Cholinomimetics Flashcards
Cholinomimetics
Mimics action of ACh in the nervous system
Synthesis, release and metabolism of acetylcholine
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Muscarinic vs nicotinic effects
Muscarinic effects are those that can be replicated by muscarine, and can be abolished by low doses of the antagonist atropine
Muscarinic actions correspond to those of parasympathetic stimulation.
After atropine blockade of muscarinic actions larger doses of acetylcholine can induce effects similar to those caused by nicotine
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Muscarinic receptors: 3 main subtypes
M1: salivary glands, stomach, CNS
M2: Heart
M3: Salivary glands, bronchial/visceral SM, sweat glands, eye
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NOTE:
All muscarinic receptors are G-protein-coupled receptors
M1, M3 and M5 = binds Gq protein, stimulates IP3 DAG
M2 and M4 = binds Gi protein, reduces cAMP
General rule = response tends to be excitatory (apart from M2 = inhibitory)
Nicotinic receptors
Ligand gated ion channels
5 subunits: alpha, beta, gamma, delta, epsilon
Subunit combination determines ligand binding properties of the receptor
Muscle type: 2alpha, beta, delta, epsilon
Ganglion type: 2 alpha, 3 beta (CNS - similar)
Effects of ACh relatively weak
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Muscarinic cholinergic target systems
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Muscarinic effects of eye
Contraction of ciliary muscle (accommodation for near vision)
Contraction of the sphincter pupillae (circular muscle of the iris): constricts pupil (miosis) and improves drainage of intraocular fluid
Lacrimation (tears)
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Aqueous humour provides oxygen and nutrients (it doesn’t have a blood supply)
NOTE: in glaucoma, the iris becomes folded/ruffled - rate of drainage is reduced (intra-ocular pressure rises - can damage retina and/or optic nerve)
Muscarinic effects in heart
M2 AChR in atria and nodes
Decrease cAMP
Decreased Ca2+ entry —> decreased cardiac output
Increased K+ efflux —> decreased heart rate
Inotropic effect
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Muscarinic effects on vasculature
Most blood vessels do not have parasympathetic innervation
Acetylcholine acts on vascular endothelial cells to stimulate No release via M3 AChR
NO induces vascular smooth muscle relaxation
Result is a decrease in TPR
This is more relevant to the clinical use of cholinomimetics than normal physiology
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Muscarinic effects on cardiovascular system
Decreased heart rate (bradycardia)
Decreased cardiac output (due to decreased atrial contraction)
Vasodilatation (stimulation of NO production)
All of these combined can lead to a sharp drop in blood pressure
Muscarinic effects on non-vascular smooth muscle
Smooth muscle that does have parasympathetic innervation responds i the opposite way to vascular muscle (i.e. it contracts(
Lung: bronchoconstriction
Gut: increased peristalsis (motility)
Bladder: increased bladder emptying
Muscarinic effects of exocrine glands
Salivation
increased bronchial secretions
Increased GI secretions (including gastric HCl production)
Increased sweating (SNS-mediated)
Muscarinic effects: summary
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Two mainn groups of drugs
Directly acting cholinomimetic drugs
Indirectly acting cholinomimetic drugs
Directly acting cholinomimetic drugs
Typical agonists at muscarinic receptors:
1, choline esters (bethanechol)
2. Alkaloids (pilocarpine)
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Pilocarpine
Non-selective muscarinic agonist; good lipid solubility
T(1/2)=3-4 hours
Particularly useful in ophthalmology as a local treatment for glaucoma (eyedrops)
Side effects: blurred vision, sweating, GI disturbance and pain, hypotension, respiratory distress
Bethanechol
Minor modification of acetylcholine, produces an M3 AChR selective agonist
Resistant to degradation, orally active and with limited access to the brain
T(1/2) = 3-4 hours
Mainly used to assist bladder emptying and to enhance gastric motility
Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty
(Cevimeline - newer M3-selective cholinomimetic)
Indirectly acting cholinomimetic drugs
Increase effect of normal parasympathetic nerve stimulation
Target site = acetylcholinesterase in synaptic cleft
Reversible anticholinesterases = physostigmine, neostigmine, donepezil (‘Aricept’ - treatment for Alzheimer’s)
Irreversible anticholinesterases = ecothiopate, dyflos, sarin
Cholinesterase enzymes
Metabolise acetylcholine to choline and acetate
Two types which differ in distribution, substrate specificity and function:
- acetylcholinesterase (true or specific cholinesterase)
- butyrylcholinesterase (pseudocholinesterase)
Acetylcholinesterase
Found in all cholinergic synapses (peripheral and central)
Very rapid action (hydrolysis; >10,000 reactions per second)
Highly selective for acetylcholine
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Butyrylcholinesterase
Found in all plasma and most tissues but not cholinergic synapses
Broad substrate specificity - hydrolyses other esters (e.g. suxamethonium)
Is principal reason for low plasma acetylcholine
Shows genetic variation
Effects of cholinesterase inhibitors
Low dose:
- enhanced muscarinic activity
Moderate dose:
- further enhancement of msucarinic activity
- increased transmission at all autonomic ganglia (nAChRs)
High dose (toxic):
- depolarising block at autonomic ganglia and NMJ
Reversible anticholinesterase drugs
Physostimine, neostigmine
Compete with acetylcholine for active site on the cholinesterase enzyme
Donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from/binding
Carbamyl group removed by slow hydrolysis mins rather than msecs)
Increase duration of acetylcholine activity in the synapse
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Physostigmine
Primarily acts at the postganglionic parasympathetic synapse
T(1/2) = 30 mins
Used in the treatment of glaucoma, aiding intraocular fluid drainage
Also used to treat atropine/poisoning, particularly in children
Irreversible anticholinesterase drugs
Organophsophate compounds: ecothiopate, dyflos, parathion and sarin
Rapidly react with the enzyme active site, leaving a large blocking group
This is stable and resistant to hydrolysis - recovery may require the production of new enzymes (days/weeks)
Only ecothiopate in clinical use, but the others are commonly used as insecticides (and as nerve gas)
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Ecothiopate
Potent inhibitor of acetylcholinesterase
Slow reactivation of the enzyme by hydrolysis takes several days
Used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with prolonged duration of action
Systemic side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
Anticholinesterase drugs and the CNs
Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross the blood brain barrier
Low doses = excitation with possibility of convulsions
High doses = unconsciousness respiratory depression, deathq
Treatment of organophosphate poisoning
Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can causes severe toxicity (increased muscarinic activity = CNS excitation = depolarising neuromuscular block)
Treatment = atropine , artificial respiration, pralidoxime
NOTE: phosphorylated enzyme ‘ages’ within few hours
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Summary
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Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?
- All autonomic synapses
- Pre- and post-ganglionic parasympathetic synapses
- Pre- and post-ganglionic sympathetic synapses
- Post-ganglionic parasmpathetic synpases only
- Pre-ganglionic sympathetic synapses only
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Anticholinesterase drugs can be used to treat which of the following conditions?
- Asthma
- Glaucoma
- Hypotension
- Motion sickness
- Peptic ulcer disease
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