Chapter 7 · Module 5

Beta-Blockers, Alpha-Blockers, Centrally Acting Agents & Vasodilators

Secondary antihypertensive classes — niches, mechanisms, and critical safety rules

Beta-Blockers — Cardioselective vs Non-Selective

Receptor Selectivity Determines Adverse Effect Profile

Beta-Blocker Subclass Comparison

Feature	Cardioselective (Beta-1 Preferential)	Non-Selective (Beta-1 + Beta-2)
Prototype agents	Metoprolol, bisoprolol, atenolol, nebivolol	Propranolol, nadolol, carvedilol, labetalol
Bronchoconstriction risk	Lower — safer in mild/moderate asthma	Higher — avoid in reactive airway disease
Glucose/insulin effects	Less impairment of insulin secretion	Greater impairment; masks more hypoglycemia symptoms
Lipid effects	Variable; nebivolol most favorable	Raise triglycerides, lower HDL (except carvedilol)
Peripheral vasoconstriction	Less	More (beta-2 blockade in vascular smooth muscle)
Heart failure evidence	Metoprolol (MERIT-HF); bisoprolol (CIBIS-II)	Carvedilol (COPERNICUS, US Carvedilol Study)
Special niches	Nebivolol: metabolic syndrome, diabetes; atenolol: avoid in uncomplicated HTN (LIFE trial inferior)	Propranolol: tremor, migraine, hyperthyroidism; carvedilol + labetalol: heart failure, emergencies

Three Situations Where Standard Instincts Cause Harm

Pheochromocytoma — Alpha Before Beta

Wrong: Give beta-blocker first → removes beta-2 vasodilation → alpha-1 vasoconstriction unopposed → hypertensive crisis
Correct: Alpha-blocker first (phenoxybenzamine or doxazosin) for 10–14 days → then add beta-blocker for rate control

Aortic Dissection — Beta-Blocker Before Vasodilator

Wrong: Give vasodilator first → reflex tachycardia → increased aortic wall stress (dP/dt) → worsens dissection
Correct: Beta-blocker first (esmolol or labetalol IV) → target heart rate below 60 bpm → then add vasodilator if needed; target systolic below 120 mm Hg

Cocaine/Amphetamine Hypertension — No Beta-Blockers

Wrong: Give beta-blocker → same unopposed alpha-adrenergic vasoconstriction as pheochromocytoma → worsens hypertension
Correct: Benzodiazepines first (reduce sympathetic drive); phentolamine IV for refractory hypertension

Centrally Acting Sympatholytic Agents

Alpha-2 Agonist

Clonidine

Stimulates presynaptic alpha-2 receptors in brainstem → reduces central sympathetic outflow
Reduces heart rate, cardiac output, total peripheral resistance, renin release
Uses: resistant hypertension (add-on); opioid withdrawal; ADHD (extended-release)
Adverse effects: dry mouth (most common), sedation, bradycardia, constipation; patch: contact dermatitis (20%)
Withdrawal warning: abrupt discontinuation → severe sympathetic rebound (hypertension, tachycardia) — always taper over 1–2 weeks

Prodrug — Alpha-2 Agonist

Methyldopa

Converted to alpha-methyl-norepinephrine in CNS → alpha-2 agonism → reduces sympathetic outflow
Primary indication: hypertension in pregnancy — most extensively studied antihypertensive in pregnancy; safe across all trimesters
First-line in pregnancy alongside labetalol and long-acting nifedipine
Outside pregnancy: sedation and fatigue are often prohibitive; clonidine preferred
Positive direct Coombs test in up to 20% of patients; hemolytic anemia rare; drug-induced lupus rare

Direct Vasodilators — Mechanism, Reflex Responses, Key Rules

Reserved for Resistant Hypertension and Specific Indications

Hydralazine, Minoxidil & Sodium Nitroprusside

Drug	Mechanism	Key Adverse Effects / Rules	Primary Indications
Hydralazine	Arteriolar smooth muscle relaxation (mechanism not fully characterized)	Reflex tachycardia + sodium retention → requires beta-blocker + diuretic; drug-induced lupus (5–10%, slow acetylators); peripheral neuropathy (high doses)	Hypertension in pregnancy (IV); HFrEF in patients intolerant of RAAS inhibitors (A-HeFT: hydralazine + isosorbide dinitrate in Black patients); add-on in resistant HTN
Minoxidil	Activates ATP-sensitive potassium channels → membrane hyperpolarization → profound arteriolar vasodilation	Mandatory: must co-administer beta-blocker (tachycardia) AND loop diuretic (severe sodium retention); hypertrichosis (most patients); pericardial effusion (prolonged use)	Severe treatment-resistant hypertension only; topical form used for hair loss
Sodium nitroprusside	Spontaneous nitric oxide release → balanced arteriolar + venodilation; onset seconds, offset 1–2 min	Cyanide toxicity with prolonged infusion (above 48 h) or high doses; light-sensitive solution; largely replaced by nicardipine/labetalol	Hypertensive emergencies requiring rapid, titratable blood pressure reduction; acute pulmonary edema; avoid in pregnancy (fetal cyanide toxicity)