Prolonging cardiac action

These are a few compounds which specifically prolong the cardiac action potential, such as amiodarone and bretylium tosylate. 

2-Butylbenzofuran-3-yl 4-(2-diethylaminoethoxy)-3, 5-diiodophenyl ketone 2-Butyl-3-benzofuranyl 4-[2-(diethylamino) ethoxy]-3,5-diiodophenyl ketone  

It is frequently employed in the control and management of ventricular and supraventricular arrhythmias, and also in the treatment of angina pectoris. 

Dose Initial (as its hydrochloride salt), 200 mg 3 times per day for a week or more and then reduced to a maintenance dose of200 mg daily 

Bretylol (American Critical Care) Bretylate (Wellcome, U.K.) 

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Biopharmaceuticals or pharmaceuticals dissolved in Tyrodes s solution to obtain at least 5 different concentrations Biopharmaceuticals and pharmaceuticals formulated by the CRO and require formulation analysis for concentration, homogeneity, and stability dl-soltalol, a P-adrenergic antagonist that prolongs cardiac action potential by selectively blocking the rapidly activating delayed rectifier potassium current (IKr)... 

Pharmacological Effects Procainamide is a blocker of open Na channels with an intermediate time constant of recovery from block. It also prolongs cardiac action potentials, probably by... 

Kvl.5 In human atria, the Kvl.5 presents the ultrarapid delayed rectifier that contributes to the repolarization in the early phase of cardiac action potential. Selective blockers of Kvl.5 channels could be potentially beneficial in the treatment of atrial fibrillation because blocking Kvl. 5 could delay repolarization and prolong refractoriness selectively in cardiac myocytes. Examples for Kvl.5 blockers include AVE0118, S9947, and analogs of diphenyl phosphine oxide (DPO). 

Studies to assess the effects of compound and any known metabolites on ECG and cardiac action potentials are recommended. Changes in action potential duration and other parameters measured are a functional consequence of effects on the ion channels which contribute to the action potential. This in vitro test is considered to provide a reliable risk assessment of the potential for a compound to prolong Q-T interval in humans. 

Kuryshev, Y.A., Wang, L., Wible, B.A., Wan, X. and Ficker, E. (2006) Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents. Molecular Pharmacology, 69, 1216-1225. 

Jurkiewicz, N.K. and Sanguinetti, M.C., Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide, Circ. Res., 72, 75-83, 1993. 

However, the reverse is not necessarily true all compounds that block the hERG channels do not prolong action potentials. Part of the reason lies in the fact that many compounds have a mixed effect on ion channels, particularly due to the blocking effect on both hERG and the L-type calcium channel [21], which is responsible for phase 2 of the cardiac action potential (Figure 16.1). Examples for such dual-blockers include bepridil, verapamil and mibefradil [22], all blocking hERG and L-type calcium channels at the therapeutic concentrations. However, only verapamil has nearly no cardiac liabilities. 

Dofetilide (Tikosyn) is a pure class III drug. It prolongs the cardiac action potential and the refractory period by selectively inhibiting the rapid component of the delayed rectifier potassium current (IKr). 

Local anaesthetics directly depress myocardial conduction and contractility in a dose-dependent manner. They bind to and inactivate myocardial sodium channels, reducing the velocity of the cardiac action potential and prolonging the QRS interval. As plasma concentrations approach toxic values sodium channels become progressively inactivated until there is a generalised reduction in automaticity (cardiac slowing) with negative inotropy. Slow increases to near- or above-toxic levels are better tolerated than rapid rises seen following intravascular injection. 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

Quinidine has actions similar to those of procainamide it slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. 

Propranolol 13- Adrenoceptor blockade Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral duration 4-6 h Toxicity Asthma, AV blockade, acute heart failure Interactions With other cardiac depressants and hypotensive drugs... 

Hall B, Jelbart ME, Gurley KE, Dorsch SE. 1990. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of CD4+ suppressor cell and its mechanisms of action. J Exp Med. 171 141-157. 

Before leaving the matter of amines, we should examine some of the known simpler ones for their effects upon the circulation, especially as to cardiac action and duration of pressor response. The former is noteworthy, as its absence is a necessary prerequisite of the Hochdruckstoff. Presumably an extended vasospastic action should also be a prerequisite. Prolonged action can be produced in at least four ways (1) by some property inherent in the structure of the molecule of the pressor agent which prevents its rapid destruction in situ or in blood (2) by slow liberation of an effector substance from a larger, more complex molecule or system (3) by inhibition of the action of an enzyme system which inactivates some naturally occurring pressor agent and (4) by continuous production from parent sources. Clear-cut examples are not evident at present, although... 

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