Cholinomimetics Flashcards
Recall the synthesis and break down of acetylcholine
Acetyl CoA + Choline => ACh + CoA; catalysed by Choline acetyltransferase (CAT)
Acetylcholine => Choline + Acetate; catalysed by Acetylcholinesterase
Why are the receptors described as nicotinic and muscarinic?
Muscarinic effects are those that can be replicated by muscarine.
Nicotinic effects are those that can be replicated by nicotine
Name a competitive muscarinic receptor antagonist
Atropine
Name a nicotinic receptor antagonist
Tubocararine
Briefly state where nicotinic and muscarinic receptors are found in the ANS
Nicotinic: found ‘between pre- and post-ganglionic neurones’ in both SNS and PNS pathways; as well as the NMJ
Muscarinic: found on PNS effectors and sweat glands (innervated by SNS)
State where you would find the different types of muscarinic receptor
M1: Salivary glands, Stomach, CNS
M2: Heart
M3: Salivary glands, Bronchial/visceral SM, Sweat glands, Eye
M4: CNS
M5: CNS
What types of receptor are each of the muscarinic receptors
M1, M3, M5 = stimulatory GPCR; IP3 and DAG mediated transduction
M2 and M4 = inhibitory GPCR; decrease cAMP production
Describe the structure of nicotinic receptors
- Ionotropic type 1/ligand-gated ion channel
- 5 subunits (any of α β γ δ ε) which determine ligand binding properties
What combination of subunits are found at the NMJ, and at ganglia
Muscle type: 2α β δ ε
Ganglion type: 2α 3β
How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?
Relatively weak on nicotinic compared to muscarinic
What three effects does muscarinic stimulation have on the eye?
- Ciliary muscle contraction => accommodation for near vision
- Sphincter pupillae contraction => constricts pupil (miosis) and improves intraocular fluid drainage
- Lacrimation
What is glaucoma?
Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness
Describe the passage of aqueous humour through the eye
- Aqueous humour is produced by capillaries in the ciliary body (via the actions of carbonic anhydrase)
- Aqueous humour passes into the anterior chamber
- Contraction of sphincter pupillae (iris circular muscle) opens pathway for aqueous humour, allowing drainage via the trabecular meshwork and canals of Schlemm => reduced intraocular pressure
Describe the muscarinic effects on the heart
Binding of ACh to the M2 receptors in the atria and nodes => decreased cAMP production => decreased Ca2+ influx and increased K+ efflux => decreased CO and decreased HR
Describe the muscarinic effects on the vasculature
- ACh binds to M3 receptors on vascular endothelial cells to stimulate NO release which induces vascular smooth muscle relaxation/vasodilation (due to K+ efflux)
- Note however that most blood vessels do not have parasympathetic innervation (only coronary) but M3 receptors ARE found in many blood vessels
Describe the muscarinic effects on Non-Vascular Smooth Muscle
Smooth muscle that does have PNS innervation responds in the opposite way to vascular muscle – i.e. it contracts (because the M3 receptor is Gq)
e.g. bronchoconstriction, increased peristalsis, increased micturition
State the muscarinic effects on exocrine glands
- Salivation
- Increased bronchial secretions
- Increased gastro-intestinal secretions (including gastric HCl production)
- Increased sweating (SNS-mediated)
What is the difference between directly and indirectly acting cholinomimetic drugs
Direct = Muscarinic receptor agonist
Indirect = Anticholinesterase (Increase effect of normal parasympathetic nerve stimulation by increasing duration of acetylcholine activity in the synapse)
Name two muscarinic receptor agonists
Bethanechol (choline esters)
Pilocarpine (alkaloids)
State the characteristics and clinical use of pilocarpine
- Non-selective; good lipid solubility; t1/2 ≈ 3-4h
- Local treatment for glaucoma
What are the side effects of pilocarpine
Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress
State the characteristics and clinical use of bethanechol
- Produced by adding methyl group to ACh => M3 selective
- Resistant to degradation, orally active and with limited access to the brain; t1/2 ≈ 3-4h
- Used to assist bladder emptying and to enhance gastric motility
What are the side effects of bethanechol
Sweating, impaired vision, bradycardia, hypotension, respiratory difficulty
Name three reversible and three irreversible anticholinesterase
Physostigmine, neostigmine, donepezil (‘Aricept’)
Ecothiopate, dyflos, sarin (organophosphates)
What are the two types of cholinesterase
Acetylcholinesterase (true or specific cholinesterase)
Butyrylcholinesterase (pseudocholinesterase)
Summarise the main differences between acetylcholinesterase and butyrylcholinesterase
Acetylcholinesterase:
- Found in all cholinergic synapses
- Very rapid action
- Highly selective for acetylcholine
Butyrylcholinesterase:
- Found in plasma and most tissues but not cholinergic synapses
- Broad substrate specificity (hydrolyses other esters e.g. suxamethonium)
- Causes low plasma acetylcholine
- Shows genetic variation
Describe the effects of increasing the dosage of cholinesterase inhibitors
LOW = enhanced muscarinic activity
MODERATE = Increased transmission at ALL autonomic ganglia (nAChRs) and further enhancement of muscarinic activity
HIGH = Depolarising block at autonomic ganglia & NMJ (toxic)
How do reversible anticholinesterase drugs work?
- They compete with acetylcholine for the active site on the cholinesterase enzyme. - They donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
- Carbamyl group is removed by slow hydrolysis
State the characteristics and clinical use of physostigmine
- Tertiary amine that primarily acts at the postganglionic parasympathetic synapse; t1/2 ≈ 30 mins
- Used to treat glaucoma and atropine poisoning
How do irreversible anticholinesterase drugs work?
- They rapidly react with the cholinesterase active site, leaving a large blocking group that is stable and resistant to hydrolysis
- Recovery may require the production of new enzymes (days/weeks)
State the characteristics and clinical use of ecothiopate
- Potent anticholinesterase
- Used as eye drops to treat glaucoma (prolonged action)
What are the side effects of ecothiopate?
Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
Which anticholinesterases can cross the blood brain barrier? State the effects of low and high doses
Non-polar anticholinesterases (e.g. physostigmine; nerve agents).
LOW = CNS excitation with possibility of convulsions
HIGH = Unconsciousness, respiratory depression, death
Describe the treatment of organophosphate poisoning
Pralidoxime (iv): ‘unblocks’ cholinesterase enzyme (used within first few hours of poisoning)
Atropine (iv): inhibit muscarinic receptors
Artificial respiration
