FIGURE 14–9 Stateand frequency-dependent block of sodium channels by antiarrhythmic drugs. Top: Diagram of a mechanism for the selective depressant action of antiarrhythmic drugs on sodium channels. The upper portion of the figure shows the population of channels moving through a cycle of activity during an action potential in the absence of drugs: R (rested) → A (activated) → I (inactivated). Recovery takes place via the I → R pathway. Antiarrhythmic drugs (D) that act by blocking sodium channels can bind to their receptors in the channels, as shown by the vertical arrows, to form drug-channel complexes, indicated as R-D, A-D, and I-D. Binding of the drugs to the receptor varies with the state of the channel. Most sodium channel blockers bind to the active and inactivated channel receptor much more strongly than to the rested channel. Furthermore, recovery from the I-D state to the R-D state is much slower than from I to R. As a result, rapid activity (more activations and inactivations) and depolarization of the resting potential (more channels in the I state) will favor blockade of the channels and selectively suppress arrhythmic cells. Bottom: Progressive reduction of inward sodium current (downward deflections) in the presence of a lidocaine derivative. The largest curve is the initial sodium current elicited by a depolarizing voltage step; subsequent sodium current amplitudes are progressively reduced owing to prior accumulated block and block during each depolarization. (Adapted, with permission, from Starmer FC, Grant AO, Strauss HC: Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 1984;46:15. Copyright Elsevier.) may be somewhat less effective than quinidine (see below) in sup-particularly with intravenous use. However, in therapeutic concenpressing abnormal ectopic pacemaker activity but more effective trations, its peripheral vascular effects are less prominent than those in blocking sodium channels in depolarized cells. of quinidine. Hypotension is usually associated with excessively rapid procainamide infusion or the presence of severe underlying left ventricular dysfunction.
Procainamide’s cardiotoxic effects include excessive action poten-Procainamide has direct depressant actions on SA and AV tial prolongation, QT-interval prolongation, and induction of nodes, and these actions are only slightly counterbalanced by torsades de pointes arrhythmia and syncope. Excessive slowing of drug-induced vagal block. conduction can also occur. New arrhythmias can be precipitated. A troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus erythematosus and usually consisting of arthralgia and arthritis. In some patients, pleuritis, Procainamide has ganglion-blocking properties. This action pericarditis, or parenchymal pulmonary disease also occurs. reduces peripheral vascular resistance and can cause hypotension, Renal lupus is rarely induced by procainamide. During long-term
TABLE 14–2 Membrane actions of antiarrhythmic drugs.
1Not available in the USA. na, data not available.
therapy, serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients, and in the absence of symptoms, these are not an indication to stop drug therapy. Approximately one third of patients receiving long-term procainamide therapy develop these reversible lupus-related symptoms.
Other adverse effects include nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (<5%), and agranulocytosis (approximately 0.2%).