Cardiac action potential effect

The cardiac action potential—effects of the administration of quinidine. 

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

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. 

Class III agents increase the refractoriness of cardiac tissue, thus preventing an aberrant impulse from propagating. A selective Class III agent has little or no effect on simple PVC s. At the cellular level, the increased refractoriness is manifest by a delay in the repolarization phase (Phase 3) of the cardiac action potential Figure 2.1), thereby increasing action potential duration. During the action potential cycle a complex series of ionic currents. 

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. 

Fig. 2. Effect of calcium antagonists (CA) on a cardiac cell. Top typical cardiac action potential. The calcium (slow) inward current flows during the characteristic plateau phase (phase 2) of the action potential. This calcium influx is selectively inhibited by CA. Activation of the sarcoplasmic reticulum (SR) and other cellular calcium pools occurs via Ca + and Na+ ions which flow into the cell. The SR and other pools donate activator Ca + ions which stimulate the contractile proteins. The presence of tubular systems (invaginations), which are characteristic of cardiac tissues, results in considerable enlargement of the cellular surface, thus enabling an effective influx of Na+ and Ca + ions. Inhibition of the calcium inward flux by a CA causes diminished activation of the contractile proteins.

The concept of calcium antagonism as a specific mechanism of drug action was pioneered by Albrecht Fleckenstein and his colleagues, who observed that verapamil and subsequently other drugs of this class mimicked in reversible fashion the effects of Ca++ withdrawal on cardiac excitability. These drugs inhibited the Ca" + component of the ionic currents carried in the cardiac action potential. Because of this activity, these drugs are also referred to as slow channel blockers, calcium channel antagonists, and calcium entry blockers. 

Cardiovascular System. Atropine is sometimes used to block the effects of the vagus nerve (cranial nerve X) on the myocardium. Release of acetylcholine from vagal efferent fibers slows heart rate and the conduction of the cardiac action potential throughout the myocardium. Atropine reverses the effects of excessive vagal discharge and is used to treat the symptomatic bradycardia that may accompany myocardial infarction.4 Atropine may also be useful in treating other cardiac arrhythmias such as atrioventricular nodal block and ventricular asystole. 

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.]... 

Figure 12.14 Effect of potassium blocker on cardiac action potential.

Recent examples include safety pharmacology s embracement of modem electrophysiological techniques to evaluate the effects of new drugs on the ionic components of the cardiac action potential (Redfem et al. 2003), and telemetry techniques to permit the... 

Drugs used in dysrhythmias can be classified in different ways, the usual classification being according to their effects on the cardiac action potential (1), as shown in Table 1. 

Drugs with membrane-stabilizing activity reduce the rate of rise of the cardiac action potential and have other electrophysiological effects. Membrane-stabilizing activity has only been shown in human cardiac muscle in vitro in concentrations 100 times greater than those produced by therapeutic doses (23). It is therefore likely to be of clinical relevance only if large overdoses are taken. 

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