6 - Cholinomimetics Flashcards
What is a cholinomimetic
A drug that stimulates the action of ACh and thus the parasympathetic nervous system
What happens to acetate produced by ACh metabolism?
It is transported away and buffered in the blood
What is a muscarinic effect?
An effect that can be replicated by muscarine and abolished by atropine.
How can stimulation similar to nicotine be achieved using atropine?
Atropine blockade of muscarinic actions
Large dose of ACh
Briefly outline structure of muscarinic receptors
type 2, metabotropic
intracellular loop with coupled G protein
there are 7 TM segments
Outline the types and locations of muscarinic receptors
M4 and M5 in CNS
M1 - Salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary glands, bronchial visceral smooth muscle, sweat glands, eye
Categorize the muscarinic receptors in terms of whether they are stimulatory or inhibitory
M1, M3 Generally excitatory
M2 Inhibitory {Heart}
M1, M3, M5 Gq, IP3 DAG (stimulatory G protein)
M2, M4 Gi, cAMP (inhibitory G protein) - inhibits adenylyl cyclase
Outline the structure of nicotinic receptors
They are ligand gated ion channels - they have 5 subunits a b d y e; the combination of subunits determines ligand properties of the receptor
Muscle 2a bde
Ganglionic 2a 3b
What is the relative strength of ACh on nicotinic receptors?
It is relatively weak
List the muscarinic targets
Eye
Heart
Vasculature
Lung
Gut
Bladder
Exocrine Glands
Outline muscarinic effects in the eye
Eye - contraction of ciliary muscle - near vision
- contraction of sphincter pupillae (circular muscle of the iris); miosis (pupil constriction), increased drainage of intraocular fluid*
- lacrimation * via canals of Schlemm; in glaucoma, iris is ruffled and angle is reduced, cholinomimetic drug flattens iris back against the lens
Outline muscarinic effects in the heart and vasculature that work in dropping BP
Heart (in nodes and atria) - decrease in cAMP; decreased cardiac output [negative inotropic], decreased HR [negative chronotropic]
Vasculature (have muscarinic receptors but no direct parasympathetic innervation) - vascular endothelial cells [M3, on endothelial cells, not muscle] produce NO which relaxes smooth muscle and decreases Total Peripheral Resistance
Outline muscarinic effects in other areas of smooth muscle
Lung - Bronchoconstriction
Gut - Increased peristalsis (motility)
Bladder - Increased bladder emptying
Outline muscarinic effects in the exocrine glands
- salivation
- bronchial secretions
- GI secretions
- increased sweating (via sympathetic nervous system)
Summarise the systemic muscarinic effects of all organs symptomatically
Decreased HR
Decreased BP
Increased sweating
Difficulty breathing
Bladder contraction
GI pain
Increased salivation and tears
What are the two types of muscarinic receptor agonists?
- Direct - target receptor, bind and have efficacy; choline esters and alkaloids
- Indirect - anticholinesterases (target one of 2), indirectly increase [ACh] by preventing breakdown, reversible or irreversible
Outline the properties of choline esters with an example
Bethanechol (or new Cevimeline - greater M3 selectivity)
M3 selective Resistant to cholinesterases Oral Limited access to brain t1/2 3-4hrs
Given post-operatively to kickstart bladder emptying and gastric motility
Side effects: bradycardia, hypotension, respiratory difficulty
What is the structure of bethanechol?
See structure
Outline the properties of alkaloids with an example
Pilocarpine
Muscarinic selective but not for subtypes
t1/2 3-4 hrs, lipid soluble
Local treatment (eye drops) for closed angle glaucoma Side effects: hypotension, respiratory distress
What are the two types of cholinesterases that anticholinesterases can act on
Vary in distribution, substrate specificity and function
- Acetylcholinesterase (true/specific) - ACh specific, fast acting, found at all cholinergic synapses, has a serine residue with OH group
- Butyrylcholinesterase (pseudo) - broad specificity e.g. suxamethonium, found in plasma + other tissues, genetic variation, responsible for low plasma ACh
Outline the mechanism of action for the two types of anticholinesterases
Reversible - PHYSOSTIGMINE, neostigmine, donepezil ‘Aricept’; donate a carbamyl group, slow hydrolysis (mins), surmountable
Irreversible - ECOTHIOPATE, dyflos, sarin; organophosphates, require new enzymes to be produced (days/weeks), insurmountable
What are the general effects of anticholinesterases by dosage level?
At low doses - enhance muscarinic activity
At medium doses - they further enhance muscarinic activity and increase transmission at autonomic ganglia
At high doses - they are toxic due to depolarising block at autonomic ganglia and NMJ
What is a depolarising block?
There are two phases to the depolarizing block. During phase I (depolarizing phase), depolarising blocking agents cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons.
At this point, full neuromuscular block has been achieved.
The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically.
Outline the properties of reversible anticholinesterases with an example
Physostigmine
Primarily acts at the post-ganglionic parasympathetic synapse
t1/2 30mins
Used for treating glaucoma and atropine poisoning in children (atropa belladonna - deadly nightshade); in latter is given via IV shot, surmounts the atropine block
