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64 Cards in this Set
- Front
- Back
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methacholine chloride (provocholine)- selectivity, usage
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used as diagnostic agent only to ID ppl who might have asthmar
selective for M receptors as an agonist (has beta? methyl) |
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methacholine chloride- how is it used as a diagnostic agent?
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induces bronchospasm that can be treated with bronchodilators
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carbachol chloride- what is it, usage (2)
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M agonist
only used in eye for glaucoma or ocular surgery |
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carbachol chloride SAR (2) and effect on route
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no alpha/beta substitution- not selective
not taken orally due to this non-selectivity even though it is metabolically stable due to no ester |
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bethanechol chloride (urecholine)- selectivity, usage
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M selective- beta substituent
used to treat urinary retention (smoove muscle) |
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bethanechol chloride (urecholine)- route, why?
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only given orally because IV/IM it can cause cholinergic crisis
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cholinergic crisis definition
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overstimulation at NMJ due to excess of ach or ach mimetic
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cholinergic crisis results in...(2)
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results in respiratory failure
flaccid paralysis |
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when is cholinergic crisis seen? (3)
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post surgical setting
OD on medication (if they are taking at home) nerve gas poisoning (sarin?) |
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pilocarpine- f or nf?
unique characteristic of SAR |
formulary
does NOT follow usual SAR rules for M agonists |
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pilocarpine- formulations (2)
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tablets
opthalmic solution |
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pilocarpine used to treat what? acts on what?
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xerostomia from radiation therapy or sjorgen's syndrome
acts on salivary glands |
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sjorgen's- aka? (2)
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mikulicz disease
sicca syndrome |
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what is sjorgen's
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autoimmune disorder that results in destruction of exocrine glands
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sjorgen's incidence
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4 million cases in US alone
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3 types of "future" M agonists for use in alzheimer's
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arecoline
oxotremorine xanomeline |
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arecoline
oxotremorine xanomeline selectivity (2) route (2) |
M1, M4 selective
not tolerated orally more for use in transdermal |
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AChE inhibitors clinical uses (4)
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improves muscle str
open angle glaucoma potential alzheimer's treatment insecticides |
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2 mechanisms of AchE hydrolysis
involvement of both |
acid catalyzed hydrolysis
base catalyzed hydrolysis BOTH are involved physiologically |
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3 steps to acid catalyzed hydrolysis
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1) protonation of carbonyl on Ach producing alcohol structure intermediate
2) H2O coordinates with positive charge- addition to structure 3) collapse of molecule and cleavage that leaves you with acetate and alcohol |
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3 steps to base catalyzed hydrolysis
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1) hydroxide ion attaches to electrophile (carbonyl)
2) formation of tetrahedral intermediate 3) NO addition to water- it just collapses and ejects the choline and acetyl |
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3 important parts on AchE
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serine residue of AchE- really critical
histamine- imidazole ring anionic site- interacts with quat ammonium |
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MoA of AchE hydrolysis mechanism (4)
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coordination of electrons from carbonyl oxygen with imidazole ring on His
then coordination with serine onto positively charged carbon of carbonyl group histadine causes protonation of that oxygen then you have collapse of the Ach molecule |
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anionic site of AchE- what does it consist of? how is N interacting with it?
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does not actually consist of anionic AA sticking there
may be cationic pi interaction?? meaning positive charge of N interacts with a pi electron system (aromatic) so it's probably tryptophan or phenylalanine |
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3 steps of AchE hydrolysis (related to the actual enzyme)
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AchE-Ser-OH + Ach = formation of unstable, tetrahedral transition state due to nuc attack of serine OH on carbonyl** critical
collapses- then you get loss of quat amine part (splits off the ester)** AchE is still inactive and attached to the acetyl part of Ach, so need H2O to cleave it off and regen enzyme |
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AchE inhibitors- targets what step in hydrolysis?
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makes the form of AchE connected to Ach part more stable- so can't regen the enzyme
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complex reversible inhibitors of AchE MoA (3)
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compounds are substrates of AchE
however they form a more stable complex (acylated on serine) causes the enzyme to regen more slowly |
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2 types of reversible AchE antagonists
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bind and block antagonists- do not acylate AchE
acylating AchE inhibitors (slow regen) |
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physostigmine type of inhibitor
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reversible AchE inhibitor
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physostigmine MoA
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binds to AchE- but after collapse of Ach, you get AchE bound to carbamic acid group which causes it to hydrolyze more slowly (more stable)
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timing difference of acetylated AchE and carbamic acid AchE
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normally takes 22 ms
when it's transesterified- takes 15 minutes |
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aryl carbamate AchE inhibitors properties (3)
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superior AchE inhibitor
high affinity for AChE very efficient at modifying enzyme |
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properties of physostigmine (4)
affinity, etc. usage |
high affinity
reversible can cross BBB used mostly in ER setting for pt who OD on anticholinergic drugs (or antidepressants/other drugs with Ach effects) |
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Ki (conc. that gives 50% inhibition) in aryl vs alkyl carbamates (like carbachol?)
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aryl has much better inhibition (~nanomolar)
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physostigmine MoA
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inhibits AchE by acting as substrate and arbamylating the enzyme
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neostigmine structure (2)
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simplified aryl carbamate
charged - no BBB crossing |
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neostigmine usage (3)
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used post op for urinary retention
for severe myasthenia gravis reversal of surgical neuromuscular blockade |
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pyridostigmine use (2)
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preferred treatment for myasthenia gravis
ppx in military against soman? nerve gas |
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pyridostigmine structure, BA, duration of action
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charged (no CNS activity)
orally bioavailable longer duration of action than neostigmine |
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aryl carbamate AchE inhibitor suffix
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-stigmines
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carbaryl
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insecticide
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AD characterized by what 2 general things
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AD is characterized by structural changes in nuronal tissue
functional disruptions in neurotransmission |
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3 disruptions of cholinergic transmission in brain
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loss of ChAT (choline Acetyltransferase)
loss of NAch receptors loss of choline transporters |
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4 Ache inhibitors FDA approved for Alzheimers
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tacrine, donepezil, rivastigmine, galantamine
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donepezil- what is it (type)?
toxicity half life |
non classical AChE (non competitive) inhibitor
low hepatotoxiity longer half life than tacrine |
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rivastigmine- type of ..drug (mechanism wise) (2)
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pseudo-irreversible AChE inhibitor
extends the regen time lag by 10 hours- so it's ALMOST irreversible |
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galantamine- what type of drug is it, where is it found?
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NP alkaloid found in daffodils
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galantamine- MoA (2)
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dual mode:
reversible inhibitor of AChE also binds to the N receptors allosterically (agonist) |
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irreversible inhibitors of AChE- what is their family called
how do they work? |
phosphate esters- emerged as being very stable to hyrdolysis and leave enzyme esterified as phosphate ester
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key difference between irreversible phosphate ester and reversible AChEI
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aging
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galantamine SAR (2)
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crosses BBB
unique structure- has 7 membered ring |
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aging- what is it (3)
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aging of the enzyme
major determinant of toxicity- means enzyme cannot regenerate |
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enzyme aging- MoA (2)
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loses functional group (ROH) off serine residue
no good leaving group- enzyme is stuck that way because phosphate is stuck there FOREVER |
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echothiopate- route, used for what (2)
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treatment for glaucoma- not commonly used
also for strabismus (uneven eye balance) topical |
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irreversible AchE inhibitor example (drug) (2)
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echothiopate
malathion |
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irreversible AChE inhibitor insecticide structural properties (2)
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very lipophilic
high vapor pressure- almost want to go to gas phase |
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irreversible AChE inhibitor insecticides- why u no kill people too?
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sulfur coordinate covalent bond gets metabolized to active oxo derivatives
this is why they kill insects but not people |
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malathion- onset, activation ,toxicity
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kills lice/eggs in 3 seconds
bioactivation ONLY occurs with insect enzyme so low toxicity in humans |
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idea behind the irreversible AChEI antidotes (2)
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essentially, water usually acts as nucleophile to hydrolyze Ach off AchE
BUT with phosphates, the phosphate esters require a much stronger nuc than water |
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hydroxylamine (3)
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strong nucleophile antidote- can cleave phosphate esters
can regen AChE but it's toxic at conc needed to work |
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pralidoxime- what is it? toxicity? efficacy? (3)
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derived from hydroxylamine- has oxime moiety that is less toxic
less toxic but still good nucleophile ONLY antidote that is good |
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oxime- how is it made
SAR |
know structure
reaction of hydroxylamine with aldehyde or ketone has nucleophilic oxygen atom that works as antidote |
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pralidoxime - how does it act on AchEI complex
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oxime attacks phosphorus and phosphate group falls off with pralidoxime
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2-PAM (pralidoxime) administration and route (3)
window of therapy |
administer within 36 hours of exposure, after that it is ineffective (aging)
injection- IV, IM, SQ |
