Alpha-2 agonists

Mechanism of Action - The Central Command Override

• Central Action: Primarily act on α2-adrenergic receptors in the brainstem (nucleus tractus solitarii).
• Sympathetic Reduction: This stimulation mimics a negative feedback loop, leading to ↓ sympathetic outflow from the CNS.
• Peripheral Effects:
  • Results in decreased norepinephrine (NE) release at peripheral nerve endings.
  • Leads to ↓ peripheral vascular resistance and ↓ cardiac output, thus lowering blood pressure.

⭐ Abrupt discontinuation, especially of clonidine, can cause severe rebound hypertension and tachycardia due to a surge in sympathetic activity.

Indications & Contraindications - Green Lights & Red Flags

Indications (Green Lights ✅)

• Hypertension: Primarily for resistant HTN. Methyldopa is a choice for pregnancy-induced hypertension.
• ADHD: Guanfacine and Clonidine serve as non-stimulant treatment options.
• Symptom Management (Clonidine):
  • Opioid & nicotine withdrawal symptoms.
  • Menopausal hot flashes.
  • Tourette syndrome tics.

Contraindications (Red Flags 🚫)

• Abrupt Discontinuation: ⚠️ High risk of severe rebound hypertension and tachycardia. Must taper dose slowly.
• Elderly Patients: Increased risk of CNS effects and orthostatic hypotension (Beers List).
• Depression: Can cause or exacerbate depressive symptoms.

⭐ Methyldopa is a key choice for hypertension in pregnancy but is famously associated with drug-induced lupus and hemolytic anemia (positive Coombs test).

Adverse Effects - The Rebound & Sedation Show

• Central Nervous System (CNS): The most frequent, dose-dependent effects.

  • Sedation, fatigue, and dizziness.
  • Depression can occur, limiting use in susceptible patients.

• Cardiovascular System:

  • ⚠️ Rebound Hypertension: Abrupt withdrawal is critical to avoid. It leads to a surge in sympathetic outflow, causing severe ↑BP, tachycardia, and nervousness. Always taper the dose slowly over several days.
  • Bradycardia and orthostatic hypotension.

• Other Common Effects:

  • Dry mouth (xerostomia) and constipation.
  • Sodium and water retention, often resulting in edema.

⭐ Methyldopa-Specific: Can cause a positive Coombs test in up to 20% of patients, which may lead to hemolytic anemia. It can also induce hepatitis or a lupus-like syndrome.

Key Agents - Clonidine, Guanfacine, Methyldopa

⭐ Methyldopa can cause a positive Coombs test, sometimes leading to hemolytic anemia. It's a classic exam question linking a drug to a specific autoimmune-like reaction.

High‑Yield Points - ⚡ Biggest Takeaways

• Mechanism: Centrally acting α2-agonists that ↓ sympathetic outflow from the brainstem, leading to reduced blood pressure.
• Clonidine is used for hypertensive urgency and ADHD; abrupt discontinuation causes severe rebound hypertension.
• α-Methyldopa is a first-line agent for hypertension in pregnancy.
• Key side effects of methyldopa include drug-induced lupus and Coombs-positive hemolytic anemia.
• Common adverse effects for the class include sedation, dry mouth, and bradycardia.