Cholinomimetics Flashcards
What are muscarinic effects
Those that can be replicated by muscarine and demolished by low doses of the antagonist atropine
Corresponds to parasympathetic stimualtion
What occurs after atropine blockade
Larger doses of acetylcholine can induce effects similar to those caused by nicotine
What are the 3 main muscarinic receptor subtypes
M1 - salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary glands, bronchial/visceral SM, sweat, eye
Describe nicotinic receptors
Ligand gated ion channels subunits: α β γ δ ε Subunit combo determines ligand binding properties of the receptor Muscle type: 2α β δ ε Ganglion type: 2α 3β (CNS - similar) Effects of ACh relatively weak
What are the muscarinic cholinergic target systems
Eye Salivary glands Sweat glands Lung Heart Gut Bladder Vasculature
What are the muscarinic effects on the eye
Contraction of the ciliary muscle (near vision)
Contraction of the sphincter papillae (iris circular muscle) - contracts pupil (miosis) and improves drainage of intraocular fluid
Lacrimation (tears)
How does the parasympathetic system act to alleviate glaucoma
Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure
Explain how muscarinic receptor activation affects heart rate
- ACh binds to M2 AChR in atria and nodes
- Decrease cAMP
- Decreased Ca2+ entry to decrease CO
- Increased K+ efflux to decrease HR
Explain how muscarinic receptor activation affects vasculature
- Acts on vascular endothelial cells to stimulate NO release via M3 AChR (no parasympathetic innervation)
- NO induces VSMC relaxation
- Decrease in TPR
What are the second messengers for the muscarinic receptors
M1,M3,M5 - IP3, DAG (Gq)
M2, M4 - cAMP (Gi)
What are the muscarinic effects on non-vascular smooth muscle
Contraction
Lung - bronchoconstriciton
Gut - increases peristalsis
Bladder - increased bladder emptying
What are the muscarinic effects on exocrine glands
Salivation
Increased bronchial secretions
Increased GI secretions (including HCl)
Increased sweating (SNS-mediated)
What are some typical agonists at muscarinic receptors
Choline esters e.g. bethanechol
Alkaloids e.g. pilocarpine
Describe pilocarpine
From pilocarpus Non-selective muscarinic agonist Half-life = 3-4hrs Has good lipid solubility Used for glaucoma
What are the side effects for pilocarpine
Blurred vision Sweating GI disturbance and pain Hypotension Resp. diseases
What are the main muscarinic effects
Decreased heart rate Decreased blood pressure Increased sweating Difficulty breathing Bladder contraction Gastrointestinal pain Increased salivation and tears
Describe bethanechol
Modification of acetylcholine to produce an M3 ‘selective’ agonist
Resistant to degradation, orally active, limited access to the brain
Half-life = 3-4hrs
Used to assist bladder emptying and enhance gastric motility
What are the side effects of bethanechol
Sweating Impaired vision Bradycardia Hypotension Respiratory difficulty
What do indirectly acting cholinomimetic drugs do
Increase the effect of normal parasympathetic nerve stimulation by targeting the enzymes that break down the NT
What are some examples of reversible anticholinesterases
physostigmine, neostigmine, donepezil (‘Aricept’)
What are some examples of irreversible anticholinesterases
ecothiopate, dyflos, sarin
What are the two types of cholinesterase enzymes
Acetylcholinesterase (true of specific)
Butyrylcholinesterase (pseudocholinesterase)
What do cholinesterase enzymes metabolise acetylcholine to
Choline and acetate
Describe acetylcholinesterase
Found in all cholinergic synapses
very rapid hydrolysis reaction (>10,000 reactions/sec)
Highly selective for acetylcholine
Describe butyrylcholinesterase
Found in plasma and most tissues, but not localised in cholinergic synapses
Broad substrate specificity (can hydrolyse other esters)
Causes low plasma acetylcholine
Genetic variation
How does increasing the dose of cholinesterase inhibitors change the effect
Low - enhanced muscarinic activity
Moderate - further enhancement, increased transmission at all autonomic ganglia
High - depolarising block at autonomic ganglia and NMJ
How do reversible anticholinesterases work
Competitive inhibitor
Donates a carbamyl group to the enzyme, blocking the active site
This group is then removed by slow hydrolysis (mins)
Describe physostigmine
Naturally occurring tertiary amine from calabar beans
Acts at the postganglionic parasympathetic synapse
Half life = 30mins
Used for glaucoma, aids intraocular fluid drainage
Used to treat atropine poisoning
How do irreversible anticholinesterases work
Rapidly react with the enzymes active site to leave a large blocking group
This is stable and resistant to hydrolysis, new enzymes must be produced
(Organophosphates compounds)
Describe ecothiopate
Potent inhibitor
Slow reactivation of the enzyme takes several days
Used as eye drops for glaucoma for prolonged drainage of intraocular fluid
What are the side effects of ecothiopate
Sweating Blurred vision GI pain Bradycardia Hypotension Respiratory difficulty
How do anti cholinesterase drugs affect the CNS
non-polar drugs (e.g. physostigmine, nerve agents) can cross the blood brain barrier
low - excitation, maybe convlusions
high - unconsciousness, respiratory depression and death
What are the treatments for organophosphate poisoning
Atropine, pralidoxime via IV
Artificial respiration
