptoms. Prolactin-mediated lactation can occur in both genders due to hypothalamic dopaminergic inhibition.
Other notable adverse effects include a positive Coombs test in 10-20% of patients after 12 months of therapy, which may complicate blood cross-matching and rarely lead to hemolytic anemia. Hepatitis and drug fever are also reported, typically resolving upon drug discontinuation.
Clonidine
Clonidine lowers blood pressure primarily through several mechanisms: decreasing cardiac output by reducing heart rate and relaxing capacitance vessels, and also by reducing peripheral vascular resistance. Additionally, it decreases renal vascular resistance while maintaining renal blood flow. Clonidine’s antihypertensive effects are not associated with postural hypotension, except in rare cases. It should be administered cautiously to patients at risk for depression, as it may exacerbate symptoms, and abrupt withdrawal can lead to a severe hypertensive crisis due to increased sympathetic nervous activity.
Conclusion
Based on the information provided about centrally acting sympathoplegic drugs like methyldopa and clonidine:
Mechanism of Action: These drugs primarily act centrally to reduce sympathetic outflow from the brainstem vasomotor centers. They enhance baroreceptor sensitivity, which helps regulate blood pressure more effectively independent of posture compared to drugs acting peripherally on sympathetic neurons.
Clinical Use: Methyldopa, once widely used, is now mainly reserved for specific cases like hypertension during pregnancy due to its ability to cross the blood-brain barrier and affect central alpha-adrenoceptors. Clonidine, similarly, is used for hypertension but requires caution due to its potential to exacerbate depression and cause severe rebound hypertension upon abrupt withdrawal.
Pharmacokinetics: Methyldopa’s peak antihypertensive effects occur 4-6 hours after oral administration, lasting up to 24 hours due to accumulation of its active metabolite. Clonidine also has a similar duration of action.
Adverse Effects: Both drugs have notable adverse effects. Methyldopa commonly causes sedation and can lead to long-term mental fatigue and concentration impairment. It also has rare but serious effects like positive Coombs test and hepatitis. Clonidine can exacerbate depression and cause a hypertensive crisis if abruptly stopped.
Conclusion:
Centrally acting sympatholytic drugs like methyldopa and clonidine offer benefits in hypertensive management by modulating sympathetic tone centrally. However, their side effect profiles and potential for severe reactions necessitate careful consideration in clinical use. Methyldopa remains particularly relevant in specific patient populations such as pregnant women, while clonidine requires vigilant monitoring for adverse effects and withdrawal symptoms.
