Nursing Pharmacology Chapter 8:   Antiarrhythmic Agents

 Influence of Membrane Resting Potential on Action Potential Properties

• The extent and synchrony of sodium channel activation is dependent on the resting membrane potential.

  • Inactivation gates of sodium channels close in the membrane potential range of -75 to -55 mV (less channels available for sodium ion inward current)

  • For example: less intense sodium current if the resting potential is - 60 mV compared to -80 mV

  • Consequences of reduced sodium activation due to reduced membrane potential (less negative)

    • Reduced of velocity upstroke (V_max) [phase 0] (maximum rate of membrane potential change)

    • Reduced excitability

    • Reduced conduction velocity which is a significant cause of arrhythmias

    • Prolongation of recovery is associated with an increase in effective refractory period

• Plateau Phase:

  • Plateau phase -- Na channels mostly inactivated

  • Repolarization (h gates reopen)

  • "Refractory period": time between phase 0 and phase 3.

    • During this time the stimulus does not result in a propagated response

  • Altered refractoriness may cause or suppress arrhythmias

• Factors that reduce the membrane resting potential and reduce conduction velocity

  • Hyperkalemia

  • Sodium pump block 

  • Ischemic cell damage

• Conduction in severely depolarized cells

  • With decreased membrane potentials (e.g., -55 mV), sodium channels are inactivated

  • Under some circumstances, increased calcium permeability or decreased potassium permeability allow for slowly conducted action potentials with slow upstroke velocity

  • Ca²⁺-inward current-mediated action potentials are normal for the specialized conducting SA nodal and AV nodal tissues, which have resting membrane potentials in the -50 to-70 mV range.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241.

•  Factors that may precipitate or exacerbate arrhythmias

  • Ischemia

  • Hypoxia

  • Acidosis

  • Alkalosis

  • Abnormal electrolytes

  • Excessive catecholamine levels

  • Autonomic nervous system effects (e.g., excess vagal tone)

  • Excessive catecholamine levels

  • Autonomic nervous system effects (e.g., excess vagal tone)

  • Drug effects: e.g., antiarrhythmic drugs may cause arrhythmias)

  • Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure)

  • Presence of scarred/diseased tissue which have altered electrical conduction properties

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241

Pathophysiology

• Arrhythmias develop because of abnormal impulse generation, propagation or both.

  • Abnormalities of Cardiac Impulse Initiation

    • Factors that influence heart rate (altered frequency of pacemaker cell firing rate)

      • Heart rate determined (interval between pacemaker firing) by the sum of: Action potential duration + Diastolic duration interval

      • More important:  Diastolic duration interval: determined by 3 factors:

        • Maximum diastolic potential (most negative membrane potential reached during diastole

        • Slope of phase 4 depolarization: (increased slope: threshold is reached quicker causing a faster heart rate; decreased slope: longer to reach threshold resulting in a slower heart rate

        • Threshold Potential (membrane potential at which in action potential is initiated)

    • Decreased Heart Rate:

      • Vagal Effects: (cholinergic influences on the heart rate)

        • More negative maximum diastolic potential (the membrane potential starts farther away from the threshold potential)

        • Reduced slope of phase 4 depolarization (takes longer to reach threshold potential)

    • Increased Heart Rate:

      • Adrenergic Effects: (sympathetic/sympathomimetic influences on heart rate)

        • β-adrenergic receptor blockers (reduced phase 4 depolarization slope)

    • Factors that can increase automaticity:

      • Hypokalemia

      • Cardiac fiber stretch

      • β-adrenergic receptor activation

      • Injury currents

      • Acidosis

    • Latent Pacemakers are cells not normally serving pacemaker function, but exhibit slow phase 4 depolarization: conditions favoring latent pacemaker activity noted above

      • All cardiac cells (including normally inactive atrial/ventricular cells) may show pacemaker activity, particularly in hypokalemic states

    • Failure of impulse initiation can lead to excessively slow heart rate, bradycardia .

      • If an impulse fails to propagate through the conduction system from the atrium to the ventricle, heart block may occur.

    • An excessively rapid heart rate, tachycardia, is also encountered clinically

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241.