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OIA1013 Anticholinesterase Agents

Anticholinesterase Overview

  • Anticholinesterase Agents: Enzymes or drugs that inhibit cholinesterase, affecting neurotransmission.

  • Main Forms of Cholinesterase:

    • Acetylcholinesterase (AChE)

    • Butyrylcholinesterase (BuChE)

Objectives of Lecture

  • Describe acetylcholinesterase and butyrylcholinesterase.

  • List examples of anticholinesterase agents.

  • Describe mechanisms of action and pharmacological actions.

  • Explain uses and adverse effects of anticholinesterase agents.

Role of Acetylcholinesterase (AChE)

  • Primary Function: Termination of neuronal transmission to prevent excess activation of receptors by acetylcholine (ACh).

Cholinesterases (ChEs)

  • Definition: Enzymes that hydrolyze ACh into choline and acetic acid.

  • Types:

    • Butyrylcholinesterase (BuChE): Also known as nonspecific cholinesterase or pseudocholinesterase. Detoxifies certain substances and provides protection against AChE inhibitors.

    • Acetylcholinesterase (AChE): Hydrolyzes ACh faster than BuChE, localized in blood, neuromuscular junctions, and synapses.

Anticholinesterase Mechanism of Action

  • Mechanism: Inhibition of AChE accumulation leads to continuous stimulation of receptors, disrupting normal nervous system functions.

  • Types of Inhibitors:

    • Prosthetic Inhibitors: Short-acting, reversible.

    • Acid-Transferring Inhibitors: Long-acting; may be reversible or irreversible.

Pharmacological Properties of Anticholinesterases

  • Effects on Cholinergic System: Excessive stimulation results in:

    • Stimulation of muscarinic receptors in autonomic organs.

    • Impact on the autonomic ganglia and CNS.

    • Increased residence time of ACh in the synapse.

  • Effects by System:

    • Cardiovascular: Bradycardia, decreased cardiac output, lower blood pressure.

    • Respiratory: Bronchospasm, increased secretions, hypoxia.

    • Gastrointestinal: Increased motility and secretion.

    • Eye: Miosis and increased secretory gland activity.

Short- and Medium-Acting Anticholinesterases

  • Short-acting:

    • Edrophonium: Differential diagnosis of myasthenia gravis.

    • Tacrine: Treatment for Alzheimer's but hepatotoxic.

  • Medium-acting:

    • Neostigmine: Treatment of myasthenia gravis and reversing muscle relaxants.

    • Physostigmine: Treats glaucoma, anticholinergic toxicity.

Clinical Applications of Anticholinesterases

  • Uses:

    • Myasthenia gravis

    • Glaucoma

    • Neuromuscular block reversal

    • Intoxication by anticholinergic drugs

    • Alzheimer's disease treatment.

Long-Acting Irreversible Anticholinesterases

  • Compounds: Organophosphates like parathion and nerve agents (e.g., sarin).

  • Mechanism: Permanently inactivate AChE, causing severe accumulation of ACh and potential death due to respiratory failure and cardiac issues.

  • Treatment for Poisoning: Atropine and oximes to reactivate AChE.

Side Effects of Anticholinesterases

  • Adverse Effects: Extensive stimulation of muscarinic receptors leading to:

    • Bradycardia, bronchospasms, increased secrecy, urination, diarrhea, miosis.

Key Takeaways

  • Important agents include:

    • Donepezil, Galantamine, Rivastigmine for Alzheimer's.

    • Neostigmine, Edrophonium for myasthenia gravis.

Review Questions

  1. What cholinesterase inhibitor is used to diagnose myasthenia gravis?

  2. Name irreversible cholinesterase inhibitors.

  3. Which agent treats neurogenic ileus and urinary retention?

  4. What drug can treat cholinesterase inhibitor poisoning?

  5. What is the treatment for antimuscarinic toxicity?