6: Cholinomimetics Flashcards
Define cholinomimetics
drugs that mimic action of ACh in the body – parasympathomimetic drugs
Eg of muscarinic antagonist
atropine - competitive muscarinic antagonist
Muscarinic effects in eye
- Ciliary muscle contraction: accommodates for near vision
- Sphincter pupillae contraction (circular muscle of the iris): this constricts the pupil (miosis) + increases drainage of intraocular fluid
- Lacrimation (tears)
How does glaucoma occur
Glaucoma is an increase in intraocular pressure - this can cause damage to the optic nerves and retina and can ultimately lead to blindness.
- Fenestrated capillaries of the ciliary body generates aqueous humour
- It flows into the anterior chamber of the eye. Role: supply O2 + nutrients to the lens + cornea bc they don’t have a blood supply.
- The aqueous humour diffuses forwards across the lens, then across the cornea and it drains through the canals of Schlemm back into the venous system.
What is angle closure glaucoma
The angle btwn the cornea + iris narrows, reducing drainage of intraocular fluid via canals of schlemm
How is angle closure glaucoma treated
Muscarinic agonist - causes iris contraction, opening of angle, incresing drainage of intraocular fluid through canals of Schlemm.
Muscarinic effects in heart
M2 receptors are INHIBITORY. It slows down the heart rate. M2 receptors are found in the atria and in both nodes. It causes a negative inotropic (contractility) and chronotropic (HR) effect. It reduces cAMP in cardiomyocytes + pacemaker cells, decreasing Ca2+ entry (decreasing CO), increasing K+ effluc (decreasing HR).
Muscarinic effects on vasculature
Receptors sit on vascular endothelial cells.
- ACh acts on vascular endothelial cells to stimulate NO release via M3 receptors.
- NO induces vascular smooth muscle relaxation - vasodilation
- This results in a decrease in TPR
Muscarinic effects on CVS
- ↓HR
- ↓CO (due to decreased atrial contraction)
- Vasodilation (via stimulation of NO release)
=Drop in BP
Muscarinic effects on non-vascular SM (lungs, gut, bladder)
Non-vascular SM that has PS innervation responds in the opposite way to vascular SM - it contracts
• Lungs - bronchoconstriction
• Gut - increased peristalsis/motility
• Bladder - increased bladder emptying
Muscarinic effects on exocrine glands
- Salivation
- ↑bronchial secretions
- ↑GI secretions (including gastric HCl production)
- ↑sweating (SNS-mediated)
2 types of cholinomimetic
Directly Acting
Indirectly acting
Directly acting cholinomimetic drugs are which type of agonist and give the 2 types
Muscarinic receptor agonists
2 types:
- choline esters
- alkaloids
Example of choline ester
bethanechol - only diff btwn that and ACh is one methyl group. So is v good muscarinic agonist
Example of alkaloid
Pilocarpine - non-selective muscarinic agonist as some structure similarity btwn it and ACh
Example of M3 receptor selective agonist
Bethanechol - v slighlty diff to ACh
Which directly acting cholinomimetic drug is used in treatment of glaucoma
pilocarpine
Which directly acting cholinomimetic drug is resistant to acetylcholinesterase
bethanechol
Uses of bethanechol
assist bladder emptying and enhance gastric motility
side effects of pilocarpine
- Blurred vision
- Sweating
- GI disturbance and pain
- Hypotension
- Respiratory distress
Side effects of bethanechol
- Sweating
- Impaired vision
- Nausea
- Bradycardia
- Hypotension
- Respiratory difficulty
How do indirectly acting cholinomimetic drugs work
Inhibit acetylcholinesterase, increasing amount of ACh building up in the synapse, thus increasing effect of normal PS nerve stimulation.
2 types of indirectly acting cholinomimetic drugs
- Reversible Anticholinesterases:
* Irreversible Anticholinesterases:
Examples of reversible anticholinesterases
PHYSOSTIGMINE, Neostigmine, Donepezil
Examples of irreversible anticholinesterases
ECOTHIOPATE, Dyflos, Sarin
2 types of cholinesterases
- Acetylcholinesterase (true or specific cholinesterase)
* Butyrylcholinesterase (pseudocholinesterase)
How does Acetylcholinesterase work
It is highly selective for acetylcholine
Serine AA residue on active site of AChE – ACh binds to this active site. Hydroxyl group of serine splits off the acetyl group into choline + acetate, inactivating it rapidly.
Found in all choliinergic synapses
Where is Butyrylcholinesterase found
plasma and in most tissues but not in cholinergic synapses. Has broad substrate specificty
How do reversibe anticholinesterases work
They compete with ACh for the active site on acetylcholinesterase. They donate a carbamyl group to the enzyme, blocking the active site and preventing ACh from binding.
• Carbamyl groups are removed by slow hydrolysis (this takes minutes rather than miliseconds)
• This increases the duration of acetylcholine activity in the synapse
Physostigmine (where it acts, half life, uses)
Where: postgang PS synapse
Half life: 30mins
Use: Glaucoma - increases drainage of intraocular fluid
Use: Atropine poisoning - a competitive muscarinic antagonist means that it’s surmountable. Physostigmine increases [ACh] at synapse so ACh can outcompete atropine.
Is non-polarso can cross BBB
How do irreversible anticholinesterase drugs work
Irreversible anticholinesterase drugs are organophosphate compounds. They rapidly react with the enzyme active site, leaving a large blocking group. The blocking group is stable and resistant to hydrolysis so recovery requires the production of new enzymes (this takes days/weeks)
Ecothiopate (how it acts, uses)
Potent inhibitor of acetylchoninesterase
Slow reactivation of the enzyme by hydrolysis takes several days
Uses: glaucoma treatment, increases drainage of intraocular fluid and has prolonged duration of action
Effects of Cholinesterase Inhibitors at low, moderate and high doses
- Low dose: enhanced muscarinic activity. CNS excitation w possibility of convulsions
- Moderate dose: Further enhancement of muscarinic activity, increased transmission at all autonomic ganglia (nAChRs). This is bc the anticholinesterase increases the [ACh] at all cholinergic synapses, muscarinic and nicotinic
- High dose: depolarising block at autonomic ganglia (block on nAChrs) and NMJ. The nicotinic receptors get overstimulated so they shut down. May see unconsciousness, respiratory depression + death
Organophosphate poisoning
Accidental exposure to organophosphates used in insecticides, or deliberate use in nerve agents can cause severe toxicity (increase in muscarinic activity = CNS excitation = depolarising NM block)
Treatment of organophosphate poisoning
IV atropine: because organophosphate poisoning results in a massive reduction in the activity of acetylcholinesterase which leads to a massive increase in synaptic [ACh]. To block the ACh from over-stimulating the receptors you give a muscarinic antagonist (atropine)
PT put on respirator bc of respiratory depression
If found in the first few hours the patient can be given Pralidoxime (IV) - this unblocks the enzymes
