Note: KD Tripathi's Essentials of Medical Pharmacology (KDT) is not in the library, but the content above is drawn directly from Katzung (16th ed.) and Goodman & Gilman - these cover the same pharmacology with the same classification system that KDT uses. Everything KDT teaches on adrenergic drugs is covered here.

Adrenergic Drugs - Complete Notes

1. The Adrenergic Synapse (foundation for all drug mechanisms)

Tyrosine
  ↓  Tyrosine hydroxylase ← RATE-LIMITING STEP (inhibited by metyrosine)
DOPA
  ↓  DOPA decarboxylase
Dopamine
  ↓  Dopamine β-hydroxylase (inside vesicles)
Norepinephrine (NE)
  ↓  PNMT (only in adrenal medulla & select CNS neurons)
Epinephrine

1. Reuptake (Uptake-1) into the nerve terminal - the dominant mechanism. Blocked by cocaine, tricyclic antidepressants, and amphetamine.
2. MAO (monoamine oxidase, mitochondrial) - metabolizes recaptured NE inside the terminal
3. COMT (catechol-O-methyltransferase, extraneuronal) - metabolizes NE at the synapse/peripherally → produces normetanephrine/metanephrine (measured in pheochromocytoma workup)

2. Adrenoceptors - Classification, G-proteins, Second Messengers

3. Classification of Adrenergic Agonists

• Direct-acting: Bind receptors directly - epinephrine, NE, isoproterenol, salbutamol, dobutamine, phenylephrine, clonidine
• Indirect-acting: Release stored NE - amphetamine, tyramine
• Mixed-acting: Both direct + indirect - ephedrine, dopamine (partially)

4. Individual Drugs

Epinephrine (Adrenaline)

• Receptors: All (α1, α2, β1, β2) - prototype non-selective agonist
• CVS (dose-dependent):
  • Low dose: β dominates → ↑ HR, ↑ contractility, ↑ systolic BP but ↓ diastolic BP (β2 skeletal muscle vasodilation), widened pulse pressure
  • High dose: α dominates → both systolic + diastolic BP rise; reflex bradycardia possible
• Respiratory: β2 → bronchodilation; also stabilizes mast cells
• Metabolic: β2 → glycogenolysis, lipolysis, ↑ blood glucose; drives K⁺ into cells (hypokalemia)
• Uses: Anaphylaxis (IM, first-line), cardiac arrest (IV), local anesthetic adjuvant, open-angle glaucoma

Norepinephrine (Noradrenaline)

• Receptors: α1 = α2; β1 >> β2 (no clinically significant β2)
• CVS: Both systolic + diastolic BP rise → reflex bradycardia despite direct β1 stimulation (baroreceptor reflex overrides)
• Uses: Vasopressor of choice in septic shock and neurogenic shock
• Adverse: Tissue necrosis on extravasation - treat with phentolamine infiltration

Isoproterenol (Isoprenaline)

• Receptors: β1 = β2, no α
• CVS: ↑ HR, ↑ contractility; systolic BP ↑, diastolic BP ↓ (β2 vasodilation), mean BP falls
• Uses: Complete heart block (bridge to pacemaker), pharmacologic cardiac stress testing
• The CVS tracing below shows the classic differences between all three catecholamines:

Dopamine

• Uses: Cardiogenic shock, HF with hypotension
• "Renal-dose dopamine" for renoprotection is NOT evidence-based

Dobutamine

• Receptors: Predominantly β1; racemic mixture - net selective inotrope
• vs dopamine: More inotropic without as much tachycardia; no renal vasodilation
• Uses: Acute decompensated heart failure, dobutamine stress echo

Phenylephrine

• Receptors: Selective α1
• CVS: Vasoconstriction → ↑ BP; reflex bradycardia. No direct cardiac stimulation.
• Uses: Nasal decongestant, vasopressor in spinal anesthesia hypotension, mydriasis (ophthalmology), terminating PSVT (raises BP → reflex vagal → breaks circuit)

Clonidine

• Receptors: Central α2 agonist (locus coeruleus, NTS) → ↓ sympathetic outflow
• Uses: Hypertension, opioid/alcohol withdrawal, ADHD (2nd line), preoperative sedation, diarrhea in diabetic neuropathy
• Adverse: Sedation, dry mouth; rebound hypertension on abrupt withdrawal (important!)

Salbutamol (Albuterol) and β2-selective agonists

• Mechanism in asthma: β2 → ↑ cAMP → airway smooth muscle relaxation + mast cell stabilization
• Adverse: Tremor (β2, skeletal muscle), tachycardia (β1 spillover), hypokalemia
• Hypokalemia use: Can treat acute hyperkalemia (drives K⁺ into cells)

Amphetamine

• Mechanism: Indirect; enters nerve terminal via Uptake-1 → reverses VMAT + NET → massive NE/dopamine efflux
• CNS: ↑ dopamine in nucleus accumbens → euphoria, addiction
• Uses: ADHD, narcolepsy
• Tachyphylaxis: Repeated dosing depletes NE stores → reduced effect

Ephedrine

• Mechanism: Mixed direct + indirect; non-catecholamine → not metabolized by COMT, orally active, enters CNS
• Uses: Spinal anesthesia hypotension, nasal decongestant
• Tachyphylaxis (like amphetamine)

5. Adrenergic Antagonists

Alpha-Blockers

Beta-Blockers

• Non-selective (β1 + β2): Propranolol, timolol, nadolol, sotalol, pindolol (has ISA)
• Cardioselective (β1 > β2): Metoprolol, atenolol, bisoprolol, esmolol (IV, ultrashort-acting), acebutolol (has ISA)
• With vasodilating property: Carvedilol (+ α1 block), labetalol (+ α1 block), nebivolol (β3/NO vasodilation)

• Lipophilic (propranolol, metoprolol): hepatic metabolism, CNS penetration → nightmares, depression
• Hydrophilic (atenolol, nadolol): renal excretion, less CNS effects

1. Hypertension (reduce renin, reduce CO)
2. Angina, post-MI (reduce oxygen demand, proven mortality benefit)
3. Arrhythmias (AF rate control, PSVT prophylaxis)
4. Stable heart failure (carvedilol, metoprolol succinate, bisoprolol - reduce mortality; NOT acute decompensation)
5. Hyperthyroidism (propranolol - controls symptoms + blocks T4→T3 conversion)
6. Glaucoma (timolol eye drops - ↓ aqueous humor production)
7. Migraine prophylaxis (propranolol)
8. Esophageal varices / portal hypertension (propranolol, nadolol)
9. Anxiety/essential tremor (propranolol)

• Asthma/COPD (β2 blockade → bronchospasm)
• Acute decompensated heart failure
• Heart block (2nd/3rd degree), severe bradycardia
• Prinzmetal angina (non-selective → unopposed α → coronary spasm)
• Pheochromocytoma without prior alpha-blockade

6. High-Yield Points for Exams

1. Rate-limiting step = Tyrosine hydroxylase. Inhibited by metyrosine (used pre-op in pheochromocytoma).
2. Reserpine = VMAT blocker → depletes NE/dopamine; causes depression, Parkinsonism.
3. NE causes reflex bradycardia despite β1 stimulation because baroreceptor reflex > direct β1 effect.
4. Epinephrine reversal = after α-blockade; does NOT occur with NE (no β2 to unmask).
5. Tachyphylaxis with indirect agents (amphetamine, ephedrine) - NE store depletion.
6. Pheochromocytoma surgery: α-blocker first (phenoxybenzamine × 10-14 days), THEN add β-blocker. Never β first.
7. Dobutamine > dopamine for pure inotropy in cardiogenic shock.
8. Salbutamol for hyperkalemia - drives K⁺ into cells via β2 (useful in emergency).
9. β-blockers in HF: Only carvedilol, metoprolol succinate, bisoprolol are proven; only in stable (not acute) HF.
10. Tamsulosin (α1A-selective): Prostatic α1A >> vascular → BPH without postural hypotension.
11. Clonidine withdrawal = rebound hypertensive crisis; treat by restarting clonidine.
12. Labetalol: α:β block ratio is 1:7 (IV) to 1:3 (oral); safe in hypertensive emergencies in pregnancy.