Cardiac Electrophysiological Considerations

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Chapter: Essential pharmacology : Cardiac Electrophysiological Considerations

Drugs having their major action on heart or blood vessels, or those used primarily for cardiovascular disorders are designated cardiovascular drugs. They can act directly on the cardiovascular structures or through the autonomic/central nervous system, kidney, autacoids or hormones which regulate cardiovascular function.


CARDIAC ELECTROPHYSIOLOGICAL CONSIDERATIONS

 

Drugs having their major action on heart or blood vessels, or those used primarily for cardiovascular disorders are designated cardiovascular drugs. They can act directly on the cardiovascular structures or through the autonomic/central nervous system, kidney, autacoids or hormones which regulate cardiovascular function.

 

Cardiac Electrophysiology

 

The properties which are especially important for understanding drug action on heart are:

 

1. Impulse Generation

 

Electrophysiologically, two types of myocardial fibres can be distinguished (Fig. VIII.1).

 

(a) Nonautomatic Fibres These are the ordinary working myocardial fibres; cannot generate an impulse of their own. During diastole, the resting membrane potential remains stable (approximately 90 mv negative inside). When stimulated, they depolarize very rapidly (fast 0 phase) with considerable overshoot (+ 30 mv) rapid return to near isoelectric level (phase1) maintenance of membrane potential at this level for a considerable period (phase2, plateau phase) during which Ca2+ ions flow in and bring about contraction relatively rapid repolarization (phase-3 during which membrane Na+K+ pump gets activated and tends to restore ionic distribution to the resting pattern. Resting membrane potential, once attained, does not decay (stable phase-4).

 

(b) Automatic Fibres These are present in the sinoatrial (SA) and atrioventricular (AV) nodes, and in the His-Purkinje system, i.e. especialized conducting tissue. In addition, patches of automatic tissue are present in the interatrial septum, AV ring and around openings of the great veins. The most characteristic feature of these fibres is phase-4 or slow diastolic depolarization, i.e. after repolarizing to the maximum value, the membrane potential decays spontaneously. When it reaches a critical threshold value—sudden depolarization occurs automatically. Thus, they are capable of generating their own impulse. The rate of impulse generation by a particular fibre depends on the value of maximal diastolic potential, the slope of phase4 depolarization and the value of threshold potential.

 


                


Normally, the SA node has the steepest phase4 depolarization, undergoes self-excitation and propagates the impulse to the rest of the heart— acts as the pacemaker. Other fibres which are also undergoing phase4 depolarization, but at a slower rate, receive the propagated impulse before reaching threshold value and remain as latent pacemakers.

 

Two types of action potential (AP) are possible. These are depicted in Fig. VIII.2. Their characteristics are given in Table VIII. 1.



 

The slow channel AP is characterised by:

 

·      Initiation at a higher threshold (less negative level).

·      Slow depolarization during 0 phase.

·      Less overshoot, low amplitude.

·      Very slow propagation, decremental conduction and a low safety factor for conduction.

·      Can arise and propagate in fibres too depolarized to support fast channel responses.

 

Slow channel AP in SA node, AV node, etc. has a shorter duration and phases 1–3 are not clearly demarkated. Slow channel AP can occur in Purkinje fibres (PF) also, but this has a much longer duration with a prominent plateau phase.

 

2. Conduction

 

The rate of conduction through a fibre is a function of its membrane responsiveness, which is defined by rate of rise of AP (dv/dt) as a function of membrane potential at which activation occurs (Fig. VIII.3); a more completely polarized membrane depolarizes faster. This type of relationship is seen in atrial, ventricular and Purkinje fibres (fast channel fibres which depolarize by Na+ current), but not in SA and AV nodal cells which remain refractory for some time even after attainment of maximal resting potential.



 

The Na+ channels get progressively inactivated as the resting membrane potential (RMP) drops over the –80 to –60 mV range. Consequently, less negative the RMP at which activation occurs, fewer are the Na+ channels available for activation—slope of ‘0’ phase depolarization, AP amplitude and conduction velocity are reduced.

 

A drug which reduces the slope of 0 phase (at any given resting membrane potential) will shift the membrane responsiveness curve to the right and impede conduction. The reverse occurs with a drug that shifts the curve to the left. Membrane responsiveness curve can also be altered by disease.

 

Small cells at the upper margin of AV node have very low conduction velocity (20 mm/sec). Normally Purkinje fibres (PFs) have the highest conduction velocity (4000 mm/sec) except near their junction with the ventricular fibres ‘gate region’, or if they change over from fast channel to slow channel response.

 

3. Excitability

 

This property of a fibre is defined by the strength of stimulus required to elicit a response or to produce an AP. Hyperpolarization decreases excitability while small reductions in resting membrane potential increase excitability by respectively increasing and decreasing the gap between it and the threshold potential. Thus, in fast channel fibres excitability

is generally supernormal during the end of phase3. However, when the resting membrane potential is reduced to a value below the threshold potential, the fibre becomes inexcitable.

 

4. Refractory Period

 

Pharmacologically, the effective refractory period (ERP) which is the minimum interval between two propagating APs, is the most important. It is closely related to the AP duration (APD). An AP can be evoked in fast channel fibres even before complete repolarization, because Na+ channels recover in a voltage-dependent manner above the threshold potential. As such ERP/APD is <1. By contrast, the Ca2+ channels recover in a time-dependent manner progressively after the fibre has fully repolarized. Thus, in slow channel fibres ERP/ APD is > 1. Most antiarrhythmic drugs increase ERP/APD ratio.

 

Autonomic Influences On Cardiac Electrophysiology And Contractility

 

It would be profitable to recapitulate the influence of sympathetic and parasympathetic stimulation on variables of cardiac function, because many cardiovascular drugs have indirect/secondary autonomic effects (Table VIII.2).

 

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