ANS-4 Flashcards
What are the 2 types of cholinesterases
acetylcholinesterase and plasma cholinesterase
Acetylcholinesterases are located in _____
synapses
Plasma cholinesterases are located in ____
plasma (non-neuronal)
Acetylcholinesterases are selective for the transmitter ____
ACh
Plasma Cholinesterases are selective for ____, ______, and ______
- ACh
- succinylcholine
- local anesthetics (procaine)
T or F: Plasma cholinesterases are more selective than acetylcholinesterases
False
Acetylcholinesterases are more selective (only ACh)
Why is AChE really cool?
it has the highest turnover rate out of all enzymes
hydrolyzes ACh 5,000 times per second
What molecule is required to reactivate AChE?
H2O
nucleophilic attack
Hydrolysis of ACh: What 3 amino acids form the catalytic triad (esteric site)?
- Ser203
- His440
- Glu327
Hydrolysis of ACh: What amino acids form the anionic site?
Phe338 and Trp86
ACh is hydrolyzed into what?
acetic acid and choline
AChE Agents: Indirectly-Acting Cholinoceptor Stimulants -
Reversible (Alcohol)
Edrophonium
AChE Agents: Indirectly-Acting Cholinoceptor Stimulants - Reversible (Carbamates)
- Physostigmine
- Neostigmine
- Pyridostigmine
AChE Agents: Indirectly-Acting Cholinoceptor Stimulants - Reversible (hope you didn’t forget lol)
Donepezil (Aricept)
AChE Agents: Indirectly-Acting Cholinoceptor Stimulants - Irreversible (Organophosphates)
- Echothiophate (used in glaucoma)
- Sarin (nerve gas/chemical warfare)
- Malathion (pesticide; head lice)
AChE inhibitor: Tetra-alkylammonium
Ion Characteristics
- Simplest structures
- Bind to anionic site and block ACh
- Reversible
- Non-covalent (no ester)
AChE inhibitor: Alcohol Characteristics
Example: Edrophoium (Tensilon)
* quaternary ammonium alcohol
* simplest structures
* bind to anionic site and block ACh
* reversible
* non-covalent
AChE inhibitors: Carbamates Characteristics
Examples: Neostigmine (Prostigmin), Pyridostigmine (Mestinon), Physostigmine (Antilirium)
* Quarternary or tertiary ammonium groups
* reversible
* covalent modifcation to AChE (Ser203)
* hydrolyzed slower than ACh
What is this?
Edrophoium (Tensilon)
What is this?
Neostigmine (Prostigmin)
What is this?
Pyridostigmine (Mestinon)
What is this?
Physostigmine (Antilirium)
Not intrinsically positive. Protonated at physiological pH.
T or F: reversible means non-covalent
False
covalent modification to AChE can occur AND be reversible
Clinical Use: Edrophonium - Time: ____-acting (unit?); diagnosis of _____
Short-acting (minutes), Myasthenia Gravis (MG)
MG - skeletal muscle weakness due to loss of Nm receptors because of autoimmune disease
Clinical Use: Pyridostigmine - Used in treatment of ____ by reversing ______________,
pretreatment for potential ______ exposure (occupy AChE so that it has nowhere to go)
MG, nondepolarazing neuromuscular blockade, nerve gas
Clinical Use: Neostigmine -Used for ____, reversal of _____, post-op _____ retention
MG, nondepolarizing neuromuscular blockade, urinary
What is the problem with AChE Inhibitors?
Excessive cholinergic receptor activation
ACh not broken down, so more receptor activation
Clinical Use: Physostigmine - Can cross ___: Antidote to ___
poisoning
BBB, antimuscarinic
Clinical Use: Physostigmine - Can cross ___: Antidote to ___
poisoning
BBB, antimuscarinic
T or F: Stigmines are hydrolyzed faster than ACh
False
Stigmines are hydrolyzed more slowly due to covalent bond
AChE Inhibitor: Organophosphates (Glaucoma) Characteristics
Examples: Isofluorophate; DFP (Floropryl), Echothiophate (Phospholine Iodine)
* irreversible
* covalent modification to AChE
* longer acting
AChE Inhibitor: Organophosphates (Nerve Gases) Characteristics
Examples: Sarin and Soman
* irreversible
* covalent modification to AChE
T or F: Most organophosphates are TOXIC
True
AChE Inhibitor: Organophosphates (Insecticides) Characteristics
Examples: Malathion, Diazinon
* irreversible
* covalent modification to AChE
* rapidly inactivated in mammals
How do insecticides (Malathion and Diazinon) not harm mammals?
Insects have a specific Cyt P450 that converts Malathion into toxic Malaoxon. Mammals metabolize Malathion into an inactive compound.
Organophosphate mechanism
P forms a super stable covalent bond with Ser203. Aging then occurs (irreversible and cannot be detoxified)
What is this?
Isofluorophate; DFP (Floropryl)
What is this?
Echothiophate (Phospholine Iodine)
What is this?
Sarin
What is this?
Soman
What is this?
Malathion
What is this?
Diazinon
What is the antidote for AChE poisioning (pesticide and nerve gas)
Pralidoxime Chloride
strong nucleophile
T or F: Pralidoxime must be administered before aging occurs (within a few hours of exposure)
True
once aging occurs, damage is irreversible.
What is this?
Pralidoxime Chloride
Because Pralidoxime Chloride cannot cross the BBB, it should be administered with ___ because….
Atropine; a muscarinic receptor antagonist that can cross the BBB. Blocks muscarinic receptor activity caused by excess ACh
Alzheimer’s Disease is due to…
Loss of cholinergic neurons in the brain caused by improper processing of B- amyloid precursor protein (B-APP) leading to toxic form (B-A42) that promotes apoptosis.
Alzheimer’s: Mechansim of Donepezil (Aricept) - Reversibly and non-covalently binds to ___ site on AChE and blocks ___ binding. Enhances ____ ability. Approved for all stages of Alzheimers
Anionic, ACh, cognitive
T or F: Donepezil slows the progression of Alzheimer’s disease
False
What is this?
Donepezil (Aricept)
Alzheimer’s: Mechanism of Rivastigmine (Exelon) - Reversible ____ AChE inhibitor. Enhances cognitive ability by increasing ___ function.
Carbamate, cholinergic
T or F: Rivastigmine loses effectiveness as Alzheimer’s progresses
True
What are the side effects of Rivastigmine?
- nausea
- vomiting
- anorexia
- weight loss
What is this?
Rivastigmine (Exelon)
Alzheimer’s: Mechanism Galantamine (Razadyne) - Reversible ___ AChE inhibitor. Extracted from ___. May be a ___ receptor agonist. Inhibitors of Cyp ___ and ___ will increase Galantamine bioavailability.
competitive, daffodil, nicotinic, 3A4, 2D6
T or F: Galantamine may slow the progression of Alzheimer’s
False
Like Rivastigmine, it loses effectiveness as Alzheimer’s progresses
What is this?
Galantamine (Razadyne)
Alzheimer’s: Memantine Mechanism - ___ receptor antagonist. These receptors are activated by ___ in the CNS in areas associated with cognition and memory.
N-methyl-D-aspartate (NDMA), glutamate
T or F: Memantine may slow the progression of Alzheimer’s
True
T or F: Neuronal loss in Alzheimer’s may be related to increased activity of glutamate
True
Because Memantine is NOT ___, it has a favorable adverse effect profile
cholinergic
What is this?
Memantine (Namenda)
What are side effects assoicated with cholinergic agonists? Hint: DUMBBELSS
diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation, sweating (SNS)
Contraindications to the use of parasympathomimetic drugs
asthma and COPD (bronchoconstriction), coronary deficiency (further lowers HR), peptic ulcer (increases acid secretion), obstruction of urinary or GI tract (contraction does not remove obstruction), and epilepsy (M1)
