ANTIARRHYTHMIC DRUGS Department of Pharmacology and Toxicology Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology ANTIARRHYTHMIC DRUGS (Summary) Assoc. Prof. Ivan Lambev www.medpharm-sofia.eu

BASIC ELECTROPHYSIOLOGY Myocardial cells maintain transmembrane ion gradients by movement of the Na+, Ca2+ and K+ through membrane channels. The resting potential of a cardiac cell is – 85 mV compared to the extracellular environment. Depolarization is initiated by a rapid influx of Na+ (phase 0).

Rapid repolarization Plateau Depolarization Final repolarization Spontaneous depolarization Resting potential

In the AV node depolarization is due to the slower influx of calcium ions. This results in slower conduction of the impulse through the AV node than in other parts of the heart.

During the period between phase 0 and the end of phase 2, the cell is refractory to the further depolarization (absolute refractory period) since the sodium channels are inactivated. During phase 3, a sufficiently large stimulus can open enough sodium channels to over- come the potassium efflux. This is the relative refractory period.

Rapid repolarization Plateau Depolarization Final repolarization Absolute refractory period Relative refractory period Threshold potential Spontaneous depolarization Resting membrane potential

The cardiac action potential

MECHANISMS OF ARRHYTHMOGENESIS Arrhythmias can arise as the result of abnormal impulse generation or abnormal impulse conduction. The main mechanisms: RE-ENTRY (the most frequently): if an impulse arrives at an area of tissue when it is refractory to the stimulus, this impulse will be conducted by an alternative route.

If the impulse again reaches the “blocked” tissue distally when it has had sufficient time to recover, the same impulse will be conducted retrogradely (re-entry). This retrograde conduction is slow, because to initiate a circuit of electrical acti- vity, the healthy tissue has to be given time to repolarize.

Such a mechanism can initiate a selfperpetuating “loop” of electrical activity which acts as a pacemaker. The re-entry circuit can be localized within small a area of the myocardium or it can exist as a large circuit, for example between the atria and ventricles.

Subsidiary (or ectopic) pacemakers may develop when a site AUTOMATICITY Subsidiary (or ectopic) pacemakers may develop when a site in the myocardium develops a more rapid phase 4 depolarization than the SA node, e.g. as a result of ischaemia. Spontaneous depolarization Threshold potential

ANTIARRHYTHMIC DRUGS (AAD) I. AAD used in tachyarrhythmias The Vaughan William’s Classification of AAD is based on their effects on the cardiac action potential (AP).

Class I (membrane stabilizers) These AAD slow the rate of raise of phase 0 of AP by inhibiting fast sodium channels. The class is subdivided according to the effects of drugs on the duration of AP. Indications: SV and ventricular arrhythmias. IA IB IC Increase the duration of AP Decrease the duration No effect on the duration

IA IB IC Disopyramide Procainamide Ajmaline - weak negative inotropic effect Quinidine Lidocaine Mexiletine Phenytoin Propafenone Flecainide ADRs: Bradycardia, AV block, (–) inotropic effect, disturbances of GIT, rashes

Cinchona succirubra Quinidine Chinine Rauwolfia serpentina Ajmaline Reserpine

Treatment: Lidocaine, Ajmaline

Treatment: Lidocaine or electrical defibrillation Ventricular fibrillation, characterized by irregular undulations without clear ventricular complexes. Treatment: Lidocaine or electrical defibrillation

Ventricular flutter

Class II (-adrenoceptor antagonists) Reduce the rate of spontaneous depo- larization of sinus and AV nodal tissue by indirect blockade of calcium channels. Indications: SV and ventricular arrhythmias. ( cAMP) Pindolol, Propranolol Atenolol, Esmolol

Esmolol (short action) Atrial flutter with a 4:1 conduction ratio.

Class III These AAD prolong the duration of the AP and increase the abso- lute refractory period. This is the result of reduced influx of K+ into the cell. Ind: SV and ventri- cular arrhythmias. Amiodarone (p.o.; i.v. inf.)   t1/2 20–100 days ADRs: bradycardia,   hypo/hyper thyreoidism,   corneal micro-deposits under   pupil, neuritis n. opticus,   pulmonary fibrosis. Dronedarone (contains no iodine   but has hepatotoxic effect) Sotalol, Bretylium

Class IV (calcium channel antagonists) Mainly Verapamil (22% oral availability) and Diltiazem (i.v.) from calcium antagonists have specific action on the SA and AV nodes. They decrease the duration of AP. ADRs: headache, edema, bradycardia, AV block Ind: SV arrhythmias.

Atrial fibrillation

Other drugs used in tachyarrhythmias Adenosine inhibits AV conduction. The duration of effect is less than 60 s. used as an i.v. bolus in SV tachycardia with narrow QRS complex. ADRs: bradycardia, AV block. Digoxin reduces conduction through the AV node and is useful in the control of atrial flutter and atrial fibrillation.

II. AAD used in bradyarrhythmias Atropine is given by bolus i.v. inj. in sinus brady- cardia and AV block. It blocks M2-receptors and increases conduction through the AV node. Isoprenaline is used in AV block Atropa belladonna L.

Pacemaker

III. AAD used in Digitalis arrhythmia Phenytoin Potassium chloride Magnesium aspartate Digoxin- specific FAB (Fragment AntiBody): Digibind® (38 mg connect 0,5 mg Digoxin) Digitalis purpurea (foxglove) Digitalis lanata Digitoxin Digoxin

PROARRHYTHMIC ACTIVITY OF AAD All AAD have the potential to precipitate serious arrhythmias, particularly ventri- cular tachycardia or fibrillation. Mainly the AAD from class IA prolong the Q–T interval which predisposes to the development of a polymorphic ventricular tachycardia known as “torsades de pointes”.

Polymorphic ventricular tachycardia with a twisting axis on the ECG Torsades de Pointes Polymorphic ventricular tachycardia with a twisting axis on the ECG

Torsades de Pointes: Treatment Treat hypokalemia if it is the precipitating factor and administer magnesium sulfate in a dose of 2–4 g i.v. initially. Magnesium is usually very effective, even in the patient with a normal magnesium level. If this fails, repeat the initial dose, but because of the danger of hypermagnesemia (depression of neuromuscular function) the patient requires close monitoring. Other therapies include overdrive pacing and isoprenaline infusion. Most (75–82%) torsade de pointes rhythms are started by a pause. Pacing at rates up to 140 bpm may prevent the ventricular pauses that allow torsade de pointes to originate. The patient with torsade who is in extremis should be treated with electrical cardioversion or defibrillation. See: http://emedicine.medscape.com/article/760667-treatment