med chem cholinergic agonists
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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