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PHARMACOLOGY - ADRENERGIC DRUGS

Complete 10-Mark Answers (KD Tripathi Style)

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1. ADRENALINE IN TREATMENT OF ANAPHYLACTIC SHOCK - Pharmacological Basis

Definition

Why Adrenaline (Epinephrine) is the Drug of Choice

Mechanism in Detail

1. α1 activation → constricts arterioles → raises blood pressure → relieves urticaria/angioedema
2. β1 activation → increases heart rate and force → combats circulatory collapse
3. β2 activation → relaxes bronchial smooth muscle → relieves bronchospasm
4. β2 on mast cells → increases cAMP → inhibits mediator release (physiological antagonism to histamine)
5. Reduces capillary permeability → reduces fluid leak into tissues (via α1)

Dose and Route

• Adults: 0.5 mg (0.5 mL of 1:1000 solution) IM into outer thigh (vastus lateralis)
• Can repeat every 5-15 minutes if no improvement
• IV route (1:10,000 solution, 0.1 mg slow IV) only in cardiac arrest or severe refractory cases under monitoring
• Children: 0.01 mg/kg IM

Why IM is preferred over IV?

• IM gives rapid, sustained absorption
• IV can cause fatal arrhythmias if given rapidly
• Sublingual/SC are slower and less predictable

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2. ADRENALINE - PHARMACOLOGICAL ACTIONS, THERAPEUTIC USES, ADVERSE EFFECTS, PRECAUTIONS

A. Pharmacological Actions

1. Cardiovascular System

• Heart (β1): Increases heart rate (positive chronotropy), force of contraction (positive inotropy), conduction velocity, and automaticity → increased cardiac output
• Blood vessels (α1 + β2):
  • Low dose: β2 predominates → vasodilation in skeletal muscle/coronary vessels → fall in diastolic BP
  • High dose: α1 predominates → generalized vasoconstriction → rise in systolic and diastolic BP
  • Net effect: Rise in pulse pressure; mean BP may rise or fall depending on dose

2. Respiratory System

• β2: Potent bronchodilation (most potent of all adrenergic drugs)
• Reduces mucosal congestion (α1) and mast cell mediator release (β2)

3. Eye

• Mydriasis (α1 on dilator pupillae) - without cycloplegia
• Reduces intraocular pressure (reduces aqueous humor formation + increases outflow)

4. Metabolic Effects

• β2: Glycogenolysis (liver + muscle) → hyperglycemia
• β3/β2: Lipolysis → increased free fatty acids
• Increases basal metabolic rate
• Increases oxygen consumption

5. CNS

• At therapeutic doses: restlessness, anxiety, tremors, headache
• Does NOT cross BBB significantly

6. Smooth Muscle

• Relaxes intestinal smooth muscle (α2 + β2)
• Contracts sphincters (α1)
• Uterus: relaxes (β2) in pregnancy; contracts in non-pregnant uterus (α1)
• Bladder: contracts trigone/sphincter (α1), relaxes detrusor (β2)

7. Local Effects

• Intense vasoconstriction at site of injection → prolongs action of local anesthetics

B. Therapeutic Uses with Justification

C. Adverse Effects

• CVS: Hypertensive crisis, palpitations, tachycardia, arrhythmias, angina, cerebral hemorrhage
• CNS: Anxiety, restlessness, tremors, headache, fear
• Local: Tissue necrosis (excessive local vasoconstriction)
• Metabolic: Hyperglycemia, hypokalemia (β2-mediated K+ uptake into cells)
• Pulmonary edema (in cardiac patients)

D. Precautions

• Do NOT use with halothane (risk of severe ventricular fibrillation - sensitizes myocardium)
• Avoid in hyperthyroidism (augmented response)
• Avoid in hypertension, coronary artery disease, cerebrovascular disease
• Do NOT inject into digits, pinna, nose, or penis (risk of ischemic necrosis due to lack of collaterals)
• Avoid IV bolus in non-emergency (use slow IV or IM)
• Cocaine/tricyclic antidepressants potentiate adrenaline (uptake-1 blocked)
• β-blocker + adrenaline → unopposed α → severe hypertension
• Store protected from light (oxidizes readily)

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3. VASOPRESSOR AGENTS - ENUMERATE FOUR

1. Noradrenaline (Norepinephrine) - α1 + β1; strong pressor
2. Dopamine - dose-dependent: D1 (renal), then β1 (cardiac), then α1 (pressor) at high doses
3. Phenylephrine - pure α1 agonist
4. Vasopressin (ADH) - V1 receptor on vascular smooth muscle → vasoconstriction

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4. ADRENALINE CONTRAINDICATED IN HYPOTENSIVE SHOCK (Non-Anaphylactic) - WHY?

Types of Shock Where Adrenaline is Contraindicated

• Hypovolemic shock (hemorrhagic, dehydration)
• Cardiogenic shock
• Septic shock (peripheral vasodilatory)

Reasons for Contraindication:

1. Peripheral Vasoconstriction Worsens Tissue Ischemia

• In hypovolemic/cardiogenic shock, peripheral vessels are already maximally constricted (compensatory)
• Adrenaline's α1 action further constricts vessels → reduces tissue perfusion → worsens end-organ ischemia (kidneys, gut, limbs)

2. Tachycardia Increases Myocardial Oxygen Demand

• β1 stimulation increases heart rate and contractility → increases O2 demand in an already compromised myocardium
• Risk of arrhythmias and myocardial infarction

3. Metabolic Derangement

• Glycogenolysis + lipolysis → hyperglycemia, lactic acidosis → worsens metabolic acidosis in shock

4. Splanchnic Vasoconstriction

• α1 reduces mesenteric blood flow → gut ischemia → risk of bacterial translocation and sepsis

5. Reflex Bradycardia

• Adrenaline-mediated BP rise may trigger baroreceptor reflex → bradycardia → paradoxical fall in cardiac output

What to use instead?

• Noradrenaline in septic shock (primarily α1 with some β1)
• Dopamine (dopaminergic at low doses preserves renal blood flow)
• Dobutamine in cardiogenic shock (β1 > β2, positive inotrope without excessive vasoconstriction)

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5. CLASSIFY ADRENERGIC DRUGS - USES AND ADVERSE EFFECTS

Classification (KD Tripathi Classification)

A. Based on Receptor Selectivity

• Adrenaline (Epinephrine) - α1, α2, β1, β2, β3
• Noradrenaline (Norepinephrine) - α1, α2, β1
• Dopamine - D1, D2, β1 (α1 at high doses)

• Non-selective: Phenylephrine (α1), Methoxamine (α1)
• Alpha-2 selective: Clonidine, Methyldopa, Dexmedetomidine

• Non-selective (β1 + β2): Isoprenaline, Dobutamine (β1 > β2)
• Beta-1 selective: Dobutamine
• Beta-2 selective: Salbutamol, Terbutaline, Salmeterol, Formoterol
• Beta-3: Mirabegron

B. Based on Mechanism (Katzung Classification)

C. Based on Chemical Structure

Uses of Major Adrenergic Drugs

Adverse Effects

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6. DRUGS USED IN GLAUCOMA - CLASSIFY, MOA, ADVERSE EFFECTS

Brief Pathophysiology

Classification of Anti-Glaucoma Drugs

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A. Beta-Adrenergic Blockers (β-Blockers)

• Block β2 receptors on ciliary body epithelium
• Reduces adenylyl cyclase activity → decreases cAMP → reduces aqueous humor secretion by ~35-50%
• No effect on pupil size or accommodation (unlike miotics)

• Local: Burning, stinging, blurred vision
• Systemic (absorbed via nasolacrimal duct): Bradycardia, bronchospasm, heart block, depression, impotence
• Betaxolol (β1 selective) is safer in asthmatics
• Contraindicated in: Asthma, COPD, heart block, cardiac failure

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B. Prostaglandin Analogues

• Act on FP prostaglandin receptors in ciliary muscle
• Increase uveoscleral (unconventional) outflow of aqueous humor (primary mechanism)
• Also increase trabecular outflow slightly
• Do NOT reduce aqueous production

• Iris/eyelid pigmentation (increased melanin synthesis) - permanent
• Eyelash growth (hypertrichosis) - may be desired cosmetically
• Conjunctival hyperemia (red eye)
• Foreign body sensation
• Prostaglandin-mediated inflammation (uveitis if pre-existing)
• No significant systemic effects (advantage)

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C. Miotics (Cholinergic Agonists)

• Pilocarpine: Direct muscarinic (M3) agonist on ciliary muscle and iris sphincter
• Ciliary muscle contraction → pulls on trabecular meshwork (scleral spur) → increases conventional (trabecular) outflow of aqueous
• Also causes miosis (iris sphincter contraction) → opens angle in narrow-angle glaucoma
• Physostigmine/Echothiophate: Cholinesterase inhibitors → accumulate acetylcholine → same effects

• Miosis → blurred vision in dim light, difficulty reading (accommodative spasm)
• Brow ache (ciliary spasm)
• Retinal detachment risk (vitreous traction)
• Systemic (especially echothiophate): increased salivation, GI cramps, bradycardia

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D. Alpha-2 Agonists

• α2-adrenergic agonists on ciliary body
• Dual mechanism:
  1. Reduces aqueous humor production (reduces cAMP via Gi protein coupling)
  2. Increases uveoscleral outflow

• Ocular: Conjunctival hyperemia, foreign body sensation, follicular conjunctivitis (chronic use)
• Systemic: Dry mouth, sedation, fatigue (more with brimonidine due to CNS penetration)
• Allergy (common with apraclonidine - used only short-term)
• Contraindicated in infants (CNS depression, apnea)

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E. Carbonic Anhydrase Inhibitors (CAI)

• Topical: Dorzolamide (2%), Brinzolamide (1%)
• Systemic: Acetazolamide (oral, 250-500 mg), Dichlorphenamide

• Inhibit carbonic anhydrase (CA II and IV) in ciliary body epithelium
• CA converts CO2 + H2O → H2CO3 → H+ + HCO3-
• Blockade → reduces Na+ and HCO3- transport into posterior chamber → reduces aqueous humor production by 25-30%
• Both systemic and topical reduce IOP

• Topical (Dorzolamide): Stinging, burning, transient blurred vision, bitter taste, corneal toxicity (avoid in corneal disease)
• Systemic (Acetazolamide):
  • Metabolic acidosis (HCO3- loss in urine)
  • Hypokalemia, polyuria, paresthesias (tingling in extremities - classic side effect)
  • Renal stones (crystalluria - use with caution in stone formers)
  • Sulfonamide allergy cross-reactivity
  • Stevens-Johnson syndrome
  • Aplastic anemia (rare)
  • Avoid in sulfa allergy

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F. Rho Kinase (ROCK) Inhibitor

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Summary Table: Anti-Glaucoma Drugs

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7. BETA-ADRENERGIC BLOCKERS - CLASSIFY, THERAPEUTIC USES

Classification

A. Based on Receptor Selectivity

• Propranolol, Nadolol, Timolol, Sotalol, Pindolol, Carteolol

• Atenolol, Metoprolol, Bisoprolol, Acebutolol, Nebivolol, Esmolol

• Labetalol, Carvedilol

B. Based on Intrinsic Sympathomimetic Activity (ISA/Partial Agonist Activity)

C. Based on Lipid Solubility

D. Based on Generation

• 1st generation: Propranolol (non-selective, no ISA)
• 2nd generation: Atenolol, Metoprolol (cardioselective)
• 3rd generation: Carvedilol (α+β), Nebivolol (β1 + releases NO → vasodilation)

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Therapeutic Uses

CARDIOVASCULAR USES

1. Hypertension
   • Block β1 → reduce heart rate and cardiac output
   • Block renin release (juxtaglomerular cells have β1 receptors) → reduce angiotensin II and aldosterone
   • Central sympatholytic effect (lipophilic drugs)
   • Drugs: Atenolol, Metoprolol, Bisoprolol
2. Angina Pectoris
   • Block β1 → reduce heart rate, contractility → reduce myocardial O2 demand
   • Prolong diastole → increase coronary perfusion time
   • Drugs: Propranolol, Atenolol, Metoprolol
3. Myocardial Infarction
   • Reduce infarct size, prevent reinfarction (reduce O2 demand)
   • Antiarrhythmic
   • Reduce mortality
   • Drugs: Metoprolol (IV in acute), Atenolol
4. Heart Failure (Chronic/Stable)
   • Counter chronic sympathetic activation → reduce remodeling
   • Counterintuitive but proven (MERIT-HF, COPERNICUS trials)
   • Drugs: Carvedilol, Bisoprolol, Metoprolol succinate (the "3 approved")
5. Arrhythmias (Class II Antiarrhythmic)
   • Slow AV nodal conduction → useful in SVT, AF/AFL rate control
   • Sotalol (Class III + II): for ventricular arrhythmias
   • Drugs: Propranolol, Atenolol, Esmolol (IV, ultra-short acting)
6. Cardiomyopathy (Hypertrophic Obstructive - HOCM)
   • Reduce heart rate → increase filling time → reduce outflow tract obstruction

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NON-CARDIOVASCULAR USES

1. Glaucoma
   • Timolol (0.5%, topical) and Betaxolol (β1 selective)
   • Reduce aqueous humor production (β2 block on ciliary body)
   • Rationale: Timolol is first-line for open-angle glaucoma; betaxolol preferred in asthmatics
2. Hyperthyroidism / Thyrotoxicosis
   • Propranolol (preferred because it also inhibits peripheral T4→T3 conversion)
   • Controls sympathomimetic symptoms: tachycardia, tremor, anxiety, sweating
   • Used pre-operatively in thyroid surgery
   • Rationale: Thyroid hormones sensitize adrenergic receptors; β-block reverses this
3. Portal Hypertension / Esophageal Varices
   • Propranolol, Nadolol - reduce portal pressure
   • Block β1 → reduce cardiac output; block β2 in splanchnic vessels → splanchnic vasoconstriction
   • Used for primary and secondary prophylaxis of variceal bleeding
4. Anxiety / Situational Tremor / Stage Fright
   • Propranolol (40 mg single dose before event)
   • Blocks peripheral β-receptors → reduces tremor, palpitations, sweating
   • Useful in performance anxiety, essential tremor
5. Migraine Prophylaxis
   • Propranolol (80-240 mg/day), Metoprolol, Timolol
   • Mechanism: reduces catecholamine-induced platelet aggregation; reduces vasomotor instability
   • Does NOT treat acute migraine
6. Pheochromocytoma
   • Propranolol (ONLY after adequate α-blockade with phenoxybenzamine)
   • Controls tachycardia/arrhythmias induced by catecholamines
   • NEVER give β-blocker alone in pheochromocytoma → unopposed α → hypertensive crisis
7. Alcohol/Opioid Withdrawal
   • Propranolol for symptomatic control (tachycardia, tremor)
8. Pediatric Hemangioma
   • Propranolol (oral) - first-line for problematic infantile hemangiomas
   • Induces vasoconstriction, inhibits angiogenesis, promotes apoptosis of endothelial cells

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8. PROPRANOLOL vs ATENOLOL - 8 CLINICALLY RELEVANT DIFFERENCES

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9. ALPHA-ADRENERGIC BLOCKERS - USES AND ADVERSE EFFECTS

Classification

• Irreversible: Phenoxybenzamine
• Reversible: Phentolamine

• Short-acting: Prazosin
• Long-acting: Terazosin, Doxazosin, Alfuzosin
• Uroselective (α1A subtype): Tamsulosin, Silodosin

• Yohimbine (pharmacological tool only)

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Uses

1. Hypertension
   • Prazosin, Doxazosin, Terazosin
   • Block α1 → vasodilation → reduced peripheral resistance → lower BP
   • Doxazosin used especially in hypertension + BPH
2. Benign Prostatic Hyperplasia (BPH)
   • Tamsulosin, Alfuzosin, Silodosin (uroselective α1A blockers)
   • α1A receptors are predominant in prostate and bladder neck
   • Block → relaxation of prostate smooth muscle → improved urine flow
   • Rationale: Most common use today; first-line for symptomatic BPH
   • Tamsulosin preferred (minimal BP effect, no dose titration needed)
3. Pheochromocytoma
   • Phenoxybenzamine (irreversible, non-selective) - preoperative preparation
   • Block α-receptors → reduce BP spikes during tumor manipulation
   • Phentolamine (IV) - intraoperative hypertensive crisis management
4. Raynaud's Phenomenon
   • Prazosin - vasodilation relieves vasospasm of digits
5. Peripheral Vascular Disease
   • Prazosin, Phentolamine
6. Clonidine Rebound Hypertension
   • Phentolamine IV
7. Post-Sympathetic Block Test
   • Phentolamine used in diagnosis of pheochromocytoma (Regitine test - obsolete)
8. PTSD-Associated Nightmares
   • Prazosin (α1 blockade reduces noradrenergic activity)

Adverse Effects

1. First-dose Phenomenon / Orthostatic Hypotension
   • Especially with Prazosin - severe postural hypotension + syncope after first dose
   • Prevention: Start with low dose at bedtime (0.5 mg), patient recumbent
   • Less with terazosin and doxazosin due to longer t½ and slow titration
2. Reflex Tachycardia
   • Non-selective agents (phentolamine) → vasodilation → baroreceptor reflex tachycardia
   • Less with selective α1 agents (no α2 block, so presynaptic inhibition of NE release intact)
3. Nasal Stuffiness (nasal mucosal vasodilation)
4. Miosis (pupillary constriction - α1 block on dilator pupillae)
5. Retrograde Ejaculation (especially tamsulosin - α1A block in vas deferens)
6. Salt and Water Retention (long-term use → edema)
7. Intraoperative Floppy Iris Syndrome - tamsulosin interferes with iris dilator → complication during cataract surgery
   • Inform ophthalmologist before surgery
8. Sedation - phentolamine

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QUICK SUMMARY TABLE: ADRENERGIC RECEPTOR PHARMACOLOGY

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MEMORY AIDS (KD Tripathi Style)

• Asthma/COPD
• Bradycardia/heart Block
• Cardiogenic shock
• Decompensated heart failure (acute)
• Exercise tolerance reduced (cautious in diabetes)

• Timolol (β-blocker)
• Increase outflow - Pilocarpine
• Miosis - Pilocarpine
• Brimonidine (α2)
• Acetazolamide (CAI)
• Latanoprost (PG analogue)

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References: Based on KD Tripathi's Essentials of Medical Pharmacology (9th Ed), supplemented by Katzung's Basic & Clinical Pharmacology (16th Ed) and Goodman & Gilman's Pharmacological Basis of Therapeutics (13th Ed).

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Index of All Answers

Key Points to Memorize for Exams

• Adrenaline is DOC for anaphylaxis because it acts on α1, β1, and β2 - counteracting ALL mediators simultaneously. No other drug does this.
• Adrenaline is CONTRAINDICATED in hypovolemic/cardiogenic shock because α1 vasoconstriction worsens tissue perfusion, and β1 increases myocardial O2 demand in an already stressed heart.
• Propranolol is non-selective (β1+β2), lipophilic, hepatically metabolized - used in thyrotoxicosis (also blocks T4→T3), anxiety, migraine, portal hypertension.
• Atenolol is cardioselective (β1), hydrophilic, renally excreted - once daily, safer in asthmatics, fewer CNS effects.
• Timolol (topical) is first-line for open-angle glaucoma (reduces aqueous production via β2 block on ciliary body).
• Latanoprost is the most effective single agent for glaucoma (increases uveoscleral outflow via FP prostaglandin receptors).
• Tamsulosin is uroselective α1A blocker - first choice for BPH, minimal BP effects.
• Phenoxybenzamine (irreversible α-blocker) is used preoperatively in pheochromocytoma.