Class I antiarrhythmics
The drugs preventing or treating cardiac arythmias are called antiarrhythmics. Antiarrythmic drugs are classified according to their mode of action in four groups: group I includes the drugs which decrease the rate of conduction and whose essential impact point is the sodium channel, group II includes the beta-blockers, group III, the drugs which prolong the duration of the action potential mainly by slowing potassium efflux and group IV, calcium-channel inhibitors.
The duration of the action potential can be prolonged by inhibition of potassium efflux but also by prolongation of the sodium influx by the slow sodium channels. Anomalies of these two mechanisms can be at the origin of a long-QT syndrome.
Class I antiarrythmics inhibit the influx of sodium by the voltage-gated channels, slow the speed of fast depolarization called phase 0, which leads to a decrease of the rate of conduction. According to their effects on the rate of repolarization linked to potassium efflux, one subdivides them in three subclasses Ia, Ib, Ic.
Class Ia antiarrythmics, in addition to their effect on the voltage-gated sodium channels, slow repolarization by inhibiting potassium efflux. They are quinidine, hydroquinidine, disopyramide.
Quinidine, isomer of quinine, has directly and indirectly acting cardiac effects:
Directly acting, related to its action on voltage-dependant sodium channels: quinidine decreases the rate of conduction and slows down slow diastolic depolarization. Moreover, it prolongs the action potential by inhibiting the repolarization by potassium efflux, which lengthens the QT interval. It has a negative inotropic effect.
- Indirectly acting: quinidine has an antimuscarinic effect and, by inhibiting the effects of acetylcholine, it tends to accelerate heart rate and to facilitate the atrioventricular conduction.
Quinidine decreases peripheral resistances by arteriolar vasodilation, probably by an alpha-adrenolytic effect. It tends to lower blood pressure by vasodilation and negative inotropic effect.
In addition quinidine has an antimalarial effect like quinine, antipyretic, oxytocic, and can have a curarizing effect.
The therapeutic plasma concentrations of quinidine considered as effective for the treatment of arrhythmias, lie between 1 and 3 mg/L. There is interaction between quinidine and digoxin, quinidine raising the concentrations of digoxin.
Quinidine is a broad spectrum antiarrhythmic used on a curative and preventive basis. Its essential therapeutic uses are the treatment of the supra-ventricular tachycardias. Its use for the treatment of muscular cramps must be avoided because of the risk of severe adverse effects which it sometimes induces.
Hydroquinidine has properties similar to those of quinidine.
Disopyramide has pharmacological properties quite similar to those of quinidine. It has also antimuscarinic effects.
The drugs of the Ib class, in addition to their effect on the sodium voltage-gated channels, accelerate cellular repolarization by increasing potassium efflux, and decrease the duration of the action potential and the refractory period. They are lidocaine, phenytoin and mexiletine.
Lidocaine and mexiletine
Lidocaine and mexiletine, Mexitil*, act on the action potential: they slow, especially at high-dose, fast diastolic depolarization (phase 0) and shorten the duration of the action potential by accelerating the repolarization.
They have a negative inotropic effect and peripheral vasodilator effect. Their action is immediate and of short duration.
The therapeutic concentration of lidocaine in plasma is about 5 mg/L, that of mexiletine ranges between 0.75 and 1.5 mg/L.
Phenytoin has schematically the same properties as the other products of the Ib. class. It was used as an antiarrhythmic in an injectable form called DILANTIN * but this form is gradually replaced by phenytoin phosphate or fosphenytoine, marketed as PRODILANTIN *, which is hydrolyzed in the body into phenytoin, the active product.
Class Ic antiarrythmics inhibit the voltage-dependant sodium channels and prolong the depolarisation phase, have little effect on the repolarization phase. They are flecainide, propafenone and aprindine.
Flecainide,Tambocor*, decreases the rate of depolarization (phase 0), but does not modify he duration of the action potential because it is without effect on potassium channels.
Propafenone, Rythmol*, decreases the rate of depolarization (phase 0) and the slow diastolic depolarization. It has a low beta-blocking activity which appears only with overdoses.
Aprindine has effects close to those of flecainide and propafenone, but it has particular adverse effects: leukopenia, even agranulocytosis, cholestatic hepatitis reversible with the interruption of the treatment.
Cibenzoline is usually attached to group Ic antiarrhythmics but has certain properties of class III and IV antiarrhythmics.
Ibutilide, Corvert*, by increasing the time during which the voltage-dependant slow sodium channels are open, prolongs the duration of the cardiac action potential. The influx of sodium which is prolonged slows the repolarization due to the potassium efflux, resulting in its classification in the group III antiarrhythmics. It is used for the treatment of atrial flutter and atrial fibrillation.
Its principal danger is arrythmias, including torsades de pointes, by prolongation of QT interval. Hypokalemia and hypomagnesemia increase this risk and must be corrected before the administration of ibutilide.
Class I antiarrythmics have common adverse effects, primarily related to the inhibition of sodium channels. These effects are more or less marked according to the drug and according to the state of the patient, in particular of his hydro-electrolytic equilibrium.
- They can induce conduction disorders at all levels: sinus, atrioventricular and intra-ventricular.
The pro-arrhythmic or arrhythmogenic effect of antiarrhythmics, appears especially in patients with hydro-electrolytic disorders, in particular hypokalemia and hypomagnesemia.
Class Ia antiarrythmics which lengthen the duration of the action potential can induce torsades de pointes and fatal ventricular fibrillation. In certain clinical studies, mortality was higher in the group of patients treated by antiarrythmics than in the control group under placebo.
- They have a negative inotropic effect and the decrease of cardiac output can sometimes induce a hemodynamic decompensation.
- The inhibition of sodium channels, responsible of a local anesthetic action, can cause digestive disorders (gastralgia, nausea, vomiting) with sometimes diarrhea or constipation.
- Antiarythmic drugs of the Ia group are likely to give headache, dizziness, visual disorders (photophobia, diplopia, blurried sight), auditive disorders (tinnitus, hypoacusia), tremors, myoclonus. Extrapyramidal syndromes and cerebellar syndromes were described, sleep disorders. With certain products, especially at high dose, delusions and convulsive attacks were sometimes observed.
- Antiarythmic drugs of the Ia group and cibenzoline which is sometimes classified in Ia because it can slow repolarization, can induce in certain patients hypoglycemias which could result from a stimulation of insulin secretion by inhibition of potassium efflux from pancreatic B cells.
- Quinidine and disopyramide have an antimuscarinic effect and the corresponding adverse effects.