Chapter 8  Medical Pharmacology:   Antiarrhythmic Agents

Cardiac Electrophysiology

• Transmembrane potential -- determined primarily by three ionic gradients

  •  Na⁺, K⁺, Ca ²⁺

    •  Water-soluble, i.e. 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, tend 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

• 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 factors are important.

  •   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⁺

    • m gate activation (activation gate); assuming inactivation (h) gates are not closed then

    • Sodium permeability dramatically increased; intense sodium current

    • Depolarization

    • h gate closure; Na⁺ current inactivation.

• 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.

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.