Bretylium Tosylate. Bretylium tosylate, (ö-bro-mobenzyl)ethyl dimethylammonium ^-toluenesulfonate (Bretylol), is an extremely bitter, white, crystalline powder. The chemical is freely soluble in water and alcohol. Bretylium tosylate is an adrenergic neuronal-blocking agent that accumulates selectively in the neurons and displaces norepinephrine. Because of this property, bretylium was used initially, under the trade name of Darenthin, as an antihypertensive agent. It caused postural decrease in arterial pressure.44 This use was discontinued because of the rapid development of tolerance, erratic oral absorption of the quaternary ammonium compound, and persistent pain in the parotid gland on prolonged therapy. Currently, bretylium is reserved for use in ventricular arrhythmias that are resistant to other therapy. Bretylium does not suppress phase 4 depolarization, a common action of other antiarrhythmic agents. It prolongs the effective refractory period relative to the action potential duration but does not affect conduction time and is categorized as a class III antiarrhythmic agent. Because bretylium does not have properties similar to those of the other antiar-rhythmic agents, it has been suggested that its action is a result of its adrenergic neuronal-blocking properties; the antiarrhythmic properties of the drug, however, are not affected by administration of reserpine. Bretylium is also a local anesthetic, but it has not been possible to demonstrate such an effect on atria of experimental animals, except at very high concentrations.45 Therefore, the precise mechanism of the antiarrhythmic action of bretylium remains to be resolved.

Bretylium (Bretylol)

Dofetilide. Dofetilide, N-[4-(3-{[2-(4-methanesul-fonylaminophenyl)ethyl]methylamino}propoxy)phenyl] methane-sulfonamide (Tikosyn), acts by blocking the cardiac ion channel carrying the rapid component of the delayed rectifier potassium currents (Ikr) and is used to terminate supraventricular arrhythmias, prevent the recurrence of atrial fibrillation, and treat life-threatening ventricular arrhythmias. Unlike sotalol and ibutilide, which are also methanesulfonanilides, it has no effect on adrener-gic receptors or sodium channels, respectively. Dofetilide has high specificity for the delayed rectifier potassium currents.46

Ibutilide. Ibutilide, N-{4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl}methanesulfonamide (Corvert), a class III antiarrhythmic belonging to the methanesulfo-nanilide class of agents, is indicated for rapid conversion of atrial fibrillation or atrial flutter to normal sinus rhythm.

Unlike dofetilide, it is not highly specific for the delayed rectifier potassium currents (Ikr) and does have some affinity for sodium channels.

Sotalol. Sotalol, 4'[1-hydroxy-2-(isopropylamino) ethyl]methylsulfonanilide (Betapace), is a relatively new antiarrhythmic drug, characterized most often as a class III agent, and although it has effects that are related to the class II agents, it is not therapeutically considered a class II antiar-rhythmic. It contains a chiral center and is marketed as the racemic mixture. Because of its enantiomers, its mechanism of action spans two of the antiarrhythmic drug classes. The l(—) enantiomer has both ^-blocking (class II) and potassium channel-blocking (class III) activities. The d(+) enantiomer has class III properties similar to those of the (— ) isomer, but its affinity for the ^-adrenergic receptor is 30 to 60 times lower. The sotalol enantiomers produce different effects on the heart. Class III action of d-sotalol in the sinus node is associated with slowing of sinus heart rate, whereas ^-adrenergic blockade contributes to the decrease in heart rate observed with 1- or d,1-sotalol. Sotalol is not metabolized, nor is it bound significantly to proteins. Elimination occurs by renal excretion, with more than 80% of the drug eliminated unchanged. Sotalol is characteristic of class III antiarrhythmic drugs, in that it prolongs the duration of the action potential and, thus, increases the effective refractory period of myocardial tissue. It is distinguished from the other class III drugs (amiodarone and bretylium) because of its ^-adrenergic receptor-blocking action.

Azimilide. Azimilide, £-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl) butyl]-2,4-imidazolidinedione, is a class III agent that sig nificantly blocks the delayed rectifier potassium current, Iks, including the Ikr component. Its ability to block multichannels may be caused by a lack of the methane sulfonamide group that is common to other class III agents, which selectively block the Ikr potassium current. It is believed that blocking both Ikr and Iks potassium currents yields consistent class III antiarrhythmic effects at any heart rate.47

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