6. Cholinomimetics Flashcards
What are cholinomimetics?
- Drugs that mimic the action of ACh in the body
* Parasympathomimetic drugs
What is muscarine?
- Selective muscarinic agonist
* Can replicate muscarinic effects
How can muscarinic effects be abolished?
Low doses of atropine
- a muscarinic antagonist
What happens after an atropine blockade?
• Muscarinic actions blocked
• Large dose of ACh produced
• Induce effects similar to those caused by nicotine
(• Nictonic receptors are in all autonomic ganglia/motor neurones)
What are the 3 main muscarinic receptors and what do they do?
M1
• CNS - excitation
• Salivary glands
• Stomach - stimulates HCl release
M2
• Heart (atria and in both nodes) - decreases heart rate
M3 • Salivary glands • Bronchial/Visceral smooth muscle • Swear glands • Eye
Where are M4 and M5 found?
CNS
Are muscarinic receptors generally excitatory or inhibitory?
Excitatory (apart from M2 on heart)
What type of receptor are muscarinic receptors?
Type 2 (G-protein coupled)
• M1, M3, M5: Gq => stimulates PLC to increase IP3 and DAG
• M2, M4: Gi => inhibitory - reduces cAMP
Describe the structure and types of nicotinic receptors
- Ligand gated ion channels
- 5 subunits (α, β, γ, δ, ε)
- Combination of subunits determines ligand binding properties
- Muscle - 2α, β, δ, ε
- Ganglion - 2α, 3β
How does the effect of ACh on nictonic receptors compare to that of muscarinic receptors?
Relatively weak on nicotinic
What are the 3 main muscarinic effects on the eye?
- Contraction of the ciliary muscle (near vision)
- Contraction of sphincter pupillae (circular muscles) - constriction of pupil (miosis) - increased drainage of intraocular fluid
- Lacrimation
What is glaucoma?
- Increase in intraocular pressure
* Can damage the optic nerves and retina => blindness
Where is the aqueous humour generated and what does it do?
- Generated by capillaries of ciliary body
- Flows into anterior chamber of the eye
- Supplies oxygen and nutrients to the lens and cornea as they don’t have a blood supply
How does the aqueous humour drain?
- Diffuses forwards across the lens then across the cornea
* Drains through the canals of Schlemm back into the venous system
What is Angle-closure glaucoma?
- Angle between cornea and iris becomes narrowed
* Reduced drainage of intraocular fluid via canals of Schlemm
How can you increase drainage of intraocular fluid in a aptient with glaucoma?
• Administer muscarinic agonist
- contraction of iris - opens up angle
• Increased drainage through the canals of Schlemm
Describe how ACh achieves its muscarinic effect on the heart
- ACh on M2 AChR
- Decrease in cAMP
- Decreased Ca2+ entry => decreased CO
- Increased K+ efflux => decreased heart rate
- Drop in BP
Describe the muscarinic effects on vasculature
- Although most blood vessles have no parasympathetic innervation, they do have receptors
- ACh acts on vascular endothelial cells (M3) => NO release => VSMC relaxation
- Decreased TPR
Describe the muscarinic effects on non-vascular smooth muscle
- Responds in opposite way to VSMCs
- Contracts
- Lungs - bronchoconstriction
- Gut - increased peristalsis/motility
- Bladder - increased emptying
What are the muscarinic effects on exocrine glands
- Salivation
- Increased bronchial secretions
- Increased GI secretions (HCl production)
- Increased sweating
Summarise the muscarinic effects in the body
- Decreased heart rate
- Decreased BP
- Increased sweating
- Difficulty breathing
- Bladder emptying
- GI pain
- Increased salivation and tears
What are the 2 types of cholinomimetics?
- Directly acting (usually muscarinic receptor agonists)
* Indirectly acting
What are the 2 types of muscarinic receptor agonists?
- Choline esters (bethanechol)
* Alkaloids (pilocarpine)
Explain the use of pilocarpine
• Derived from leaves of the plant Pilocarpus
- Non-selective muscarinic agonist (stimulates ALL muscarinic receptors)
- Good lipid solubility and half life of 3-4 hours
- Useful to treat glaucoma - constricts sphincter pupillae and opens up canals of Schlemm
What are the side effects of Pilocarpine and Bethanechol
General effects of parasympathetic discharge • blurred vision • sweating • GI pain/nausea • hypotension • bradycardia • respiratory difficulty
Explain the use of Bethanechol
- Very similar to ACh - M3 receptor SELECTIVE agonist
- Resistant to degradation by acetylcholinesterase
- Limited access to brain
- Half life of 3-4 hours
- Used to assist bladder emptying and enhance gastric motility
What are indirectly acting cholinomimetic drugs?
- Drugs that inhibit acetylcholinesterase
- This increases ACh in the synapse
- This increases the effect of normal parasympathetic nerve stimulation
Give some examples of reversible anticholinesterases
- Physostigmine
- Neostigmine
- Donepezil
Give some examples of irreversible anticholinesterases
- Ecothiopate
- Dyflos
- Sarin
What do cholinesterase enzymes do and what are the 2 different types?
• Metabolise ACh to choline and acetate
- Acetylcholinesterase
- Butyrylcholinesterase
Describe the 2 cholinesterases
Acetylcholinesterase
• In all cholinergic synapses (peripheral and central)
• Very rapid action
• Highly selective for ACh
Butyrylcholinesterase
• Found in plasma and most tissues - NOT cholinergic synapses
• Broad substrate specificity - hydrolyses other esters
• Principle reason for low plasma ACh
• Variation of effects in populations (genetic variation)
What is the effect of a low dose of cholinesterase inhibitor?
Enhanced muscarinic activity
What is the effect of a moderate dose of cholinesterase inhibitor?
- Further enhancement of muscarinic activity (than low dose)
* Increased transmission at ALL autonomic ganglia (muscarinic and nicotinic)
What is the effect of a high dose of cholinesterase inhibitor?
- Depolarising block at autonomic ganglia and neuromuscular junction
- Nicotinic receptors overstimulated - shut down
How do reversible anticholinesterase drugs work?
- Physostigmine and neostigmine
- Donate a carbamyl group to the enzyme - blocking active site
- ACh blocked from binding
- ACh activity therefore increases
- Carbamyl group removed by slow hydrolysis
How does physostigmine specifically work and what it it used for?
(• Reversible anticholinesterase)
• Naturally occurring tertiary amine from Calabar beans
• Acts at postganglionic parasympathetic synapse
• Half life of 30mins
• Used in glaucoma - drainage of intraocular fluid
• Treats atropine poisoning - increases ACh to outcompete atropine (atropine is a competitive muscarinic antagonist - surmoutable)
What type of compounds are irreversible anticholinesterase drugs?
Organosphosphate compounds
Give some examples of irreversible anticholinesterase drugs
- Ecothiopate (only one in clinical use - others are insecticides/nerve gas)
- Dyflos
- Sarin
- Parathion
How do irreversible anticholinesterase drugs work
- Rapidly react with enzyme active site
- Leave a large blocking group - stable and resistant to hydrolysis
- Recovery requires production of new enzymes (days/weeks)
What is ecothiopate used for and what are the side-effects?
(• Irreversible anticholinesterase)
• Eye drops in treatment of glaucoma
• Has prolonged duration of action
• Side-effects are that of parasympathetic discharge (sweating, blurred vision, GI pain etc.)
What type of anticholinesterases can cross the blood-brain barrier?
Non-polar e.g. physostigmine, nerve agents
What is the effect of a low dose of anticholinesterase drugs on the CNS?
- CNS excitation
* Possibility of convulsions
What is the effect of a high dose of anticholinesterase drugs on the CNS?
- Unconsciousness
- Respiratory depression
- Death
What is Donepezil and Tacrine useful in treating and why?
- Alzheimer’s disease
- ACh important in learning and memory
- Potentiation of central cholinergic transmission relieves AD symptoms
- Does not affect degeneration
What does exposure to nerve agents lead to and how can it be treated?
- Increased muscarinic activity => CNS excitation => depolarising NM block
- Reduction in acetylcholinesterase - too much ACh
Treatment
• IV atropine - blocks ACh overstimulation
• respirator (due to respiratory depression)
• IV pralidoxime - unblocks enzymes
