Pharmacology of Choline Esters

Therapeutic Uses of Choline Esters

• Ach is not used clinically due to its short duration of action, widespread effects, and ineffectiveness when taken orally.
• Bethanechol is the only clinically used choline ester, and it lacks cardiovascular adverse effects, making it useful for:
  • Treating atony of the gastrointestinal tract (gastric atony, paralytic ileus, and congenital megacolon).
  • Treating postoperative and postpartum urinary retention, as well as neurogenic bladder.
  • Increasing salivary secretion in cases of xerostomia.

Side Effects and Toxic Manifestations of Choline Esters

• Nausea, vomiting, and diarrhea.
• Spasm of accommodation.
• Salivation, sweating, lacrimation, and cutaneous vasodilation (flushing).
• Hypotension, bradycardia, syncope, and cardiac arrest.
• Bronchospasm and pulmonary edema in severe cases due to increased secretions.
• Treatment of toxicity involves atropine and supportive and symptomatic treatments.

Pilocarpine

• Pilocarpine is a naturally occurring alkaloid derived from the pilacarpus leaflet.
• It acts by directly stimulating muscarinic receptors.
• Pharmacokinetics:
  • Absorbed orally.
  • Distributed throughout the body and crosses the blood-brain barrier.
  • Not metabolized by cholinesterase enzyme, but partially metabolized by the liver.
  • Excreted by the kidney unchanged.
• Mechanism of action:
  • Increases secretion in exocrine glands, especially sweat glands.
  • Affects smooth muscles, including:
    • Eye (miosis and accommodation for near vision, decreases IOP).
    • Intestine (increases motility).
    • Bronchial (bronchospasm).
  • Initial stimulation followed by depression in the CNS.

Organophosphorus Compounds

• These agents bind covalently to the enzyme and are extremely toxic.
• They are mainly used as:
  • Insecticides (e.g., parathion, malathion).
  • War gases (e.g., sarin, soman, tabun).
• The only clinically used organophosphorous compounds include:
  • Di-isopropyl-fluro-phosphate (DFP) or isoflurophate, used as an eye ointment in treating glaucoma.
  • Echothiophate (phospholine), used as eye drops in managing glaucoma.

Pharmacological Actions and Treatment of Organophosphorus Poisoning

• Generalized cholinergic stimulation.
• Paralysis of motor function, causing breathing difficulties, and convulsions.
• Intense miosis.
• Symptoms:
  • Muscarinic effects: lacrimation, miosis, salivation, bradycardia, hypotension, bronchospasm, excessive secretion, colic, and diarrhea.
  • Nicotinic effects: initial skeletal muscle twitches followed by paralysis.
  • CNS: convulsions followed by coma and death.
• Cause of death: respiratory failure due to peripheral and central mechanisms.
• Treatment:
  • Respiratory support: care of respiration via endotracheal intubation, artificial respiration.
  • Atropine in high doses can reverse many of the muscarinic and central effects.