Chapter 8  Medical Pharmacology:   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-- a significant cause of arrhythmias

    • Prolongation of recovery:-- 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 & 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 & 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 & 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 -- cells not normally serving pacemaker function, but exhibits 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 & Lange, 1998, pp 216-241.