Pharm 8.1 - anticholinesterase agents Flashcards Preview

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Flashcards in Pharm 8.1 - anticholinesterase agents Deck (74)
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anticholinesterase agens

indirect acting cholinergic drugs by inhibiting the enzyme AChE and hence protect Ach from hydrolysis - inc levels of Ach

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two type so ACE agens

reversible and irreversible

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reversible short acting

edrophonium

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reversible intermediate actin

neostigmine, physostigmine

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long acting ACE agent

Pyridostigmine, Tacrine, Ambenonium

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irreversible

insectisides, nerve gas poison, organophosphorous compounds, carbamates

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organphosphorus compunds

parathion, malathion, diazinon (TIK-20), Echotiopate, Soman, Sarnin, Tabun (nerve gase poisons)

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To differentitat muscle weaknes of myastienia gravis from cholinergic crisis

edrophonium

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Carbamates

carbaryl, proppoxur

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Acetylcholinesterasae

is an enzyme with anionic and esteratic site, hydrolysis of Ach infolves attraction of popitve N+ of Ach at anionic site and acetylatio nof serine leading to acetylated enzyme, acetylated enzyme reacts with water to produce acetic acid and enzyme is free within milliseconds

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reversible anticholinesterases work by

comining with ChE and carbamylated enzyme (carbamyl binds at anionic site) is slow to hydorlyze and free the enzyme (in 30 mins), increaseing ach that_s left around

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Physostigmine

naturally occuring alkaloid (nature is basic)

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Physostigmine can enter cells bec

it is a tertiary amine - uncharged lipid soluble, corsses BBB, aosl good oral abs

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Physositgmine duration of action

2-4 hrs

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Physostigmine actions

reversibly inhibits acetylcholinesterase, wide actions, stimulates muscarinic and nicotinic sites of ANS by increasing the concentration of Ach, also stimulates cholinergic sites in the CNS

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Physostigmine therapuetic uses

glaucoma - to lower IOT and produce mosis, bladder and intestinal atony - increases intestinal bladder motility, antidote in atropine overdoes (bc it can cross BBB)

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Neostigmine structure

synthetic quarterary amine - charged - poor oral abs

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Neostigmine CNS action

absent as it does not enter the CNS so no CNS side effects and can't be used to overcome toxicity of central acting antimuscarinic agents such as atropoine

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Neostigmine works by

reversibly inhibits acetylcholinesterase in a manner similar to physostigmine

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Neostigmine effects

skeletal musles, stimulates bladder and GIT, used in paralytic ileus, urinary retention, symptomatic treatment of myasthenia gravis, antidote for tubocurarine and other competitive neuromuscular blocking agens

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Neostigmine duration of action

0.5 - 2hrs

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Pyridostigmine and ambenonium

cholinesterase inhibitors in the chronic management of myasthenia gravis

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Pyridostigmine duration of action

3-6hrs

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Amebenonium duration of action

4-8hrs

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Edrophonium

short acting anticholinesterase drug (10-20 minutes)

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Edrophonium actions

similar to neostigmine, used for diagnosis of myasthenia gravis and also used to differentiate myasthenia from cholinergic crisis

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Demecarium structure

quarternary amine, structurally related to neostigmine

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Demecarium is used to

treat chronic open-angle closed angle glaucoma

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Edrophonium can be sued to diagnose

myasthenia gravis and then can give neostigmine or physostigmine

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if patient comes in with weakness

give small dose of edrophonium, if myasthenia gravis the patient will impover, but if it is due to increased Ach activty in neuromuscular jn by giving Edrophonium it worsens

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anticholinesterase drugs used in Alzhimers to inc Ach and help improve memory

tacrine, donepezil, rivastigmine, galantamine

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irreversible anticholinesterases

echothiophate

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Echothiophate action

an organophosphate that binds covalently via its phosphate group to the serine -OH group at the active site of acetylcholinesterase leading to permanently inactivation of the enzyme acetylcholinesterase

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Echothiophate and aging

after covalent modification AChE, the phosphorylaated enzyme slowly releases on of its etyl groups

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Aging makes it impossible for

enzyme reactivator such as pralidoxime to break the bond btw the remaining drug and the enzyme

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how do reactivators work

the drug has the organic group and phosphate and they work to break the bond btw drug and enzyme. As long as alky group is attached to the phosphate it can regenerate. But if not then it cant.

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actions of Echothiophate

generalized cholinergic stimulation, paralysis of motor functin (causing breathing difficulties) and convulsions, produces intense mios (basis of therapeutic application)

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Echothiophate can lead to paralysis due to

over stimulation at the NM jn and desensitization

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Echothiophate therapuetic uses

chronic treatment of open angle glaucoma but potential risk of cataracts

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Edrophonium usues

myasthenia gravis, ileus

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Edrophonium duration of action

10 - 20 minutes

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Neostigmine uses

myasthenia gravis, ileus

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Pyridostigmine uses

myasthenia gravis

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Ambenonium uses

myasthenia gravis

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Demecarium duration of action

4-6hrs

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Echothiphate duration of action

100 hours

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Common adverse effects of AchE inhibitors

generalized cholinergic stimulation, salivation, flushing, dec BP, nausea, abdominal pain, diarrhea and bronchospasm, CNS effects like convulsions like Physostigmine (at high doses)

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organophosphorous compounds

parathion, malathion (insecticides)

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organophosphorus compounds react with

esteratic site which is hydrolized extremely slowly with water or not at all, enzyme can also undergo aging

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Cholinesterase reactivator

Pralidoxime

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the Phosphorylated ChE react very slowly or not at all with

water

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oximes like pralidoxime bind with

anionic site of ChE and undergoes reaction to cause hydroylysis of phosphoserine bond, resulting in free enzyme

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Pralidoxime should be administered

as early as possible followed by OP poisoning (not later than 24hrs max, as aging occurs)

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Edrophonium characteristics

short acting

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Pyridostigmine sturcture

quarternary amine

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Donepezil and tacrine characteristics

lipid soluble for CNS entry in treatment of Alzheimers

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organophosphate caracteristics

lipid soluble ireerversible inhibitors to treat glaucoma, as an insectaside, and a nerve gas (sarin)

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how are organopphosphates irreversible

the organophosphate phosphorylates the enzyme and undergoes aging, losing one of the alkylyl groups and becoming totally resistant to hydrolysis

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reactivators can't work on

carbamates bc they take up the anionic site but they might be helpful for organophoshphates before aging

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Pralidoxime is a

cholinesterase reactivator

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phosphorylated choline esterates reacts with water

very slowly or not at all - no hydrolysis means drug is not able to reverse its effect

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pralidoxime (PAM) is eneffective in case of

physostigmine or neostigmine because they are carbamates that bind the anionic site and so PAM is not able to bind

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organophosphorous poisoning acute toxicity

excessive muscarinic and nicotinic stimulations

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Dumbbelss - muscaranic effects of organophosphates

diarrhea, urination, miosis, bradycardia, bronchoconstriction, exciatation (CNS and muscle), lacrimation, salivation, and sweating

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Acetylcholinesterasae inhibitors acute toxicity - nicotinic effects

skeletal muscle excitation followed by paralysis, CNS stimulation

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to counteract muscarinic effects give

atropine

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for regeneration of AChE give

pralidoxime as soon as possible to avoid aging

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treat open/wide angle gaucoma with

piocarpine, physostigmine

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treat myasthenia gravis with

neostigmine, pyridostigmine

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treat urinary retention with

neostigmine, pyridostigmine

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treat parlytic ileus/congenital megacolon with

neostigmine, pyridostigmine

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for drug poisoning with atropine, TCA, or phenothiazines use

physostigmine

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for Alzheimers diesease use

donepezil, galantamine, rivastigmine, tarcrine

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for Sjogren's syndrom use

Pilocarpine