Study Notes on Parasympathetic Pharmacology

Autonomic Nervous System

General Overview

• Focus on the Parasympathetic Nervous System and its pharmacological implications.
• Presenter: Dr. Amal Youssef, Assistant Professor of Pharmacology, Faculty of Medicine, Cairo University.

Parasympathomimetics (Cholinomimetics)

Definition

• Drugs that stimulate muscarinic receptors.

Peripheral Muscarinic Receptors

Types of Receptors and Functions

• M3 Receptors: Associated with various physiological responses.

  • Eye: Induces miosis (constriction of the pupils) and regulates intraocular pressure.
  • Lungs: Causes bronchoconstriction leading to decreased airway diameter.
  • GIT & Bladder: Promotes contraction of the wall and relaxation of the sphincter.
  • Heart: Decreases heart rate (negative chronotropic effect) and decreases contractility (negative inotropic effect).

• M2 Receptors: Found primarily in the heart, contributing to the decrease in heart rate.

Nicotinic Actions

Overview

1. Skeletal Muscle: Induces muscle contraction manifesting as muscle twitches.
2. Autonomic Ganglia: Stimulates both sympathetic and parasympathetic ganglia as well as the suprarenal medulla.

• Nicotinic Acetylcholine Receptor (nAChR): Receptor type activated at the ganglia and by motor neurons.

Mechanism of Action

Direct and Indirect Acting Agents

• Direct Acting Agents:

  • Acetylcholine (both muscarinic & nicotinic actions).
  • Other examples:
  • Carbachol: Acts on both M & N receptors.
  • Methacholine: Primarily acts on M receptors.
  • Bethanechol: Selective M receptor action.
  • Pilocarpine: Primarily M receptor action.

• Indirect Acting Agents (AChE Inhibitors):

  • Mechanism: Inhibit cholinesterase enzymes, leading to increased accumulation of endogenous ACh.
  • Reversible Agents:
  • Physostigmine
  • Neostigmine
  • Edrophonium (short-acting)
  • Irreversible Agents:
  • Organophosphates

Clinical Applications

1. Ocular Therapeutics

• Treats glaucoma by mimicking ACh effects (use of Pilocarpine and Physostigmine).
• Counteracts actions of mydriatic agents.
• Facilitates adhesion separation in cases of recent synechiae (adhesions between iris and lens).

2. Treatment of Xerostomia (Dry Mouth)

• Pilocarpine used to stimulate salivation.

3. Gastrointestinal Treatments

• Post-operative paralytic ileus treated with Bethanechol and Neostigmine.

4. Urinary Retention Treatments

• Patients post-operatively or after spinal cord injury may be treated with Bethanechol and Neostigmine.

5. Myasthenia Gravis Diagnosis and Treatment

• Edrophonium: Used for diagnosis due to its short-acting properties.
• Neostigmine and Pyridostigmine: Long-acting agents used for treatment.

6. Neuromuscular Block Reversal

Mechanism:

1. Non-depolarizing neuromuscular blocker (e.g., Rocuronium, Vecuronium): Competes with ACh at the nicotinic receptor, preventing muscle contraction.
2. Atropine: Administered first to mitigate muscarinic effects from neostigmine (e.g., bradycardia, excessive salivation).
3. Neostigmine/Edrophonium: Inhibit AChE leading to increased ACh levels, outcompeting the neuromuscular blockers and facilitating muscle contraction.
   • Administered at doses of 2.5-5 mg IV for Neostigmine and 0.4-0.6 mg IV for Atropine.
4. Resultant muscle contraction following ACh accumulation.

7. Atropine Poisoning Treatment

• Physostigmine or Neostigmine are used as treatments.

8. Alzheimer’s Disease Treatment

Mechanism of Action

• Donepezil: An anticholinesterase that enhances memory, communication, and overall daily performance, and reduces behavioral symptoms related to Alzheimer's Disease.

Contraindications for Cholinomimetics

• Not recommended in cases of:
  • Coronary insufficiency
  • Hypotension
  • Severe bradycardia: Could result in extreme heart rate decrease, avoiding IV routes.
  • Hyperthyroidism: Risk of precipitating atrial fibrillation.
  • Bronchial asthma: Potential for exacerbation.
  • Urinary urgency and obstruction issues.

Organophosphate Poisoning

Pathophysiology

• High levels of ACh due to inhibition of its breakdown leading to significant toxicity.
• Symptoms include SLUDGE (salivation, lacrimation, urination, diarrhea, gastrointestinal distress, and emesis) plus central nervous system effects.
• Cause of Death: Respiratory failure.

Management of Organophosphate Poisoning

1. Positioning: Lateral positioning with head down and neck extension to minimize aspiration risks.
2. Respiratory Care: Administer oxygen, artificial respiration, and aspiration of secretions.
3. Decontamination Steps: Remove contaminated clothing; wash skin; stomach washing if ingested. Also, activated charcoal can be used to reduce toxin absorption.
4. Antidotes:
   • Atropine: Administered to counteract ACh effects.
   • Cholinesterase Regenerators: Pralidoxime (2-PAM).
   • Anticonvulsants: Such as Diazepam or Barbiturates.

Cholinergic Receptors Antagonists

Types

Anti-Muscarinic (Parasympatholytics)

• Examples include Atropine, Scopolamine, and Ipratropium.

Anti-Nicotinic Types

• Ganglion Blockers (NN) e.g., Trimethaphan.
• Neuromuscular Blockers (NM) e.g., Tubocurarine and Pancuronium.

Pharmacodynamics of Antimuscarinics

Mechanism

• Compete with ACh at muscarinic receptors, inhibiting the parasympathetic "rest and digest" functions.

Atropine Specifics

• Blocks M2 muscarinic receptors showing competitive antagonism with ACh.

Pharmacokinetics of Antimuscarinics

• Absorption: Well absorbed from GI tract and mucous membranes.
• Distribution: Crosses the blood-brain barrier (BBB).
• Metabolism: Occurs in the liver.
• Excretion: Via urine, with acidification enhancing excretion.

Clinical Uses of Antimuscarinics

1. Preanesthetic Medication: Prevents bradycardia and reduces secretions due to excessive vagal tone during procedures.

2. Ocular Uses: Induces mydriasis and cycloplegia for eye examinations and treatment of iritis.

3. Cardiovascular Uses: Manage bradycardia and cardiovascular heart block.

4. Gastrointestinal Uses: Provides relief from intestinal and biliary colic; Hyoscine preferred for antispasmodic effects.

5. Urinary Tract Uses: Treat renal colic and hyperhidrosis (excess sweating).

Toxicity of Anticholinergic Drugs

Symptoms

• Dry mouth, blurred vision, tachycardia, constipation, urinary retention, flushing, and hyperthermia.
• CNS Symptoms: Include excitation, hallucination, convulsions, possibly leading to coma.
• Mnemonic: “Dry as a bone, red as a beet, hot as a hare, blind as a bat, mad as a hatter.”

Treatment of Atropine Toxicity

• Physostigmine: An AChE inhibitor that crosses the BBB, used for severe cases.
• Supportive care: Involves cooling and sedation using benzodiazepines.

Contraindications of Atropine

• Can exacerbate conditions related to:
  • Tachycardia
  • Glaucoma
  • Constipation/Pyloric Stenosis
  • Urinary retention due to benign prostatic hyperplasia.

Comparison Between Atropine & Scopolamine

Synthetic & Semi-Synthetic Atropine Substitutes

1. Mydriatics

   • Prototype: Tropicamide, Cyclopentolate
   • Features: Short-acting; used for eye exams and refractive testing.

2. Antisecretory/Antispasmodic

   • Prototype: Hyoscine, Pirenzepine, Telenzepine
   • Clinical Use: Gastrointestinal/biliary/urinary tract spasm; M1-selective agents inhibit gastric acid secretion (used less due to PPIs).

3. Antiasthmatic

   • Prototype: Ipratropium and Tiotropium bromide
   • Clinical Use: Given via inhalation to minimize systemic side effects in conditions like COPD and asthma.

4. Urinary Antispasmodic

   • Prototype: Oxybutynin, Tolterodine, Solifenacin
   • Features: Used to reduce symptoms of an overactive bladder (urgency, incontinence), often M3 selective.

5. Antiparkinsonian

   • Prototype: Benztropine, Trihexyphenidyl
   • Clinical Use: Reduces tremors and rigidity in Parkinson's disease.by correcting excess central cholinergic activity.

Conclusion

• Understanding the various pharmacological entities within the autonomic nervous system, particularly the parasympathetic divisions, helps in addressing numerous clinical conditions ranging from hypertension to neurological disorders while being aware of the potential toxicities and contraindications associated with these treatments.