Antiadrenergic agents, peripherally acting

Introduction

Antiadrenergic agents are drugs that inhibit the effects of the sympathetic nervous system (SNS) by reducing adrenergic signaling. They can act either centrally (in the brainstem) or peripherally (at nerve endings, adrenergic receptors, or within the synapse).

This article focuses on peripherally acting antiadrenergic agents, which work outside the central nervous system to reduce blood pressure and modulate cardiovascular tone. These drugs block adrenergic activity either by:

1. Inhibiting adrenergic nerve function (adrenergic neuron blockers)

2. Blocking peripheral adrenergic receptors (alpha- and beta-receptor antagonists)

While some of these drugs are now rarely used due to side effects or availability of safer alternatives, they remain important in understanding cardiovascular pharmacology and are still used in specific conditions.

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Classification of Peripherally Acting Antiadrenergic Agents

1. Adrenergic Neuron Blocking Agents

• Reserpine

• Guanethidine

• Guanadrel

2. Alpha-Adrenergic Receptor Blockers

• Non-selective α-blockers: Phenoxybenzamine, Phentolamine.

• Selective α1-blockers: Prazosin, Doxazosin, Terazosin, Alfuzosin, Tamsulosin, Silodosin.

3. Beta-Adrenergic Receptor Blockers (Peripheral beta-blockers)

• Non-selective: Propranolol, Nadolol, Timolol.

• Selective (β1 blockers): Atenolol, Metoprolol, Bisoprolol, Nebivolol.

• Mixed α- and β-blockers: Labetalol, Carvedilol.

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Mechanisms of Action

1. Adrenergic Neuron Blocking Agents

• Reserpine: Irreversibly blocks vesicular monoamine transporter (VMAT), preventing storage of norepinephrine (NE), dopamine, and serotonin in presynaptic vesicles. Leads to depletion of NE → reduced sympathetic tone → lower blood pressure.

• Guanethidine and Guanadrel: Enter adrenergic nerve terminals via uptake-1 transport, replace NE in vesicles, and inhibit its release → decreased vasoconstriction.

2. Alpha-Adrenergic Blockers

• Non-selective α-blockers (Phenoxybenzamine, Phentolamine): Irreversibly (phenoxybenzamine) or reversibly (phentolamine) block α1 and α2 receptors → vasodilation → reduced blood pressure.

• Selective α1-blockers (Prazosin, Doxazosin, Terazosin, Tamsulosin): Block α1 receptors in vascular smooth muscle → vasodilation, ↓ peripheral resistance. In the prostate and bladder, they reduce smooth muscle tone → relieve symptoms of benign prostatic hyperplasia (BPH).

3. Beta-Adrenergic Blockers

• Block β-receptors, reducing adrenergic effects.

  • β1-blockers: Decrease heart rate, contractility, and renin release.

  • β2-blockers: Cause bronchoconstriction and vasoconstriction (adverse effect).

  • Mixed α/β-blockers: Provide vasodilation (via α-blockade) plus cardiac suppression (via β-blockade).

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Therapeutic Uses

1. Adrenergic Neuron Blocking Agents

• Reserpine: Historically used for hypertension; now rarely used due to CNS depression and severe side effects.

• Guanethidine, Guanadrel: Used in resistant hypertension (limited role today).

2. Alpha-Adrenergic Blockers

• Hypertension: Prazosin, Doxazosin, Terazosin.

• Benign Prostatic Hyperplasia (BPH): Tamsulosin, Alfuzosin, Silodosin (selective for α1A receptors in prostate).

• Pheochromocytoma: Phenoxybenzamine (preoperative control of blood pressure), Phentolamine (short-term management).

• Raynaud’s phenomenon: Prazosin sometimes used off-label.

3. Beta-Adrenergic Blockers

• Hypertension (especially with comorbidities such as coronary artery disease, arrhythmias).

• Ischemic heart disease / Angina pectoris.

• Arrhythmias (atrial fibrillation, supraventricular tachycardia).

• Heart failure (carvedilol, bisoprolol, metoprolol succinate).

• Glaucoma (timolol, betaxolol eye drops).

• Thyrotoxicosis (propranolol).

• Migraine prophylaxis (propranolol, timolol).

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Generic Names and Doses

1. Adrenergic Neuron Blocking Agents

• Reserpine: 0.05–0.25 mg PO daily.

• Guanethidine: 10–50 mg PO daily.

• Guanadrel: 10–75 mg PO daily.

2. Alpha-Blockers

• Prazosin: 1–5 mg PO two to three times daily.

• Doxazosin: 1–8 mg PO once daily.

• Terazosin: 1–20 mg PO once daily.

• Tamsulosin: 0.4–0.8 mg PO once daily.

• Phenoxybenzamine: 10–40 mg PO two to three times daily.

• Phentolamine: 5–10 mg IV bolus (pheochromocytoma crisis).

3. Beta-Blockers

• Propranolol: 40–160 mg/day PO in divided doses.

• Atenolol: 25–100 mg PO daily.

• Metoprolol: 25–200 mg PO daily (succinate for HF, tartrate for arrhythmias).

• Bisoprolol: 5–10 mg PO daily.

• Carvedilol: 12.5–50 mg/day PO divided doses.

• Labetalol: 200–1200 mg/day PO in divided doses, or IV infusion in hypertensive emergencies.

• Timolol (ophthalmic): 0.25–0.5% eye drops twice daily.

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Adverse Effects

Adrenergic Neuron Blockers

• Depression, sedation (reserpine).

• Orthostatic hypotension.

• Diarrhea, nasal congestion.

• Sexual dysfunction.

Alpha-Blockers

• First-dose hypotension (especially prazosin).

• Dizziness, syncope.

• Reflex tachycardia (more with non-selective agents).

• Nasal congestion.

• Fluid retention.

Beta-Blockers

• Bradycardia, AV block.

• Bronchospasm (non-selective).

• Fatigue, depression, impotence.

• Rebound hypertension/angina with abrupt withdrawal.

• Masking of hypoglycemia symptoms in diabetics.

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Contraindications

• Neuron blockers: Depression, peptic ulcer disease (reserpine).

• Alpha-blockers: Severe hypotension, history of orthostatic hypotension.

• Beta-blockers: Severe bradycardia, 2nd/3rd degree AV block, uncompensated heart failure, asthma/COPD (for non-selective).

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Precautions

• Use low initial doses of α1-blockers to avoid first-dose syncope.

• Titrate beta-blockers gradually, avoid abrupt withdrawal.

• Monitor blood pressure, heart rate, and electrolytes.

• Adjust doses in renal/hepatic impairment.

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Drug Interactions

• Reserpine + MAO inhibitors: Risk of hypertensive crisis.

• Alpha-blockers + PDE-5 inhibitors (sildenafil, tadalafil): Severe hypotension.

• Beta-blockers + non-dihydropyridine CCBs (verapamil, diltiazem): Excessive bradycardia, AV block.

• Beta-blockers + insulin/oral hypoglycemics: Mask hypoglycemia symptoms.

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Clinical Efficacy and Limitations

• Adrenergic neuron blockers are rarely used today due to CNS and systemic side effects.

• Alpha-blockers are effective for both hypertension and BPH, but not first-line for hypertension alone (due to higher risk of heart failure in ALLHAT trial). They are primarily used in patients with concurrent hypertension and BPH.

• Beta-blockers remain a cornerstone for patients with ischemic heart disease, arrhythmias, and heart failure, but are no longer first-line for uncomplicated hypertension.

• Mixed α/β-blockers (labetalol, carvedilol) are very useful in hypertensive emergencies and chronic heart failure, respectively.