2 - AChE Flashcards
What are the two types of cholinesterases? What differentiates them?
AchE: in synapses, ACh only
plasma cholinesterase in plasma: Ach, succinylchline, local anesthetics (procaine)
Describe the active site of AChE. What are the functions of the different amino acids.
esteratic site: Ser, His, Glu
Ser attacks electrophilic carbonyl of ester.
His and Glu proton bond to weaken serine O-H bond. water hydrolyzes off acetate.
anionic site: Trp and Phe stabilize charged amine through pi cation interaction
Why are AChE considerd indirect-acting parasympathomimetics?
increase the amount of ACh in the synapse available to activate postsynaptic receptors.
What are the three main structure types of reversible AChEIs? Contrast their molecular interactions with AChE.
tetraalkylammonium ions, quaternary ammonium alcohol (edrophonium): bind to anionic site and block ACh binding, reversible, non-covalent
carbamates: these quaternary or teriary ammonium groups are reversible inhibitors that COVALENTLY modify AChE
Contrast the S/fxn of the three carbamate AChEs
neostigmine: quaternary ammonium group
pyrido and physo tertiary ammonium groups.
neo and pyrido are most charged at pysio pH.
physo is least chargd, less polar, can cross BBB, more systemic SEs.
How do the carbamates interact with AChE?
inhibiting covalently.
pi-pi or pi-cation interaction in anionic site
serine in esteractic site attacks carbamyl. carbamate very slowly hydrolyzed.
Describe the moa of organophosphates as AChE inhibitors. Contrast their uses.
irreversible covalent modification to AChE.
long acting. the phosphate is a very strong electrophile.
isofluorophate
echothiophate used in glaucoma
sarin and soman and nerve gases. lipophilic-abs’d through skin.
insecticies such as malathion and diazinon are rapidly inactivated by mammals (prodrug d/t S)
Compare the toxicity of malathion and diazinon in mammals and insect.
insection: CYP450 activates to malaoxon; toxic
mammals, birds: carboxyesterase inactivates into diacid ; nontoxic
Why do organophosphate selectively affect the cholinergic system?
they don’t. those are just the primary effects we see since AChE is so important.
Contrast the moa of organophosphate (including the “aging effect”and the reversible inhibitors of AChE.
organophosphate phosphorylate serine. hydrolysis is so slow that it is essentially irreversible. must make new AChE. partial hydrolysis strenghts the bond = aging
reversible AChE inhibitors are either competitive or experience slow but still appreciable hydrolysis (carbamates)
What is the anticodote for AChE poisoning by organophosphates (pesticides or nerve gases)?
pralidoxime chloride (protopam; 2-PAM)
most effecive if given w/in a few hours of exposure (before aging)
moa: nucleophilic attack on phosphate to remove it from enzyme
What is an appropriate AChEI for myasthenia gravis?
edrophonium
neostigmine gravis
What is an appropriate AChEI for treatment of post-op ileus and bladder distention or as a surgical adjunct?
neostigmine
What is an appropriate AChEI for treatment of glaucoma?
physostigmine
isofluorophate
echothiophate
What are AChEIs used for treatment of Alzheimer’s disease?
physostigmine tacrine donepezil (riva/eptastigmine) galantamine
Which AChEIs are used as an antidote to anticholinergic overdose?
physostigmine
Explain why parasympathomimetic drugs shold not be used in asthma, peptic ulcer , or bowel and urinary obstructions?
activate M receptors
asthma/COPD: bronchoconstriction
peptic ulcer: increase acid secretion
obstruction: stimulate movement of food/urine, exacerbating blockage.
SLUDGE describes the S/Sx of ____. What are other S/Sx?
SLUDGE: salivation, lacrimation, urination, defecation, GI, emesis
parasympathetic toxicity (overactivation)
also incr sweating, decreased heart rate, pupils constricted, CNS activation/hallucination
What are appropriate treatments for parasympathomimetic toxicity?
cholinergic receptor antagonist such as atropine
if irreversible AChE then 2-PAM (pralidoxime)
Describe pathogenesis of Alzeimer’s disease.
widening of sulci and thinning of gyri –> atrophy of brain
improper prrocesses of beta-amyloid precursor protein leads to toxic form that promtoes paoptosis
loss of cholinergic neurons in brain
Compare and contrast the moa for the agents used to treat Alzheimer’s dz.
tacrine (Cognex): bind to anionic site and compete, rev, non-cov [also donepezil (Aricept)] ;
rivastigmine (Exelon) is reversible carbamate AChE inhibitor; [New: eptastigmine]
galantamine (Razadyne): reversible competitive AChE inhibitor, natural produce, may be nicR ag; incr BA with P450 inhib
memantine (Namenda) is N-methyl-D-aspartate receptor antag. these R can’t be activated by glutamate. incr activity glutamate is assoc’d w neuronal loss. –> mayslow progression of disease. favorable ADR profile.
