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Here is a full structured answer for Chapter 10: Adrenergic Transmission and Adrenergic Drugs covering all the question types from the image.
Chapter 10: Adrenergic Transmission and Adrenergic Drugs
LONG/ESSAY QUESTIONS (10 Marks)
Q1. Classify Sympathomimetic Drugs. Explain with pharmacological actions, clinical uses, and adverse effects.
Classification
Sympathomimetic drugs are classified by their mechanism of action:
A. Direct-acting - Act directly on adrenergic receptors
- Non-selective (α + β): Adrenaline (epinephrine), noradrenaline
- α-selective: Phenylephrine, methoxamine, clonidine (α2)
- β-selective: Isoprenaline (β1+β2), salbutamol/terbutaline (β2), dobutamine (β1)
B. Indirect-acting - Release stored NE from nerve terminals or inhibit its reuptake
- Release NE: Amphetamine, tyramine
- Inhibit NE reuptake: Cocaine, tricyclic antidepressants
- Inhibit MAO: Phenelzine, tranylcypromine
C. Mixed-acting - Both direct receptor action + indirect NE release
- Ephedrine, pseudoephedrine
Rank order of potency at α receptors: Epinephrine ≥ Norepinephrine >> Isoproterenol
Rank order of potency at β receptors: Isoproterenol > Epinephrine > Norepinephrine
Pharmacological Actions (by receptor):
| Receptor | Location | Effect |
|---|---|---|
| α1 | Vascular smooth muscle, iris | Vasoconstriction, mydriasis |
| α2 | Presynaptic nerve terminals, pancreas | Inhibits NE release, decreases insulin |
| β1 | Heart, kidney | ↑ HR, ↑ contractility, renin release |
| β2 | Bronchi, blood vessels, uterus | Bronchodilation, vasodilation, uterine relaxation |
| β3 | Adipose tissue, bladder | Lipolysis, bladder relaxation |
Clinical Uses:
- Anaphylactic shock (adrenaline)
- Bronchial asthma (salbutamol, terbutaline)
- Cardiogenic shock (dopamine, dobutamine)
- Nasal decongestants (xylometazoline, oxymetazoline)
- Hypertensive emergencies (phenylephrine)
- Overactive bladder (mirabegron - β3 agonist)
- Local anesthesia adjunct (adrenaline to prolong action)
Adverse Effects:
- Tachycardia, palpitations, arrhythmias
- Hypertension (risk of stroke, pulmonary edema)
- Anxiety, tremors, headache
- Hyperglycemia (especially in diabetics)
- Tissue necrosis if IV extravasates
- Pulmonary edema with non-selective agents
Q2. Therapeutic Uses of Adrenergic Drugs Under Various Disorders
Vascular Disorders:
- Hypotensive shock: Noradrenaline or dopamine (maintains BP)
- Spinal anesthesia hypotension: Ephedrine or phenylephrine
- Orthostatic hypotension: Midodrine (α1 agonist)
- Bleeding: Adrenaline for local hemostasis
Cardiac Disorders:
- Cardiac arrest: Adrenaline (IV/intraosseous) - restores electrical activity
- Cardiogenic shock: Dobutamine (β1) - increases cardiac output without excessive tachycardia
- Heart block with bradycardia: Isoprenaline (β1 + β2)
- Congestive heart failure: Low-dose dopamine (dopaminergic receptors increase renal blood flow)
Respiratory Disorders:
- Acute bronchospasm: Adrenaline (SC/IM)
- Bronchial asthma (long-term): Salbutamol, terbutaline, salmeterol (β2 agonists)
- COPD: Salmeterol, formoterol
Ocular Disorders:
- Open-angle glaucoma: Brimonidine (α2 agonist - decreases aqueous humor production)
- Closed-angle glaucoma: Avoid sympathomimetics
- Mydriasis for examination: Phenylephrine
Allergic Disorders:
- Anaphylaxis: Adrenaline is drug of choice (reverses bronchospasm, hypotension, angioedema)
- Urticaria/angioedema: Adrenaline SC
CNS Disorders:
- ADHD: Amphetamine, methylphenidate
- Narcolepsy: Amphetamine, modafinil
- Obesity: Phentermine (indirect sympathomimetic)
SHORT ESSAY QUESTIONS (3-5 Marks)
Q1. Catecholamines
Catecholamines are compounds with a catechol nucleus (benzene ring with two adjacent hydroxyl groups) and an ethylamine side chain.
Endogenous catecholamines: Adrenaline, noradrenaline, dopamine
Synthesis pathway: Tyrosine → DOPA → Dopamine → Noradrenaline → Adrenaline (in adrenal medulla by PNMT enzyme)
Properties:
- Water soluble, poorly lipid soluble (poor CNS penetration)
- Rapidly degraded by MAO and COMT
- Short duration of action
- Not effective orally (gut MAO destroys them)
Used clinically: Adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline
Q2. Drugs That Modify Adrenergic Transmission
| Stage | Drug | Mechanism |
|---|---|---|
| Synthesis inhibition | α-Methyltyrosine | Inhibits tyrosine hydroxylase |
| Storage depletion | Reserpine | Blocks VMAT (vesicle uptake) |
| Release inhibition | Guanethidine, bretylium | Block vesicle exocytosis |
| Release facilitation | Amphetamine, tyramine | Displace NE from vesicles |
| Reuptake inhibition | Cocaine, TCAs | Block NET (NE transporter) |
| MAO inhibition | Phenelzine, tranylcypromine | Block NE metabolism |
| COMT inhibition | Entacapone, tolcapone | Block peripheral NE degradation |
Q3. Adrenergic Receptors - Classification, Distribution, Selective Agonists/Antagonists
| Receptor | Location | Selective Agonist | Selective Antagonist |
|---|---|---|---|
| α1 | Vascular SM, iris, prostate | Phenylephrine, methoxamine | Prazosin, tamsulosin |
| α2 | Presynaptic (brain, periphery), pancreas | Clonidine, brimonidine | Yohimbine, idazoxan |
| β1 | Heart, kidney (JGA) | Dobutamine | Metoprolol, atenolol |
| β2 | Bronchi, uterus, skeletal vessels | Salbutamol, terbutaline, salmeterol | Butoxamine |
| β3 | Adipose, detrusor muscle | Mirabegron | - |
| D1 | Renal/mesenteric vessels | Fenoldopam | - |
| D2 | Presynaptic (nerve terminals) | - | Domperidone |
Signal transduction:
- α1: Gq → PLC → IP3 + DAG → ↑Ca2+
- α2: Gi → ↓cAMP
- β1, β2, β3: Gs → ↑cAMP → PKA activation
Q4. Compare Pharmacological Actions of Adrenaline, Noradrenaline, and Isoprenaline
| Action | Adrenaline (EPI) | Noradrenaline (NE) | Isoprenaline (ISO) |
|---|---|---|---|
| Receptors | α1, α2, β1, β2 | α1, α2, β1 (weak β2) | β1, β2 (no α) |
| Heart rate | ↑ (β1) | ↓ (reflex bradycardia due to ↑BP) | ↑↑ (β1) |
| BP (systolic) | ↑↑ | ↑↑↑ | ↑ or unchanged |
| BP (diastolic) | ↓ (β2 vasodilation) | ↑↑ (α vasoconstriction) | ↓↓ (β2 vasodilation) |
| Peripheral resistance | ↑ (high dose) / ↓ (low dose) | ↑↑↑ | ↓↓ |
| Bronchi | Dilates (β2) | Minimal effect | Dilates (β2) |
| Vasomotor reversal | Yes (Dale's vasomotor reversal) | No | No |
| Main use | Anaphylaxis | Hypotensive shock | Heart block, cardiogenic shock |
Q5. Differentiate Between α and β Adrenergic Receptors
| Feature | α Receptors | β Receptors |
|---|---|---|
| Subtypes | α1, α2 | β1, β2, β3 |
| Second messenger | Gq-IP3/DAG (α1); Gi-↓cAMP (α2) | Gs-↑cAMP (all β) |
| Major location | Vascular smooth muscle, presynaptic | Heart (β1), Bronchi (β2), Adipose (β3) |
| Rank order potency | NE ≥ EPI >> ISO | ISO > EPI > NE |
| Blocked by | Phentolamine (non-selective), Prazosin (α1) | Propranolol (non-selective), Metoprolol (β1) |
| Main effect | Vasoconstriction, mydriasis | Cardiac stimulation, bronchodilation |
Q6. Dopamine - Pharmacological Actions, Therapeutic Uses, Adverse Effects
Mechanism: Acts on dopaminergic (D1, D2) and adrenergic (β1, α1) receptors in a dose-dependent manner:
- Low dose (1-2 mcg/kg/min): Dopaminergic (D1) - renal and mesenteric vasodilation → ↑ urine output
- Medium dose (2-10 mcg/kg/min): β1 stimulation → ↑ cardiac output, ↑ heart rate
- High dose (>10 mcg/kg/min): α1 stimulation → vasoconstriction → ↑ BP
Therapeutic Uses:
- Cardiogenic shock (drug of choice)
- Septic shock with oliguria
- Acute heart failure
- Acute renal failure (low dose to preserve renal function - though evidence is debated)
Adverse Effects:
- Tachycardia, arrhythmias
- Nausea, vomiting
- Hypertension at high doses
- Tissue necrosis if extravasation occurs (treat with phentolamine injection)
- Contraindicated in pheochromocytoma
Q7. Mechanism of Action and Uses of Dobutamine
Structure: Synthetic catecholamine, structural analogue of dopamine
Mechanism:
- Primarily β1 receptor agonist (some β2 and mild α1 effects)
- Increases myocardial contractility (positive inotrope) WITHOUT significant increase in heart rate
- Increases cardiac output, decreases filling pressures
- Does NOT increase renal blood flow (unlike dopamine)
Therapeutic Uses:
- Short-term management of acute decompensated heart failure
- Cardiogenic shock
- Dobutamine stress echocardiography (to detect coronary artery disease)
- Bridge to cardiac transplantation
Advantage over dopamine: Less tachycardia, less arrhythmogenic at therapeutic doses
Q8. Amphetamines
Mechanism: Indirect sympathomimetic - enters presynaptic terminal via NET, displaces NE from vesicles (via VMAT reversal), also inhibits MAO. Net effect: massive increase in synaptic NE, dopamine, and serotonin.
Pharmacological Actions:
- CNS stimulation - wakefulness, euphoria, decreased appetite, stereotyped behavior
- Cardiovascular: tachycardia, ↑ BP
- Anorexia
Therapeutic Uses:
- ADHD (methylphenidate, lisdexamphetamine preferred now)
- Narcolepsy
- Obesity (short-term, limited use)
Adverse Effects:
- Insomnia, agitation, anxiety
- Hypertension, arrhythmias
- Psychosis (amphetamine psychosis resembles paranoid schizophrenia)
- High abuse potential - Schedule II controlled substance
- Tolerance and dependence develop
Q9. Mirabegron in Overactive Bladder
Mechanism: Selective β3 adrenoceptor agonist. β3 receptors on detrusor muscle mediate relaxation → increases bladder capacity → reduces urgency/frequency without causing urinary retention.
Advantage over antimuscarinics (oxybutynin, solifenacin):
- No anticholinergic side effects (no dry mouth, blurred vision, constipation, cognitive impairment)
- Safe in elderly and patients with cognitive issues
Dose: 25-50 mg once daily orally
Adverse Effects:
- Hypertension (most common - monitor BP)
- Tachycardia
- Urinary tract infection
- Contraindicated in severe uncontrolled hypertension
Q10. Vasomotor Reversal of Dale
When a large dose of adrenaline is given, it produces a rise in BP (α1 effect). If an α-blocker (e.g., phentolamine, ergotamine) is given beforehand, the same dose of adrenaline now produces a FALL in blood pressure - this is "Dale's vasomotor reversal."
Explanation: Adrenaline acts on both α1 (vasoconstriction) and β2 (vasodilation) receptors. The α-blocker blocks the vasoconstrictive (pressor) component, unmasking the β2-mediated vasodilation, which is now dominant → blood pressure falls instead of rising.
Significance:
- Demonstrates the dual action of adrenaline
- Shows that β2 effects exist but are normally masked by α effects
- Clinical relevance: Why phentolamine is used to treat adrenaline extravasation
Q11. Nasal Decongestants
Drugs: Xylometazoline, oxymetazoline, naphazoline (topical); pseudoephedrine, phenylephrine (oral)
Mechanism: α1/α2 agonists → constrict nasal mucosal blood vessels → reduce congestion and rhinorrhea
Clinical Use: Allergic rhinitis, common cold (symptomatic)
Adverse Effects (topical):
- Rebound congestion (rhinitis medicamentosa) with prolonged use (>3-5 days)
- Burning, stinging
- Systemic absorption can cause hypertension and tachycardia
Oral decongestants (pseudoephedrine):
- Hypertension, tachycardia, insomnia, urinary retention in BPH
Q12. Pharmacological Treatment of Cardiogenic Shock
Cardiogenic shock = reduced cardiac output despite adequate filling pressures
Goals: Restore cardiac output, maintain perfusion pressure, avoid worsening ischemia
| Drug | Dose | Mechanism | Role |
|---|---|---|---|
| Dopamine | 5-15 mcg/kg/min | β1 (+ α at higher doses) | ↑ CO + maintains BP |
| Dobutamine | 2.5-15 mcg/kg/min | β1 primarily | ↑ contractility, ↓ filling pressure |
| Noradrenaline | 0.1-2 mcg/kg/min | α1 + β1 | Maintains MAP when BP very low |
| Adrenaline | 0.05-0.5 mcg/kg/min | α + β | Last resort, refractory shock |
Current evidence favors dobutamine as first-line inotrope in cardiogenic shock with adequate BP, and noradrenaline if BP is too low.
SCENARIO-BASED QUESTIONS (5-10 Marks)
Scenario 1: 25-year-old man with anaphylactic shock (insect bite)
a. Drug of choice: Adrenaline (Epinephrine)
Why: It acts on all adrenergic receptors:
- α1: Vasoconstriction → reverses hypotension, reduces laryngeal edema
- β1: ↑ cardiac output → reverses cardiovascular collapse
- β2: Bronchodilation → reverses bronchoconstriction; also stabilizes mast cell membranes, inhibiting further mediator release
b. Pharmacological actions on heart, bronchi, blood vessels:
- Heart (β1): ↑ contractility, ↑ HR → ↑ cardiac output
- Bronchi (β2): Bronchodilation, ↓ mast cell histamine/LTC4 release
- Blood vessels (α1): Constricts skin/visceral vessels → ↑ BP; β2 dilates skeletal muscle vessels
c. Routes and doses in anaphylaxis:
- IM (anterolateral thigh) - PREFERRED: 0.3-0.5 mg of 1:1000 (1 mg/mL) solution; repeat every 5-15 min if needed
- SC: 0.3-0.5 mg of 1:1000 (slower absorption, not preferred in shock)
- IV: 0.1 mg of 1:10,000 (only in cardiac arrest / severe refractory anaphylaxis with IV access)
- Autoinjector (EpiPen): 0.3 mg IM for self-administration
d. Two contraindications/precautions:
- Hypertension / cardiovascular disease - risk of hypertensive crisis, stroke, MI (use with caution; anaphylaxis itself is a stronger indication)
- Patients on non-selective β-blockers (e.g., propranolol) - β-blockade can make adrenaline less effective (β-blocker blocks β effects, leaving unopposed α → paradoxical severe hypertension); use glucagon as alternative
Scenario 2: 30-year-old asthmatic with bronchospasm given inhaled adrenergic agonist
a. Drug: Salbutamol (Albuterol) - selective β2 agonist
Receptor selectivity: β2 adrenoceptor selective (20:1 selectivity for β2 over β1)
b. Mechanism of bronchodilation:
- Salbutamol binds β2 receptors on bronchial smooth muscle
- Gs protein activation → ↑ adenylyl cyclase → ↑ cAMP → activates PKA
- PKA phosphorylates myosin light chain kinase (inactivates it) and opens K+ channels → smooth muscle relaxation
- Also stabilizes mast cell membranes → inhibits mediator release
c. Other selective β2 agonists used in asthma:
- Short-acting (SABA): Terbutaline, levosalbutamol, fenoterol, bitolterol
- Long-acting (LABA): Salmeterol, formoterol (used with ICS, not as monotherapy)
- Ultra-long-acting: Indacaterol (LABA for COPD, once daily)
d. Important adverse effects of β2 agonists:
- Tremors (skeletal muscle β2 stimulation)
- Tachycardia, palpitations (some β1 spillover)
- Hypokalemia (β2 stimulation on skeletal muscle drives K+ into cells via Na+/K+ATPase)
- Paradoxical bronchospasm (rare, with overuse)
- Tolerance with long-term SABA use (downregulation of β2 receptors)
- Metabolic: Hyperglycemia, hypomagnesemia
Scenario 3: 50-year-old woman - spinal anesthesia with hypotension and bradycardia, given drug acting on both α and β receptors
a. Drug used: Ephedrine
Ephedrine acts on both α (vasoconstriction → ↑ BP) and β1 (positive chronotrope → corrects bradycardia) receptors. It is the classic drug used for spinal/epidural anesthesia-induced hypotension.
b. Mechanism in raising blood pressure:
- Direct action: Mild direct stimulation of α1 and β receptors
- Indirect action (main mechanism): Displaces NE from presynaptic vesicles → released NE stimulates α1 (vasoconstriction) and β1 (↑ HR, ↑ contractility) receptors → ↑ BP
- Net effect: Raises both systolic and diastolic BP, increases cardiac output
c. Compare with noradrenaline:
| Feature | Ephedrine | Noradrenaline |
|---|---|---|
| Mechanism | Mixed (direct + indirect) | Direct |
| Receptors | α1, β1, β2 (weak) | α1, α2, β1 |
| Heart rate | ↑ (β1 effect) | ↓ (reflex bradycardia) |
| Duration | Longer (30-60 min oral) | Short (IV infusion needed) |
| Route | IM/IV/oral | IV only |
| CNS | Stimulant effect | Minimal CNS |
| Tachyphylaxis | Yes (repeated doses) | No |
| Vasomotor reversal | No | No |
d. Other clinical uses of ephedrine:
- Myasthenia gravis (improves neuromuscular transmission)
- Nasal decongestion (oral pseudoephedrine is its stereoisomer)
- Narcolepsy, chronic fatigue (CNS stimulant)
- Urinary incontinence (α effect on bladder neck sphincter)
- Bronchial asthma (now replaced by selective β2 agonists)
Scenario 4: 55-year-old woman with raised intraocular pressure (glaucoma)
The adrenergic drug prescribed is most likely Brimonidine (α2 agonist) or Timolol (β-blocker) in the context of the question.
For open-angle glaucoma (raised IOP + halos):
- Brimonidine (α2 agonist): Reduces aqueous humor production via α2 on ciliary epithelium; increases uveoscleral outflow
- Apraclonidine: Another α2 agonist used topically
- Dipivefrin: Prodrug of adrenaline (converted to adrenaline in the eye) → ↑ outflow
Higher doses of adrenergic drugs can cause cardiac stimulation, which explains the footnote visible at the bottom of the image about "cardiac stimulation" and "heart rate."
Sources: Lippincott Illustrated Reviews: Pharmacology (6th ed.), Goodman & Gilman's Pharmacological Basis of Therapeutics (13th ed.)
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