AchE inhibitors Flashcards

1
Q

AChE

A

most significant physiological mech which cholinergic is terminated - enzyme may exist in monomeric, dimeric, or multimeric forms and is attached to the extracellular surface of neurons by glycosylphophatidylinositol anchoring

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2
Q

AChE belongs ti the ___ family of enzymes

A

serine hydrolase - all use a similar triad of amino acids to carry out the esterase activity within the active site - all human AChE is coded by a single gene, alternative slicing of the pre-mRNA may lead to different splice varients

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3
Q

what happens if there is alternative slicing of the pre-mRNA

A

may lead to different splice variants - possibly leading to difference in drug binding

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4
Q

ACh capability is limited by

A

how easily it can diffuse to the active site- the enzyme has one of the highest turn over rates of any known enzyme

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5
Q

where is AChE located

A

at every cholinergic synapse and is responsible for the termmination of cholinergic transmission by hydrolyzing ach to choline and acetate

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6
Q

catalytic triad composed of

A

serine, histamine, glutamate - also cationic binding for the charged nitrogen tryptophan residue rather than anionic amino acid such as asp or glu

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7
Q

process by which AChE hydrolyzes Ach is

A

through a two-step acyl substitution reaction:

  1. nucleophillic attack of the choline ester by the serine hydroxyl, releasing choline.
  2. acetylated enzyme is then hydrolyzed to release acetate and the enzyme is returned to its original state
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8
Q

similarities of neostigmine and ach

A

quant ammonium, alcoxy

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9
Q

what are some differences of ach and neostigmine

A

ring, carbamate, looks enough like ach to get into the active site

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10
Q

regeneration time (hydrolysis of carbamate ester) usually longer than with the acetylated form. tell how this would effect duration of action correlated to plasma drug levels with these types of drugs

A

drug is active when broken down, the plasma conc may decrease as AchE handled, usually think parent to metabolite will end drug action - stigmines work when AChE acetyles carbamalating the enzyme

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11
Q

what do all stigmines have in common

A

all have one ring, carbamate ester

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12
Q

reversible inhibiotrs

A

not carbamilated, increase the plasma level which inc the effect, prevents AChE from getting to the active site endophonium, galantamine, donepezil

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13
Q

organophosphates

A

extremely toxic to mammals and humans. similar mech to carbamates the phosphorylated enzyme resistant to hydrolysis which prevents regeneration of functional enzyme

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14
Q

why would removal of OR2 with OH hinder the hydrolysis and slow the regeneration of enzyme-

A

P not electrophilic and not susceptible to nucleophilic attack - aging is leaving group going away and can’t phosphorylate

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15
Q

what is needed to break the serine-o-phosphoryl bond

A

very strong nuc much stronger than water. nuc also needs to be drawn in the active site and bind with some specificity with AChE

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16
Q

oximes

A

strong nucleophiles and used for synthesis of 2-pyriding-aldoxime methyl chloride

17
Q

2-PAM

A

Increases the rate of AChE regeneration from organophophate exposure a million-fold- must be given before the aging occurs - only treats peripheral symptoms NOT cns

18
Q

inhibition of AChE by an organophosphate would cause what?

A

increase in SLUD, inc in ach would stimulate muscle spasms, increase respiration and bronchoconstriction

19
Q

there are several reasons we want to give an AChE

A

all inc synaptic ach - myasthenia gravis, reveral of non-depolarizing nm blockade, alzheimers

20
Q

drugs help with myasthenia gravis

A

neostymine, pyrdo, edrophonium- ox short acting

21
Q

myasthenia gravis

A

autoimmune, nicotinic of NMJ, ach, fewer receptors bc body is destroying them and need more ach

22
Q

Alzheimer’s

A

dec ach, want to give an ach inhib, amaloyd plaque, neuro deg of cholinergic synapse

23
Q

alzheimers drugs

A

rivastigmine, galant, dneprezil, physo

24
Q

glaucoma drugs

A

prevent breakdown of ach already there, eclothiophate

25
Q

SAR neostigmine

A

ring, ester, h, ammonium