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Wednesday, August 20, 2025

Antiadrenergic agents, centrally acting


Introduction

Centrally acting antiadrenergic agents are drugs that reduce sympathetic nervous system (SNS) activity by stimulating inhibitory pathways within the central nervous system (CNS). Unlike peripherally acting antiadrenergics, which block adrenergic receptors or nerve terminals outside the CNS, centrally acting drugs act at the brainstem (medullary vasomotor center) to reduce sympathetic outflow to the heart, blood vessels, and kidneys.

The net effect is:

  • Decreased heart rate (negative chronotropy).

  • Reduced cardiac contractility (negative inotropy).

  • Vasodilation via reduced sympathetic tone.

  • Reduced blood pressure by lowering both cardiac output and peripheral vascular resistance.

Although highly effective, their use has declined because of frequent CNS-related adverse effects (sedation, dry mouth, rebound hypertension). However, they remain important in specific clinical contexts, particularly resistant hypertension, pregnancy-induced hypertension, and hypertensive urgencies.

Classification of Centrally Acting Antiadrenergic Agents

  1. Alpha-2 Adrenergic Agonists

    • Clonidine

    • Methyldopa

    • Guanfacine

    • Guanabenz

  2. Imidazoline Receptor Agonists (newer agents, overlap with α2 action)

    • Moxonidine

    • Rilmenidine

Mechanisms of Action

1. Alpha-2 Adrenergic Agonists

  • Stimulate presynaptic α2-adrenergic receptors in the brainstem (nucleus tractus solitarius and rostral ventrolateral medulla).

  • This reduces release of norepinephrine from sympathetic nerves, suppressing sympathetic outflow.

  • Result: ↓ heart rate, ↓ peripheral resistance, ↓ renin secretion, and ultimately ↓ blood pressure.

2. Imidazoline Receptor Agonists

  • Bind to imidazoline I1 receptors in the rostral ventrolateral medulla.

  • Reduce sympathetic nerve activity with fewer α2-related side effects (less sedation, dry mouth).

  • Still lower blood pressure effectively.

Major Centrally Acting Antiadrenergic Drugs

Clonidine

  • Mechanism: Central α2-agonist, also weak imidazoline agonist.

  • Uses:

    • Hypertension (oral, transdermal patch).

    • Hypertensive urgencies (IV, oral).

    • ADHD (extended-release).

    • Tourette’s syndrome (off-label).

    • Opioid/nicotine/alcohol withdrawal (reduces sympathetic overactivity).

  • Doses:

    • Hypertension: 0.1–0.3 mg PO twice daily.

    • Transdermal patch: 0.1–0.3 mg/day, changed weekly.

  • Adverse effects: Sedation, dry mouth, bradycardia, constipation, sexual dysfunction, rebound hypertension on abrupt withdrawal.

Methyldopa

  • Mechanism: Prodrug converted in CNS to α-methylnorepinephrine, a selective α2-adrenergic agonist.

  • Uses:

    • Hypertension in pregnancy (safe, long history of use).

    • Chronic hypertension (less common now).

  • Doses: 250–500 mg PO two to three times daily.

  • Adverse effects: Sedation, fatigue, dry mouth, orthostatic hypotension, positive Coombs test (hemolytic anemia), hepatotoxicity, hyperprolactinemia (gynecomastia, galactorrhea).

Guanfacine

  • Mechanism: Central α2-adrenergic agonist (more selective than clonidine).

  • Uses:

    • Hypertension (not commonly used anymore).

    • ADHD (extended-release).

  • Doses: 1–3 mg PO once daily (hypertension); 1–4 mg PO daily (ADHD).

  • Adverse effects: Sedation, dry mouth, dizziness, fatigue; less rebound hypertension compared to clonidine.

Guanabenz

  • Mechanism: Central α2 agonist, similar to clonidine.

  • Uses: Hypertension (rarely used today).

  • Doses: 4–8 mg PO twice daily.

  • Adverse effects: Similar to clonidine, but shorter half-life.

Moxonidine

  • Mechanism: Selective imidazoline I1 receptor agonist, minimal α2 activity.

  • Uses: Hypertension (especially in patients intolerant to clonidine).

  • Doses: 0.2–0.6 mg PO once daily.

  • Adverse effects: Drowsiness, dry mouth (less than clonidine), headache, dizziness, hypotension.

Rilmenidine

  • Mechanism: Imidazoline I1 receptor agonist.

  • Uses: Hypertension (Europe, not widely available worldwide).

  • Doses: 1 mg PO once or twice daily.

  • Adverse effects: Similar to moxonidine but milder sedation.

Therapeutic Uses

  1. Hypertension

    • Used when other agents fail or in resistant hypertension.

    • Methyldopa remains the drug of choice in pregnancy-induced hypertension.

    • Clonidine is useful in hypertensive urgencies (oral/IV).

  2. ADHD (Attention Deficit Hyperactivity Disorder)

    • Clonidine XR and Guanfacine XR approved as adjuncts to stimulants.

  3. Withdrawal Syndromes

    • Clonidine reduces sympathetic symptoms of opioid, alcohol, or nicotine withdrawal.

  4. Other Uses (off-label in some regions)

    • Tourette’s syndrome (clonidine).

    • Menopausal hot flashes (clonidine).

Adverse Effects

  • CNS effects: Sedation, fatigue, drowsiness, dizziness, depression (rare).

  • Autonomic effects: Dry mouth, constipation, orthostatic hypotension, sexual dysfunction.

  • Cardiovascular effects: Bradycardia, rebound hypertension with abrupt withdrawal (especially clonidine).

  • Hematologic effects (methyldopa): Hemolytic anemia (positive Coombs test), hepatotoxicity.

Contraindications

  • Depression (relative, due to CNS depressive effects).

  • Severe liver disease (methyldopa).

  • Bradyarrhythmias (due to risk of worsening bradycardia).

  • Hypersensitivity to drug components.

Precautions

  • Taper gradually (especially clonidine) to avoid rebound hypertension.

  • Use cautiously with other CNS depressants (additive sedation).

  • Monitor liver function and Coombs test with methyldopa during long-term use.

  • Adjust dosing in renal impairment (most are renally excreted).

Drug Interactions

  • Clonidine + β-blockers: Dangerous rebound hypertension if clonidine is abruptly withdrawn.

  • Tricyclic antidepressants (TCAs): May reduce antihypertensive effect of clonidine and methyldopa.

  • CNS depressants (alcohol, benzodiazepines, opioids): Additive sedation.

  • Methyldopa + iron supplements: Reduced absorption.

  • Methyldopa + levodopa: Reduced efficacy due to competition for dopa decarboxylase.

Clinical Efficacy and Limitations

  • Centrally acting antiadrenergic drugs are effective antihypertensives, but side effects limit long-term use.

  • Methyldopa remains highly valuable in hypertensive pregnancy due to safety profile.

  • Clonidine is particularly useful in hypertensive urgencies, ADHD, and withdrawal syndromes, but long-term use is limited by sedation and risk of rebound hypertension.

  • Moxonidine and rilmenidine offer improved tolerability, but are not universally available.

Conclusion

Centrally acting antiadrenergic agents reduce blood pressure by suppressing sympathetic outflow from the brainstem. They include alpha-2 agonists (clonidine, methyldopa, guanfacine, guanabenz) and imidazoline receptor agonists (moxonidine, rilmenidine).

  • Clonidine is versatile (hypertension, withdrawal, ADHD) but limited by sedation and rebound hypertension.

  • Methyldopa is uniquely important in pregnancy-induced hypertension.

  • Moxonidine and rilmenidine are newer, better-tolerated alternatives for hypertension.

Although not first-line agents today, centrally acting antiadrenergics remain important in resistant hypertension, special populations (pregnant women), and select conditions like ADHD and withdrawal syndromes.



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