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Therapeutics > Exam 1 Cholinesterase Inhibitors > Flashcards

Exam 1 Cholinesterase Inhibitors Flashcards

1
Q

What are the two types of cholinesterases?

A

acetylcholinesterase and plasma cholinesterase

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2
Q

What is acetylcholinesterase?

A
  1. located in neuron synapses

2. has substrate selectivity for only acetylcholine

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3
Q

What is plasma cholinesterase?

A
  1. located in plasma (non-neuronal)
  2. has substrate selectivity for acetylcholine (not as efficient as acetylcholinesterase), succinylcholine, and local anesthetics (like procaine) → has a broader substrate selectivity
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4
Q

What is important to note about acetylcholinesterase (AChE)?

A
  1. it has the highest turnover rate of any known mammalian enzyme
  2. hydrolyzes acetylcholine molecules with a turnover time of 150 microseconds
  3. reaction requires water and three amino acid residues that form a catalytic triad (at the esteric site)
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5
Q

What are the two main binding sites of acetylcholinesterase?

A
  1. anionic site → in which the positively charged choline side of acetylcholine binds to via ionic interaction
  2. esteric site → in which the acetyl moiety of acetylcholine binds to using a transient covalent bond formation (hydrogen bond?)
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6
Q

What are the products of the hydrolysis of acetylcholine by acetylcholinesterase?

A

acetic acid and choline

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7
Q

What is the catalytic triad that is required for the hydrolysis of acetylcholine at the esteric site?

A

glutamic acid, histidine, and serine

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8
Q

What are the steps of the hydrolysis of acetylcholine by acetylcholinesterase?

A
  1. nucleophilic attack by serine to the acetyl group so that choline is free
  2. water comes in → nucleophilic attack by water that releases acetate
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9
Q

What is the basic process of the hydrolysis of acetylcholine?

A

acetylcholine → choline + acetylated enzyme (inactive) → reactivated enzyme after acetate leaves via nucleophilic attack by water

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10
Q

What are the classification of anticholinesterase agents?

A
  1. reversible

2. irreversible

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11
Q

What are the different classes of reversible anticholinesterase agents?

A
  1. alcohol → edrophonium
  2. carbamates → physostigmine, neostigmine, pyridostigmine
  3. others → donzepezil (Aricept) which is used in Alzheimer’s
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12
Q

What are the different classes of irreversible anticholinesterase agents?

A

organophosphates → echothiophate (used in glaucoma), sarin (nerve gas/chemical warfare agents), malathion (pesticide, head lice) → mainly toxic

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13
Q

What is the typical structure of acetylcholinesterase inhibitors?

A
  1. tetra-alkylammonium ions (nitrogen bound to 4 R groups)
  2. bind to anionic site and block acetylcholine from binding
  3. reversible
  4. non-covalent
  5. optimal R group has 3 carbons since you want it a little bigger to inhibit the binding site but not too big that it blocks the site
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14
Q

What is important to know about edrophonium (Tensilon)?

A
  1. quaternary ammonium alcohol
  2. binds to the anionic site to block acetylcholine from binding
  3. reversible
  4. non-covalent binding
  5. R groups include CH3, CH3, C2H5, and a phenol ring
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15
Q

What is important to know about edrophonium (Tensilon)?

A
  1. quaternary ammonium alcohol
  2. binds to the anionic site to block acetylcholine from binding
  3. reversible
  4. non-covalent binding
  5. can’t be hydrolyzed like acetylcholine
  6. R groups include CH3, CH3, C2H5, and a phenol ring
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16
Q

What are important things to know about neostigmine (Prostigmin), pyridostigmine (Mestinon), and physostigmine (Antilirium)?

A
  1. carbamates → have a carbamate group
  2. quaternary or tertiary ammonium groups
  3. reversible
  4. covalent modification to acetylcholinesterase
  5. more slowly hydrolyzed than acetylcholine
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17
Q

What is special about physostigmine (Antilirium)?

A

the nitrogen on the most right hand side of the molecule (side with the rings) is the most basic nitrogen that is protonated at physiological pH → CAN CROSS THE BLOOD BRAIN BARRIER SINCE IT IS NOT CHARGED, TERTIARY AMINE

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18
Q

What is so special about tertiary amine groups?

A

since there isn’t a quaternary amine group, it won’t have the positive charge so it has the potential to cross the blood brain barrier

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19
Q

What is the mechanism of the inhibition of acetylcholinesterase by neostigmine?

A
  1. the OH group on serine at the esteric site does a nucleophilic attack on the carbon of the carbamate group which displaces the carbamate group as it is bonded to it and the rest of the molecule is free
  2. the positively charged quaternary amine leaves
  3. water comes in and attacks the carbamate group to form a (carboxylic acid?) which is then released from the esteric site
20
Q

What are the actions of the therapeutic AChE inhibitors (edrophonium, neostigmine, pyridostigmine)?

A
  1. inhibition of acetylcholinesterase → edrophonium does via noncolvalent, reversible while the “stigmines” as substrates that are more slowly hydrolyzed than acetylcholine
  2. does not readily cross the BBB
21
Q

What are the clinical uses of the therapeutic AChE inhibitors (edrophonium, neostigmine, pyridostigmine)?

A
  1. edrophonium → very short acting (minutes), used in diagnosis of Myasthenia Gravis (MG) which is skeletal muscle weakness due to loss of skeletal muscle nicotinic receptors because of autoimmune disease
  2. pyridostigmine → used in treatment of MG, reversal of nondepolarizing neuromuscular (nicotinic receptor) blockade, pretreatment for potential nerve gas exposure (occupies AChE so that nerve gas has nowhere to go)
  3. neostigmine → used for MG, reversal of nondepolarizing neuromuscular (nicotinic receptor) blockade, post-operational urinary retention
22
Q

What are the problems associated with the therapeutic AChE inhibitors (edrophonium, neostigmine, pyridostigmine)?

A

excessive cholinergic receptor activation

23
Q

What are some other MG treatments?

A
  1. immunomodulators → glucocorticoids, azathioprine, mycophenolate, cyclosporine
  2. rapid immunotherapies
  3. thymectomy
24
Q

What are the actions, clinical uses, and problems of the therapeutic AChE inhibitor physostigmine?

A
  1. action → inhibition of acetylcholinesterase: “stigmines” as substrates that are more slowly hydrolyzed than acetylcholine
  2. clinical use → antidote to antimuscarinic poisoning (since it can cross the BBB because it is a tertiary amine and is thus not charged)
  3. problem → excessive cholinergic receptor activation
25
Q

What are important things to know about isofluorophate, DFP (Floropryl) and echothiophate (phospholine iodide)?

A
  1. organophosphates → most are TOXIC and have a phosphate
  2. irreversible
  3. covalent modification to acetylcholinesterase
  4. longer acting
  5. used in the treatment of glaucoma
26
Q

What are the hydrolysis times of various drugs by acetylcholinesterase?

A
  1. acetylcholine → 150 microseconds
  2. edrophonium → minutes
  3. neostigmine → hour
  4. echothiophate → several hours
27
Q

What are the actions, clinical uses, and problems of echothiophate?

A
  1. action → inhibition of acetylcholinesterase: long acting (essentially irreversible)
  2. clinical use → originally for glaucoma (increase acetylcholine and enhance muscarinic activation and subsequent outflow of aqueous humor) but is not used currently due to availability of better drugs)
  3. problems → excessive cholinergic receptor activation (including miosis)
28
Q

What are important things to know about sarin and soman?

A
  1. organophosphates
  2. nerve gases
  3. irreversible
  4. covalent modification to acetylcholinesterase
29
Q

What are important things to know about malathion and diazinon?

A
  1. organophosphates
  2. insecticides
  3. irreversible → can’t be reversed by water
  4. covalent modification to acetylcholinesterase
  5. rapidly inactivated in mammals
  6. longer lasting
30
Q

What is the biotransformation of insecticides?

A

malathion can be converted to malaoxon by cytochrome P450 (in insects) while it can also be converted to the inactive form by carboxyesterase (in mammals and birds)

31
Q

What is the mechanism of inhibition of acetylcholinesterase by organophosphates?

A
  1. OH of serine does a nucleophilic attack on the phosphate group so that the O of serine replaces by the fluorine of the organophosphate
  2. aging occurs (important for poisoning) in which the phosphate is ionized (negatively charged)
32
Q

Why do these drugs selectively affect the cholinergic system?

A

by the modification of acetylcholinesterase

33
Q

What is the antidote for acetylcholinesterase poisoning?

A

pralidoxime chloride (Protopam, 2-pyridine aldoxime methyl chloride, 2-PAM) → antidote for pesticide or nerve gas poisoning → is most effective if given within a few hours of exposure

34
Q

What is the mechanism of the regeneration of acetylcholinesterase by pralidoxime?

A
  1. the oxygen of pralidoxime attacks the phosphate of the organophosphate and is thus hydrolyzed
  2. has to happen before aging occurs → if not, 2-PAM cannot reverse and regenerate acetylcholinesterase
35
Q

What is the action and clinical use of pralidoxime (2-PAM)?

A
  1. action → an acetylcholinesterase inhibitor antidote in which it is a strong nucleophile so it will hydrolyze organophosphate IF TREAT BEFORE AGING OCCURS → will regenerate acetylcholinesterase → DOES NOT CROSS THE BLOOD BRAIN BARRIER (has to be combined with the muscarinic receptor antagonist atropine)
  2. clinical use → treatment of organophosphate toxicity
36
Q

Why does 2-PAM need to be combined with atropine?

A

2-PAM does not have CNS access so it is not sufficient by itself due to lack of CNS access

37
Q

Why does atropine need to be administered with 2-PAM?

A

it blocks access to muscarinic receptor (antagonist) but it can’t block action at nicotinic receptors

38
Q

What is Alzheimer’s Disease?

A
  1. most common cause of dementia after the age of 50
  2. atrophy of the brain
  3. widening of sulci and thinning of gyri
  4. improper processing of beta-amyloid precursor protein (beta-APP) leads to toxic form (beta-A42) that promotes apoptosis
  5. on pathological exam: senile plaques (beta-amyloid) and neurofibrillary tangles
  6. loss of cholinergic neurons in brain
39
Q

What are important things to know about tacrine (Cognex) as a treatment of Alzheimer’s disease?

A
  1. binds to anionic site and blocks acetylcholine from binding
  2. reversible
  3. non-covalent
  4. enhances cognitive ability
  5. does not slow the progression of the disease
  6. newer agent is donepezil (Apricept)
40
Q

What are important things to know about rivastigmine (Exelon) as a treatment of Alzheimer’s Disease?

A
  1. reversible carbamate acetylcholinesterase inhibitor
  2. enhances cognitive ability by increasing cholinergic function
  3. loses effectiveness as disease progresses → does not help disease progression
  4. side effects → nausea, vomiting, anorexia, and weight loss
  5. newer longer acting carbamate → eptastigmine
41
Q

What are important things to know about galantamine (Razadyne) as a treatment of Alzheimer’s Disease?

A
  1. reversible competitive acetylcholinesterase inhibitor
  2. extract from daffodil (Narcissus pseudonarcissus) bulbs
  3. loses effectiveness as disease progresses
  4. may be a nicotinic receptor agonist
  5. inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability
42
Q

What are important things to know about memantine (Namenda) as a treatment of Alzheimer’s Disease?

A
  1. N-methyl-D-aspartate (NMDA) receptor antagonist
  2. NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory
  3. neuronal loss in Alzheimer’s may be related to increased activity of glutamate
  4. MAY SLOW THE PROGRESSION OF THE DISEASE
  5. favorable adverse effect profile
43
Q

What is the clinical pharmacology of acetylcholinesterase inhibitors?

A

drug → type of inhibition → route of administration → clinical use

  1. edrophonium → reversible → IM or IV → diagnostic for MG
  2. neostigmine → reversible → IM, IV, or oral → MG, post operative ileus and bladder distention, surgical adjunct
  3. physostigmine → reversible → IM, IV, or oral → glaucoma, Alzheimer’s, antidote to anticholinergic overdose
  4. tacrine → reversible → oral → Alzheimer’s
  5. donepezil → reversible → oral → Alzheimer’s
  6. echothiophate → irreversible (organophosphate) → local → glaucoma
44
Q

What are cholinergic agent side effects?

A

SLUD → salivation, lacrimation, urination, defecation + increased sweating, decreased heart rate, pupils constricted, CNS activation

45
Q

What are treatments for cholinergic agent toxicity?

A
  1. cholinergic receptor antagonist (atropine)

2. if irreversible acetylcholinesterase inhibitor, use 2-PAM (pralidoxime) + atropine

46
Q

What are contraindications to the use of parasympathomimetic drugs?

A
  1. asthma and COPD → increase bronchoconstriction
  2. coronary deficiency → further lower heart rate
  3. peptic ulcer → would increase acid secretion
  4. obstruction of the urinary or GI tract → increased contraction does not remove obstruction
  5. epilepsy → M1 receptors (have CNS effect) and CNS penetrable drugs (pilocarpine, physostigmine)

Therapeutics (15 decks)

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