T3 - IE2 - Cardiology - Kaur - Anti-arrhythmic Drugs

Class I Sodium Channel Blockers

Quinidine

Procainamide

Disopyramide

Lidocaine

Mexiletine

Flecainide

Propafenone

Class IA anti arrhythmic drugs

Quinidine

Procainamide

Disopyramide

Quinidine

-prototype drug for class IA

-alkaloid found in Cinchona bark

-diastereomer of quinine

-quinoline ring and bicyclic quinuclidine ring system w/ hydroxymethylene bridge connecting them

-can be given IV as the gluconate salt

-good oral absorption of salt forms of quinidine (95%)

Quinidine structure

Because of the basic character, quinidine is always used as __________ __________ _________ _________

water soluble salt form

ex: sulfate, gluconate

Metabolites of quinidine

-hydroxylated derivatives at either quinoline ring, or at the quinuclidine ring

-metabolites have only 1/3 activity of quinidine

Digoxin-quinidine interaction

-quinidine (P-gp substrate) competitively inhibits renal tubular secretion of digoxin via P-gp efflux pump

-reduces digoxin renal secretion by 60%

-increases plasma conc. of digoxin to toxic lvls

Procainamide

-can be effective in pts unresponsive to quinidine

-peak plasma levels 45-90 mins after oral administration

-70%-80% of dose is bioavailable

Procainamide structure

Metabolites of procainamide

p-aminobenzoic acid and N-acetylprocainamide

(less common metabolites)

The acetylated metabolite of procainamide is also active as an _____________.

Antiarrhythmic

-formation accounts for up to 1/2 of administered dose and catalyzed by N-acetyltransferase

Disopyramide

-used orally to treat ventricular and atrial arrhythmias (well behaved drug)

-structural dissimilarity to procainamide, but similar cardiac effects

-rapidly & completely absorbed from GI tract

-peak plasma levels 1-3hrs

-plasma half life 5-7 hrs

Disopyramide metabolites

-N-dealkylated metabolite by CYP3A4

-retains approx 1/2 of anti arrhythmic activity

Disopyramide structure

Phase I and II metabolism

-Phase 1: P450 hydroxylation to make molecule more reactive, polar, and hydrophilic (phenol)

-Phase 2: glucuronide conjugation to increase charge and polarity (glucuonide)

Class IB anti arrhythmic drugs

Lidocaine

Mexiletine

Lidocaine

-drug of choice for emergency tx of ventricular arrhythmias

-rapid onset of anti arrhythmic effects on IV

-therapy can be rapidly modified

-effective as anti arrhythmic only when given parenterally (IV route most common)

-rapid.hepatic metabolism

-plasma half life 15-30mins

Metabolites of lidocaine

N-deethylation, followed by amidase-catalyzed hydrolysis into N-ethylglycine and 2,6-dimethylaniline

Lidocaine structure

Mexiletine

-similar to lidocaine in effects and therapeutic

-treats and prevents ventricular arrhythmia

-very good oral activity and absorption

-long plasma half life (12-16 hrs)

Mexiletine structure

alpha methyl group slows rate of metabolism and contributes to oral activity

Class IC anti arrhythmic drugs

Flecainide

Propafenone

Flecainide

-fluorinated benzamide derivative

-available as acetate salt

-oral form well absorbed

-plasma half life 14 hrs

Flecainide structure

Flecainide metabolism

-1/2 oral dose is CYP2D6 metabolized in liver

-1/3 excreted unchanged in urine

Propafenone

-structurally related to IC aa's and B-blockers

-oral and IV, parenteral not in US

-rapidly & almost completely absorbed from GI tract after oral administration

Propafenone metabolism

-hepatic CYP2D6 enzymes

-90% of pts, rapidly & extensively metabolized (elimination half life: 2-10 hrs)

-slow metabolizers elimination half life: 10-32 hrs

Propafenone structure

-phenyloxypropanolamine pharmacophore

-phenyl ring gets hydroxylated by CYP2D6

Class II Antiarrhythmic Drugs

B-adrenergic receptor blockers

ex:

propranolol (phenyloxypropanolamine)

sotalol (methanesulfonanilide derivative)

Propranolol

Phenyloxypropanolamine

(nonselective)

Sotalol

-Phenylethanolamine

-methanesulfonanilide derivative

(nonselective)

Propranolol structure

Sotalol structure

-can make a salt

-charged->can help with receptor

Sulfonamide is an __________ functional group

acidic

Class III Potassium Channel Blockers

Amiodarone

Dronedarone

Ibutilide

Dofetilide

Amiodarone

-also acts as class I, II, and IV anti arrhythmic

-structural analog of thyroid hormone

-aa actions & toxicity from interaction w/ nuclear thyroid hormone receptors

-highly lipophilic, eliminated slowly (several wks)

-AEs may resolve very slowly

-bioactive major metabolite: desethylamiodarone

Amiodarone structure

Drug interactions of amiodarone

-substrate for CYP3A4

-conc. increased by drugs that inhibit CYP3A4 (ex: histamine H2 blocker cimetidine)

-drugs that induce CYP3A4 decrease conc. (ex: rifampin)

-inhibits cytochrome P450 enzymes causing high lvls of statins, digoxin, and warfarin

Dronedarone

-benzofuran non iodinated derivative of amiodarone

-methylsufonamido group and dibutyl substitution on basic nitrogen

-less lipophilic than amiodarine

-elimination half life of 24 hrs

-oral bioavailability very poor (4%)

-high fat meal increases bioavailability (15%)

Dronedarone structure

-iodine groups of amiodarone removed to reduce toxic effects on thyroid

-methylsulfonamido group reduces lipophilicity and neurotoxic effects

Dronedarone metabolism

after PO, metabolized by liver CYP3A4 N-debutylation into active metabolite

Ibutilide

-methanesulfonanilide derivative

-IV infusion only as its fumarate salt

-lacks any B-blocking activity unlike sotalol

-electrophysiologic effects characteristic of class III

Ibutilide structure

Ibutilide liver metabolism

high first pass metabolism, poor oral bioavailability

2 IV anti arrhythmic drugs

Lidocaine and Ibutilide

Dofetilide

-bis-methanesulfonanilide derivative

-non-B-blocking moiety of sotalol molecule

-lacks B-blocking activity

-exhibits only class III electrophysiologic effects

-more potent & selective than other class III methanesulfonanilides

Dofetilide metabolism

-hepatic CYP3A4 enzyme system via N-dealkylation & N-oxidation

-inactive or minimally active metabolites

Dofetilide structure

PO, well absorbed from GI tract (96-100% bioavailability)

Class IV Calcium Channel Blockers

Verapamil and diltiazem (non-DHPs)

dihydropyridines are less effective in cardiac tissues

Digoxin

-cardiac glycoside or positive inotropic drug

-from digitalis purpurea or foxglove plant

-only oral positive inotropic agent

-actively secreted into urine by renal tubular cell via p-gp efflux pump

Digoxin structure

-polysaccharide (sugar) and steroid

-steroid portion has 3 hydroxyls

-C3 hydroxyl is conjugated to polysaccharide

PK and metabolism of digoxin

-oral bioavailability ranges from 70-85% of dose

-interindividual variability attributes to intestinal P-gp efflux and P-gp dependent renal elimination

-t1/2 in pts w/ normal renal function is 1.5-2 days

Basis for digoxin-drug interactions and digoxin toxicity

alterations to p-gp transport

P-gp substrates that can alter control of arrhythmias during concurrent use of cardiac glycosides (digoxin)

-antiarrhythmics

-sympathomimetics

-B-adrenergic blockers

-calcium channel blockers

Digoxin-verapamil interaction

-verapamil inhibits intestinal P-gp efflux of digoxin

-blocks intestinal secretion of digoxin into lumen

-raises digoxin blood to toxic lvls

Rifampin-digoxin interaction

-rifampin induces intestinal p-gp expression

-increases p-gp mediated secretion of digoxin

-lowers digoxin blood lvls to sub therapeutic concentrations