This pathway illustrates the disopyramide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Disopyramide is a Class 1A antiarrhythmic drug with similar electrophysiological effects as quinidine. Disopyramide blocks sodium channels in their open state leading to an increased threshold of excitability. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization phase of the cardiac contractile cell action potentials. Inhibition of I-Na results in delayed excitability of the cell. Disopyramide also prolongs action potential duration likely through potassium channel blocking. Disopyramide is administered as a racemic mixture. In vitro studies have demonstrated that the S-(+) isomer has pharmacological action similar to quinidine. The R-(-) isomer blocks sodium channels, but does not prolong action potential duration. Disopyramide may be used to maintain rhythm in atrial fibrillation or flutter or to prevent recurrence of ventricular tachycardia or fibrillation. Disopyramide may depress cardiac contractility, which could precipitate heart failure or Torsades de Pointes.

Disopyramide Pathway References

Striated Muscle Contraction References