6: Cholinomimetics Flashcards
What kind of drug is Atropine?
It is a kompetitive Muscarinic receptor antagonist
What does muscarine do?
Agonist of the Muscarinic receptor
–> Stimmulation (not broken down by Ach-esterase)
- tears
- saliva
- miosis
- sweating etc.
Where are the M1 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
•M1:
- Salivary glands
- Stomach
- CNS
Activate Gq-Protein: exitory
- IP3 + DAG (–> increases Ca2+ influx)
Where are the M2 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
•M2: Heart
- are inhibitory
Activate Gi-protein
- downregulation of cAMP
Where are the M3 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
M3:
- Salivary glands
- Bronchial/visceral SM
- Sweat glands
- Eye
Are exitory: Activate Gq protein
- increase in IP3 and DAG
What are the structural features of the Muscarinic receptor?
Has 7 transmembrane regions
connencted to loop + G-protein in the inside
Explain the structure of a nicotinic receptor
- Ionotropic receptor
- Has 5 subunites (alpha-epsylon)
- Binding property is determines by the combination of Subunits
- •Effects of ACh relatively weak
What are the effects of muscarinic exitation in the eye?
Contraction of the 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)
What is the effect of contraction of the spincter puppilare?
How can this be used in glaucoma treatment?
Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage
–> reducing intra-ocular pressure
–> in some form of glaucoma, iris is deformed, blocking fluid drainage and hence increasing intraoccular pressure
What are the effects of muscarinic stimmulation on the heart?
Which effect does Ach has on the vasculature?
No direct PNS innervation but has M3 receptors:
- stimmulation causing endothelial NO release
- SM relaxation
Which effect does parasympathetic innervation has on the non-vascular smooth muscle?
–> Constriction:
- Lung: Bronchoconstriction
- Gut: Increased peristalsis (motility)
- Bladder: Increased bladder emptying
Which effect does stimmulation of muscarinic Ach receptor have on excretions?
Exitory:
- Salivation
- •Increased bronchial secretions
- •Increased gastro-intestinal secretions (including gastric HCl production)
- •Increased sweating (SNS-mediated)
What directly acting cholinomimetic drugs are there?
- Alkaloids (Pilocarpine)
- Choline esters (Bethanechol)
What are the characteristics of Pilocarpine?
What kind of drug is it?
It is a non-selective muscarenic agonist
–> good lipid solubility
–> half life around 3-4h
What is the clinical use of pilocarpine?
Mostly used for local treatment of glaucoma
(non-selective muscarenic agonist)
What are possible side effects of pilocarpine? Why?
- Blurred vision (–> PNS stimmulation of eye)
- sweating (SNS stimmulation)
- gastro-intestinal disturbance and pain
- hypotension
- respiratory distress
–> all others: PNS stimmulation
What kind of drug is Bethanechol?
What are its characteristics?
M3 Acetylcholinereceptor selective agonist
- no degradation
- orally active (can be orally given)
- half life: 3-4h
What is the clinical use of Bethanechol?
To assist bladder emptying and enhance gastric motility
What are the side effects of Bethanechol administration?
- Sweating
- imparied vision
- bradycardia
- hypotension
- respiratory distress
What is the function of Acetylcholinesterase?
Where is it found?
Break down ACh to acetate and choline
- found in all cholinergic synapses
- very fast and highly selective
What is the function of Butyrylcholinesterase?
Where is it found?
What are its characteristics?
- Break down ACH
- found in plasma and most tissues, not in synapse –> reason for low ACh plasma levels
- •Broad substrate specificity - hydrolyses other esters e.g. suxamethonium
- Genetic variation
What happens at a low, medium and high dose of cholinesterase inhibitors?
Low dose
- Enhanced muscarinic activity (see above)
Moderate dose
- Further enhancement of muscarinic activity
- Increased transmission at ALL autonomic ganglia (nAChRs)
High dose (toxic)
- Depolarising block at autonomic ganglia & NMJ (see PT9 NMJ lecture) –> too much fiering –> receptors shout down –> paralysis
Which drug is a reversibel Anticholinesterase drug?
Why is it reversible?
Physostigmine and Neostigmine
- competitive inhibitor –> binds to active side
- Donates Carbamyl group that blocks the receptor
- Carbamyl group removed by slow hydrolysis (mins rather than msecs)
What is physiostigme?
What are its characteristics?
A reversibele indirectly cholinomimetic drug
- reversibly blocks Cholinesterase (get freed again after minutes)
- Primarily acts on postganglionic parasympathetic synapse
- Half life about 30m
What is the clinical use of physiosigme?
Clinical use:
- Glaucoma treatment
- To treat atropine poisoning (particularly in children)
What kind of drugs are irreversibel Anticholinesterase Drugs?
How do they act?
- ecothiopate (only one with clinical use)
- dyflos, parathion and sarin used as pestisides or chemical weapons
React with enzyme active side
- Make a stable block, resistant to hydrolysis
- –> recovery may require production of new enzymes
What is Ecothiopate?
Potent inhibitor of acetylcholinesterase
–> Slow reactivation of the enzyme by hydrolysis takes several days
What is the clinical use of Ecothiopate?
Irreversible anticholinesterase inhibitor
Used in treatment of glaucoma
- prolonged effect in fluid drainage
What are the side effect of Ecothiopate?
- Sweating
- blurred vision
- GI pain
- bradycardia
- hypotension
- Respiratory problems
–> PNS stimmulation
What are the effect of Anicholinestases in the CNS?
Non-polar Anticholinesterases can cross BBB
Low doses
- exitation with possibility of convulsions (Krämpfe)
High dose:
Unconsciousness, respiratory depression, death
What are possible treatments for Organophosphate Poisonings?
Organophsphate = irreversible anticholinesterase
Can be treated via
- Atropine (Muscarenic antagonist)
- Parlidoxime within first hours –> displaces the bound organophsphate from enzyme
