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