Amiodarone

Structural formula
General
Non-proprietary name	Amiodarone
other names	(2-Butylbenzofuran-3-yl) - [4- (2-diethylaminoethoxy) -3,5-diiodophenyl] methanone ( IUPAC )
Molecular formula	C 25 H 29 I 2 NO 3 (amiodarone) C 25 H 29 I 2 NO 3 HCl (amiodarone hydrochloride )
External identifiers / databases
CAS number 1951-25-3 (amiodarone) 19774-82-4 (amiodarone hydrochloride) EC number 217-772-1 ECHA InfoCard 100.016.157 PubChem 2157 ChemSpider 2072 DrugBank DB01118 Wikidata Q410061
Drug information
ATC code	C01 BD01
Drug class	Class III antiarrhythmic
properties
Molar mass	645.31 g · mol -1 (amiodarone) 681.77 g · mol -1 (· amiodarone hydrochloride)
Physical state	firmly
Melting point	156 ° C (amiodarone hydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Hydrochloride Caution H and P phrases H: 312-332-315-319-361d-373-410 P: 260-280-305 + 351 + 338
Toxicological data	> 3000 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Volume of Distribution	20 to 200 L / kg
Fat solubility	very high
Plasma half-life	4.8 to 68.2 hours
Elimination half-life	13 to 103 days
elimination	Liver 99%
Plasma protein binding	95%
Bioavailability	20-80%
Usual loading dose	600-1400 mg / day
Cumulative loading dose	10-12 g in 3-4 weeks
Maintenance dose	200 mg

Amiodarone is a drug that is used as an antiarrhythmic for the treatment of numerous cardiac arrhythmias . Amiodarone is a very effective drug against tachycardiac arrhythmias, but it is also fraught with serious side effects.

properties

Amiodarone, a benzofuran derivative, has structural similarities to thyroxine and procainamide . It was originally developed in Belgium for the treatment of angina pectoris since 1961, due to its ability to dilate peripheral and coronary arteries , until it was discovered by chance that it had an extremely inhibitory effect on ventricular and supraventricular arrhythmias. Even when used in patients with severe pump dysfunction of the left ventricle, there is hardly any deterioration in cardiac output, although the drug has a moderate negative inotropic effectiveness. Its extreme solubility in adipose tissue causes the extraordinarily high volume of distribution and is also responsible for the long and individually very variable half-life of 30 to well over 100 days.

Mode of action

Amiodarone is an antiarrhythmic with a complex mode of action that is not yet fully understood in detail. Because of its property, the refractory period and action potential to prolong the cardiac muscle tissue, there is indeed such as Sotalol Class III according to Vaughan Williams (see FIG. Antiarrhythmic agent associated) in a strong inhibition of potassium channels, but it also has a moderately strong inhibitory effect on α -, β - (Class II) and muscarinic receptors and has some blocking effect on both fast and medium sodium (Class IA and IB) and calcium channels (Class IV). It shares with all known antiarrhythmics the ability to trigger cardiac arrhythmias. While this occurs less often than with other antiarrhythmics, on the other hand, serious undesirable effects outside the heart are to be expected comparatively often. Amiodarone also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

application

The Food and Drug Administration of the USA recommends amiodarone because of its high toxicity only in life-threatening ventricular arrhythmias that do not respond to other therapeutic measures. The slow intravenous dose is 5 mg / kg or 300 mg for adults, possibly followed by a continuous infusion of 10 to 20 mg / kg / 24 hours.

In Germany the approval is valid for

• symptomatic tachycardiac supraventricular arrhythmias requiring treatment such as
  • AV junctional tachycardia ( AV node reentry tachycardia ),
  • supraventricular tachycardia in WPW syndrome or
  • ( paroxysmal ) atrial fibrillation and flutter as well as
• serious symptomatic tachycardiac ventricular arrhythmia
  • in patients "for whom the use of other antiarrythmics is not justifiable in the medical judgment".

So far, it has been the drug of choice for patients with ventricular tachycardia or ventricular fibrillation during resuscitation and for patients with structural heart disease with severely restricted pumping functions, when a pacemaker (ICD) cannot be implanted.

Amiodarone reduces the rate of ventricular tachycardia in patients with an already implanted pacemaker .

Patients with structural heart disease (such as infarct scar or decreased pump function) can receive amiodarone to stabilize the sinus rhythm after successful cardioversion of atrial fibrillation. Oral or intravenous administration of amiodarone can stop atrial fibrillation, but it is neither as reliable nor tolerable as electrical cardioversion by means of an electric shock under short anesthesia.

Contraindications and restrictions on use

Caution is advised when bradycardic heart rhythm disorders, allergy to iodine or (also deferred) overactivity of the thyroid gland .

If the QT time in the ECG is longer than 25% of the norm or more than 500 ms, as amiodarone itself extends the Qt time , dangerous cardiac arrhythmias must be expected and the treatment terminated if necessary. In the case of conduction disorders , amiodarone may only be used under the protection of a pacemaker and in an intensive care unit.

Amiodarone cannot be used if there is a possibility of pregnancy. Women of childbearing potential must use safe contraception during therapy .

Side effects

While amiodarone was initially celebrated as a well-tolerated and “ideal antiarrhythmic” after its introduction, it was only in the course of time that the numerous undesirable effects, some of which were life-threatening, became apparent.

lung

The most serious side effect is the development of fatal interstitial pulmonary fibrosis , which seems to be more common in patients with previously damaged lung tissue. This inflammation of the alveoli with an increase in connective tissue occurs in around 5% of treated patients, which is known as fibrosing alveolitis . This side effect was observed after only a few months of treatment. In addition to the pharmacological properties of amiodarone, which leads to an accumulation of surfactant phospholipids due to its pronounced inhibition of phospholipase in the lungs, a particular genetic susceptibility to pulmonary fibrosis is suspected. If the fibrosis in its preliminary stage, called pneumonitis , is detected in time, it is completely reversible. Therefore, you must be searched for at regular intervals. Repeated chest x-rays are suitable for this. Functional examinations of the lungs are also recommended, but only become noticeable at an advanced stage. Most specifically for damage caused by amiodarone is a dramatically reduced diffusion capacity of the lungs (DL _CO in the lung function test).

Amiodarone has also been causally linked to pleural effusion .

thyroid

Thyroid dysfunction occurs because of the high iodine content of the drug (37%). Amiodarone-induced hypothyroidism occurs in patients in whom large amounts of iodine produce an inhibitory effect. This effect was used for the treatment of hyperthyroidism in the context of the Plummer . Over- or under-functioning of the thyroid gland can be found in up to 40% of long-term treatment. The thyroid function should be monitored every six months with a TSH measurement. Relatively often, the biologically much more effective fT3 falls into hypothyroid areas without clinical hypothyroidism. The reason for this is a conversion disorder in the conversion of fT4 to fT3, which is expressed in a reduced total activity of peripheral deiodinases . Amiodarone partially blocks the deiodases responsible for this process. The sole determination of the free thyroxine FT4 is considered unreliable in the case of amiodarone thyroid disease.

The most feared side effect is amiodaroninduzierte thyrotoxicosis (AIT, metabolism disorder by thyroid dysfunction ), which can be fatal in severe cases. It is based on two different mechanisms (see table). Their dangerousness is based, among other things, on the fact that the previously damaged heart of patients treated with amiodarone has a particularly low tolerance for a hyperthyroid metabolic situation.

	AIT type 1	AIT type 2
Occur	early (weeks)	late (months)
Pre-existing thyroid disease	common (e.g. autonomy or Graves disease )	Rare
mechanism	Increased production of thyroid hormones	Increased release of thyroid hormones
Iodine - or technetium - Uptake	increased	reduced
Interleukin-6 levels	normal	elevated
course	heavy	mild to heavy
Discontinuation of amiodarone	required	not mandatory
therapy	Perchlorate , anti-thyroid drugs , surgery	Steroids

eye

Micro-deposits in the cornea of ​​the eye are found in more than 90% of patients who have been taking the drug for more than half a year ( cornea verticillata , also known as vortex keratopathy ). The deposits can be reliably detected by the ophthalmologist using a slit lamp examination . 1 to 10% of patients report a slight bluish cast in their visual perception. The corneal deposits should only lead to discontinuation of the drug in the case of pronounced visual impairments. For some cardiologists, however, keratopathy is more an indication of the reliable use of the drug and not a significant side effect. However, 1 to 2% of patients suffer from optical neuropathy with visual field deficits that force them to discontinue the drug.

Gastrointestinal tract

Around half of the patients show a reversible increase in liver enzymes as a sign of liver cell damage. This can go away again despite continued use of the drug. In very rare cases, amiodarone can lead to acute hepatitis or chronic liver damage or even liver cirrhosis . The cirrhosis caused by amiodarone appears similar to alcohol cirrhosis under a light microscope. The distinction can be made by electron microscopy.

skin

Sun-exposed skin may turn ash gray or bluish in fair-skinned people. The skin discoloration may fade after stopping the drug, but does not always normalize completely.

An increased sensitivity of the skin to light as a reaction to UV-A rays can be reduced by using appropriate creams.

Nervous system

The drug can lead to a demyelinating polyneuropathy , which clinically is almost indistinguishable from other demyelinating neuropathies.

The drug can cause sleep disorders (bad dreams and nightmares). The frequency is given as “often”.

Monitoring parameters

Serial laboratory tests for amiodarone-related side effects are expensive and of limited value. At the beginning of treatment, however, it makes sense to carry out a blood count and other blood tests, to test the function of the thyroid gland and lungs and to have an ophthalmologist perform a slit lamp examination . The medical attention should be directed to the clinical symptoms to be expected in the event of possible side effects: dry cough, load-dependent dyspnoea, visual disturbances, fatigue and skin changes give rise to further diagnostics.

Inhibition of vitamin A absorption

Amiodarone inhibits the enzyme retinyl ester hydrolase in both the liver and the intestine, according to a study in rats. Long-term intake therefore creates an artificial vitamin A deficiency that cannot be remedied even by taking the vitamin.

interaction

Amiodarone can have a lasting effect on other drugs - and vice versa. This is the case with many antiarrhythmics, which can lead to a critical slowdown in heart rate or, conversely, to the dreaded torsade de pointes tachycardias . Spontaneous bleeding can occur when the effects of coumarin are increased by amiodarone.

The saturation with amiodarone leads on average to a doubling of the plasma level of the beta blocker metoprolol via an interaction via the cytochrome P450 2D6 .

Conversely, the intake of grapefruit juice can significantly increase the plasma concentration of amiodarone by completely inhibiting the production of N- desethylamiodarone .

literature

• RL Woosley, JH Indic: Antiarrhythmic Drugs. In: V. Fuster, W. Alexander, RA O'Rourke (ed.): Hurst's The Heart. 11th edition. McGraw-Hill, New York 2004, ISBN 0-07-142264-1 , pp. 949-973.
• LA Siddoway: Amiodarone: Guidelines for Use and Monitoring. In: American Family Physician. Dec. 1, 2003. ( full text in English )
• PJ Kudenchuk, LA Cobb, MK Copass, RO Cummins, AM Doherty, CE Fahrenbruch, AP Hallstrom, WA Murray, M. Olsufka, T. Walsh: Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. In: N Engl J Med . 341 (12), 1999 Sep 16, pp. 871-878. PMID 10486418 .
• T. Guarnieri, S. Nolan, SO Gottlieb, A. Dudek, DR Lowry: Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial. In: J Am Coll Cardiol . 34 (2), 1999, Aug, pp. 343-347. PMID 10440143 .
• Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185-283, here: pp. 263-265 ( amiodarone ).

Trade names

Monopreparations

Amiodares (D), Amiogamma (D), Cordarex (D), Cordarone (CH), Cornaron (D), Escordaron (CH), Sedacoron (A), various generics (D, A, CH)

Individual evidence

1. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 81.
2. ↑ ^{a b c} data sheet Amiodarone hydrochloride, ≥98% from Sigma-Aldrich , accessed on December 1, 2019 ( PDF ).
3. ^ MH Crawford, JP DiMarco, WJ Paulus (ed.): Cardiology. 2nd Edition. Mosby, Edinburgh 2004, ISBN 0-323-02405-X , p. 603.
4. ↑ J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer, G. Spitzer, K. Liedl, E. Gulbins, P Tripal: Identification of Novel Functional Inhibitors of Acid Sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
5. ^ RL Woosley, JH Indic: Antiarrhythmic Drugs. In: V. Fuster, W. Alexander, RA O'Rourke (ed.): Hurst's The Heart. 11th edition. McGraw-Hill, New York 2004, ISBN 0-07-142264-1 , pp. 949-973.
6. ↑ Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York et al. 1999, ISBN 3-540-65024-5 , p. 76 f .; here: p. 77.
7. ↑ Federal Association of the Pharmaceutical Industry eV (BPI), Association of Researching Pharmaceutical Manufacturers eV (VFA), Federal Association of Pharmaceutical Manufacturers eV (BAH), Deutscher Generikaverband eV (Hrsg.): Red List 2006. List of pharmaceuticals for Germany (including EU approvals and certain Medical devices). Rote Liste Service GmbH, Frankfurt am Main 2006, ISBN 3-939192-00-7 .
8. ↑ C. Mewis, R. Riessen, I. Spyridopoulos (ed.): Kardiologie compact. Everything for ward and specialist examination . Georg Thieme Verlag, Stuttgart / New York 2004, ISBN 3-13-130741-2 , pp. 782–783.
9. ^ SG Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, AJ Camm, R. Cappato, SM Cobbe, C. Di Mario, BJ Maron, WJ McKenna, AK Pedersen, U. Ravens, PJ Schwartz, P. Trusz-Gluza, P. Vardas, HJJ Wellens, DP Zipes: Task Force on Sudden Cardiac Death of the European Society of Cardiology. In: Eur Heart J . 22 (16), 2001 August 2, pp. 1374-1450. PMID 11482917 .
10. ↑ Ernst Mutschler, Gerd Geislinger, Heyo K. Kroemer, Sabine Menzel, Peter Ruth: Mutschler drug effects - pharmacology, clinical pharmacology, toxicology. 10th edition. Stuttgart 2013, p. 558.
11. ^ W. Seeger: Diseases of the respiratory organs. In: Jürgen Schölmerich et al.: Medical Therapy 2005/2006. 2nd Edition. Springer, Berlin / Heidelberg / New York 2005, ISBN 3-540-21226-4 , p. 1005.
12. ↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.
13. ↑ ^{a b} George J. Kahaly, Markus Dietlein, Roland Gärtner, Klaus Mann, Henning Dralle: Amiodarone and Thyroid Dysfunction, Amiodarone-Induced Thyroid Dysfunction. In: Deutsches Ärzteblatt. 104 (51-52), 2007, pp. A-3550 / B-3129 / C-3021.
14. ↑ Jules L. Tuesday: Toxic and Drug-Induced Hepatitis. In: Anthony Fauci et al .: Harrison's Principles of Internal Medicine. 17th edition. New York 2007, p. 1953.
15. Jump up ↑ R. Schindler, T. Fielenbach, G. Rave: A comparative study on the effects of oral amiodarone and trimeprazine, two in vitro retinyl ester hydrolase inhibitors, on the metabolic availability of vitamin A in rats . In: Br. J. Nutr. tape 94 , no. 5 , November 2005, pp. 675-683 , PMID 16277768 .
16. ↑ D. Werner, H. Wuttke, MF Fromm, S. Schaefer, T. Eschenhagen: Effect of amiodarone on the plasma levels of metoprolol. In: Am J Cardiol. 94 (10), November 15, 2004, pp. 1319-1321. doi: 10.1016 / j.amjcard.2004.07.125 .
17. ↑ Christian C Libersa et al .: Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. In: Br J Clin Pharmacol . 2000 Apr; 49 (4): 373-378. doi: 10.1046 / j.1365-2125.2000.00163.x .
18. ↑ Red List Online, as of August 2009.
19. ↑ entry for Cordarone in the pharmaceutical compendium of Switzerland, accessed on 22 April 2018th
20. ↑ AGES-PharmMed, as of August 2009.

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