Refractory period, cardiac

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

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. 

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. 

Phase 2 A plateau occurs owing to the opening of L-type Ca2+ channels, which offset the action of K+ channels and maintain depolarization. During this phase, no further depolarization is possible. This is an important point to demonstrate and explains why tetany is not possible in cardiac muscle. This time period is the absolute refractory period (ARP). The plateau should not be drawn completely horizontal as repolarization is slowed by Ca2+ channels but not halted altogether. 

While most -blocking agents on acute administration have little direct electrophysiological effects, studies in rabbits [94] and man [95] have shown that chronic administration of y -blockers increases APD. This increase in APD (and hence refractory period) has been postulated to contribute to the effectiveness of -receptor blocking agents in the prevention of sudden cardiac death [94]. Direct Class III action has been claimed for the y -blockers oxprenolol (30) [96,97], nadolol (31) [96] and atenolol (10) [98] in addition... 

Mechanism of action - Disopyramide is a class lA antiarrhythmic agent that decreases the rate of diastolic depolarization (phase 4), decreases the upstroke velocity (phase 0), increases the action potential duration of normal cardiac cells, and prolongs the refractory period (phases 2 and 3). It also decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium and does not affect alpha- or beta-adrenergic receptors. 

In the undamaged myocardium, cardiac impulses travel rapidly antegrade through the Purkinje hbers to deliver the excitatory electrical impulse to the ventricular myocardium. During the normal activation sequence, retrograde conduction from ventricular myocardium to the conducting hbers is prevented by the longer duration of the membrane action potential and thus the refractory period in the Purkinje hbers. 

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). 

Mechanism of Action A cardiac agent that prolongs duration of myocardial cell action potential and refractory period by acting directly on all cardiac tissue. Decreases AV and sinus node function. Therapeutic Effect Suppresses arrhythmias. Pharmacokinetics ... 

Mechanism of Action An antiarrhythmic that prolongs the refractory period of the cardiac cell by direct effect, decreasing myocardial excitability and conduction velocity. Therapeutic Effect Depresses myocardial contractility. Has anticholinergic and negative inotropic effects. 

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. 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

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.]... 

Drugs that block beta-1 receptors on the myocardium are one of the mainstays in arrhythmia treatment. Beta blockers are effective because they decrease the excitatory effects of the sympathetic nervous system and related catecholamines (norepinephrine and epinephrine) on the heart.5,28 This effect typically decreases cardiac automaticity and prolongs the effective refractory period, thus slowing heart rate.5 Beta blockers also slow down conduction through the myocardium, and are especially useful in controlling function of the atrioventricular node.21 Hence, these drugs are most effective in treating atrial tachycardias such as atrial fibrillation.23 Some ventricular arrhythmias may also respond to treatment with beta blockers. 

Class III antiarrhythmic agent with additional classes I, II, III, and IV actions. Prolongs action potential duration and effective refractory period in all cardiac tissues,... 

Endogenous norepinephrine stimulates cardiac beta receptors. Receptor-linked cAMP-dependent protein kinases phosphorylate calcium channels to increase intracellular calcium. Elevated intracellular calcium increases conduction velocity (phase 0) and decreases the threshold potential in normal SA and AV node cells (see Figure 12.13). Beta blockers slow spontaneous conduction velocity in the SA node by approximately 10-20 percent. In addition, beta blockers can slow conduction velocity while increasing the refractory period of the AV node. These effects control the ventricular rate in atrial fibrillation or flutter and terminate paroxysmal supraventricular tachycardias. They are also safer, although somewhat less effective, than other drugs for suppression of premature ventricular complexes (PVCs). Drugs in this class approved by the FDA for treatment of various arrhythmias include propranolol, acebutolol, and esmolol. Problems with the beta blockers include drowsiness, fatigue, impotence, and depressed ventricular performance. 

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