Antiarrhythmic agents metabolism

The only other anesthetic to cause serious toxicity for which a metabolic drug interaction has been reasonably well characterized is the local anesthetic and antiarrhythmic agent lidocaine. Amiodarone decreased lidocaine systemic clearance in a patient (primarily by inhibition of CYP3A4 N-dealkylation of lidocaine) and yielded concentrations of lidocaine that led to seizures (78,79). 

The antiarrhythmic agent quinidine is metabolized by allylic hydroxylation to 3-hydroxyquinidinc. the principal plasma metabolite found in humans. This metabolite shows significant antiarrhythmic activity in animals and po.s-sibly in humans. -"... 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Encainide, a class 1C antiarrhythmic agent, is available on a limited basis only to patients with life-threatening ventricular arrhythmias. Encainide slows conduction velocity, inhibits automaticity, and increases the ratio of the effective refractory period to action potential duration. It blocks the sodium channel of Purkinje fibers and the myocardium. Encainide is absorbed well, reaches peak plasma level in 30 to 90 minutes, becomes metabolized to 0-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), which are active antiarrhythmic agents, and the metabolites are excreted by the kidneys. In renal impairment, the clearance of ODE and MODE is decreased, and hence the dosage should be reduced. Encainide may either worsen or create new arrhythmias, especially in electrolyte-imbalanced patients. Encainide is known to have caused sinus bradycardia, sinus pause, or sinus arrest (see also Eigure 84). 

Esmolol is a class 11 antiarrhythmic agent with ultra-short-acting beta-adrenergic-blocking activity that is used (50 to 200 mcg/kg/minute) to treat supraventricular tachycardia such as atrial fibrillation or atrial flutter. It is rapidly metabolized by erythrocyte esterases via hydrolysis of the methyl ester. Unlike succinylcholine, esmolol is not metabolized by plasma cholinesterase (see also Eigures 67 and 83). 

Flecainide is absorbed well, has a long half-hfe of 3 to 5 days, is metabolized to -O-deaUcylated flecainide (active antiarrhythmic agent with less potency than flecainide) and to -0-deaUcylated lactam of flecainide, which is an inactive metabolite. A portion of flecainide is excreted unchanged. Flecainide, like other antiarrhythmic agents, can cause new or worsen supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in frequency of premature ventricular complexes (PVCs) to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. 

Azimilde is another Class III antiarrhythmic agent structurally unrelated to any of the above agents (Fig. 26.15). Azimilide is not available in the United States it is only available in Europe. Following oral administration, the drug is oompletely absorbed, with no effect of food. Protein binding is 94%. It is metabolized in the liver to an aotive carboxylate metabolite, but its concentration in plasma is less than 5% of the parent oompound. Thus, it is considered to be therapeutically inactive. Renal excretion is approximately 10%. Its elimination half-life is 3 to 4 days. 

Conn HL Jr, Luchi RJ. Some cellular and metabolic considerations relating to the action of quinidine as a prototype antiarrhythmic agent. Am J Med 1964 37 685-699. 

Differences in metabolism among patients can lead to differences in susceptibility to ADRs e.g. patients with abnormal pseudocholinesterase levels have prolonged apnea after receiving succi-nylcholine patients with low activity of A-acetyl transferase are more likely to develop lupus-like reactions to procainamide, hydralazine, and isonia-zid and variants of the cytochrome P-450 family of enzymes can lead to altered metabolism of a variety of drugs, including antidepressants, antiarrhythmic agents, codeine, metoprolol terfenadine, cyclosporine, calcium channel blockers, and others (Peck et al 1993). 

Although the chiral antiarrhythmic agents possess some similarities, they also display a number of features that make them unique. From the perspective of stereoselectivity, a range of differences between the enantiomers of each of these drugs exists in their metabolism, excretion, degree of plasma protein binding and volume of distribution, and pharmacodynamic properties. 

Amide-type agents include articaine, lidocaine, bupivacaine, prilocaine, mepivacain and ropiva-caine. These are metabolized in the liver by microsomal enzymes with amidase activity. The amide group is preferred for parenteral and local use. If by accident rapidly administered intravascularly these agents, especially bupivacaine but also lidocaine, can produce serious and potentially lethal adverse effects including convulsions and cardiac arrest. They can more easily accumulate after multiple administrations. Intravenous lidocaine is sometimes used for regional anesthesia, for infiltration procedures, for the induction of nerve blockade and for epidural anesthesia. However, it is also used as an antiarrhythmic. Bupivacaine is a long-acting local anesthetic used for peripheral nerve blocks and epidural anesthesia. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

One of the more common pathways for the metabolic transformation of tertiary amines involves A -dealkylation to a secondary amine. The observation that those products often show the same biological activity as the parent dmg in many cases confounds the issue of the identity of the chemical species responsible for the drug s action. The fact that the dealkylation product of disobutamide shows antiarrhythmic activity in its own right prompted the synthesis of the acetyl derivative of that secondary amine this agent may be considered a latent form of the active metabohte. This compound is prepared by first repeating the penultimate step in the disobutamide synthesis using (Af-benzyl-Af-isopropyl)-2-chloroethylamine instead of the diisopropyl intermediate. The product from that reaction (56-1) is then hydrolyzed to the... 

Equally as important, and potentially more clinically relevant, are the indirect mechanisms responsible for the antiarrhythmic activity of calcium inhibitory agents, including coronary vasodilation and subsequent increases in coronary artery blood flow (47, 114, 124, 157) decreased cardiac contractility, metabolism, and arterial vasodilation resulting in decreases in myocardial oxygen consumption and wall tension (92) and reflex alterations in autonomic regulation of heart rateToverdrive supression) and AV conduction (114) ... 

---