Cholinomimetics Flashcards
Muscarinic eye effects
- ciliary muscle contraction (allows for accommodation for near vision as contraction causes lens to bulge)
- sphincter pupillae contraction (causes miosis and improves drainage of intraocular fluid=important for glaucoma
- increased lacrimation
Muscarinic heart effects
- Inhibitory M2 Acetylcholine Receptor in atria and (SA/AV) nodes
- Ach Binding to receptors leads to decreased cAMP production
- Decreased cAMP production leads to decreased calcium ion entry and hence decreased cardiac output (negative inotropic)
- Decreased cAMP production also leads to increased potassium ion efflux and hence decreased heart rate (negative chronotropic)
Muscarinic vasculature effects
NOT DIRECT PARASYMPATHETIC INNERVATION
- ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR
- NO is a powerful vasodilator which induces vascular smooth muscle relaxation (decreased TPR)
Muscarinic exocrine gland effects
- salivation
- increased bronchial secretions
- increased gastro-intestinal secretions (includes gastric HCL production)
- increased sweating (SNS-mediated)
Muscarinic non-vascular smooth muscle effects
SMOOTH MUSCLE IN OTHER ORGANS OF THE BODY DOES NOT HAVE PARASYMPATHETIC INNERVATION SO RESPONDS IN OPPOSITE WAY TO VASCULAR SMOOTH MUSCLE
- Lung: bronchoconstriction
- Gut: increased peristalsis (gut motility)
- Bladder: contraction of bladder smooth muscle leads to increased bladder emptying/urination
Pilocarpine
- non-selective muscarinic agonist (doesn’t select subtypes but overall selectivity for muscarinic over nicotinic receptors)
- good lipid solubility
- half life ~3-4 hours
- useful as local treatment for closed angle glaucoma (causes pupil constriction and hence aids fluid drainage)
- can be given locally as eye drops
- side effects include blurred vision, sweating, GI disturbance and pain, hypotension and respiratory distress
Directly acting cholinomimetic drugs
CLASS OF CHOLINOMIMETIC DRUG
- typical agonists at muscarinic receptors (target site is receptor)
- includes choline esters (bethanechol) and alkaloids (pilocarpine)
Cholinesterases
-metabolise ACh to choline and acetate
The two types of cholinesterases:
- Acetylcholinesterase (true/specific cholinesterase)
- Butyrylcholinesterase (pseudocholinesterase)
TYPES DIFFER IN DISTRIBUTION, SUBSTRATE SPECIFICITY AND FUNCTIONS
Indirectly acting cholinomimetic drugs
CLASS OF CHOLINOMIMETIC DRUG
- target site is acetylcholinesterase enzyme in synaptic cleft
- inhibition of acetylcholinesterase prevents acetylcholine breakdown, hence increasing endogenous acetylcholine concentrations->increases effect of normal parasympathetic nerve stimulation (increased cholinergic activity at all cholinergic synapses)
- includes reversible anticholinesterases (eg: physostigmine, neostigmine etc) and irreversible anticholinesterases (eg: ecothiopate, sarin etc)
Butyrylcholinesterase
- widespread->found in plasma and most tissues (eg: liver, skin etc) but not cholinergic synapses
- broader substrate specificity than acetylcholinesterases, hydrolysing other esters such as suxamethonium (neuromuscular blocking drug)
- principal reason for low plasma ACh
- shows genetic variation->influences duration of action of the drug which the enzyme typically metabolises
Effects of Cholinesterase inhibitors
Low dose: enhanced muscarinic activity Moderate dose: further enhancement of muscarinic activity and increased transmission at all autonomic ganglia High dose (toxic): depolarising block at autonomic ganglia and neuromuscular junction giving rise to respiratory depression
Reversible Anticholinesterase drugs
- Eg: physiostigmine, neostigmine
- compete with ACh for active site on cholinesterases
- donates a carbamyl group to enzyme to block active site and prevent ACh accessing and binding=enzyme inactivation
- carbamyl group removed by slow hydrolysis (mins)=reactivation of carbamylated enzyme
- works to increase duration of ACh activity in synapse
Physostigmine
- naturally occurring tertiary amine
- acts at postganglionic parasympathetic synapse
- half life ~30 mins (short)
- indirect treatment for glaucoma (helps intraocular fluid drainage)->eye drop administration (ophthalmic route of administration)
- used to treat atropine poisoning, mainly in children (atropine=competitive muscarinic antagonist)->intravenous administration of physostigmine inhibits acetylcholinesterase, hence raising the concentration of the agonist acetylcholine (reduced acetylcholine breakdown) for competition with atropine
Irreversible Anticholinesterase drugs
-Organophosphate compounds (eg: ecothiopate in clinical use, sarin, dyflos, parathion etc) possessing a labile group (fluoride or organic)
-React rapidly with enzyme active site to leave large, stable blocking group (phosphorylation of serine residue in binding site inactivates the enzyme)
-blocking group is stable and resistant to hydrolysis (irreversible block)-> means that new enzyme production is required to recover (takes days/weeks)
-only ecothiopate in clinical use, but other organophospate compounds listed are commonly used
in agriculture/horticulture (insecticides) and in biological warfare (nerve gas)
Ecothiopate
- potent acetylcholinesterase inhibitor (phosphorylation of acetylcholinesterase)
- potency allows for slow enzyme reactivation by hydrolysis (takes several days)
- used as eye drops in glaucoma treatment (increases intraocular fluid drainage with prolonged duration of action)
- systemic side effects include sweating, blurred vision, GI pain, bradycardia, hypotension and respiratory difficulty
