2 - AChE

Question 1

What are the two types of cholinesterases? What differentiates them?

Answer 1

AchE: in synapses, ACh only

plasma cholinesterase in plasma: Ach, succinylchline, local anesthetics (procaine)

Question 2

Describe the active site of AChE. What are the functions of the different amino acids.

Answer 2

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

Question 3

Why are AChE considerd indirect-acting parasympathomimetics?

Answer 3

increase the amount of ACh in the synapse available to activate postsynaptic receptors.

Question 4

What are the three main structure types of reversible AChEIs? Contrast their molecular interactions with AChE.

Answer 4

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

Question 5

Contrast the S/fxn of the three carbamate AChEs

Answer 5

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.

Question 6

How do the carbamates interact with AChE?

Answer 6

inhibiting covalently.
pi-pi or pi-cation interaction in anionic site

serine in esteractic site attacks carbamyl. carbamate very slowly hydrolyzed.

Question 7

Describe the moa of organophosphates as AChE inhibitors. Contrast their uses.

Answer 7

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)

Question 8

Compare the toxicity of malathion and diazinon in mammals and insect.

Answer 8

insection: CYP450 activates to malaoxon; toxic

mammals, birds: carboxyesterase inactivates into diacid ; nontoxic

Question 9

Why do organophosphate selectively affect the cholinergic system?

Answer 9

they don’t. those are just the primary effects we see since AChE is so important.

Question 10

Contrast the moa of organophosphate (including the “aging effect”and the reversible inhibitors of AChE.

Answer 10

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)

Question 11

What is the anticodote for AChE poisoning by organophosphates (pesticides or nerve gases)?

Answer 11

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

Question 12

What is an appropriate AChEI for myasthenia gravis?

Answer 12

edrophonium

neostigmine gravis

Question 13

What is an appropriate AChEI for treatment of post-op ileus and bladder distention or as a surgical adjunct?

Answer 13

neostigmine

Question 14

What is an appropriate AChEI for treatment of glaucoma?

Answer 14

physostigmine
isofluorophate
echothiophate

Question 15

What are AChEIs used for treatment of Alzheimer’s disease?

Answer 15

physostigmine
tacrine
donepezil
(riva/eptastigmine)
galantamine

Question 16

Which AChEIs are used as an antidote to anticholinergic overdose?

Answer 16

physostigmine

Question 17

Explain why parasympathomimetic drugs shold not be used in asthma, peptic ulcer , or bowel and urinary obstructions?

Answer 17

activate M receptors

asthma/COPD: bronchoconstriction

peptic ulcer: increase acid secretion

obstruction: stimulate movement of food/urine, exacerbating blockage.

Question 18

SLUDGE describes the S/Sx of ____. What are other S/Sx?

Answer 18

SLUDGE: salivation, lacrimation, urination, defecation, GI, emesis

parasympathetic toxicity (overactivation)

also incr sweating, decreased heart rate, pupils constricted, CNS activation/hallucination

Question 19

What are appropriate treatments for parasympathomimetic toxicity?

Answer 19

cholinergic receptor antagonist such as atropine

if irreversible AChE then 2-PAM (pralidoxime)

Question 20

Describe pathogenesis of Alzeimer’s disease.

Answer 20

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

Question 21

Compare and contrast the moa for the agents used to treat Alzheimer’s dz.

Answer 21

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.