European Review for Medical and Pharmacological Sciences 2005; 9: 183-190 Use of amiodarone in emergency A. TESTA, V. OJETTI, A. MIGNECO, M. SERRA, C. ANCONA, A. DE LORENZO*, N. GENTILONI SILVERI Department of Emergency Medicine, Catholic University – Rome (Italy) *Human Nutrition Unit, Tor Vergata University – Rome (Italy) Abstract. – Amiodarone is one of the drugs, frequently used in the Emergency De- most common anti-arrhythmic drugs used in the partment. In the last decade many trials and Emergency Department. Recent guidelines on meta-analysis described amiodarone as anti- cardiac arrest with shockable rhythm [refractory ventricular fibrillation (VF)/pulseless ventricular arrhythmic agent of first choice in the treat- tachycardia (VT)] recommend amiodarone as an- ment of hemodynamically unstable ventricu- ti-arrhythmic of first choice. Amiodarone is also lar tachycardia (VT), of hemodynamically first choice drug in the treatment of various ven- stable wide-complex tachycardias1, and of tricular and supra-ventricular tachyarrhythmias. many supraventricular tachyarrhythmias1,2. This paper deals with the main therapeutical in- The European Resuscitation Council recom- dications of amiodarone in emergency medi- mends its use in shockable cardiac arrest cine: dosage, side effects, contraindications and pharmacological interactions are reviewed. [ventricular fibrillation (VF) and pulseless 3 Amiodarone is effective for control of hemody- VT] . Finally, its use has been suggested in namically stable VT, polymorphic VT and wide- post-infarction patients, either presenting fre- complex tachycardia of uncertain origin. It is al- quent or repetitive extra systolic beats and/or so helpful for ventricular rate control of rapid VT4 or presenting low left ventricular ejec- atrial arrhythmias in patients with severely im- tion fraction (below 40%)5. paired left ventricular (LV) function, when digital- is has been ineffective, and is an adjunct to elec- Up to 2% of the patients admitted to the trical cardioversion. The major side effects of Emergency Department present tach- amiodarone are hypotension, bradycardia and yarrhythmias. In more than 90% these are peripheral phlebitis. Major contraindications to narrow QRS arrhythmias, such as atrial fibril- the intravenous (iv) injection of amiodarone are lation (AF) (45%), paroxysmal supraventric- bradycardia, senoatrial block, severe disturbs of ular tachycardia (35%) and atrial flutter conduction, second or third degree atrio-ventric- (8%). Around 50% of large QRS tach- ular blocks. Other contraindications are hy- potension, severe respiratory failure, hepatocel- yarrhythmias are supraventricular tachycar- lular failure and hyperthyroidism. Pharmacologi- dias. VT are in most cases hemodynamically cal interactions are reported with HMG-CoA re- stable, while only a small part of large QRS ductase inhibitors, class I antiarrhythmic agents tachyarrhythmia are hemodynamically unsta- and other drugs which contribute to prolong QT ble VT or shockable cardiac arrest (VF/pulse- interval, digoxin, oral anticoagulants and gener- less VT)6. al anaesthesia. Often tachyarrhythmia end spontaneously Key Words: or resolve after appropriate treatment in the Amiodarone, Emergency, Arrhythmias, Tachycar- Emergency Department, and around half of dias, Cardiac arrest, Ventricular tachycardia, Atrial fib- the patients can be discharged after a short rillation. period of observation. Pharmacodynamic Properties Introduction Electrophysiologic Effects Amiodarone, a derivative of benzofuran, is Amiodarone exerts a non-competitive one of the most common anti-arrhythmic block of alpha and beta-adrenergic receptors 183 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri antagonizing tachycardia, hypertension and Pharmacokynetic Properties oxygen consumption of the myocardium in- duced by circulating catecholamines. These Amiodarone’s chemical structure can be effects contribute to the anti-arrhythmic and summarised in three points: (1) presence of anti-anginal properties of amiodarone7. After aromatic rings; (2) a relatively high iodine amiodarone administration there is no signifi- content; (3) presence of an aliphatic chain cant decrease of the myocardial contractility8. with low polarity. The most relevant effects of amiodarone This chemical structure highlights some on cardiac cells are the reduction of the depo- specific pharmacological characteristics like larization (phase 4)9, the late repolarization, the high lipophylia, the low oral absorption caused by a prolongation of the action poten- rate, the extended tissue distribution, the tial (phase 3) and the prolongation of the ef- slow elimination rate and finally the late ther- fective refractory period10. Therefore amio- apeutic response during oral treatment21. darone is included among class III anti-ar- After intravenous (iv) administration plas- rhythmic drugs. It is known that torsades de ma peak concentration is reached in 6-8 pointes are the classic form of proarrhythmia hours. Drug tissue distribution occurs differ- observed during therapy with any drug that ently after acute administration (lungs, liver, prolongs repolarization. Among the class III heart and kidney)22 and after the achieve- drugs the proarrhythmic risk appears to be ment of dynamic equilibrium (mainly in the lowest for amiodarone, probably due to its liver, fat tissue and in the lungs)21. complex electrophysiologic profile that may Drug clearance occurs mainly through the create significant myocardial electrical homo- liver and only 1% is excreted through the geneity. kidneys. Amiodarone cannot be dialysed and crosses easily the placenta (10-50%). N-de- Mechanisms of Action sethyl-amiodarone (DEA) is its main active Some chemical peculiarities of the drug metabolite. After a single oral dose, amio- (high iodine’s content and structural analo- darone’s half life is calculated to be around 24 gies with thyroid hormones) suggested possi- h, during long-term therapy it increases ble influences of amiodarone on the thyroid reaching 28 days21; while DEA’s half life is function11. Furthermore, it is known that around 60 days23. some of the cardio-electrophysiologic effects of the chronic administration of amiodarone are very similar to those of hypothy- roidism12,13. Actually, it has been shown a Therapeutic Indications in Emergency competition or an interaction between amio- darone and the thyroid hormones at many Cardiac Arrest With Shockable Rhythm levels (i.e. deiodases, trans-membrane ionic (Refractory FV/Pulseless VT) channels)14,15. Two main mechanisms concern- The Resuscitation 2000 Guidelines recom- ing the antiarrhythmic activity of amiodarone mend amiodarone as the antiarrhythmic drug have been suggested: of choice in treatment of resistant VF or pulseless VT24. • The “T3-mediated” hypothesis: amio- Even if the administration of amiodarone darone antagonizes the thyroid hormones may cause a slight delay during the resurrec- on the nuclear receptor and/or on trans- tion procedure, evidence supports its use af- membrane carrier of T3 at cardiac lev- ter epinephrine administration in the treat- el16,17. This T3-mediated mechanism ment of shock-refractory cardiac arrest due could explain the non-competitive adren- to VF or pulseless VT (Class of evidence ergic block of amiodarone. IIb)25. Some studies demonstrate that amio- •The “Membrane-active” hypothesis: amio- darone, like any other antiarrhythmic agent, darone impairs the lipid environment of must be given before the fourth shock in or- the cell membranes where the main ionic der to be effective. channels are located, directly modulating In patients with out-of-hospital cardiac ar- the ionic myocardial transmembran cur- rest, due to refractory ventricular arrhyth- rents18-20. mias, treatment with amiodarone resulted in 184 Use of amiodarone in emergency a higher rate of survival to hospital admis- complex tachycardia of unknown origin. Pro- sion. Whether this benefit extends to survival cainamide, amiodarone, and sotalol are effec- to discharge from the hospital merits further tive in the treatment of VT and supraventric- investigation26. ular tachycardias with an accessory pathway In the CASCADE trial, carried out in sur- conduction. On the other hand, depressants vivors of cardiac arrest, the administration of of the AV node conduction (such as adeno- amiodarone in patients with an implanted au- sine, beta-adrenergic receptor blockers, and tomatic defibrillator significantly reduced the calcium channel blockers) are hazardous in number of defibrillation shocks27. patients with preexcited atrial arrhythmias. Amiodarone 300 mg (made up to 20 ml Therefore, the therapeutic options are re- with dextrose) should be administered into a duced to DC cardioversion, or procainamide peripheral vein. A further dose of 150 mg or amiodarone. At presentation in the Emer- may be given for recurrent or refractory gency Department, most of the patients with VT/VF, followed by an infusion of 1 mg min-1 VT are hemodynamically stable, thus allow- for 6 hours and then 0.5 mg min-1, to a maxi- ing first-line antiarrhythmic drug administra- mum daily dose of 2 g. This maximum dose tion. However, in the course of the disease, is larger than the current European half of the patients need electrical therapy for datasheet recommendation of 1.2 g. Pre- definitive termination of the tachycardia31. loaded syringes are not available because Therefore, DC-cardioversion must be avail- amiodarone adheres to the plastic