Cholinomimetics Flashcards
What are the 5 muscarinic receptor subtypes?
M1 - Salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary and sweat glands, bronchial/visceral SM, Eye
M4, M5 - CNS
How can muscarinic affects be abolished?
Using low doses of the antagonist atropine
What do larger doses of ACh do to the body after an atropine blockade of muscarinic receptors?
Induce effects similar to those caused by nicotine
Where do nicotine receptors exist?
On all post ganglionic neuronal cell bodies
Where do all ACh receptors exist?
On all post ganglionic neuronal cell bodies in ANS
What are nicotinic receptors?
FASTER ligand gated ion channels
What are the 5 subunits of nicotinic receptors?
alpha beta, gamma, delta, epsilion
What are the muscle types of subunits of nicotinic receptors?
2alpha, beta, delta, epsilion
What are the ganglion types of subunits of nicotinic receptors?
2alpha, 3beta
What does the subunit combination determine?
Ligand binding properties of the receptor
What are the effects of ACh like on nicotinic receptors?
Relatively weak
What does cholinergic innervation mediate in the eye?
- ciliary muscle contraction - near vision
- sphincter pupillae contraction - miosis and drainage of intra-ocular fluid
- lacrimation - tears
What is impeded in a glaucoma?
Contraction of the sphincter pupillae opens a pathway for aqueous humour, allowing drainage via the Canals of Schlemm thus reducing IOP
Where are the muscarinic receptors mainly located in the heart?
M2 AChR are located mainly in the atria and the nodes
What effects do the muscarinic receptors have on the cardiovascular system?
Decreased HR, CO, vasodilation
Depresses the heart by:
- Reduction of cAMP
- Decrease Ca2+ entry leading to lower CO
- Increase K+ efflux therefore decreasing HR
What does ACh act on in the vasculature?
Acts on vascular endothelial cells to stimulate NO release via M3 AChR
What is PNS innervation like in the vasculature?
Most blood vessels don’t have PNS innervation
What are the muscarinic effects on non vascular SM?
SM with PNS innervation contracts instead of relaxes so:
Lungs - bronchoconstriction
Gut - Increased peristalsis (can lead to GI pain)
Bladder - increased bladder emptying
What are the muscarinic effects on exocrine glands?
Salivation
Increased bronchial and GI secretions
Increased sweating
What are 2 examples of directly acting cholinomimetic drugs?
Bethanechol - choline ester
Pilocarpine - alkaloid
What is bethanechol?
A choline ester - M2 AChR selective antagonist that is resistant to degradation, orally active and has limited access to the brain. Half life is 3-4 hrs.
What is bethanechol used for?
Aid bladder emptying and enhance GI motility
What is philocarpine?
A non-selective muscarinic agonist with good lipid solubility - attaches to any subtype of muscarinic receptor
What is philocarpine used to treat?
Glaucoma
What are indirectly acting cholinomimetic drugs used for?
Increasing the effect of normal PNS stimulation
What are the two types of cholinesterase enzymes that are used to metabolise ACh to choline and acetate?
Acetylcholinesterase
Butyrylcholinesterase
What are the properties of acetylcholinesterase? (3)
Found in synapses
Rapid
Highly selective for ACh
Where is butyrylcholinesterase found?
in plasma and most tissues but not in synapses
What is the specificity of butyrylcholinesterase?
Broad substrate specificity?
What are the effects of cholinesterase inhibitors?
Low dose - causes enhanced muscarinic activity
Moderate dose - further enhancement, increased transmission of all ANS ganglia (inc nAChRs)
High dose TOXIC - depolarising block at ANS ganglia and NMJ
What are examples of reversible antocholinesterases?
Physostigmine, neostigmine, donepezil
What do reversible anticholinesterases do?
Donate a carbamyl gropu to the enzyme active site, blocking the active site - competitive
What is physostigmine?
Tertiary amine that acts at post ganglionic PNS synapse
What is physostigmine used to treat
Glaucoma (aids IOP reduction)
Atropine poisoning
What are examples of irreversible anticholinesterases?
Ecothiopate, dyflos, sarin (all organophosphate compounds)
What do irreversible anticholinesterases do?
Rapidly react to enzyme active site and leave a large blocking group - stable and resistant to hydrolysis
What is ecothiopate?
A potent inhibitor of anticholinesterase?
What is ecothiopate used to treat?
Glaucoma (eye drops) but it has a prolonged duration of action
What are the side effects of ecothiopate?
Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
What is special about non- polar anticholinesterases and needs to be considered when giving doses?
They can cross the blood brain barrier therefore lose doses can cause excitation with possibility of convulsions and high doses can lead to unconsiousness, respiratory depression and death
What drugs are used to treat alzheimers?
Donepezil and Tacrine
How do the drugs that are used to teat alzheimers help?
They potentiate the central cholinergic transmission, relieving AD symptoms but does not affect degeration
What is organophosphate poisoning?
Accidental exposure to organophosphates in insecticides or deliverate use as nerve agents can cause servere toxicity causing increase in muscarinic activity, CNS excitation and depolarising NM block
What is the treatment for organophosphate poisoning?
Atropine in IV
Artificial respiration
Pralidoxime in IV
