Amiodarone channel inhibition

The Vaughan-Williams classification of antiarrhythmic drugs has been criticized for a number of reasons. The classification is based on the effects of drugs on normal, rather than diseased, myocardium. In addition, many of the drugs may be placed into more than one class. For example, the class IA drugs prolong repolarization/refractoriness, either via the parent drug8,9 or an active metabolite,10 and therefore also maybe placed in class III. Sotalol is also a 3-blocker, and therefore fits into class II. Amiodarone inhibits sodium and potassium channels, is a non-competitive inhibitor of 3-receptors, and inhibits calcium... 

At the cellular level, the major electrophysiological effect appears to be rate-dependent blockade of sodium channels [22]. The onset for this Class I effect (64 + 9% of the final depression of between the first and second beat of the train) was similar to that for Class IB agents [23]. The offset rate (recovery of from rate-dependent depression) for amiodarone was 1.48 s. This value falls between those seen for Class IB agents (200-500 ms) and lA agents (2.3-12.2 s) [23]. Amiodarone inhibited the binding of pH]ba-trochotoxinin A 20a-benzoate to the sodium channel, suggesting that it binds to inactivated sodium channels [24]. 

Commonly listed under a separate rubric (Class 111) are amiodarone and the P-blocking agent sotalol, which both inhibit K+-channels and which both cause marked prolongation of the AP with a lesser effect on Phase 0 rate of rise. 

Class III drugs currently in use include amiodarone, bretylium, dofetilide, and ibutilide (see Table 23-2). These drugs all exert their primary effects by prolonging repolarization in cardiac cells. Amiodarone, however, also appears to have some properties similar to drugs in other classes, and may help control arrhythmias by inhibiting sodium channel function (class I effect), by beta blockade (class II effect), or even by blocking calcium channels (class IV effect).5... 

The antiarrythmic drug amiodarone inhibits reserpine binding in a concentration-dependent manner and has a sympatholytic, anti-adrenergic effect in the heart, inhibiting the uptake of norepinephrine (Haikerwal et al., 1999). Blockers of VMAT and L-type calcium channels have also been reported to exert reciprocal inhibitory actions (Mahata et al., 1996). 

AMIODARONE CALCIUM CHANNEL BLOCKERS Risk of bradycardia, AV block and 1 BP when amiodarone coadministered with diltiazem or verapamil Additive negative inotropic and chronotropic effect. Also, amiodarone inhibits intestinal P-gp, which t the bioavailability of diltiazem and verapamil Monitor PR, BP and ECG closely watch for heart failure... 

AMIODARONE POTASSIUM-SPARING DIURETICS Risk of T levels of eplerenone with amiodarone risk of hyperkalaemia directly related to serum levels Calcium channel blockers inhibit CYP3A4-mediated metabolism of eplerenone Restrict dose of eplerenone to 25mg/day. Monitor serum potassium concentrations closely watch for hyperkalaemia... 

Tamargo et al gave a very recent review.139 They point out that KATP channels are inhibited by ATP and activated by Mg ADP, so that the channel activity is influenced by the ATP/ADP ratio. They also draw attention to the fact that mitochondrial KATp channel is responsible for ischemic preconditioning. They suggest that these channels are not blocked only by sulfonylureas, but also by many antiarrhythmic drugs, such as bretylium, disopyramide, flecainide and propafenone, and also by diltiazem and verapamil, but not by amiodarone or dronedarone, which will be addressed later. 

Amiodarone inhibits the activity of both vascular calcium channels, and ct-adrenoceptors. Thus, a net vasodilatation is produced. This effect occurs mainly with intravenous administration. 

Answer A. Amiodarone is a highly effective antiarrhythmic drug, in part because of its multiple actions, which include Na channel block, beta adrenoceptor block, K channel block, and Ca channel block. Drugs that block channels (which include class lA and class III antiarrhythmics) prolong APD and ERP and predispose toward torsades de pointes ventricular arrhythmias. Flecamide is a class IC drug, lidocaine and phenytoin are class IB, and verapamil is class IV, none of which inhibits the delayed rectifier K+ current responsible for membrane repolarization during the cardiac action potential. 

Induction of hepatic metabolism 2. Inhibition of phenytoin metabolism (parecoxib - CYP2C9 calcium channel blockers -CYP3A4 mianserin -unknown) 3. Uncertain amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism and inhibits Intestinal P-gp, which may t bioavailability of phenytoin. Theophylline i absorption of phenytoin... 

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