Pharm 8.1 - anticholinesterase agents Flashcards
anticholinesterase agens
indirect acting cholinergic drugs by inhibiting the enzyme AChE and hence protect Ach from hydrolysis - inc levels of Ach
two type so ACE agens
reversible and irreversible
reversible short acting
edrophonium
reversible intermediate actin
neostigmine, physostigmine
long acting ACE agent
Pyridostigmine, Tacrine, Ambenonium
irreversible
insectisides, nerve gas poison, organophosphorous compounds, carbamates
organphosphorus compunds
parathion, malathion, diazinon (TIK-20), Echotiopate, Soman, Sarnin, Tabun (nerve gase poisons)
To differentitat muscle weaknes of myastienia gravis from cholinergic crisis
edrophonium
Carbamates
carbaryl, proppoxur
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
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
Physostigmine
naturally occuring alkaloid (nature is basic)
Physostigmine can enter cells bec
it is a tertiary amine - uncharged lipid soluble, corsses BBB, aosl good oral abs
Physositgmine duration of action
2-4 hrs
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
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)
Neostigmine structure
synthetic quarterary amine - charged - poor oral abs
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
Neostigmine works by
reversibly inhibits acetylcholinesterase in a manner similar to physostigmine
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
Neostigmine duration of action
0.5 - 2hrs
Pyridostigmine and ambenonium
cholinesterase inhibitors in the chronic management of myasthenia gravis
Pyridostigmine duration of action
3-6hrs
Amebenonium duration of action
4-8hrs
Edrophonium
short acting anticholinesterase drug (10-20 minutes)
Edrophonium actions
similar to neostigmine, used for diagnosis of myasthenia gravis and also used to differentiate myasthenia from cholinergic crisis
Demecarium structure
quarternary amine, structurally related to neostigmine
Demecarium is used to
treat chronic open-angle closed angle glaucoma
Edrophonium can be sued to diagnose
myasthenia gravis and then can give neostigmine or physostigmine
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
anticholinesterase drugs used in Alzhimers to inc Ach and help improve memory
tacrine, donepezil, rivastigmine, galantamine
irreversible anticholinesterases
echothiophate
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
Echothiophate and aging
after covalent modification AChE, the phosphorylaated enzyme slowly releases on of its etyl groups
Aging makes it impossible for
enzyme reactivator such as pralidoxime to break the bond btw the remaining drug and the enzyme
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.
actions of Echothiophate
generalized cholinergic stimulation, paralysis of motor functin (causing breathing difficulties) and convulsions, produces intense mios (basis of therapeutic application)
Echothiophate can lead to paralysis due to
over stimulation at the NM jn and desensitization
Echothiophate therapuetic uses
chronic treatment of open angle glaucoma but potential risk of cataracts
Edrophonium usues
myasthenia gravis, ileus
Edrophonium duration of action
10 - 20 minutes
Neostigmine uses
myasthenia gravis, ileus
Pyridostigmine uses
myasthenia gravis
Ambenonium uses
myasthenia gravis
Demecarium duration of action
4-6hrs
Echothiphate duration of action
100 hours
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)
organophosphorous compounds
parathion, malathion (insecticides)
organophosphorus compounds react with
esteratic site which is hydrolized extremely slowly with water or not at all, enzyme can also undergo aging
Cholinesterase reactivator
Pralidoxime
the Phosphorylated ChE react very slowly or not at all with
water
oximes like pralidoxime bind with
anionic site of ChE and undergoes reaction to cause hydroylysis of phosphoserine bond, resulting in free enzyme
Pralidoxime should be administered
as early as possible followed by OP poisoning (not later than 24hrs max, as aging occurs)
Edrophonium characteristics
short acting
Pyridostigmine sturcture
quarternary amine
Donepezil and tacrine characteristics
lipid soluble for CNS entry in treatment of Alzheimers
organophosphate caracteristics
lipid soluble ireerversible inhibitors to treat glaucoma, as an insectaside, and a nerve gas (sarin)
how are organopphosphates irreversible
the organophosphate phosphorylates the enzyme and undergoes aging, losing one of the alkylyl groups and becoming totally resistant to hydrolysis
reactivators can’t work on
carbamates bc they take up the anionic site but they might be helpful for organophoshphates before aging
Pralidoxime is a
cholinesterase reactivator
phosphorylated choline esterates reacts with water
very slowly or not at all - no hydrolysis means drug is not able to reverse its effect
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
organophosphorous poisoning acute toxicity
excessive muscarinic and nicotinic stimulations
Dumbbelss - muscaranic effects of organophosphates
diarrhea, urination, miosis, bradycardia, bronchoconstriction, exciatation (CNS and muscle), lacrimation, salivation, and sweating
Acetylcholinesterasae inhibitors acute toxicity - nicotinic effects
skeletal muscle excitation followed by paralysis, CNS stimulation
to counteract muscarinic effects give
atropine
for regeneration of AChE give
pralidoxime as soon as possible to avoid aging
treat open/wide angle gaucoma with
piocarpine, physostigmine
treat myasthenia gravis with
neostigmine, pyridostigmine
treat urinary retention with
neostigmine, pyridostigmine
treat parlytic ileus/congenital megacolon with
neostigmine, pyridostigmine
for drug poisoning with atropine, TCA, or phenothiazines use
physostigmine
for Alzheimers diesease use
donepezil, galantamine, rivastigmine, tarcrine
for Sjogren’s syndrom use
Pilocarpine
