Sympathomimetic Drugs

1. Definition and Overview

• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Goodman & Gilman's Pharmacological Basis of Therapeutics

2. Classification

By Mechanism of Action

3. Adrenergic Receptor Subtypes and Their Effects

4. Structure-Activity Relationships (SAR)

• Greatest sympathomimetic activity occurs when two carbon atoms separate the ring from the amino group
• Catecholamines = compounds with -OH groups at positions 3 and 4 of the benzene ring (NE, EPI, DA, isoproterenol)
• Amino group substitution: Larger alkyl substituents increase β-receptor activity (isoproterenol is a pure β agonist). Smaller amino substitution favors α activity
• Aromatic ring substitution: Maximal α and β activity requires -OH at positions 3 and 4. -OH at positions 3 and 5 with large amino group confers β2 selectivity (e.g., terbutaline)
• Lipophilicity: Absence of polar hydroxyl groups increases CNS penetration (amphetamine, ephedrine cross the blood-brain barrier readily)
• Oral bioavailability: Catecholamines are metabolized by COMT in gut/liver - poor oral bioavailability. Non-catecholamines are not COMT substrates, so they have better oral bioavailability and longer duration

5. Specific Drugs

Endogenous Catecholamines

• Agonist at α1, α2, β1, and β2 receptors
• Low dose: β2 effects predominate (vasodilation in skeletal muscle, bronchodilation, fall in diastolic BP)
• High dose: α effects predominate (vasoconstriction, rise in both systolic and diastolic BP)
• Uses: Anaphylaxis (first-line), cardiac arrest (CPR), local vasoconstriction with local anesthetics, acute asthma
• Route: IV, IM, SC, inhalation, topical

• Agonist at α1, α2, and β1 receptors; minimal β2 activity
• Increases both systolic and diastolic BP, increases peripheral resistance
• Compensatory baroreflex counters direct chronotropic effect (net: reflex bradycardia)
• Uses: Vasopressor of first choice in septic shock (provides balance of α and modest β1 activity)

• Dose-dependent effects:
  • Low dose (2-5 mcg/kg/min): D1 receptor activation → renal and mesenteric vasodilation, natriuresis
  • Medium dose (5-15 mcg/kg/min): β1 stimulation → increased cardiac output
  • High dose (>15 mcg/kg/min): α1 stimulation → vasoconstriction
• Note: Dopamine is now NOT preferred over norepinephrine in septic shock due to higher incidence of arrhythmias and mortality

Synthetic Catecholamines

• Predominantly β1 agonist with some β2 and weak α1 activity
• Increases myocardial contractility (positive inotropy) with less tachycardia than epinephrine
• Uses: Acute heart failure, pharmacologic stress testing (dobutamine stress echo)
• Agent of choice when increased cardiac output is needed

• Pure β agonist (β1 + β2); no α activity
• Increases HR and contractility; causes vasodilation → fall in diastolic BP
• Now rarely used; replaced by selective β2 agonists

Non-Catecholamine Sympathomimetics

• Pure α1 agonist; not a catecholamine (not inactivated by COMT - longer duration)
• Uses: Nasal decongestant, mydriasis (eye drops), blood pressure support in anesthesia
• Raises BP, causes reflex bradycardia

• Prodrug → desglymidodrine (selective α1 agonist) after enzymatic hydrolysis
• Orally active; peak effect ~1 hour
• Use: Orthostatic hypotension (autonomic failure)
• Caution: Causes supine hypertension

• Selective β2 agonist (short-acting)
• Use: Acute bronchospasm in asthma and COPD; hyperkalemia (IV)
• Best delivered by inhalation (greatest local bronchial effect, minimal systemic toxicity)
• 80-90% of inhaled dose deposits in mouth/pharynx - optimal particle size 2-5 μm

• Long-acting β2 agonists (LABAs)
• Use: COPD maintenance; asthma (always combined with inhaled corticosteroid - LABA monotherapy in asthma associated with increased mortality)
• Indacaterol, olodaterol, vilanterol: ultra-long-acting, once-daily dosing in COPD

• Mixed-acting (both direct β2 activity + indirect NE release)
• Oral activity; CNS stimulant (no ring hydroxyl → crosses BBB)
• Uses: Nasal decongestion, orthostatic hypotension, bronchospasm
• Rebound congestion ("rhinitis medicamentosa") can follow nasal decongestants

• Direct α agonist; long-acting nasal decongestant (OTC)
• Risk of rebound hyperemia with prolonged use

6. Clinical Uses

7. Mechanism: β2 Agonists and Bronchodilation

8. Adverse Effects

9. Pharmacokinetics Summary

• Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 233-238, 550-551
• Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 272-275
• Guyton and Hall Textbook of Medical Physiology
• Barash, Cullen, and Stoelting's Clinical Anesthesia, 9e

Introduction to the Autonomic Nervous System (ANS)

1. Overview and Definition

1. Sympathetic (thoracolumbar)
2. Parasympathetic (craniosacral)
3. Enteric (intrinsic nervous system of the gut)

• Costanzo Physiology, 7th Edition

2. General Organization - Two-Neuron Chain

1. Preganglionic neuron - cell body in CNS; axon travels to an autonomic ganglion
2. Postganglionic neuron - cell body in the ganglion; axon innervates the effector organ

3. Sympathetic vs. Parasympathetic: Anatomical Comparison

• Costanzo Physiology, Table 2.1

4. Neurotransmitters and Receptor Terminology

• Cholinergic neurons release acetylcholine (ACh)
• Adrenergic neurons release norepinephrine (NE)

Key Rule (memorize this):

ALL preganglionic neurons (sympathetic AND parasympathetic) release ACh → act on nicotinic (N2) receptors in ganglia

Postganglionic sympathetic neurons release NE → act on α or β adrenoreceptors (EXCEPTION: sweat glands and some blood vessels get cholinergic sympathetic innervation → muscarinic receptors)

Postganglionic parasympathetic neurons release ACh → act on muscarinic receptors

Adrenal medulla = modified sympathetic ganglion. Preganglionic ACh → chromaffin cells release epinephrine (80%) + NE (20%) directly into circulation

• Costanzo Physiology, p. 55-57

5. Sympathetic Nervous System

Anatomy

• Preganglionic neurons originate in the intermediolateral cell column (lateral horn) of spinal cord segments T1-L3
• Axons exit through ventral roots → form the paravertebral sympathetic chain (22 pairs of ganglia running alongside the vertebral column)
• Some fibers pass through the chain without synapsing and synapse in prevertebral ganglia (celiac, superior mesenteric, inferior mesenteric) to reach abdominal viscera

Function - "Fight or Flight"

• ↑ Arterial blood pressure
• ↑ Heart rate and contractility
• ↑ Blood flow to skeletal muscles
• ↑ Blood glucose (glycogenolysis)
• ↑ Mental alertness
• Bronchodilation
• Pupil dilation (mydriasis)
• Inhibition of GI motility
• Costanzo Physiology, p. 55

6. Parasympathetic Nervous System

Anatomy (Craniosacral)

• Cranial component - preganglionic fibers travel in 4 cranial nerves:
  • CN III (oculomotor) → Edinger-Westphal nucleus → ciliary ganglion → pupil constriction, accommodation
  • CN VII (facial) → lacrimal & salivatory nuclei → pterygopalatine / submandibular ganglia → lacrimal, nasal, submandibular/sublingual glands
  • CN IX (glossopharyngeal) → inferior salivatory nucleus → otic ganglion → parotid gland
  • CN X (vagus) → dorsal motor nucleus → ganglia in/near target organs → heart, lungs, GI tract (down to splenic flexure)
• Sacral component (S2-S4) → pelvic splanchnic nerves → pelvic ganglia → descending colon, rectum, urinary bladder, genitalia

Function - "Rest and Digest"

• ↓ Heart rate and contractility (vagal tone)
• ↑ GI motility and secretion
• Pupil constriction (miosis)
• Increased salivation, lacrimation, bronchial secretion
• Bronchoconstriction
• Bladder detrusor contraction (micturition)
• Penile erection

7. Effects on Major Organ Systems

8. Neuroeffector Junctions

1. Varicosities - beaded swellings along postganglionic axon branches that contain neurotransmitter in vesicles
2. Diffuse, branching networks - overlap from multiple postganglionic neurons can innervate the same target tissue (en passant transmission)
3. No motor end plate - receptors are distributed widely over the target tissue surface, not concentrated in a specialized region

• Costanzo Physiology, p. 55

9. Receptors: Summary Table

• Costanzo Physiology, Table 2.2

10. Enteric Nervous System

11. Central Control of the ANS

• Hypothalamus - the principal integrating center; regulates temperature, thirst, hunger, and cardiovascular/endocrine homeostasis
• Medulla oblongata - cardiovascular and respiratory centers; dorsal motor nucleus of vagus
• Spinal cord - contains preganglionic neurons in the intermediolateral column (T1-L3 for sympathetic; S2-S4 for parasympathetic)
• Limbic system and prefrontal cortex - emotional and behavioral influence on ANS

12. Key Mnemonic: Sympathetic vs. Parasympathetic

• Costanzo Physiology, 7th Edition, pp. 54-65
• Guyton and Hall Textbook of Medical Physiology
• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Goodman & Gilman's Pharmacological Basis of Therapeutics