📚 Antiadrenergic Agents (Sympatholytic Drugs) — Exam Summary

🔑 BIG PICTURE — What Are These Drugs?

PART 1: α (ALPHA) ADRENERGIC BLOCKERS

General Effects of α-Blockers (Important for MCQs!)

Classification of α-Blockers

α-Blockers
├── Non-selective
│   ├── Irreversible: Phenoxybenzamine
│   ├── Reversible: Phentolamine, Tolazoline
│   └── Ergot alkaloids: Dihydroergotamine, Methysergide
└── Selective
    ├── α1-selective: Prazosin
    └── α2-selective: Yohimbine

NON-SELECTIVE α-BLOCKERS

1. Phenoxybenzamine (Irreversible / Non-equilibrium)

• Class: Haloalkylamine
• Type: Irreversible (non-competitive) blocker of both α1 and α2
• Also blocks: Acetylcholine, histamine, and serotonin receptors (non-specific)
• MOA (Very Important for Exams!):
  • Drug forms a reactive aziridinium ion (ethylene iminium ion)
  • This positively charged ion acts as an electrophile
  • It reacts with a nucleophilic group on the α-receptor
  • Forms a covalent bond → irreversible blockade
  • Problem: Also alkylates other biomolecules → toxicity
• Side effects: Miosis, tachycardia, nasal stuffiness, postural hypotension
• Use: Preoperative management of pheochromocytoma (adrenal tumor)

2. Phentolamine & Tolazoline (Reversible / Equilibrium type)

• Type: Competitive (reversible) α-blockers
• Tolazoline structure: Similar to imidazoline α1-agonists but lacks lipophilic groups needed for agonist activity
• Both drugs: Stimulate GI smooth muscle + increase gastric secretion (via histamine release)
• Use: Treatment of pheochromocytoma and hypertensive crises from illicit drugs

3. Ergot Alkaloids (Non-selective)

• Source: Fungus Claviceps purpurea (grows in the ovary of rye plant) — very common exam fact!
• Chemical nature: Amide derivatives of lysergic acid
• First isolated alkaloid: Ergotoxin
• Receptor actions: Block adrenergic, tryptaminergic (serotonin), and dopaminergic receptors

• Non-selective α-antagonist
• Uses: Migraine, medication-overuse headache, vasoconstriction, oxytocic (uterine contraction)

• Adrenergic AND serotonin antagonist

SELECTIVE α1-BLOCKER

Prazosin

• Antihypertensive agent
• Key advantage: Causes peripheral vasodilation WITHOUT increase in heart rate or cardiac output (unlike non-selective blockers)
• Why? Blocks only postjunctional α1-receptors, leaving presynaptic α2-receptors intact → noradrenaline feedback loop preserved → no reflex tachycardia
• "First-dose phenomenon" (Important exam term!): Marked excessive postural hypotension after first dose — minimized by giving initial low dose at bedtime

PART 2: β (BETA) ADRENERGIC BLOCKERS

Classification

β-Blockers
├── Non-selective (1st generation)
│   └── Propranolol, Sotalol, Timolol (no ISA)
│       Pindolol (with ISA)
├── Cardioselective β1 (2nd generation)
│   └── Metoprolol, Atenolol, Bisoprolol, Esmolol, Betaxolol
└── α + β blocking (3rd generation)
    └── Labetalol, Carvedilol

Uses of β-Blockers (Exam Favorites!)

• Hypertension (antihypertensive)
• Glaucoma (first-line treatment)
• Alcohol withdrawal symptoms
• Migraine prophylaxis
• Tremor
• Angina pectoris
• Post-myocardial infarction

SAR (Structure-Activity Relationship) — Very Important for Chemistry Exams!

1. Arylethanolamine — direct aryl-ethanol-amine chain
2. Aryloxypropanolamine — has –OCH₂– linking group (prototype: Propranolol)

SAR Rules for Arylethanolamines:

• Replacing –OH of agonist with other groups (sulphonamido or nitro) → converts to antagonist
• N,N'-disubstituted → inactive
• Cyclic alkyl on N → better activity than open-chain
• α-methyl on chain → decreases activity

SAR Rules for Aryloxypropanolamines:

• –OCH₂ group was considered essential but not unique
• Naphthyl ring replaceable with indole (pindolol) or phenylether (oxprenolol)
• Alkenyl or alkenyloxy at ortho position → good β-blocking activity (e.g., Alprenolol)
• Isopropyl or t-butyl on N → favors β-blocking activity
• Para substitution (sufficient size) → contributes to β1 selectivity (cardioselectivity)
• Meta substitution absent = β1 selective
• Isosteric replacement of –O– with –CH₂–, –S–, –NCH₃ → decreases activity
• Secondary amines → optimum activity
• β-OH group in S configuration → maximal activity
• Most β-blockers used as racemic mixture EXCEPT levobunolol, timolol, penbutolol (pure S-enantiomer used)

Stereochemistry (Exam Point!):

• In arylethanolamines → R configuration needed for binding
• In aryloxypropanolamines → insertion of –O– changes CIP priority → S configuration now has the required spatial arrangement

KEY β-BLOCKER DRUGS

1. Propranolol (Non-selective, 1st generation)

• Blocks β1 and β2 equally
• No ISA, competitive blocker
• Most lipophilic → enters CNS
• Membrane-stabilizing activity at very high doses
• Uses: Hypertension, arrhythmias, angina, post-MI, pheochromocytoma, migraine prophylaxis, schizophrenia, alcohol withdrawal
• Contraindication: Asthma and bronchitis (blocks β2 in bronchi → bronchoconstriction)
• Metabolism: N-dealkylation, deamination, oxidation → active metabolite 4-hydroxypropranolol (potent β-blocker with some ISA)

2. Metipranolol

• Used topically for open-angle glaucoma
• Lowers intraocular pressure without changing pupil size (big advantage!)
• Mechanism: Reduces production of aqueous humor
• Risk: Systemic absorption → bradycardia, bronchospasm

3. Cardioselective β1-Blockers (2nd generation)

• Do NOT block β2 in bronchi → safe for asthma/bronchitis patients
• Selectivity lost at higher doses (important point!)

• Designed for rapid onset + very short duration of action
• Half-life: 9 minutes
• Used for: Atrial flutter, atrial fibrillation, sinus tachycardia (ventricular rate control)
• Useful during/after surgery for short-term heart rate control
• Effects disappear 20–30 minutes after infusion stopped

4. Third Generation — α + β Blockers

• Phenylethanolamine derivative
• Competitive blocker of α1, β1, and β2 receptors
• Exists as 4 isomers (very commonly asked!):
  • R,R-isomer → mainly β-blocking
  • S,R-isomer → mainly α-blocking
  • S,S-isomer → some α-blocking, NO β-blocking
  • R,S-isomer → devoid of activity at both
• Undergoes extensive first-pass metabolism
• Used as mixed α+β blocker in clinical practice

• β-blocker + α1-blocking activity
• Only (S) enantiomer → β-blocking activity
• Both enantiomers → α1-blocking activity
• Extra benefits: antioxidant activity + antiproliferative effect on vascular smooth muscle
• Neuroprotective and provides cardiovascular organ protection
• Uses: Hypertension + congestive heart failure

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