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93 Cards in this Set

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interaction of ACh with muscarinic receptor - onium group
onium group - ionic interaction with Asp
SAR (structure activity relationship) of onium group
if CH3 replaced by larger groups - antagonist
1 CH3 replaced by larger group, agonist activity declines
successive replacement of CH3 with H dimishes activity
if ester moiety is greater or less than __ carbons, activity decreases
two
SAR of alkyl substitution of chain (alpha & beta)
alpha group - more nicotinic
beta group - more muscarinic, lower rate of hydrolysis by AChE due to steric hindrance
ACh cannot be used as a therapeutic agent b/c?
easily hydrolyzed
permanent + charge - can't pass through membranes
non-selective
direct acting cholinergic agonist
drugs that bind to muscarinic receptors & directly produce ACh-like effects
brand name for methacholine chloride
provocholine
brand name for carbachol chloride
miostat
brand name for bethanechol chloride
urecholine
brand name for pilocarpine HCl
pilocar
pilocarpine MOA
directly stimulates cholinergic receptors in the eye causing miosis, spasm of accommodation, lowering of intraocular pressure; incr efficiency of outflow channels
pilocarpine used to treat
glaucoma - 0.5% soln
glaucoma
increased intraocular pressure -> damage to optic nerve -> blindness
open angle glaucoma
aka wide angle
after age 35
90% of cases
obstruction in trabecular mesh
closed angle glaucoma
aka acute angle, narrow angle
very sudden - medical emergency
direct acting cholinergic agonist drugs
methacholine Cl
carbachol Cl
bethanechol Cl
pilocarpine HCl
what are the 2 classes of indirect acting cholinergic agonists
reversible AChEI (enz will be regenerated over time)
irreversible AChEI (enz will not be regenerated)
indirect acting cholinergic agonists MOA
inhibit the enzyme - spare the ACh ~ not hydrolyzed as quickly
reversible inhibitors of AChE
-substrates for AChE that react to form acylated enzyme (more stable)
-bind to enz with greater affinity than ACh but do not react with it
brand name for physostigmine
eserine
physostigmine uses
treatment of glaucoma
treat overdoses of anticholinergics
investigational in Alzheimer's disease
enzyme AChE will be carbamylated more ______ if the drug is ____ _____ _______
slowly
more highly substituted
neostigmine bromide
dimethylcarbamate group meta to trimethylammonium group
more resistant to hydorlysis, so longer DOA
MOA: inhibition of AChE
neostigmine bromide uses
primarily to prevent post surgical atony of muscles
to treat glaucoma
myasthenia gravis
myasthenia gravis
nicotinic receptors in skeletal muscle are destroyed
-ptosis (dropping eyelids)
-diplopia (double vision)
-weakness of the jaw
-weakness of proximal muscles
is neostigmine or pysostigmine affected by pH?
neostigmine - no
pysostigmine - yes, activity decr as pH incr
brand name for pyridostigmine bromide
mestinon
brand name for edrophonium chloride
tensilon
brand name for ambenonium chloride
mytelase
brand name for demecarium bromide
humorsol
brand name for tacrine HCl
cognex
brand name for donepezil HCl
aricept
Alzheimer's disease
impairment of cognitive functions
memory loss
senile plaques
AChE & choline acetyl transferase reduced
brand name for rivastigmine
exelon
reversible inhibitors of acetylcholine esterase drugs
physostigmine
neostigmine Br
pyridostigmine Br
edrophonium Cl
ambenonium Cl
demecarium Br
tacrine HCl
donepezil HCl
rivastigmine
drugs used to treat AD
tacrine HCl
donepezil HCl
rivastigmine
irreversible inhibitors of AChE
organophosphate esters
organophosphate esters
very toxic (agricultural pesticides & chemical warfare)
very low therapeutic index
organophosphates MOA
permit the accumulation of ACh at nerve endings and produce an exacerbation of ACh-like actions
aging of phosphorlyated enzymes
very stable to hydrolysis
long DOA ~ irreversible
aging occurs when a phosphoester bond is cleaved
isofluorophate
floropryl
treatment of glaucoma (very dilute soln, last up to 4 weeks, can cause retinal detachment)
must be handled with extreme care
echothiophate iodide
phospholine iodide
treatment of glaucoma
long lasting (irreversible AChEI)
less systemic effect (b/c charged)
sarin
irreversible AChEI
used in chemical warfare
aka nerve gas
paraoxon & paration
irreversible AChEI
agricultural insecticide
parathion bioactivates to paraoxon by microsomal oxidation in insects & humans
highly lipophilic
high vapor pressure
pralidoxime chloride
2-PAM or protopam
antidote for irreversible AChEI
hydroxylamine nucleophile & charged center for binding AChE
effective if given within a few hours of poisoning
hydroxylamine
can cleave a phosphate ester (antidoe of irrevesible AChEI)
highly toxic
interaction of ACh with muscarinic receptor - ester group
hydrogen bond with Thr, Asn
interaction of ACh with muscarinic receptor - ethylene group
hydrophobic interaction with hydrophobic aa
methacholine is used as a diagnostic agent for?
bronchospasms / asthma
which enantiomer of methacholine is active
s enantiomer (counterclockwise)
carbachol acts on which cholinergic receptor
both nicotinic and muscarinic
carbachol is hydrolyzed slower than ACh, which means it has a longer
duration of action
carbachol used to treat
glaucoma
also used in eye surgery where miosis required for a longer time than ACh can produce
what ester does carbachol have
carbamyl ester
what is the DOA of bethanechol
1-6hrs b/c of low rate of hydrolysis
MOA of bethanechol
stimulates cholinergic receptors in the smooth muscle of the urinary bladder and GIT
bethanechol used to treat
post-surgical urinary retention and atony of muscles in GIT
bethanechol is like a combinatino of what 2 drugs
methacholine and carbachol
what 2 plants is pilocarpine derived from?
pilocarpus jaborandi
pilocarpus microphyllus
systemic effects of pilocarpine
copious sweating
salivation
gastric secretion
the aqueous humor of the eye fills the space between
the cornea and the lens
what maintains intraocular pressure in the eye
aqueous humor
intraocular pressure is BALANCED by
rate os secretion
resistance to flow
resistance to resorption through canal
what is the canal of schlemm?
opening in anterior chamber where aqueous umor passes through and enters venous circulation
physostigmine is isolated from what plant?
physostigma venenosum
physostigmine MOA
inhibition of AChE
catalytic triad involved in hydrolysis of ACh
serine 200
histidine 440
glutamate 327
function of serine in the catalytic triad
ser OH group makes a nucleophilic attack on acetyl carbon
how is the acetylated enzyme regenerated (hydrolysis of ACh)
base-catalyzed hydrolysis
DOA of pyridiostigmine
fairly long
3-6hrs
pyridiostigmine used to treat
myasthenia gravis
what ring structure does pyridiostigmine have?
pyridine
DOA of edrophonium
short - few minutes (pharmacological challenge - transitory but dramatic improvement)
edrophium used for
diagnostic agent for MG
reversal of curare overdose
edrophonium does not form a covalent bond with the enz b/c? this means it _______ with ACh
it has no carbamate structure
competes
ambenonium is used to treat:
MG in patients who don't respond to neostigmine or pyridiostigmine
relative DOA of ambenonium
long
MOA of ambenonium
competes with ACh to bind wih enzyme AChE
is demecarium lipophilic or hydrophilic
lipophilic
demecarium is used to treat
wide angle glaucoma
DOA of demecarium
very long - 2 days
what ring structure does tacrine have?
tetrahydroacridine ring
MOA of tacrine
centrally acting AChE inhibitor
tacrine used to treat
Alzheimers (1st drug approved to treat AD)
why is the use of tacrine limited
hepatotoxic - necrosis of liver in 50% of patients
donepezil used to treat
AD
donepezil MOA
centrally acting, reversible inhibitor of AChE
donepezil has a greater affinity for AChE in the _____ than in the _________
brain
periphery
when compared to tacrine, donepezil's DOA & hepatotoxicity:
DOA: longer
no potential hepatotoxicity
what is 6-desmethyldonazepil
11% active metabolite of donepezil
microsomal mixed fxn oxidases
MOA of rivastigmine
centrally acting AChE inhibitor
rivastigmine is called a pseudo-irreversible inhibitor b/c
it has a long DOA (10hrs)
rivastigmine is used to treat
AD