Chapter 18: Cholinesterase Inhibitors and Clinical Management of Myasthenia Gravis

Overview of Cholinesterases and Cholinesterase Inhibitors

  • Cholinesterase Definition: An essential enzyme required for normal function within the nervous system, responsible for breaking down acetylcholine.

  • Cholinesterase Enzyme Classes: The term cholinesterase refers to a broader family of enzymes, which includes:

    • Acetylcholinesterase

    • Butylcholinesterase

  • Role of Acetylcholinesterase:

    • Cleaves acetylcholine into an inactive metabolite.

    • Reduces nerve cell-to-cell communication that relies on acetylcholine as a chemical signal.

    • Anatomical Location: Found primarily at postsynaptic neuromuscular junctions, particularly in muscles and nerves.

  • Definition of Cholinesterase Inhibitors:

    • Also termed acetylcholinesterase inhibitors.

    • Medications that prevent the enzymatic breakdown of acetylcholine in the body, raising local neurotransmitter levels.

  • Functional Subclasses:

    • Reversible cholinesterase inhibitors

    • Irreversible cholinesterase inhibitors

  • Therapeutic Indications and Limitations:

    • Due to a lack of organ and receptor selectivity, cholinesterase inhibitors have limited overall therapeutic applications.

    • Indications include:

    • Myasthenia gravis

    • Glaucoma

    • Alzheimer's disease

    • Parkinson's disease dementia

    • Poisoning by muscarinic antagonists

    • Reversal of competitive neuromuscular blockade in specialty settings

    • Individual agent applications are detailed in Table 18.1.

Pharmacodynamics and Effects of Pyridostigmine

  • Prototype Agent: Pyridostigmine.

  • Mechanism of Action:

    • Inhibits the breakdown of acetylcholine, thereby increasing its concentration and availability.

    • Intensifies neurotransmission at virtually all sites where acetylcholine serves as the transmitter.

  • Dose-Dependent Systemic Actions:

    • Sufficient / High Doses:

    • Skeletal muscle stimulation

    • Ganglionic stimulation

    • Activation of peripheral muscarinic receptors

    • Activation of cholinergic receptors in the central nervous system (CNS)

    • Therapeutic Doses:

    • Selective effect; usually affects only muscarinic receptors on effector organs and nicotinic receptors at the neuromuscular junction.

    • Ganglionic transmission and CNS function typically remain unaltered.

  • Muscarinic Response:

    • Produces responses identical to direct-acting muscarinic agonists due to acetylcholine accumulation:

    • Bradycardia

    • Bronchial constriction

    • Urinary urgency

    • Increased glandular secretions

    • Increased tone and motility of gastrointestinal smooth muscle

    • Miosis (pupillary constriction) and lens accommodation/focusing for near vision

  • Neuromuscular Junction Response:

    • Therapeutic Doses: Increases the force of skeletal muscle contraction.

    • Toxic Doses: Reduces the force of contraction.

    • Excessive accumulation of acetylcholine keeps the motor endplate in a state of continuous depolarization, producing a depolarizing neuromuscular blockade.

  • Adverse Effects:

    • Excessive muscarinic stimulation, which can progress to a muscarinic or cholinergic crisis (terms used synonymously).

    • Neuromuscular blockade.

    • Toxic doses can induce respiratory paralysis, leading rapidly to death if untreated.

Drug Interactions

  • Muscarinic Antagonists:

    • Effects at muscarinic receptors directly oppose those of atropine and other muscarinic antagonists.

    • Cholinesterase inhibitors can be utilized to overcome excessive muscarinic blockade caused by trophine or atropine.

    • Conversely, atropine can be administered to reduce excessive muscarinic stimulation triggered by cholinesterase inhibitors.

  • Competitive Neuromuscular Blockers:

    • By driving acetylcholine accumulation at the neuromuscular junction, cholinesterase inhibitors can reverse muscle relaxation or paralysis induced by pankuronium and other competitive (non-depolarizing) neuromuscular blocking agents.

  • Depolarizing Neuromuscular Blockers:

    • Cholinesterase inhibitors do not reverse the muscle relaxant actions of succinylcholine (a depolarizing neuromuscular blocker).

    • Because cholinesterase inhibitors reduce the metabolic breakdown of succinylcholine by cholinesterase, co-administration intensifies and prolongs the neuromuscular blockade caused by succinylcholine.

Myasthenia Gravis Pathophysiology and Clinical Management

  • Pathophysiology:

    • An autoimmune neuromuscular disorder.

    • Autoantibodies attack nicotinic receptors at the neuromuscular junction.

  • Clinical Manifestations:

    • Fluctuating muscle weakness and rapid muscular fatigue.

    • Ptosis (drooping upper eyelids).

    • Difficulty swallowing (dysphagia).

    • Weakness of generalized skeletal muscles.

    • Respiratory distress or failure in severe disease.

  • Pharmacotherapy Guidelines:

    • Reversible cholinesterase inhibitors are the primary therapeutic agents.

    • Dosing Goal: Provide sufficient muscle strength without inducing adverse muscarinic side effects.

    • Administration Protocol: "Start low and move slow" by adjusting the dose gradually until therapeutic effects are achieved.

  • Patient Self-Management Instructions:

    • Maintain a detailed record tracking:

    • Time of medication administration

    • Time of fatigue onset

    • Muscle strength prior to and following medication intake

    • Signs of muscarinic stimulation

    • Instruct patients to increase medication dosage prior to physical exertion.

    • Administer atropine as the drug of choice if serious muscarinic side effects develop.

    • Recommend wearing a Medic Alert bracelet.

Differential Diagnosis: Myasthenic Crisis vs. Cholinergic Crisis

  • Myasthenic Crisis:

    • Underlying Etiology: Inadequate medication dosage (insufficient acetylcholine at the neuromuscular junction).

    • Core Clinical Features: Extreme muscle weakness and potential paralysis. Unmanaged cases result in fatal paralysis of respiratory muscles.

    • Common Triggers and Causes:

    • Infection

    • Systemic stress

    • Surgery

    • Abrupt cessation of myasthenia gravis medications

    • Underdosing or ineffective cholinesterase inhibitor regimens

    • Concomitant medications that exacerbate weakness (e.g., specific antibiotics)

    • Key Symptoms:

    • Severe muscle weakness

    • Dyspnea, shortness of breath, and breathing difficulties

    • Speech difficulties and trouble swallowing

    • Depressed cough or gag reflex

    • Drooling or total inability to swallow

    • Treatment: Increase acetylcholine availability by administering a cholinesterase inhibitor.

  • Cholinergic Crisis (Cholinergic Toxicity):

    • Underlying Etiology: Overdose or accumulation of cholinesterase inhibitors (excessive acetylcholine at the neuromuscular junction).

    • Core Clinical Features: Extreme muscle weakness or frank paralysis accompanied by explicit signs of muscarinic excess.

    • Common Triggers and Causes:

    • Overdose of cholinesterase inhibitors

    • Accidental double dosing

    • Ingestion at overly frequent intervals

    • Drug interactions

    • Key Symptoms:

    • Muscle weakness, twisting, twitching, or fasciculations

    • Excessive salivation and tearing (lacrimation)

    • Diarrhea, nausea, and vomiting

    • Urinary incontinence

    • Bradycardia (slow heart rate)

    • Miosis (constricted pupils)

    • Profuse sweating (diaphoresis)

    • Treatment Protocol:

    • Provide immediate respiratory support and oxygenation.

    • Administer atropine.

    • Withhold the offending cholinesterase inhibitor until baseline muscle strength returns.

  • Diagnostic Differentiation Method (Edrophonium Test):

    • Clinical history (medication log) and physical signs of muscarinic excess are typically sufficient to make a differential diagnosis.

    • When history and physical signs are ambiguous, a challenging dose of edrophonium (an ultrashort-acting cholinesterase inhibitor) may be administered:

    • Myasthenic Crisis Response: Symptoms are relieved as edrophonium elevates acetylcholine levels.

    • Cholinergic Crisis Response: Symptoms are intensified because edrophonium adds to acetylcholine toxicity.

    • Safety and Controversy:

    • Because edrophonium intensifies a cholinergic crisis and can precipitate life-threatening complications, atropine and oxygen must be immediately available during testing.

    • Due to these risks and the relative rarity of cholinergic crisis, the diagnostic use of edrophonium is controversial.

  • Diagnostic Mnemonics:

    • Diagnostic Summary Rule: Myasthenic crisis represents insufficient acetylcholine; cholinergic crisis/toxicity represents excessive acetylcholine.

    • Symptom Mnemonic Systems:

    • SLUDGE and the Killer Bees

    • DUMBBELLS

Irreversible Cholinesterase Inhibitors and Toxicology

  • Chemical Characteristics:

    • Represented primarily by organophosphate compounds.

    • Possess extremely high lipid solubility, permitting rapid penetration through biological membranes and skin.

  • Applications and Compounds:

    • Insecticides / Pesticides: Malathion (organophosphate pesticide).

    • Nerve Agents: Tabun (organophosphate nerve gas).

    • Therapeutic Applications: Irreversible cholinesterase inhibitors are not used clinically, with one exception:

    • Ecathiophate: Utilized clinically in the treatment of glaucoma.

  • Organophosphate Poisoning and Toxicity:

    • Produces a systemic cholinergic crisis.

    • Key Clinical Manifestations (DUMBBELLS mnemonic):

    • Increased salivation

    • Increased tear production (lacrimation)

    • Diarrhea

    • Vomiting

    • Constricted pupils (miosis)

    • Sweating

    • Muscle tremors

    • Confusion

Lehne’s Pharmacology, “Key Points”

  • Cholinesterase inhibitors prevent breakdown of ACh by AChE

    • ACh accumulates in synapses

    • Activates muscarinic receptors, nicotinic receptors in the NMJ, and cholinergic receptors in the CNS

  • Reversible cholinesterase inhibitors are used to treat myasthenia gravis

    • Benefits are from accumulation of ACh at the NMJ

  • Secondary uses: reversal of competitive neuromuscular blockade and treatment of glaucoma, AD, PD, and muscarinic antagonist poisoning

  • Physostigmine crosses membranes easily and is drug of choice for muscarinic antagonist poisoning

  • Irreversible cholinesterase inhibitors (organophosphates) are primarily insecticides

    • The only indication for these potentially toxic drugs is glaucoma

    • Highly lipid soluble and easily absorbed and distributed

  • Overdose of cholinesterase inhibitors: cholinergic crisis

    • Depolarizing neuromuscular blockade and S/S of muscarinic stimulation

      • Hypersalivation, tearing, sweating, bradycardia, incontinence, miosis, respiratory depression

  • Poisoning by reversible cholinesterase inhibitors is treated with atropine (to revere muscarinic stimulation) plus mechanical ventilation

  • Poisoning by organophosphates are treated with atropine, ventilation, pralidoxime (to reverse inhibition of cholinesterase at the NMJ), and diazepam (to suppress seizures)