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 [image] [image] two basic nitrogens, with the quinuclidine nitrogen being stronger water soluble salt: sulfate (82% quinidine), gluconate (62% quinidine). [image] [image] [image] if both N's have a + charge, then 2 sulfates are used in the salt form |
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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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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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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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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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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 [image] |
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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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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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[image] 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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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 [image] fosphenytoin sodium is a soluble prodrug disodium phosphate ester of phenytoin developed as a replacement for phenytoin Na to circumvent pH and solubility problems [image] |
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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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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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metabolism of flecainide metabolized by 2D6 |
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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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[image] 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 [image] propafenone |
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[image] 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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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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amiodarone - class III antiarrhythmic agent metabolites: N-desethylamiodarone (equipotent) |
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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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