anticholinesterases Flashcards
physiological effect of all cholinesterase inhibitors
increase in acetylcholine at cholinergic synapses by blocking its synaptic degradative pathway
Effect of tertiary amines is seen where
CNS
effect of quaternary amines action is confined where
peripheral nervous system
AChE expression in the brain
catalytic subunit tetramers are linked directly to a membrane- anchoring protein at synapse
reversible cholinesterase inhibitors
from transient complexes with the cholinesterases
compete for ACh and the enzyme active site
quaternary ETOHs -> simple competitive inhibitors binding and blocking access to the active site
carbamates -> slowly hydrolyzed substrates which both block access and tie up the active site of serine
Endrophonium
reversible inhibitor -> steric block of access of ACh to AChE active site
- quaternary amine - brief duration of action
- used to test for myasthenia gravis: rapid iv administration of small dose will result in brief improvement of strength
Physostigmine
Carbamate (reversible inhib)-> blocks active site while undergoing slow hypdrolysis by AChE
- tertiary amine used in treatment of wide angle glaucoma
- acts to facilitate efflux of aqueous humor via canal of schlemm
- can enter CNS and will reverse effects of atropine and other drugs with antimuscarinic properties
- adverse effect: can facilitate formation of cataracts
Neostigmine
carbamate
- quaternary amine - short duration
- drug of choice for use in paralytic loss of tone in the GI tract and bladder
- drug standard for use in myasthenia gravis
Pyridostigmine
carbamate
- used in myasthenia gravis- when effective drug of choice owing to long duration of action
- maybe a pretreatment to decrease risk of mortality on exposure to nerve gases
irreversible cholinesterase inhibitors
inactivate the AChE active sit by covalent attachment
- organophosphates
- form highly stable (covalent) phospho-intermediates
- bind to and undergo initial hydrolysis by AChE but the acyl intermediate is replaced by a phosphoryl moiety which is cleaved extremely slowly
- full recovery of cholinesterase activity , requires do novo biosynthesis of AChE
how to get recovery of cholinesterase activity in tissues
to reactive the phosphoryl enzyme using a strong nucleophile, at an early stage of inhibition
-accomplished by using an oxime ( pralidoxime 2-PAM)
and later stages of inhibition the phosphoryl group on the enzyme will undergo aging where in an alkyl group is lost from the phosphoryl moiety rendering it resistant to oxime attack
organophosphates (4)`
**Echothiophate - only clinically useful one, used in glaucoma
Malathion- pro drug insecticide which once activate undergoes “detox” in mammals via plasma esterases
Parathion- potent insecticie - poising and death occur alot from this drug
Sarin/soman - “nerve gas”
Toxicity- acute intoxication
symptoms cholinergic toxidrome
SLUDGE-BAM
salivaation/ sweating lacrimation urination defecation GI upsest Emesis bradycardia /bronchoconstriction/ bowel movement abdominal cramps/ anorexia miosis
symptoms of muscarinic excess in parasympathetic system
bronchospasm, bronchorrhea, miosis, lacrimation, urination, diarrhea, bradycardia, vomiting, salivation and sweating
nicotinic excess in symp system
hypotension (desensitization of receptors on sym gang)
sweating
