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Medical Pharmacology  Cardiovascular Pharmacology Lecture: Antiarrhythmic Agents slide 1

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Table of Contents

  • Electrophysiology

    • Cardiac Rhythm

    • Cardiac Electrophysiology

      • Transmembrane Potential

      • Sodium

      • Potassium

      • Spontaneous Depolarization

      • Channel Activation

  • Five Phases: cardiac action potential associated with HIS-purkinje fibers or ventricular muscle and ionic and electrophysiological changes are associated with normal cardiac rhythm

  • Resting membrane potential and conduction velocity

  • Pathophysiology

  • Introduction: Arrhythmias & Drug Therapy

  • Abnormalities of Cardiac Impulse Initiation

  • Mechanism of Action of Antiarrhythmic Agents

  • Antiarrhythmic Drug Classes

  • Antiarrhythmic Drugs


Electrophysiology and Cardiac Arrhythmias


  • Cardiac Rhythm

    • Normal rate: 60-100 beats per minute

    • Impulse Propagation: sinoatrial node to the  atrioventricular (AV node) to the His-Purkinje followed by distribution throughout the ventricle

    • Normal AV nodal delay (0.15 seconds) -- sufficient to allow atrial ejection of blood into the ventricles

    • Definition: arrhythmia -- cardiac depolarization different from above sequence --

      •  abnormal origination (not SA nodal)

      •  abnormal rate/regularity

      •  abnormal conduction characteristics


Cardiac Electrophysiology

  • Transmembrane potential -- determined primarily by three ionic gradients:

    •  Na+, K+, Ca 2+

      •  water-soluble, -- not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins)

    • Movement through channels depend on controlling "molecular gates"

      •  Gate-status controlled by:

        • Ionic conditions

        • Metabolic conditions

        • Transmembrane voltage

    • Maintenance of ionic gradients:

      •  Na+/K+ ATPase pump

        •  termed "electrogenic" when net current flows as a result of transport (e.g., three Na+ exchange for two K+ ions)

    • Initial permeability state -- resting membrane potential

      • sodium -- relatively impermeable

      • potassium -- relatively permeable

    • Cardiac cell permeability and conductance:

      •  conductance: determined by characteristics of ion channel protein

      •  current flow = voltage X conductance

      •  voltage = (actual membrane potential - membrane potential at which no current would flow, even with channels open)


    • Sodium

      • Concentration gradient: 140 mmol/L Na+ outside: 10 mmol/L Na+ inside;

      • Electrical gradient: 0 mV outside; -90 mV inside

      • Driving force -- both electrical and concentration -- tending to move Na+ into the cell.

      • In the resting state: sodium ion channels are closed therefore no Na+ flow through the membrane

      • In the active state: channels open causing a large influx of sodium which accounts for phase 0 depolarization

Cardiac Cell Phase 0 and Sodium Current

  • Note the rapid "upstroke" characteristic of Phase 0 depolarization.

  • This abrupt change in membrane potential is caused by rapid, synchronous opening of Na+ channels.

  • Note the relationships between the the ECG tracing and phase 0


  • Potassium:

    • Concentration gradient (140 mmol/L K+ inside; 4 mmol/L K+outside)

    • Concentration gradient -- tends to drive potassium out

    • Electrical gradient tends to hold K+ in.

    • Some K+ channels ("inward rectifier") are open in the resting state -- however, little K+ current flows because of the balance between the K+ concentration and membrane electrical gradients

    •  Cardiac resting membrane potential: mainly determined

      1. By the extracellular potassium concentration and

      2. Inward rectifier channel state

  • Spontaneous Depolarization (pacemaker cells)--  phase 4 depolarization

    • Spontaneous Depolarization occurs because:

      • Gradual increase in depolarizing currents (increasing membrane permeability to sodium or calcium)

      • Decrease in repolarizing potassium currents (decreasing membrane potassium permeability)

      • Both

    •  Ectopic pacemaker: (not normal SA nodal pacemakers) --

      • Facilitated by hypokalemic states

      • Increasing potassium: tends to slow or stop ectopic pacemaker activity

  • Channel Activation Sequence:

    • Depolarization to threshold voltage--Na+

      • In the resting membrane state, the m gates are closed and the h gates are open: essentially no Na+ flow.

      • Then with depolarization, there is m gate activation (activation gate); assuming inactivation (h) gates are not closed (when h gates are closed no sodium can enter), then

      • Sodium permeability dramatically increased; intense sodium current

      • Depolarization

      • h gate closure; Na+ current inactivation

    • Ca2+ --

Ca2+:  Channel Activation Sequence similar to sodium; but occurring at more positive membrane potentials (phases 1 and 2)

  • Following intense inward Na+ current (phase 0), Ca2+currents:

  • Phases 1 & 2, are slowly inactivated.   (Ca2+channel activation occurred later than for Na+)



Channel Inactivation, Re-establishing the Resting Membrane Potential

  • Final repolarization (phase 3):

    • complete Na+ and Ca2+ channel inactivation

  • Increased potassium permeability

  • Membrane potential approaches K+ equilibrium potential -- which approximates the normal resting membrane potential


Five Phases:   cardiac action potential associated with HIS-purkinje fibers or ventricular muscle   

  • Phase 0 corresponds to Na+ channel activation.

    • The maximum upstroke slope of phase 0 is proportional to the sodium current.

    • Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.

  • Phase 1 corresponds to an early repolarizing K+ current.

    •  rapidly inactivated.

  • Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by an outward, repolarizing K+ current (delayed rectifier).

  • Phase 3 is also the combination of Ca2+ and K+ currents.

    • Phase 3 is repolarizing because the outward (repolarizing) K+ current increases while the inward (depolarizing) Ca2+ current is decreasing.

  • Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current.

    • As a result, the resting membrane potential would normally be flat.

    • In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold.

    • This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrhythmogenesis.


Influence of Membrane Resting Potential on Action Potential Properties

  • Overview:


  • 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 (Vmax) [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


 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)

  •  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.


  • 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:

      1. Maximum diastolic potential (most negative membrane potential reached during diastole

      2. 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

      3. 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)

      • Beta adrenergic receptor blockers (reduced phase 4 depolarization slope)

 Factors that can increase automaticity


cardiac fiber stretch

beta-adrenergic receptor activation

injury currents


  • 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.


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