ANTIARITMICI

• post-depolarizzazione ritardata

• rientro • attività pacemaker ectopica • blocco cardiaco.

Mechanisms

Re-entry

Re-entry describes the situation in which the impulse re-excites regions of the myocardium after the refractory period has subsided, causing continuous circulation of action potentials. It can result from anatomical anomalies or, more commonly, from myocardial damage. Re-entry underlies many types of dysrhythmia, the pattern depending on the site of the re-entrant circuit, which may be in the atria, ventricles or nodal tissue.

Delayed after-depolarisation

The main cause of delayed after-depolarisation is abnormally raised [Ca2+]i, which triggers inward current and hence a train of abnormal action potentials. After-depolarisation is the result of a net inward current, known as the transient inward current. A rise in [Ca2+]i activates Na+/Ca2+ exchange. This transfers one Ca2+ out of the cell in exchange for entry of three Na+, resulting in a net influx of one positive charge and hence membrane depolarisation. Additionally, Ca2+ opens non-selective cation channels in the plasma membrane, causing depolarisationanalogous to the endplate potential at the neuromuscular junction. Consequently, hypercalcaemia can delay repolarisation.

Ectopic pacemaker activity is encouraged by sympathetic activity and by partial depolarisation, which may occur during ischaemia. Catecholamines, acting on β1

adrenoceptors (see below), increase the rate of depolarisation during phase IV and can cause normally quiescent parts of the heart to take on a spontaneous rhythm.

ectopic pacemaker activity

Heart block results from fibrosis of, or ischaemic damage to, the conducting system (often in the AV node).

heart block

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The action potential of an idealised cardiac muscle cell is shown in figure and is divided into five phases: 0 (fast depolarisation), 1 (partial repolarisation), 2 (plateau), 3 (repolarisation) and 4 (pacemaker).

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© 2005 Elsevier

Downloaded from: StudentConsult (on 25 November 2011 07:39 AM)

© 2005 Elsevier

Downloaded from: StudentConsult (on 25 November 2011 07:39 AM)

© 2005 Elsevier

There are four classes (see Table 18.2).

•Class I: drugs that block voltage-sensitive sodium channels. They are subdivided: Ia, Ib and Ic(see below). •Class II: β-adrenoceptorantagonists. •Class III: drugs that substantially prolong the cardiac action potential. •Class IV: calcium antagonists.

Class III drugs

The class III category was originally based on the unusual behaviour of a single drug, amiodarone

The mechanism of this effect is not fully understood, but it involves blocking some of the potassium channels involved in cardiac repolarisation, including the outward (delayed) rectifier

AMIODARONEUsato per la prevenzione della fibrillazione atriale e in altre tachiaritmie

sopraventricolari, oltre che nelle tachiaritmie ventricolari, soprattutto in quelle postinfartuali.

Farmacodinamica

▪ blocco dei canali del sodio; recupero da blocco relativamente veloce (1,2-1,6 sec);

▪ interazione con i canali del calcio e con alcuni canali del potassio;

▪ prolungamento della durata del potenziale d’azione;

▪ prolungamento della refrattarietà in TUTTI i tessuti cardiaci;

▪ è tra i farmaci meno cardiodepressivi e ha un rischio ridotto di dare un effetto proaritmico

▪ effetto antiadrenergico.

Class IV drugsClass IV agents act by blocking voltage-sensitive calcium channels. Class IV drugs in therapeutic use as antidysrhythmicdrugs (e.g. verapamil) act on L-type channels. Class IV drugs slow conduction in the SA and AV nodes where action potential propagation depends on slow inward Ca2+ current, slowing the heart and terminating SVT by causing partial AV block. They shorten the plateau of the action potential and reduce the force of contraction. Reduced Ca2+ entry reduces after-depolarisationand thus suppresses premature ectopic beats.

Verapamil and diltiazem (class IV)

Verapamil is given by mouth. It has a plasma half-life of 6-8 hours and is subject to quite extensive first-pass metabolism, which is more marked for the isomer that is responsible for its cardiac effects. A slow-release preparation is available for once-daily use, but it is less effective when used for prevention of dysrhythmia than the regular preparation because the bioavailability of the cardioactive isomer is reduced through the presentation of a steady low concentration to the drug-metabolising enzymes in the liver. If verapamil is added to digoxin in patients with poorly controlled atrial fibrillation, the dose of digoxin should be reduced and plasma digoxin concentration checked after a few days, because verapamil both displaces digoxin from tissue-binding sites and reduces its renal elimination, hence predisposing to digoxin accumulation and toxicity (see Ch. 52).

Verapamil is contraindicated in patients with Wolff- Parkinson-White syndrome, and is ineffective and dangerous in ventricular dysrhythmias. Adverse effects of verapamil and diltiazem are described below in the section on calcium channel antagonists.

Diltiazem is similar to verapamil but has relatively more smooth muscle-relaxing effect and produces less bradycardia.

β-Adrenoceptor antagonists (class II)

Propranolol, like several other drugs of this type, has some class I action in addition to blocking β adrenoceptors. This may contribute to its antidysrhythmic effects, although probably not very much, because an isomer with little β antagonist activity has little antidysrhythmic activity, despite similar activity as a class I agent.

Adverse effects are described in Chapter 11, the most important being worsening bronchospasm in patients with asthma, a negative inotropic effect, bradycardia and fatigue.

Class II drugs

Class II drugs comprise the β-adrenoceptor antagonists (e.g. propranolol).

Adrenaline can cause dysrhythmias by its effects on the pacemaker potential and on the slow inward Ca2+ current