Refractory period, effective

Indeca.inide. Indecainide hydrochloride is a po active antiarrhythmic agent that received PDA approval in 1989, but it has not been marketed as of this writing. Chemically, it is 9-[3-(isopropylamino)propyl]fiuorine-9-carboxamide [74517-78-5]. The dmg has potent activity against premature ventricular complexes (PVCs) and ventricular tachycardias. Indecainide has no effect on sinus node function, atrial or ventricular effective refractory periods (32,33). 

The Class III antiarrhythmic agents markedly prolong action potential duration and effective refractory period of cardiac tissue. The QT interval of the ECG is markedly prolonged. 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Discuss the mechanism and physiological significance of the effective refractory period... 

The effective refractory period is followed by a relative refractory period that lasts for the remaining 50 msec of the ventricular action potential. During this period, action potentials may be generated however, the myocardium is more difficult than normal to excite. 

Cardiac APD is controlled by a fine balance between inward and outward currents in the repolarization phase. Since outward K+ currents, especially the delayed rectifier repolarizing current, IK (which is the sum of two kinetically and pharmacologically distinct types of K+ currents a rapid, 1k and a slow, IKs, component), play an important role during repolarization and in determining the configuration of the action potential, small changes in conductance can significantly alter the effective refractory period, hence the action potential duration. 

The Pfizer group in the United Kingdom has been actively involved in the search for new Class III antiarrhythmic agents. It has patented a variety of structural types that make extensive use of the methylsulphonylamino moiety. These include indanes [173,174], pyridines [175,176], piperazines [177-179], benzazepines [180], bisarylalkylamines [181] and diazabicyclic compounds [182], From this extensive work, two compounds, UK-66914 (65) and UK-68798 (66), have entered clinical trials. Compound (65) increases the effective refractory period (ERP) of ferret papillary muscle by 25% at a concentration of 0.5 //M [183]. Whole-cell patch-clamp studies... 

Like RS-87337, Win 54177-4 (72) is reported to be a combined Class I/III antiarrhythmic agent. At a dose of 3 mg/kg, the compound increased effective refractory period by 2f% in anaesthetized guinea-pigs [204]. The com-... 

Drugs used for treating arrhythmia can have an effect on the electrical conduction system of the heart, its excitability, automatism, the size of the effective refractory period, and adrenergic and cholinergic heart innervation. Accordingly, compounds of various chemical classes can restore heart rate disturbances. 

Propranolol slows heart rate, increases the effective refractory period of atrioventricular ganglia, suppresses automatism of heart cells, and reduces excitability and contractibihty of the myocardium. It is used for supraventricular and ventricular arrhythmias. Synonyms of this drug are anaprilin, detensiel, inderal, novapranol, and others. 

Pharmacology Procainamide, a class lA antiarrhythmic, increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. 

Pharmacology Therapeutic concentrations of lidocaine attenuate phase 4 diastolic depolarization, decrease automaticity and cause a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period (ERP) of Purkinje fibers and ventricular muscle are decreased, while the ratio of ERP to action potential duration is increased. Lidocaine raises ventricular fibrillation threshold. AV nodal conduction time is unchanged or shortened. Lidocaine increases the electrical stimulation threshold of the ventricle during diastole. 

Mechanism - Structurally like lidocaine, mexiletine inhibits the inward sodium current, thus reducing the rate of rise of the action potential. Phase 0. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in ERP/APD ratio. 

K, clecrease in conduction velocity I, increase in conduction velocity —, no known conduction effects APD, action potential duration ERP, effective refractory period (ventricular). 

Amiodarone prolongs the action potential in atrial muscle and increases the absolute and effective refractory periods. 

Mechanism of Action An antiarrhythmic that shortens duration of action potential and decreases effective refractory period in the His-Purkinje system of the myocardium by blocking sodium transport across myocardial cell membranes. Therapeutic Effect Suppresses ventricular arrhythmias. 

Mechanism of Action An antiarrhythmicthat prevents sodium current across myocardial cell membranes. Has potent local anesthetic activity and membrane stabilizing effects. Slows AV and His-Purkinje conduction and decreases action potential duration and effective refractory period. Therapeutic Effect Suppresses ventricular arrhythmias. 

The answer is c. (Hardman, pp 813-814.) Digoxin is used in AF to slow the ventricular rate, not usually the AF itself. Digoxin acts to slow the speed of conduction, increase the atrial and AV nodal maximal diastolic resting membrane potential, and increase the effective refractory period in the AV node, which prevents transmission of all impulses from the atria to the ventricles. It exerts these effects by acting directly on the heart and by indirectly increasing vagal activity. 

Atropine initially decrease the heart rate due to stimulation of vagal centre followed by tachycardia due to peripheral vagal block on SA node. It also shortens effective refractory period of AV node and facilitates AV conduction. In therapeutic doses, atropine completely blocks the peripheral vasodilatation and decrease in blood pressure produced by cholinergic agents. 

Ill Class III Drugs that prolong effective refractory period by prolonging action potential ... 

It decreases the rate of rise of action potential and prolongs the effective refractory period. 

It is an amide local anaesthetic and has rapid onset of action. It depresses diastolic depolarization and automaticity in ectopic foci in ventricular tissue. Phase 4 depolarization in partially depressed Purkinje fibres and after depolarizations are antagonised. It does not depress AV conduction and decreases action potential duration, effective refractory period. It has no effect on BP. 

The antiarrhythmic action is due to cardiac adrenergic blockade. It decreases the slope of phase 4 depolarization and automaticity in SA node, Purkinje fibres and other ectopic foci. It also prolongs the effective refractory period of AV node and impedes AV conduction. ECG shows prolonged PR interval. It is useful in sinus tachycardia, atrial and nodal extrasystoles. It is also useful in sympathetically mediated arrhythmias in pheochromocytoma and halothane anaesthesia. 

These drugs inhibit Ca + mediated slow channel inward current, thus inhibiting Ca + mediated depolarization. Phase 4 depolarization in SA node and Purkinje fibres is reduced. They also prolong AV nodal effective refractory period thus AV conduction is slowed. There is also negative inotropic action. 

Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. The major mechanisms currently available for accomplishing these goals are (1) sodium channel blockade, (2) blockade of sympathetic autonomic effects in the heart, (3) prolongation of the effective refractory period, and (4) calcium channel blockade. 

Drugs that Prolong Effective Refractory Period by Prolonging the Action Potential (Class 3)... 

Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the sinoatrial and atrioventricular nodes. Atrioventricular nodal conduction time and effective refractory period are invariably prolonged by therapeutic concentrations. Verapamil usually slows the sinoatrial node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of sinoatrial nodal rate. 

Dofetilide IKr block Prolongs action potential, effective refractory period Maintenance or restoration of sinus rhythm in atrial fibrillation Oral renal excretion Toxicity Torsade de pointes (initiate in hospital) Interactions Additive with other QT-prolonging drugs... 

FIGURE 23-1 T The cardiac action potential recorded from a Purkinje cell. The effective refractory period is the time during which the cell cannot be depolarized, and the relative refractory period is the time in which a supranormal stimulus is required to depolarize the cell. Action potential phases [0-4] and the ionic basis for each phase are discussed in the text. From Keefe DLD, Kates RE, Harrison DC. New antiarrhythmic drugs their place in therapy. Drugs. 1981 22 363 with permission.]... 

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