Acetylcholinesterase Inhibitors
1. Why are AChE inhibitors important?
a. Drugs b. Insecticides c. Chemical weapons
2. Chemical classes: 3. Pharmacology:
4. Toxicology:
Acetylcholinesterase
Ach is not detectable In blood. Why?
Acetylcholinesterase
Cleaved
Acetylcholinesterase
• Mechanism:
• Inhibitors:
Acetylcholinesterase Inhibitors
1. Competitive: Do not covalently modify ACHe
1. Carbamate:
2. Organophosphate:
1. Competitive Inhibitors
• Alcohol bearing a quaternary ammonium • Very short duration • Rapidly excreted by the kidneys
2. Carbamate Inhibitors: Physostigmine
Esters that have a quaternary or tertiary Ammonium group
Physostigma venenosum
Carbamate Inhibitors
• Covalently modified Ache • Some are used as insecticides
3. Organophosphates
Mechanism of Action
Phosphorylating the active Site of serine. Covalent modification Duration: days
a. Organophosphate Drugs
b. Organophosphate Insecticides
Insecticides Selective toxins that Are inactive pro-drugs that are converted to the active agents by mixed function oxygenases. Unfortunately, insects and mammals are capable of doing this.
Malathion
c. Organophosphate Weapons
• Chemical warfare agents
“Aging” of Organophosphates
Pharmacology of AChE Inhibitors Act at both muscarinic and nicotinic synapses? They potentiate synaptic transmission both parasympathetic and sympathetic
1. Central nervous system: Ache inhibitors are Lipid soluble Cross BBB Low doses: CNS activation High: coma and respiratory arrest
b. Eye, respiratory tract, GI & urinary tract: The same as muscarinic agonists (regulated by parasympathetic neurons) c. Cardiovascular: Bradycardia, decrease contraction, cardiac output Blood vessels? No effect
d. Neuromuscular junction: Increase force of contraction (low dose) Muscle fasciculations and depolarizing blockade (high dose)
Therapeutic Uses
A. Eye: Miosis and constriction of the ciliary muscle, and are used to treat glaucoma B. GI and urinary tract: Treat: paralysis of the stomach and intestines Postpartum urinary retention
C. Neuromuscular junction: Myastenia Gravis D. CNS:
Myasthenia Gravis
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction
Myasthenia Gravis – Effect on the Neuromuscular Junction
Normal
Myasthenia gravis
Myasthenia Gravis
• Symptoms: specific muscle weakness, and not of generalized fatigue. Ocular motor disturbances, ptosis or diplopia, Oropharyngeal muscle weakness, difficulty chewing, swallowing, or talking, limb weakness. The severity of weakness fluctuates during the day, usually being least severe in the morning and worse as the day progresses, especially after prolonged use of affected muscles. • Demographics: 36,000 cases in the United States. women are more often affected than men. The most common age at onset is the second and third decades in women and the seventh and eighth decades in men. • Prognosis: With treatment, most MG patients will have excellent improvement of their muscle weakness.
Myasthenia Gravis
Drugs Used in Myasthenia Gravis
Drug Diagnosis:
Edrophonium iv (improvement) 5-15 min
Duration of Action
Treatment:
Neostigmine (do not cross BBB) 0.5-2 hours Pyridostigmine 3-6 hours Ambenonium 4-8 hours
Alzheimer’s Disease - Symptoms
1. Early:
2. Middle:
3. Late:
Alzheimer’s Disease Pathology
Cholinergic Neurons
AChE Inhibitors Used to Treat Alzheimer’s Disease
• The first to become available
• The first to become passé
AChE Inhibitors Used to Treat Alzheimer’s Disease
Are They Worth It?
Effect of Rivastigmine in Alzheimer’s Disease Rivastigmine Placebo Improved 37% 20% Adverse Effects 23% 7%
Adverse Effects
• Cardiovascular: Bradycardia • Gastrointestinal: Nausea, vomiting, diarrhea
• Urinary tract: Incontinence, urinary urgency
• Glands: Salivation, lacrimation, sweating
Toxicity of AChE Inhibitors
1. Autonomic Nervous System: a. Eye: Miosis, blurred vision b. Cardiovascular: Bradycardia, hypotension c. Glands: extreme salivation, lacrimation, sweating d. Gastrointestinal: anorexia, nausea, vomiting, diarrhea e. Respiratory: bronchoconstriction, bronchial secretion 2. Skeletal Muscle: Fasciculations, weakness, paralysis
3. CNS: Ataxia, confusion, convulsions, coma, paralysis 4. Death: Respiratory depression due to bronchoconstriction, increased secretions, paralysis of diaphragma and intercostal muscles and central respiratory depression
Treatment of AChE Poisoning
1. Atropine: Reverses muscarinic but not nicotinic
1. Pralidoxime (2-PAM):
Pralidoxime (2-PAM)
Mechanism of Action of Pralidoxime
Summary
1. Mechanism of ACh hydrolysis: 2. Mechanism of action of inhibitors:
a. Competitive b. Carbamate c. Organophosphate
3. Therapeutic Use:
a. Drugs b. Insecticides c. Nerve gas
4. Adverse Effects:
a. Therapeutic b. Toxicology