Term
quinidine - Class 1A antiarrhythmic agent
its diastereomer is quinine (antimalaria), which is markedly less potent than quinidine
structure: quinoline and quinuclidine (bicyclic) with a hydroxy-methylene bridge
 
two basic nitrogens, with the quinuclidine nitrogen being stronger
water soluble salt: sulfate (82% quinidine), gluconate (62% quinidine).
  
if both N's have a + charge, then 2 sulfates are used in the salt form |
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Definition
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Term
metabolism of quinidine
quinidine is a substrate of P-gp and can increase plasma concentrations of digoxin
dihydroquinidine, a common contaminant in quinidine preparations, is derived from reduction of the vinyl in quinuclidine to an ethyl |
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Definition
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Term
procainamide - class 1A antiarrhythmic
procaine was modified by replacing ester with amide
procaine has a very short duration of action b/c of esterases
half the dose is extreted unchanged, the other half is metabolized.
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Definition
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Term
metabolism of procainamide
the acetylated metabolite is also very active - variability in the amount of this metabolite is observed from patient to patient
a substantial percentage of patients show levels of antinulear antibodies after a few months (60-70%)
of these patients, 20-30% develop lupus like syndrome due to the aromatic amine (slow acetylators) |
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Definition
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Term
disopyramide - Class 1A antiarrhythmic agents
half of the dose is excreted unchanged
plasma binding is highly correlated to lipophilicity - ***omission of amide and pyridyl groups results in a two fold increase in the extent of plasma binding***
the other half is metabolized to the N-dealkylated product - metabolite retains 50% of its activity |
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Definition
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Term
lidocaine - class 1B antiarrhythmic agent
clinically useful local anesthetic like procaine
tertiary amine, pKa = 7.6-8
penetrates site in unionized forms and binds as 'onium' forms to the channel receptors
lipophilic portion important: o,o-dimethyl provides protection from amide hydrolysis
lengthening chain impacts pKa, reduces potency
hydrophilic is a tertiary amine, salt formation
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Definition
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Term
metabolism of lidocaine
protein binding 60-70% when given parenterally
given IV only
not effective orally due to metabolism
metabolism: de-ethylation and dimethyl-aniline, monoethyl-metabolite maintains activity, but not clinically useful due to rapid hydrolysis (amidases vs peptidases)
toxicities are possible due to removal of N-ethyl groups of lidocaine after crossing BBB |
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Definition
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Term
tocainide - Class 1B antiarrhythmic agent
similar to lidocaine de-ethylated metabolite
given orally (methyl protects it from amidases)
50% excreted unchanged
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Definition
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Term
aspartate in amidases functions as a general base abstracting the proton from serine OH side chain. Now the serine can act as a nucleophile for the carbonyl group of the amide bond within the substrate |
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Definition
| mechanism of action of amidases |
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Term
phenytoin - class 1B antiarrhythmic agent
an epileptic used for the treatment of arrhythmias resulting from digitalis toxicity
oral or IV
extensive protein binding - 90%
hydantoin structure (2 nitrogens as a urea)
poor water solubility, pKa = 8.06-8.33, but Na salt feasible
problems of phenytoin Na include absorption of CO2, resulting in free phenytoin
fosphenytoin sodium is a soluble prodrug disodium phosphate ester of phenytoin developed as a replacement for phenytoin Na to circumvent pH and solubility problems
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Definition
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Term
metabolism of phenytoin
metabolism by CYP2C9 (60-75% excreted as conjugated metabolites)
about 1% of oral dose excreted unchanged
also an inducer of CYP3A4: reduces plasma levels of valproate, carbamazepine, methadone, warfarin, others; agents affecting phenytoin metabolism and/or displace it (it is extensively plasma protein bound) could cause intoxication |
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Definition
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Term
flecainide - class IC antiarrhythmic agent
fluorinated benzamide available as acetate salt
it has a pKa=9.3 (charged at physiological pH)
due to its charge, it binds to channels once they are open vs lidocaine which binds to the inactivated state |
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Definition
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Term
metabolism of flecainide
metabolized by 2D6 |
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Definition
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Term
propafenone - class 1C antiarrhythmic agent
side chain similarities to BBs
at higher concentrations also exhibits properties of a class II and class IV drug
like other BBs, S isomer is a more potent B-antagonist |
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Definition
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Term
R1: aromatic substitution of the nitrogen abolishes cardiac effects, while non-aromatic substitution is tolerated
R2: phenethyl can be replaced by Me or an Et
propafenone |
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Definition
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Term
only 50% of tumors are susceptible to chemotherapy, and of these more than 50% develop resistance during therapy
overexpression of P-gp results in multiple drug resistance
P-gp is an efflux pump that transports a wide variety of anticancer agents out of tumor cells
propafenone is an inhibitor of P-gp |
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Definition
| what substituents on propafenone is required for it to maintain its ability to inhibit P-gp? |
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Term
bretylium tosylate - class III antiarrhythmic agent
only in intensive care
the primary mode of action is thought to be inhibition of voltage-gated K channels
recent evidence has shown that bretylium may also inhibit the Na/K/ATPase by binding to the extracellular K site |
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Definition
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Term
amiodarone - class III antiarrhythmic agent
metabolites: N-desethylamiodarone (equipotent) |
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Definition
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Term
metabolism of azimilide - in development (phase III)
K channel antagonist
completely absorbed
it is metabolized to an active carboxylic acid, but only at 5% concentration - flavin monoxidase (FMO) contributes to its metabolism |
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Definition
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