Cholinomimetics Flashcards
(33 cards)
How do directly acting cholinomimetics produce their biological actions?
- Muscarinic receptor agonists
- Stimulate muscarinic receptors
- Similar structure to ACh
- Can be choline esters or alkaloids
How do indirectly acting cholinomimetics produce their biological actions?
- Inhibit acetylcholinesterase
- Tf increase [ACh] in synapse
- Increase effect of normal parasympathetic nerve stimulation
- Can be reversible or irreversible
Why are directly acting cholinomimetics more selective?
You can use an M1, M2, M3 etc. receptor selective agonist, whereas indirectly acting cholinomimetics inhibit acetylcholinesterase everywhere
What are muscarinic receptor agonists used for clinically?
- Glaucoma
- Xerostomia (radiation-induced dry mouth)
- Acute post-operative and postpartum non-obstructive urinary retention
What are the pharmacokinetic properties of muscarinic receptor agonists?
- Half-life = 3-4 hours
- Admin: pilocarpine -eye drops - glaucoma
- Admin: bethanecol - orally active
What are anticholinesterases used for clinically?
Physostigmine:
- Glaucoma
- To treat atropine poisoning i.v.
Neostigmine:
- Reversal of non-depolarising NM block (tubocurarine)
- Myasthenia gravis
Ecothiopate:
- Glaucoma
Donepezil + tacrine = Alzheimer’s
What are the signs and symptoms of anticholinesterase poisoning?
CNS excitation Convulsions Unconsciousness Resp depression Death
How is anticholinesterase poisoning treated?
- IV atropine (competitive reversible muscarinic receptor antagonist) to block overstimulation
- Artificial respiration
- IV pralidoxime to unblock enzymes
Where are muscarinic M3 receptors found?
Salivary glands
Bronchial/visceral smooth muscle
Sweat glands
Eye
Where are muscarinic M4 and M5 receptors found?
CNS
Are muscarinic receptors generally excitatory of inhibitory?
Excitatory except M2 receptors on heart - inhibitory - decrease HR
What type of receptors are muscarinic receptors?
Type 2
G-protein coupled
What specific type of G-protein coupled receptors are M1, 3 and 5 Rs?
Gq protein linked
Stimulates PLC to increase production of IP3 and DAG
What specific type of G-protein coupled receptors are M2 and 4 Rs?
Gi protein linked
Inhibitory
Reduces cAMP production
How does the structure of nicotinic receptors in muscle and in ganglion differ?
Muscle = 2 alpha + beta + delta + epsilon subunits
Ganglion = 2 alpha + 3 beta
Subunit combination determines ligand binding properties
What are nicotinic receptors?
Ligand gated ion channels
How do ACh effects on nicotinic vs. muscarinic receptors differ?
Relatively weak on nicotinic
What are the general effects of cholinomimetics?
- Decrease HR and CO
- Increase exocrine gland activity
- Increase non-vascular SM contractility
- Miosis (constriction)
How do the effects of anticholinesterases (indirect cholinomimetics) differ with dosage?
Low dose: enhanced muscarinic activity
Moderate dose:
Further enhancement of muscarinic activity
Increased transmission at all autonomic ganglia
High dose:
Depolarising block at autonomic ganglia and NMJ
Nicotinic receptors overstimulated and shut down
How do reversible anticholinesterase drugs work?
Alkaloids, e.g. physostigmine, neostigmine
- Carbamyl esters inactivate enzyme by transferring their carbamyl group
- Carbamylated enzyme reactivated by slow (mins) hydrolysis
- Increases duration of ACh activity in synapse
Which anticholinesterases can cross the BBB?
Physostigmine
Non-polar
How do irreversible anticholinesterase drugs work?
- Organophopshate compounds
- Labile group (flouride or organic) inactivate enzyme by phosphorylation
- Inactivated phosphorylated enzyme is stable
- Tf recovery depends upon synthesis of new enzyme (weeks)
Why does recovery from irreversible anticholinesterases take days or weeks?
Recovery requires production of new enzymes, which takes time
Where are nicotinic cholinoceptors found other than the ANS?
Somatic NS
But they differ pharmacologically from those found in the ANS
