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Adrenergic Receptor Blockers

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Classification of α-Blockers

α-Blockers
├── Nonselective (α₁ and α₂)
│   ├── Reversible: Phentolamine, Tolazoline
│   └── Irreversible: Phenoxybenzamine
├── Selective α₁-Blockers
│   └── Prazosin, Terazosin, Doxazosin, Tamsulosin, Silodosin, Alfuzosin
└── Selective α₂-Blocker
    └── Yohimbine

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Pharmacological Effects of α-Blockade (Fig. 2.24)

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Individual Drugs

1. Phenoxybenzamine (Irreversible Nonselective)

• Binds covalently to α₁ and α₂ receptors - irreversible (noncompetitive) blockade
• Also inhibits reuptake of NA into adrenergic nerve endings
• Blocks histamine (H₁), cholinergic, and serotonin receptors at higher doses
• PVR is reduced; has a predominant venodilating effect
• Given orally or slow IV infusion - slow onset, long duration
• Side effects: Postural hypotension (mainly from venodilatation), tachycardia, palpitation, diarrhoea, nasal stuffiness, giddiness, impotence
• Main use: Pheochromocytoma (preoperative preparation)

2. Phentolamine (Reversible Nonselective)

• Imidazoline derivative; competitive antagonist at α₁ and α₂
• Venodilatation > arteriolar dilatation
• Also blocks 5-HT receptors, K⁺ channels; causes histamine release from mast cells
• Given intravenously - rapid onset, short duration
• Adverse effects: Tachycardia, palpitation, arrhythmias; angina and MI may be precipitated

3. Tolazoline

• Similar to phentolamine; rarely used

4. Ergot Alkaloids (nonselective competitive)

• Ergotamine, ergotoxine, dihydroergotamine

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Selective α₁-Blockers

Prazosin (Prototype)

• Potent and selective α₁-blocker; given orally
• Well absorbed from GIT but undergoes extensive first-pass metabolism
• Unlike nonselective blockers, produces minimal or no tachycardia (presynaptic α₂ not blocked)
• Causes both arteriolar and venodilatation; arteriolar dilatation more prominent
• First-dose phenomenon: Within 30-90 min of first dose - postural hypotension + syncopal attacks
  • Give small initial dose (1 mg) at bedtime to reduce syncope risk
• Other ADRs: Nasal stuffiness, tachycardia, impaired ejaculation, impotence

Other Selective α₁-Blockers

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Selective α₂-Blocker

Yohimbine

• Alkaloid; competitively blocks α₂-receptors
• Also has 5-HT receptor blocking effect
• Acts as an aphrodisiac but rarely used therapeutically

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Therapeutic Uses of α-Blockers

1. Pheochromocytoma

• Diagnosis: Elevated catecholamines, VMA in blood/urine (normal VMA: 4-8 mg/24h), CT/MRI
• Definitive treatment: Surgery
• Preoperative: Phenoxybenzamine to control hypertension and restore blood volume (nonselective, irreversible → prolonged BP control)
• ⚠️ β-blockers MUST NOT be given alone in phaeochromocytoma - blockade of vascular β₂ receptors causes unopposed α₁ action → severe rise in BP (vasoconstriction) → fatal
  • α-blocker must always precede β-blocker
• Intraoperatively (handling tumour causes sudden catecholamine surge): IV phentolamine (rapid onset, short duration)
• Metyrosine: Adjuvant - inhibits tyrosine hydroxylase → reduces catecholamine synthesis

2. Hypertensive Emergencies (IV Phentolamine used for):

• Intraoperative hypertensive episodes during pheochromocytoma surgery
• Hypertensive crisis due to clonidine withdrawal
• Hypertensive crisis due to "cheese reaction" (tyramine + MAO inhibitor)

3. Essential Hypertension

• Selective α₁-antagonists preferred over nonselective for mild-to-moderate hypertension
• Cause less tachycardia and have favourable effects on lipid profile

4. Benign Prostatic Hyperplasia (BPH)

• Selective α₁-blockers decrease smooth muscle tone in bladder neck and prostate → reduced urinary resistance
• Prazosin, doxazosin, terazosin, alfuzosin - preferred in patients who also have hypertension
• Tamsulosin - preferred in normotensive BPH patients (uroselective, minimal BP effect)

5. Tissue Necrosis

• Phentolamine infiltrated locally to prevent tissue necrosis due to extravasation of α-agonists (e.g., noradrenaline IV extravasation)

6. Male Sexual Dysfunction

• Local injection of phentolamine + papaverine for erectile dysfunction

7. Other Uses

• Congestive cardiac failure (afterload/preload reduction)
• Peripheral vascular diseases

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High-Yield Exam Points to Remember

• Phenoxybenzamine = irreversible, noncompetitive, longest duration - used in phaeochromocytoma prep
• Phentolamine = reversible, competitive, rapid IV - used intraoperatively and in hypertensive emergencies
• Prazosin = selective α₁, first-dose syncope, give 1 mg at bedtime
• Tamsulosin = uroselective (α₁A), best for BPH in normotensive patients
• Doxazosin = longest acting among selective α₁-blockers
• Yohimbine = only selective α₂-blocker
• Never give β-blocker alone in phaeochromocytoma - always give α-blocker first

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Sympathetic Nervous System & Adrenergic Pharmacology

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1. Overview of the Autonomic Nervous System

Autonomic Nervous System (ANS)
├── Sympathetic (Thoracolumbar - T1 to L2)
│   ├── Preganglionic: Short, myelinated
│   ├── Postganglionic: Long, unmyelinated
│   ├── Neurotransmitter (preganglionic): Acetylcholine (ACh)
│   └── Neurotransmitter (postganglionic): Noradrenaline (NA) ← ADRENERGIC
│       Exception: Sweat glands → ACh (cholinergic)
│       Exception: Adrenal medulla → ACh → releases Adrenaline + NA into blood
└── Parasympathetic (Craniosacral)
    ├── Preganglionic: Long
    ├── Postganglionic: Short
    └── Neurotransmitter: ACh (cholinergic) at all synapses

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2. Adrenergic Neurotransmission

SYNTHESIS OF NORADRENALINE (NA)
─────────────────────────────────────────────────────────
Tyrosine
   ↓ (Tyrosine hydroxylase) ← Rate-limiting step
   ↓ Blocked by: Metyrosine
DOPA
   ↓ (DOPA decarboxylase)
Dopamine
   ↓ (Dopamine β-hydroxylase)
Noradrenaline (NA) ← stored in vesicles
   ↓ (PNMT - in adrenal medulla only)
Adrenaline (Epinephrine)
─────────────────────────────────────────────────────────

RELEASE
• Action potential → Ca²⁺ influx → exocytosis of NA
• Blocked by: Guanethidine, Bretylium
• Enhanced by: Amphetamine, Tyramine (indirect sympathomimetics)

FATE OF RELEASED NA
• Reuptake 1 (Uptake 1): Back into nerve terminal (main route) → Blocked by: Cocaine, TCAs
• Reuptake 2 (Uptake 2): Into effector cells
• MAO (Monoamine Oxidase): Breaks down NA inside nerve terminal
• COMT (Catechol-O-Methyl Transferase): Breaks down NA in synapse/blood
• Final metabolite: VMA (Vanillylmandelic Acid) → excreted in urine

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3. Adrenergic Receptors - Complete Chart

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4. Adrenergic Drugs Classification

ADRENERGIC (SYMPATHOMIMETIC) DRUGS
├── Direct Acting (act on receptors directly)
│   ├── Non-selective (α + β): Adrenaline, NA, Isoprenaline (β only)
│   ├── Selective α: Phenylephrine (α₁), Clonidine (α₂), Xylometazoline
│   └── Selective β:
│       ├── β₁: Dobutamine
│       ├── β₂: Salbutamol, Terbutaline, Salmeterol, Ritodrine
│       └── β₃: Mirabegron
├── Indirect Acting (release NA from terminals)
│   └── Amphetamine, Tyramine, Ephedrine (mixed)
└── Mixed Acting: Ephedrine, Dopamine

ADRENERGIC BLOCKING DRUGS
├── α-Blockers (see previous summary)
│   ├── Non-selective: Phenoxybenzamine (irreversible), Phentolamine (reversible)
│   ├── Selective α₁: Prazosin, Terazosin, Doxazosin, Tamsulosin, Alfuzosin, Silodosin
│   └── Selective α₂: Yohimbine
├── β-Blockers
│   ├── Non-selective β₁+β₂: Propranolol, Timolol, Nadolol, Sotalol
│   ├── Selective β₁ (Cardioselective): Metoprolol, Atenolol, Bisoprolol, Nebivolol
│   └── α+β Blockers: Labetalol, Carvedilol
└── Adrenergic Neuron Blockers (block NA release)
    └── Guanethidine, Reserpine, Bretylium

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5. Adrenaline vs Noradrenaline vs Isoprenaline

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6. Key Effects of Sympathetic Stimulation by Organ

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7. High-Yield Memory Points

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