Questions and Answers
Which of the following is a common adverse effect of cholinergic stimulation?
What is the primary therapeutic use of Neostigmine?
Which cholinesterase inhibitor is used as an antidote to competitive neuromuscular blockers?
What is the duration of action for Pyridostigmine?
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Which of the following is NOT an adverse effect of Neostigmine?
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Which drug is used to treat Alzheimer's disease but is also hepatotoxic?
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What type of agent is Parathion, and for what is it primarily used?
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Echothiophate permanently inactivates which enzyme?
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In the context of cholinesterase inhibitors, what does the term 'aging' refer to?
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Which of the following conditions is a contraindication for using Neostigmine?
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Study Notes
Release of ACh
- Action potentials in cholinergic neurons open sodium channels, leading to increased intracellular calcium.
- Elevated calcium levels trigger the release of neurotransmitter vesicles into the synaptic cleft.
- Release can be inhibited by botulinum toxin and stimulated by black widow spider venom.
Binding of ACh
- Acetylcholine (ACh) binds to two types of receptors: muscarinic and nicotinic.
Degradation of ACh
- ACh is degraded in the postjunctional site by acetylcholine esterase, resulting in choline and acetate.
Recycle of Choline
- Choline re-enters the presynaptic neuron along with sodium for the synthesis of acetylcholine.
Direct Cholinergic Agonists
- Mimic acetylcholine by binding directly to nicotinic or muscarinic receptors.
- Two groups:
- Choline esters (carbachol, bethanechol)
- Alkaloids (nicotine, pilocarpine)
- Cholinergic agonists generally have a longer action than ACh.
Acetylcholine Characteristics
- Limited therapeutic impact due to rapid inactivation and broad activity.
- Heart effects: decreases heart rate (HR), stroke volume (SV), and blood pressure (BP) through M3 receptor stimulation causing vasodilation.
- Gastrointestinal (GI) effects: increases saliva secretion, intestinal motility, and secretion.
- Pulmonary effects: stimulates bronchial secretions and bronchoconstriction.
- Urinary tract effects: contracts detrusor muscle facilitating urination.
- Eye effects: causes pupil constriction (miosis).
- Antidote for acetylcholine toxicity is atropine.
Bethanechol
- A carbamoyl ester that is not hydrolyzed by acetylcholine esterase.
- Strong agonist for muscarinic receptors with little to no nicotinic activity.
- Therapeutic uses include:
- Urologic treatment for atonic bladder (post-operative and postpartum).
- Treatment for non-obstructive urine retention.
- GI treatment for megacolon and neurogenic atony.
- Adverse effects: sweating, flushing, decreased BP, nausea, abdominal pain, diarrhea, and bronchospasm.
- Atropine serves as the antidote.
Carbachol
- Acts on both muscarinic and nicotinic receptors.
- Poor substrate for acetylcholine esterase.
- Induces miosis, spasm, and accommodation in the eye.
- Atropine can reverse effects of carbachol.
- Used commonly as a topical ophthalmic solution for open-angle glaucoma but rarely due to risk of cataracts.
Toxicology of Anticholinesterase Agents
- Irreversible acetylcholinesterase inhibitors, often organophosphates, lead to cholinergic crisis.
- Commonly found in agricultural insecticides with potential for poisoning.
- Examples include nerve gases such as sarin used in warfare.
Reactivation of Acetylcholine Esterase
- Pralidoxime can reactivate inhibited AChE.
- Acts peripherally and does not penetrate the CNS, thus ineffective for CNS effects of organophosphates.
- Can reverse peripheral effects of irreversible AChE inhibitors but not those from reversible inhibitors.
Other Treatments for Organophosphate Toxicity
- Atropine is used to alleviate muscarinic symptoms such as bronchial secretions and bradycardia.
- Diazepam may help reduce persistent convulsions.
- Supportive care includes maintaining airway, oxygenation, and artificial respiration.
Cholinergic Antagonists
- Agents that block cholinergic receptors (muscarinic and nicotinic) and inhibit the action of ACh.
- Divided into:
- Antimuscarinic antagonists (most clinically significant).
- Ganglionic antagonists (affect nicotinic receptors in sympathetic and parasympathetic ganglia, least clinically useful).
- Neuromuscular blocking agents (mainly nicotinic antagonists) used for muscle relaxation in surgery.
Neostigmine
- A reversible acetylcholinesterase inhibitor with intermediate action (30 min - 2 hrs).
- Therapeutic applications include stimulating bladder and GI function as well as reversal of neuromuscular blockade.
- Adverse effects include generalized cholinergic stimulation without convulsions due to peripheral action.
Pyridostigmine and Ambenonium
- Used for chronic management of myasthenia gravis with a longer action than neostigmine (3-6 hours for pyridostigmine, 4-8 hours for ambenonium).
- Side effects similar to neostigmine.
Tacrine, Donepezil, Rivastigmine, Galantamine
- Utilize in treating Alzheimer’s disease related to cholinergic neuron deficiency.
- Tacrine is hepatotoxic; these drugs aim to delay progression of Alzheimer’s.
- Primary adverse effect across these medications is gastrointestinal distress.
Indirect Acting Cholinergic Agonists
- Synthetic organophosphates irreversibly inhibit acetylcholinesterase, leading to prolonged ACh action and toxicity.
- Parathion and malathion are used as insecticides.
Echothiophate
- An organophosphate that permanently inactivates acetylcholinesterase through phosphorylation.
- Requires new enzyme synthesis for restoration.
- Actions include generalized cholinergic effects and miosis.
- Potential risks include paralysis and convulsions due to respiratory difficulties.
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Description
This quiz covers the release, binding, and degradation of acetylcholine in cholinergic neurons. It includes the effects of botulinum toxin and black widow spider venom on acetylcholine release, as well as the recycling process of choline. Test your knowledge on these critical neurotransmitter functions!
