Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Amiodarone: Difference between pages

{{Short description|Antiarrhythmic medication used for various types of irregular heartbeats}}

{{Use dmy dates|date=December 2023}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 464394155

| image = Amiodarone structure.svg

| alt =

| image2 = Amiodarone-based-on-hydrochloride-xtal-3D-bs-17.png

| alt2 =

<!-- Clinical data -->

| pronounce = {{IPAc-en|ˌ|æ|m|i|ˈ|oʊ|d|ə|r|oʊ|n}} or {{IPAc-en|ə|ˈ|m|iː|oʊ-|d|ə|ˌ|r|oʊ|n}}<!--Major medical and pharmaceutical dictionaries disagree on which pronunciation is listed, not listed, preferred, or not preferred; as with many drug names, predictably variable [[spelling pronunciation]]s are a powerful force in the real-world usage of clinicians and pharmacists.-->

| tradename = Cordarone, Nexterone, Pacerone, others

| DailyMedID = Amiodarone

| pregnancy_AU = C

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]], [[intraosseous]]

| ATC_prefix = C01

| ATC_suffix = BD01

| legal_AU = S4

| legal_CA = Rx-only

| legal_US = Rx-only

| legal_US_comment = <ref name="DailyMed-Pacerone-2022">{{cite web | title=Pacerone- amiodarone hydrochloride tablet | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c4ec9b0-13a5-49a8-b57b-b3f64e4316a7 | access-date=8 September 2021 | archive-date=29 December 2022 | archive-url=https://web.archive.org/web/20221229200210/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c4ec9b0-13a5-49a8-b57b-b3f64e4316a7 | url-status=live }}</ref><ref name="DailyMed-2018">{{cite web | title=Cordarone (amiodarone) tablets, for oral use Initial U.S. Approval: 1985 | website=DailyMed | date=30 October 2018 | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=350496 | access-date=8 September 2021 | archive-date=29 December 2022 | archive-url=https://web.archive.org/web/20221229200207/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=350496 | url-status=live }}</ref><ref name="DailyMed-Nexterone-2022">{{cite web | title=Nexterone- Amiodarone HCl injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d4d66f7-fa14-e832-e053-2a95a90a8b62 | access-date=8 September 2021 | archive-date=29 December 2022 | archive-url=https://web.archive.org/web/20221229200210/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d4d66f7-fa14-e832-e053-2a95a90a8b62 | url-status=live }}</ref>

<!-- Pharmacokinetic data -->

| bioavailability = 20–55%

| protein_bound = 96%

| elimination_half-life = 58 d (range 15–142 d)

| excretion = Primarily liver and bile

<!-- Identifiers -->

| IUPHAR_ligand = 2566

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

<!-- Chemical data -->

| IUPAC_name = (2-<nowiki/>{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine

| C=25 | H=29 | I=2 | N=1 | O=3

| SMILES = CCN(CC)CCOc1c(I)cc(cc1I)C(=O)c2c3ccccc3oc2CCCC

<!-- Definition and medical uses -->

'''Amiodarone''' is an [[antiarrhythmic medication]] used to treat and prevent a number of types of [[cardiac dysrhythmia]]s.<ref name=AHFS2016/> This includes [[ventricular tachycardia]], [[ventricular fibrillation]], and [[wide complex tachycardia]], [[atrial fibrillation]], and [[paroxysmal supraventricular tachycardia]].<ref name=AHFS2016/> Evidence in [[cardiac arrest]], however, is poor.<ref name=Ali2018>{{cite journal | vauthors = Ali MU, Fitzpatrick-Lewis D, Kenny M, Raina P, Atkins DL, Soar J, Nolan J, Ristagno G, Sherifali D | title = Effectiveness of antiarrhythmic drugs for shockable cardiac arrest: A systematic review | journal = Resuscitation | volume = 132 | pages = 63–72 | date = November 2018 | pmid = 30179691 | doi = 10.1016/j.resuscitation.2018.08.025 | s2cid = 52154562 | url = http://wrap.warwick.ac.uk/113491/1/WRAP-effectiveness-antiarrhythmic-drugs-cardiac-review-Nolan-2018.pdf | access-date = 17 December 2019 | archive-date = 5 March 2020 | archive-url = https://web.archive.org/web/20200305122730/http://wrap.warwick.ac.uk/113491/1/WRAP-effectiveness-antiarrhythmic-drugs-cardiac-review-Nolan-2018.pdf | url-status = live }}</ref> It can be given by mouth, [[intravenously]], or [[intraosseously]].<ref name=AHFS2016/> When used by mouth, it can take a few weeks for effects to begin.<ref name=AHFS2016/><ref name="Xavier-Research-Press-2018">{{cite book|isbn=978-1-7242-7798-5 |title=Review of the Medical Use of Amiodarone (Nexterone, Pacerone) |date=24 July 2018 |publisher=Xavier Research Press }}</ref>

<!-- Side effects and mechanism -->

Common side effects include feeling tired, tremor, nausea, and constipation.<ref name=AHFS2016/> As amiodarone can have serious side effects, it is mainly recommended only for significant ventricular arrhythmias.<ref name=AHFS2016/> Serious side effects include lung toxicity<ref name="pmid33262034">{{cite journal |vauthors=Feduska ET, Thoma BN, Torjman MC, Goldhammer JE |title=Acute Amiodarone Pulmonary Toxicity |journal=J Cardiothorac Vasc Anesth |volume=35 |issue=5 |pages=1485–1494 |date=May 2021 |pmid=33262034 |doi=10.1053/j.jvca.2020.10.060 |s2cid=227253264 |url=}}</ref> such as [[interstitial pneumonitis]], [[liver problems]], heart arrhythmias, vision problems, [[thyroid problems]], and death.<ref name=AHFS2016/> If taken during [[pregnancy]] or [[breastfeeding]] it can cause problems in the fetus or the infant.<ref name=AHFS2016/> It is a [[Antiarrhythmic agent#Class III agents|class III antiarrhythmic medication]].<ref name=AHFS2016/> It works partly by increasing the time before a heart cell can contract again.<ref name=AHFS2016>{{cite web|title=Amiodarone Hydrochloride|url=https://www.drugs.com/monograph/amiodarone-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=22 August 2016|url-status=live|archive-url=https://web.archive.org/web/20160919085754/https://www.drugs.com/monograph/amiodarone-hydrochloride.html|archive-date=19 September 2016}}</ref><ref name="Xavier-Research-Press-2018"/>

<!-- History, society and culture -->

Amiodarone was first made in 1961 and came into medical use in 1962 for [[angina|chest pain believed to be related to the heart]].<ref>{{cite book|title=Analytical Profiles of Drug Substances and Excipients|date=1992|publisher=Academic Press|isbn=978-0-08-086115-9|page=4|url=https://books.google.com/books?id=IMCH-05Z6-EC&pg=PA4|language=en|url-status=live|archive-url=https://web.archive.org/web/20170908192558/https://books.google.com/books?id=IMCH-05Z6-EC&pg=PA4|archive-date=8 September 2017}}</ref> It was pulled from the market in 1967 due to side effects.<ref name=Fis2005/> In 1974 it was found to be useful for arrhythmias and reintroduced.<ref name=Fis2005>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2005 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=12 |url= https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA12 |language=en|url-status=live |archive-url= https://web.archive.org/web/20170908192558/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA12 |archive-date=8 September 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016/> In 2021, it was the 235th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Amiodarone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Amiodarone | access-date = 14 January 2024 | archive-date = 18 January 2024 | archive-url = https://web.archive.org/web/20240118021939/https://clincalc.com/DrugStats/Drugs/Amiodarone | url-status = live }}</ref><ref name="Xavier-Research-Press-2018"/>

==Medical uses==

Amiodarone has been used both in the treatment of acute life-threatening arrhythmias as well as the long-term suppression of arrhythmias.<ref name="pmid32166725">{{cite journal |vauthors=Hamilton D, Nandkeolyar S, Lan H, Desai P, Evans J, Hauschild C, Choksi D, Abudayyeh I, Contractor T, Hilliard A |title=Amiodarone: A Comprehensive Guide for Clinicians |journal=Am J Cardiovasc Drugs |volume=20 |issue=6 |pages=549–558 |date=December 2020 |pmid=32166725 |doi=10.1007/s40256-020-00401-5 |s2cid=212682149 |url=}}</ref> Amiodarone is commonly used to treat different types of abnormal heart rhythms, such as atrial arrhythmias (supraventricular arrhythmias) and ventricular arrhythmias.<ref name="pmid32166725"/>

Atrial arrhythmias and supraventricular arrhythmias are terms often used interchangeably to refer to abnormal heart rhythms originating from the upper chambers of the heart, known as the atria. These types of arrhythmias include conditions such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. They are collectively referred to as supraventricular or atrial arrhythmias because they occur above (supra) the ventricles in the electrical conduction system of the heart.<ref name="pmid30675928">{{cite journal |vauthors=Mori S, Tretter JT, Spicer DE, Bolender DL, Anderson RH |title=What is the real cardiac anatomy? |journal=Clin Anat |volume=32 |issue=3 |pages=288–309 |date=April 2019 |pmid=30675928 |pmc=6849845 |doi=10.1002/ca.23340 |url=}}</ref>

Ventricular arrhythmias are abnormal heart rhythms that originate in the ventricles, which are the lower chambers of the heart. These arrhythmias can be potentially life-threatening and may disrupt the heart's ability to pump blood effectively.<ref name="pmid30675928"/>

Amiodarone can be effective in treating conditions like ventricular fibrillation (a rapid and irregular heartbeat), ventricular tachycardia (fast heartbeat originating from the lower chambers), and cardiac arrest due to shock-resistant ventricular fibrillation.<ref name="pmid32166725"/>

In cases where a patient is experiencing shock-resistant ventricular arrhythmias including stable ventricular tachycardia or unstable ventricular fibrillation, amiodarone may be used.<ref name="Larson_2022">{{cite journal | vauthors = Larson J, Rich L, Deshmukh A, Judge EC, Liang JJ | title = Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs | journal = Journal of Clinical Medicine | volume = 11 | issue = 11 | pages = 3233 | date = June 2022 | pmid = 35683620 | pmc = 9181251 | doi = 10.3390/jcm11113233 | doi-access = free }}</ref> A recent study suggested that another antiarrhythmic, procainamide, may be more effective in stopping ventricular tachycardia – with less side effects and a higher survival rate in patients requiring multiple shocks.<ref name="Ortiz_2017">{{cite journal | vauthors = Ortiz M, Martín A, Arribas F, Coll-Vinent B, Del Arco C, Peinado R, Almendral J | title = Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study | journal = European Heart Journal | volume = 38 | issue = 17 | pages = 1329–1335 | date = May 2017 | pmid = 27354046 | pmc = 5410924 | doi = 10.1093/eurheartj/ehw230 | url = }}</ref> However, due to a small sample size and lack of statistical significance, more evidence is required, and amiodarone remains the drug of choice in ventricular arrythmias.<ref name="Larson_2022" /><ref name="Ortiz_2017" />

Amiodarone is also commonly used as the first-line therapy for patients who receive shocks from implantable cardioverter defibrillators caused by ventricular arrhythmias. Combining amiodarone with beta-blockers has been shown to reduce the likelihood of experiencing appropriate shocks from implantable cardioverter defibrillators.<ref name="pmid32166725"/>

===Cardiac arrest===

[[Defibrillation]] is the treatment of choice for [[ventricular fibrillation]] and pulseless [[ventricular tachycardia]] resulting in [[cardiac arrest]]. While amiodarone has been used in shock-refractory cases, evidence of benefit is poor.<ref name=Ali2018/> Although amiodarone does not appear to improve survival in those who had a cardiac arrest in-hospital,<ref>{{cite journal | vauthors = Laina A, Karlis G, Liakos A, Georgiopoulos G, Oikonomou D, Kouskouni E, Chalkias A, Xanthos T | title = Amiodarone and cardiac arrest: Systematic review and meta-analysis | journal = International Journal of Cardiology | volume = 221 | pages = 780–788 | date = October 2016 | pmid = 27434349 | doi = 10.1016/j.ijcard.2016.07.138 }}</ref> some studies suggested that early administration of amiodarone was associated with better survival and positive outcomes for people who had a cardiac arrest out-of-hospital.<ref>{{cite journal | vauthors = Lupton JR, Neth MR, Sahni R, Jui J, Wittwer L, Newgard CD, Daya MR | title = Survival by time-to-administration of amiodarone, lidocaine, or placebo in shock-refractory out-of-hospital cardiac arrest | journal = Academic Emergency Medicine | volume = 30 | issue = 9 | pages = 906–917 | date = September 2023 | pmid = 36869657 | doi = 10.1111/acem.14716 }}</ref><ref>{{cite journal | vauthors = Perry E, Nehme E, Stub D, Anderson D, Nehme Z | title = The impact of time to amiodarone administration on survival from out-of-hospital cardiac arrest | journal = Resuscitation Plus | volume = 14 | pages = 100405 | date = June 2023 | pmid = 37303855 | pmc = 10250159 | doi = 10.1016/j.resplu.2023.100405 }}</ref>

===Ventricular tachycardia===

Amiodarone may be used in the treatment of ventricular tachycardia in certain instances.<ref name="pmid36818930">{{cite journal |vauthors=Medić F, Bakula M, Alfirević M, Bakula M, Mucić K, Marić N |title=Amiodarone and Thyroid Dysfunction |journal=Acta Clin Croat |volume=61 |issue=2 |pages=327–341 |date=August 2022 |pmid=36818930 |pmc=9934045 |doi=10.20471/acc.2022.61.02.20 |url=}}</ref> Individuals with hemodynamically ''unstable'' ventricular tachycardia ''should not'' initially receive amiodarone. These individuals should be [[cardioversion|cardioverted]].

Amiodarone can be used in individuals with hemodynamically stable ventricular tachycardia. In these cases, amiodarone can be used regardless of the individual's underlying heart function and the type of ventricular tachycardia; it can be used in individuals with [[monomorphic ventricular tachycardia]], but is contraindicated in individuals with [[polymorphic ventricular tachycardia]] as it is associated with a prolonged [[QT interval]] which will be made worse with anti-arrhythmic drugs.<ref>Resuscitation Council (UK) [https://www.resus.org.uk/resuscitation-guidelines/ Peri-arrest arrhythmias – Tachycardia algorithm] {{webarchive|url=https://web.archive.org/web/20160103224521/https://www.resus.org.uk/resuscitation-guidelines/ |date=3 January 2016 }} Retrieved 25 January 2016</ref>

===Atrial fibrillation===

Individuals who have undergone [[coronary artery bypass surgery|open heart surgery]] are at an increased risk of developing [[atrial fibrillation]] (or AF) in the first few days post-procedure.<ref name="pmid32166725"/><ref>{{cite web | url=https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery | title=UpToDate | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery | url-status=live }}</ref><ref>{{cite web | url=https://www.health.harvard.edu/heart-health/atrial-fibrillation-after-surgery-common-and-undertreated | title=Atrial fibrillation after surgery: Common and undertreated? | date=October 2022 | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://www.health.harvard.edu/heart-health/atrial-fibrillation-after-surgery-common-and-undertreated | url-status=live }}</ref> In the ARCH trial, [[intravenous]] amiodarone (2 g administered over 2 d) has been shown to reduce the incidence of atrial fibrillation after open heart surgery when compared to placebo.<ref>{{cite web | url=https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2010/02/22/19/19/ARCH | title=Amiodarone Reduction in Coronary Heart Trial | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195137/https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2010/02/22/19/19/ARCH | url-status=live }}</ref><ref>{{cite journal | vauthors = Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR | title = Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial | journal = Journal of the American College of Cardiology | volume = 34 | issue = 2 | pages = 343–347 | date = August 1999 | pmid = 10440143 | doi = 10.1016/S0735-1097(99)00212-0 | s2cid = 24714524 }}</ref> However, clinical studies have failed to demonstrate long-term efficacy and have shown potentially fatal side effects such as pulmonary toxicities. While amiodarone is not approved for AF by the [[Food and Drug Administration|US Food and Drug Administration]] (FDA), it is a commonly prescribed off-label treatment due to the lack of equally effective treatment alternatives.<ref name="pmid14677664">{{cite journal | url=https://www.aafp.org/pubs/afp/issues/2003/1201/p2189.html | title=Amiodarone: Guidelines for Use and Monitoring | journal=American Family Physician | date=December 2003 | volume=68 | issue=11 | pages=2189–2197 | pmid=14677664 | vauthors=Siddoway LA | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://www.aafp.org/pubs/afp/issues/2003/1201/p2189.html | url-status=live }}</ref><ref>{{cite journal | url=https://www.aafp.org/pubs/afp/issues/2005/0401/p1434.html | title=Practice Guideline Briefs | journal=American Family Physician | date=April 2005 | volume=71 | issue=7 | pages=1434 | vauthors=Neff MJ | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://www.aafp.org/pubs/afp/issues/2005/0401/p1434.html | url-status=live }}</ref>

So-called 'acute onset atrial fibrillation', defined by the North American Society of Pacing and Electrophysiology (NASPE) in 2003, responds well to short-duration treatment with amiodarone.<ref name="pmid14677664" /><ref>{{cite journal | url=https://www.aafp.org/pubs/afp/issues/2002/0715/p249.html | title=Acute Management of Atrial Fibrillation: Part I. Rate and Rhythm Control | journal=American Family Physician | date=15 July 2002 | volume=66 | issue=2 | pages=249–257 | pmid=12152960 | vauthors=King DE, Dickerson LM, Sack JL | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://www.aafp.org/pubs/afp/issues/2002/0715/p249.html | url-status=live }}</ref> This has been demonstrated in seventeen randomized controlled trials, of which five included a placebo arm. The incidence of severe side effects in this group is low.<ref>{{cite journal | url=https://bmjopen.bmj.com/content/10/3/e034774 | pmid=32209631 | date=2020 | title=Managing new-onset atrial fibrillation in critically ill patients: A systematic narrative review | journal=BMJ Open | volume=10 | issue=3 | pages=e034774 | doi=10.1136/bmjopen-2019-034774 | pmc=7202704 | vauthors=O'Bryan LJ, Redfern OC, Bedford J, Petrinic T, Young JD, Watkinson PJ | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://bmjopen.bmj.com/content/10/3/e034774 | url-status=live }}</ref><ref>{{cite journal | url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/215367 | doi=10.1001/archinte.163.7.777 | title=Effectiveness of Amiodarone for Conversion of Atrial Fibrillation to Sinus Rhythm | date=2003 | journal=Archives of Internal Medicine | volume=163 | issue=7 | pages=777–785 | pmid=12695268 | vauthors=Letelier LM, Udol K, Ena J, Weaver B, Guyatt GH | url-access=subscription | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195136/https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/215367 | url-status=live }}</ref><ref>{{cite web | url=https://www.nice.org.uk/guidance/ng196/chapter/Recommendations | title=Recommendations &#124; Atrial fibrillation: Diagnosis and management &#124; Guidance &#124; NICE | date=27 April 2021 | access-date=5 February 2024 | archive-date=5 February 2024 | archive-url=https://web.archive.org/web/20240205195137/https://www.nice.org.uk/guidance/ng196/chapter/Recommendations | url-status=live }}</ref>

Amiodarone is an effective, antiarrhythmic-of-choice in achieving cardioversion to sinus rhythm in critical care populations with new onset atrial fibrillation (NOAF). However, other anti-arrhythmic agents may exert superior rhythm control, rate control and lower mortality rate which may be more favourable than amiodarone in specific cases.<ref>Johnston BW, Chean CS, Duarte R, Hill R, Blackwood B, McAuley DF, Welters ID. Management of new onset atrial fibrillation in critically unwell adult patients: a systematic review and narrative synthesis. British Journal of Anaesthesia. 2022 May 1;128(5):759-71.</ref>

==Contraindications==

Women who are [[pregnant]] or may become pregnant are strongly advised not to take amiodarone. Since amiodarone can be expressed in breast milk, women taking the drug are advised to stop nursing.

It is contraindicated in individuals with [[sinus node|sinus nodal]] [[bradycardia]], [[atrioventricular node|atrioventricular]] block, and second or third-degree heart block who do not have an [[artificial pacemaker]].

Individuals with baseline depressed lung function should be monitored closely if amiodarone therapy is to be initiated.

Formulations of amiodarone that contain benzyl alcohol should not be given to neonates, because the benzyl alcohol may cause the potentially fatal "gasping syndrome".<ref>{{cite journal | title = Neonatal deaths associated with use of benzyl alcohol--United States | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 31 | issue = 22 | pages = 290–291 | date = June 1982 | pmid = 6810084 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm | url-status = live | archive-url = https://web.archive.org/web/20120830225243/http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm | archive-date = 30 August 2012 | author1 = Centers for Disease Control (CDC) }}</ref>

Amiodarone can worsen the cardiac arrhythmia brought on by [[digitalis]] toxicity.

Contraindications of amiodarone also include:

* hypersensitivity to amiodarone or any of its components;<ref name="pmid32166725"/>

* severe [[hepatic impairment]];<ref name="pmid32166725" />

* [[sinus node dysfunction]], including severe [[sinus bradycardia]] or [[sinoatrial block]], since amiodarone can cause significant [[bradycardia]] and sinus nodal arrest;<ref name="pmid32166725" />

* second- or third-degree [[Atrioventricular block|atrioventricular (AV) block]], due to its negative [[chronotropic]] (affecting the heart rate) and [[dromotropic]] (affecting the conductivity) effects on the AV conduction system, unless a [[Artificial cardiac pacemaker|pacemaker]] is implanted;<ref name="pmid32166725" />

* [[thyrotoxicosis]] that cannot be controlled by conventional means, such as [[Graves' disease]].<ref name="pmid32166725"/>

There are no specific guidelines for endurance or high-intensity exercise while taking amiodarone. However, since amiodarone may cause bradycardia and QTc prolongation which can affect exercise capacity and increase the risk of arrhythmias during intense exercise, it would generally be advisable for patients taking this medication to consult their healthcare provider before engaging in high-intensity physical activities such as strenuous endurance exercises.<ref name="pmid32166725"/>

== Side effects ==

At oral doses of 400&nbsp;mg per day or higher, amiodarone can have serious, varied [[side effect]]s, including [[toxicity]] to the [[thyroid]] gland,<ref name="pmid37731073"/> liver, lung, and [[retina]]l functions, requiring clinical surveillance and regular laboratory testing.<ref name="Drugs.com-2022">{{cite web |title=Amiodarone |url=https://www.drugs.com/amiodarone.html |publisher=Drugs.com |access-date=25 July 2022 |date=18 May 2022 |archive-date=25 July 2022 |archive-url=https://web.archive.org/web/20220725164122/https://www.drugs.com/amiodarone.html |url-status=live }}</ref><ref name="pmid32368381"/> [[Allergic reaction]]s to amiodarone may occur.<ref name="Drugs.com-2022"/> Most individuals administered amiodarone on a chronic basis will experience at least one side effect.<ref name="pmid32368381"/> In some people, daily use of amiodarone at 100&nbsp;mg oral doses can be effective for arrhythmia control with no or minimal side effects.<ref name="pmid32368381"/>

Some common side effects include:

* nausea and vomiting;<ref name="pmid32166725" />

* taste disturbances (changes in taste perception, often described as a metallic or bitter taste in the mouth);<ref name="pmid32166725" />

* [[Photodermatitis|photosensitivity]] of the skin, also known as [[photodermatitis]], where exposure to sunlight or ultraviolet radiation may lead to skin reactions such as rashes or sunburn-like symptoms;<ref name="pmid32166725" />

* corneal microdeposits (deposits may accumulate on the [[cornea]] over time, resulting in blurred vision or visual halos{{--}}bright circles or rings around a light source, such as headlights; still, these corneal deposits typically do not affect vision significantly);<ref name="pmid32166725" /><ref name="pmid31447894">{{cite journal |vauthors=Colunga Biancatelli RM, Congedo V, Calvosa L, Ciacciarelli M, Polidoro A, Iuliano L |title=Adverse reactions of Amiodarone |journal=J Geriatr Cardiol |volume=16 |issue=7 |pages=552–566 |date=July 2019 |pmid=31447894 |pmc=6689516 |doi=10.11909/j.issn.1671-5411.2019.07.004 |doi-broken-date=22 March 2024 |url=}}</ref>

* thyroid dysfunction<ref name="pmid37547257">{{cite journal |vauthors=Gašparini D, Raljević D, Pehar-Pejčinović V, Klarica Gembić T, Peršić V, Turk Wensveen T |title=When amiodarone-induced thyroiditis meets cardiomyopathy with excessive trabeculation: a case report |journal=[[Front Cardiovasc Med]] |volume=10 |issue= |pages=1212965 |date=2023 |pmid=37547257 |pmc=10401478 |doi=10.3389/fcvm.2023.1212965 |doi-access=free }}</ref> (in approximately 15-20% of patients, amiodarone treatment results in thyroid dysfunction, either amiodarone-induced hypothyroidism or amiodarone-induced thyrotoxicosis; the drug can lead to both hypo- and hyperthyroidism);<ref name="pmid37731073"/>

* pulmonary toxicity<ref name="pmid37123694">{{cite journal |vauthors=Scaramozzino MU, Sapone G, Plastina UR, Nucara M |title=Amiodarone-Induced Lung Toxicity: A Case Initially Not Correctly Framed |journal=[[Cureus]] |volume=15 |issue=3 |pages=e36818 |date=March 2023 |pmid=37123694 |pmc=10146449 |doi=10.7759/cureus.36818 |doi-access=free |url=}}</ref><ref name="pmid37249923">{{cite journal |vauthors=Tsai IL, Huang LT, Yu YT, Lee CT, Huang TH |title=Variable radiographic and histologic presentations of amiodarone-related interstitial lung disease and the importance of avoiding re-exposure |journal=Respirol Case Rep |volume=11 |issue=6 |pages=e01165 |date=June 2023 |pmid=37249923 |pmc=10209837 |doi=10.1002/rcr2.1165 |url=}}</ref><ref name="pmid36553223">{{cite journal |vauthors=Budin CE, Cocuz IG, Sabău AH, Niculescu R, Ianosi IR, Ioan V, Cotoi OS |title=Pulmonary Fibrosis Related to Amiodarone-Is It a Standard Pathophysiological Pattern? A Case-Based Literature Review |journal=[[Diagnostics (journal)|Diagnostics]] |volume=12 |issue=12 |date=December 2022 |page=3217 |pmid=36553223 |pmc=9777900 |doi=10.3390/diagnostics12123217 |doi-access=free }}</ref><ref name="pmid36176494">{{cite journal |vauthors=Mitrofan CE, Cretu A, Mitrofan C, Bar C, Ghiciuc CM |title=Amiodarone induced lung disease |journal=Arch Clin Cases |volume=9 |issue=3 |pages=126–132 |date=2022 |pmid=36176494 |pmc=9512125 |doi=10.22551/2022.36.0903.10217 |url=}}</ref> (lung problems such as pulmonary fibrosis or interstitial lung disease may occur rarely but have the potential for serious consequences if left untreated);<ref name="pmid33262034"/><ref name="pmid32166725" />

* liver abnormalities (liver damage, including elevated liver enzymes ([[Aspartate transaminase|AST]]/[[Alanine transaminase|ALT]]) and hepatotoxicity, although severe cases are rare);<ref name="pmid32166725" />

* bradycardia and heart block (since it slows down heart rate by affecting the sinus node function and AV conduction system, it can increase the risk of heart block);<ref name="pmid32166725" />

* QT Interval prolongation.<ref name="pmid32166725" />

Amiodarone can potentially cause renal toxicity, but solid studies on whether amiodarone may be toxic to the kidneys are lacking.<ref name="pmid37743903">{{cite journal |vauthors=Duineveld MD, Kers J, Vleming LJ |title=Case report of progressive renal dysfunction as a consequence of amiodarone-induced phospholipidosis |journal=[[Eur Heart J Case Rep]] |volume=7 |issue=9 |pages=ytad457 |date=September 2023 |pmid=37743903 |pmc=10516635 |doi=10.1093/ehjcr/ytad457 |url=}}</ref>

===Lung===

[[Image:IPF amiodarone.JPG|thumb|upright=1.3|A chest X-ray demonstrating [[pulmonary fibrosis]] due to amiodarone.]]

Side effects of oral amiodarone at doses of 400&nbsp;mg or higher include various [[pulmonary]] effects.<ref name="Drugs.com-2021">{{cite web | url = https://www.drugs.com/sfx/amiodarone-side-effects.html#professional | title = Amiodarone Side Effects | publisher = Drugs.com | date = 25 April 2021 | access-date = 25 July 2022 | archive-date = 24 February 2016 | archive-url = https://web.archive.org/web/20160224012131/http://www.drugs.com/sfx/amiodarone-side-effects.html#professional | url-status = live }}</ref> The most serious reaction is [[interstitial lung disease]]. Risk factors include high cumulative dose, more than 400 milligrams per day, duration over two months, increased age, and preexisting pulmonary disease. Some individuals were noted to develop [[pulmonary fibrosis]] after a week of treatment, while others did not develop it after years of continuous use.<ref name="Drugs.com-2021"/> Common practice is to avoid the agent if possible in individuals with decreased lung function.

The most specific test of pulmonary toxicity due to amiodarone is a dramatically decreased [[Dlco|DL_CO]] noted on [[pulmonary function test]]ing.

=== Thyroid ===

Induced abnormalities in [[thyroid]] function are common.<ref name="pmid37547257"/><ref name="Drugs.com-2022"/> In approximately 15-20% of patients, amiodarone treatment results in thyroid dysfunction, either amiodarone-induced hypothyroidism or amiodarone-induced thyrotoxicosis.<ref name="pmid19584973">{{cite journal |vauthors=Tsang W, Houlden RL |title=Amiodarone-induced thyrotoxicosis: a review |journal=Can J Cardiol |volume=25 |issue=7 |pages=421–4 |date=July 2009 |pmid=19584973 |pmc=2723027 |doi=10.1016/s0828-282x(09)70512-4}}</ref><ref name="pmid29489285"/><ref name="pmid37731073">{{cite journal |vauthors=Cappellani D, Bartalena L, Bogazzi F |title=Short review: novel concepts in the approach to patients with amiodarone-induced thyrotoxicosis |journal=J Endocrinol Invest |volume= 47|issue= 2|pages= 275–283|date=September 2023 |pmid=37731073 |doi=10.1007/s40618-023-02168-3 |s2cid=262088052 |doi-access=free |pmc=10859339 }}</ref><ref name="pmid36818930"/> Both under- and overactivity of the thyroid may occur.<ref name="Drugs.com-2022"/>

Amiodarone is structurally similar to [[thyroxine]] and also contains [[iodine]]. Both of these factors contribute to the effects of amiodarone on thyroid function.<ref name="pmid36818930"/><ref name="pmid19584973"/><ref>{{cite journal | vauthors = Lombardi A, Inabnet WB, Owen R, Farenholtz KE, Tomer Y | title = Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 1 | pages = E1-10 | date = January 2015 | pmid = 25295624 | pmc = 4283007 | doi = 10.1210/jc.2014-2745 }}</ref><ref>{{cite book| vauthors = Hall GM, Hunter JM, Cooper MS |title=Core Topics in Endocrinology in Anaesthesia and Critical Care|date=2010|publisher=Cambridge University Press|isbn=978-1-139-48612-5|page=170|url=https://books.google.com/books?id=3xd9O-W1HE8C&pg=PA170|language=en|url-status=live|archive-url=https://web.archive.org/web/20170908192558/https://books.google.com/books?id=3xd9O-W1HE8C&pg=PA170|archive-date=8 September 2017}}</ref> Amiodarone also causes an anti-thyroid action, via [[Plummer effect|Plummer]] and [[Wolff–Chaikoff effect]]s, due its large amount of iodine in its molecule, which causes a particular "cardiac hypothyroidism" with bradycardia and arrhythmia.<ref>{{cite journal| vauthors = Venturi S |title=Evolutionary Significance of Iodine|journal=Current Chemical Biology|volume=5 |pages=155–162|year=2011|issn=1872-3136|doi=10.2174/187231311796765012|issue=3}}</ref><ref>{{cite journal| vauthors = Venturi S |title=Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective|journal=Human Evolution|volume= 29 |issue= 1–3|pages=185–205|year=2014|issn=0393-9375}}</ref>

Thyroid function should be checked at least every six months.<ref name="pmid29594056">{{cite journal | vauthors = Bartalena L, Bogazzi F, Chiovato L, Hubalewska-Dydejczyk A, Links TP, Vanderpump M | title = 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction | journal = European Thyroid Journal | volume = 7 | issue = 2 | pages = 55–66 | date = March 2018 | pmid = 29594056 | pmc = 5869486 | doi = 10.1159/000486957 }}</ref>

* [[Hypothyroidism]] (slowing of the thyroid) occurs frequently; in the SAFE trial, which compared amiodarone with other medications for the treatment of atrial fibrillation, biochemical hypothyroidism (as defined by a TSH level of 4.5–10 mU/L) occurred in 25.8% of the amiodarone-treated group as opposed to 6.6% of the control group (taking placebo or [[sotalol]]). Overt hypothyroidism (defined as TSH >10 mU/L) occurred at 5.0% compared to 0.3%; most of these (>90%) were detected within the first six months of amiodarone treatment.<ref name="pmid17904459">{{cite journal | vauthors = Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM | title = Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation | journal = The American Journal of Medicine | volume = 120 | issue = 10 | pages = 880–885 | date = October 2007 | pmid = 17904459 | doi = 10.1016/j.amjmed.2007.04.022 | url = https://zenodo.org/record/1258726 | access-date = 27 August 2020 | archive-date = 9 August 2020 | archive-url = https://web.archive.org/web/20200809085816/https://zenodo.org/record/1258726 | url-status = live }}</ref>

* [[Amiodarone induced thyrotoxicosis]] (AIT), can be caused due to the high iodine content in the drug via the [[Jod-Basedow phenomenon|Jod-Basedow effect]]. This is known as Type 1 AIT, and usually occurs in patients with an underlying predisposition to hyperthyroidism such as [[Graves' disease]], within weeks to months after starting amiodarone. Type 1 AIT is usually treated with anti-thyroid drugs or [[thyroidectomy]]. Type 2 AIT is caused by a destructive [[thyroiditis]] due to a direct toxic effect of amiodarone on thyroid follicular epithelial cells.<ref name="pmid19584973"/><ref name=Ylli/> Type 2 AIT can occur even years after starting amiodarone, is usually self-limited and responds to [[anti-inflammatory]] treatment such as [[corticosteroid]]s.<ref name=Ylli>{{cite journal | vauthors = Ylli D, Wartofsky L, Burman KD | title = Evaluation and Treatment of Amiodarone-Induced Thyroid Disorders | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 106 | issue = 1 | pages = 226–236 | date = January 2021 | pmid = 33159436 | doi = 10.1210/clinem/dgaa686 | s2cid = 226275566 | doi-access = free }}</ref> In practice, often the type of AIT is undetermined or presumed as mixed with both treatments combined.<ref name=Ylli/> Thyroid uptake measurements (I-123 or I-131), which are used to differentiate causes of hyperthyroidism, are generally unreliable in patients who have been taking amiodarone. Because of the high iodine content of amiodarone, the thyroid gland is effectively saturated, thus preventing further uptake of isotopes of iodine. However, positive radioactive iodine can be used to rule in type 1AIT .{{Citation needed|date=September 2007}}

<gallery>

Amiodarone structure.svg|Amiodarone

Thyroxine.svg|[[Thyroxine]]

</gallery>

=== Eye ===

[[Cornea]]l micro-deposits ([[cornea verticillata]],<ref name="pmid7116220">{{cite journal | vauthors = Chew E, Ghosh M, McCulloch C | title = Amiodarone-induced cornea verticillata | journal = Canadian Journal of Ophthalmology. Journal Canadien d'Ophtalmologie | volume = 17 | issue = 3 | pages = 96–99 | date = June 1982 | pmid = 7116220 }}</ref> also called vortex or whorl keratopathy) are almost universally present (over 90%) in individuals taking amiodarone longer than 6 months, especially doses greater than 400&nbsp;mg/day. These deposits typically do not cause any symptoms. About 1 in 10 individuals may complain of a bluish halo. Anterior subcapsular lens deposits are relatively common (50%) in higher doses (greater than 600&nbsp;mg/day) after 6 months of treatment.

[[Optic neuropathy]], nonarteritic anterior ischemic optic neuropathy (N-AION), occurs in 1–2% of people and is not dosage dependent.<ref>{{cite journal | vauthors = Passman RS, Bennett CL, Purpura JM, Kapur R, Johnson LN, Raisch DW, West DP, Edwards BJ, Belknap SM, Liebling DB, Fisher MJ, Samaras AT, Jones LG, Tulas KM, McKoy JM | title = Amiodarone-associated optic neuropathy: a critical review | journal = The American Journal of Medicine | volume = 125 | issue = 5 | pages = 447–453 | date = May 2012 | pmid = 22385784 | pmc = 3322295 | doi = 10.1016/j.amjmed.2011.09.020 }}</ref> Bilateral optic disc swelling and mild and reversible visual field defects can also occur.

[[Madarosis|Loss of eyelashes]] has been linked to amiodarone use.<ref>{{cite book| vauthors = Roy FH |title=Ocular differential diagnosis |date=2012 |publisher=Jaypee Highlights Medical Publishers|location=Panama City, Panama |isbn=978-93-5025-571-1 |page=94 |edition=9th |url=https://books.google.com/books?id=94WZpuXSTasC&pg=PA94|url-status=live |archive-url=https://web.archive.org/web/20170908192558/https://books.google.com/books?id=94WZpuXSTasC&pg=PA94|archive-date=8 September 2017}}</ref>

===Liver===

Abnormal [[liver enzyme]] results are common in people taking amiodarone.<ref name="Drugs.com-2022"/> Much rarer are [[jaundice]], [[hepatomegaly]] (liver enlargement), and [[hepatitis]] (inflammation of the liver).<ref>{{cite journal | vauthors = Flaharty KK, Chase SL, Yaghsezian HM, Rubin R | title = Hepatotoxicity associated with amiodarone therapy | journal = Pharmacotherapy | volume = 9 | issue = 1 | pages = 39–44 | year = 1989 | pmid = 2646621 | doi = 10.1002/j.1875-9114.1989.tb04102.x | s2cid = 37972060 }}</ref>

In clinical observations, it has been noted that the administration of amiodarone, even at lower therapeutic doses, has been associated with the development of a condition mimicking alcoholic cirrhosis. This condition, often referred to as pseudo-alcoholic cirrhosis, presents with similar histopathological features to those observed in patients with alcoholic cirrhosis.<ref>{{cite journal | vauthors = Singhal A, Ghosh P, Khan SA | title = Low dose amiodarone causing pseudo-alcoholic cirrhosis | journal = Age and Ageing | volume = 32 | issue = 2 | pages = 224–225 | date = March 2003 | pmid = 12615569 | doi = 10.1093/ageing/32.2.224 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Puli SR, Fraley MA, Puli V, Kuperman AB, Alpert MA | title = Hepatic cirrhosis caused by low-dose oral amiodarone therapy | journal = The American Journal of the Medical Sciences | volume = 330 | issue = 5 | pages = 257–261 | date = November 2005 | pmid = 16284489 | doi = 10.1097/00000441-200511000-00012 }}</ref> However, this extreme adverse event manifestation—pseudo-alcoholic cirrhosis caused by low dose amiodarone—is very rare.<ref name="pmid32368381">{{cite journal |vauthors=Chokesuwattanaskul R, Shah N, Chokesuwattanaskul S, Liu Z, Thakur R |title=Low-dose Amiodarone Is Safe: A Systematic Review and Meta-analysis |journal=J Innov Card Rhythm Manag |volume=11 |issue=4 |pages=4054–4061 |date=April 2020 |pmid=32368381 |pmc=7192149 |doi=10.19102/icrm.2020.110403 |url=}}</ref>

===Skin===

Long-term administration of amiodarone (usually more than eighteen months) is associated with a light-sensitive blue-grey discoloration of the skin, sometimes called [[ceruloderma]]; such patients should avoid exposure to the sun and use [[sunscreen]] that protects against [[ultraviolet]]-A and -B. The discoloration will slowly improve upon cessation of the medication, however, the skin color may not return completely.<ref>{{cite journal | vauthors = Murphy RP, Canavan M | title = Skin Discoloration from Amiodarone | journal = The New England Journal of Medicine | volume = 382 | issue = 3 | pages = e5 | date = January 2020 | pmid = 31940702 | doi = 10.1056/NEJMicm1906774 | s2cid = 210333420 }}</ref>

===Pregnancy and breastfeeding===

Use during pregnancy may result in a number of problems in the infant including thyroid problems, heart problems, neurological problems, and preterm birth.<ref name=AmiPreg>{{cite web |title=Amiodarone Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/amiodarone.html |website=Drugs.com |access-date=8 December 2021 |language=en |archive-date=15 October 2020 |archive-url=https://web.archive.org/web/20201015165300/https://www.drugs.com/pregnancy/amiodarone.html |url-status=live }}</ref> Use during breastfeeding is generally not recommended though one dose may be okay.<ref name=AmiPreg/>

===Other===

Long-term use of amiodarone has been associated with [[peripheral neuropathies]].<ref>{{cite journal | vauthors = Fraser AG, McQueen IN, Watt AH, Stephens MR | title = Peripheral neuropathy during long-term high-dose amiodarone therapy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 48 | issue = 6 | pages = 576–578 | date = June 1985 | pmid = 2989436 | pmc = 1028375 | doi = 10.1136/jnnp.48.6.576 }}</ref>

Amiodarone is sometimes responsible for [[epididymitis]]. Amiodarone accumulates in the head of the organ and can cause unilateral or bilateral inflammation. It tends to resolve if amiodarone is stopped.<ref>{{cite journal | vauthors = Thomas A, Woodard C, Rovner ES, Wein AJ | title = Urologic complications of neurologic medications | journal = The Urologic Clinics of North America | volume = 30 | issue = 1 | pages = 123–131 | date = February 2003 | pmid = 12580564 | doi = 10.1016/S0094-0143(02)00111-8 }}</ref>

Some cases of [[gynecomastia]] have been reported in men on amiodarone.<ref name="Gynecomastia: Its features, and when and how to treat it">[http://www.ccjm.org/content/71/6/511.full.pdf] {{Webarchive|url=https://web.archive.org/web/20090709184316/http://www.ccjm.org/content/71/6/511.full.pdf|date=9 July 2009}} Gynecomastia: Its features, and when and how to treat it</ref>

A retrospective cohort study found an increased risk of digestive, liver, head and neck and liver cancers amongst male patients exposed to amiodarone versus female participants in the same study and the general population.<ref name="Su_2013">{{cite journal |vauthors=Su VY, Hu YW, Chou KT, Ou SM, Lee YC, Lin EY, Chen TJ, Tzeng CH, Liu CJ |date=May 2013 |title=Amiodarone and the risk of cancer: a nationwide population-based study |journal=Cancer |volume=119 |issue=9 |pages=1699–1705 |doi=10.1002/cncr.27881 |pmid=23568847 |s2cid=24144312 |doi-access=free}}</ref> This study also identified that the Standardized Incidence Ratio of cancer occurrence increased significantly in males aged 20-59 and >80 years old who were exposed to a higher dose of Amiodarone in comparison to those exposed to a lower dose. This suggests that there is a dose-effect relationship.<ref name="Su_2013" /> These results should be interpreted with caution due to limitations of the study design and care should be taken prior to altering current clinical and prescribing practices. Amiodarone and its effect on cancer is still a topic that requires more robust research.

== Drug-drug interactions ==

The [[pharmacokinetics]] of numerous [[medication|drugs]], including many that are commonly administered to individuals with [[heart]] disease, are affected by amiodarone.{{medical citation needed|date=March 2024}}

Amiodarone has particularly important interactions with the following drugs:

* [[class I antiarrhythmic]]s (amiodarone should not be combined with other class I antiarrhythmic drugs, such as [[disopyramide]], [[flecainide]], [[procainamide]], [[quinidine]], etc., due to an increased risk of QTc prolongation and potential arrhythmias);<ref name="pmid32166725"/>

* [[beta blocker]]s and [[calcium channel blocker]]s (combining amiodarone with beta-blockers or calcium channel blockers, such as [[sotalol]], can further slow down heart rate and cause bradycardia or heart block);<ref name="pmid32166725"/>

* [[digoxin]] (amiodarone inhibits a protein called P-glycoprotein (P-gp), which transports digoxin out of cells in the gut, liver, and kidneys, therefore, concurrent use of these medications increases [[digoxin]] levels in the body, potentially leading to digoxin toxicity)<ref name="pmid32166725"/>

* [[statin]]s (amiodarone can inhibit enzymes in the liver responsible for metabolizing certain statins, such as [[simvastatin]], [[atorvastatin]], etc., therefore interaction elevates plasma concentrations of these [[statin]]s, increasing the risk of [[myopathy]], that is muscle damage, or [[rhabdomyolysis]], that is severe muscle breakdown);<ref name="pmid32166725"/>

* [[warfarin]] (since the [[Anticoagulant|anticoagulation]] effects of [[warfarin]] depend on metabolism of warfarin by both cytochromes [[CYP2C9]] and [[CYP3A4]], coadministation leads to rise in [[International Normalized Ratio|international normalized ratio]] (INR)—the amount of time taken for the blood to form a clot—placing patient at higher bleeding risks);<ref name="pmid32166725"/> Amiodarone potentiates the action of [[warfarin]] by inhibiting the clearance of both (S) and (R) warfarin. Individuals taking both of these medications should have their warfarin doses adjusted based on their dosing of amiodarone and have their anticoagulation status (measured as [[prothrombin time]] (PT) and [[international normalized ratio]] (INR)) measured more frequently. Dose reduction of warfarin is as follows: 40% reduction if the amiodarone dose is {{Val|400|u=mg}} daily, 35% reduction if the amiodarone dose is {{Val|300|u=mg}};mg daily, 30% reduction if the amiodarone dose is {{Val|200|u=mg}} daily, and 25% reduction if amiodarone dose is {{Val|100|u=mg}} daily.{{medical citation needed|date=March 2024}} The effect of amiodarone on the warfarin concentrations can be as early as a few days after initiation of treatment; however, the interaction may not peak for up to seven weeks;{{medical citation needed|date=March 2024}}

* [[anti-HIV medications]] (several [[HIV]] medications, such as [[ritonavir]], [[indinavir]], etc., interact with amiodarone by inhibiting [[CYP3A4]] enzyme hence leading to decreased clearance of amiodarone, i.e., increasing the concentration of amiodarone in the organism).<ref name="pmid32166725"/><ref name="FDA-2010">{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018972s042lbl.pdf|title=Cordarone (amiodarone HCl) tables|publisher=FDA|year=2010|access-date=22 March 2024|archive-date=3 August 2023|archive-url=https://web.archive.org/web/20230803071828/http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018972s042lbl.pdf|url-status=live}}</ref>

Amiodarone inhibits the action of the [[cytochrome P450]] [[isozyme]] family; such inhibition reduces the clearance of many drugs, including the following:{{medical citation needed|date=March 2024}}

* [[ciclosporin]],

* [[digoxin]],

* [[flecainide]],

* [[procainamide]],

* [[quinidine]],

* [[sildenafil]],

* [[simvastatin]],

* [[theophylline]],

* [[warfarin]].

In 2015, [[Gilead Sciences]] warned healthcare providers about people who began taking the hepatitis C drugs [[ledipasvir/sofosbuvir]] or [[sofosbuvir]] along with amiodarone, who developed abnormally slow heartbeats or died of [[cardiac arrest]].<ref>West, Stephen. [https://www.bloomberg.com/news/articles/2015-03-21/gilead-warns-after-hepatitis-patient-on-heart-drug-dies "Gilead Warns After Hepatitis Patient on Heart Drug Dies"] {{webarchive|url=https://web.archive.org/web/20170322104145/https://www.bloomberg.com/news/articles/2015-03-21/gilead-warns-after-hepatitis-patient-on-heart-drug-dies |date=22 March 2017 }}. Published 21 March 2015.</ref>

==Metabolism==

Amiodarone is extensively metabolized in the liver by CYP3A4, a member of the cytochrome P450 superfamily of enzymes, therefore, amiodarone and can affect the metabolism of numerous other [[medication|drugs]] that depend on cytochrome P450, such as [[digoxin]], [[phenytoin]], [[warfarin]], etc.<ref name="pmid14677664"/><ref name="Amiodarone-Deranged-Physiology">{{cite web | url=https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%20967/amiodarone | title=Amiodarone &#124; Deranged Physiology | access-date=22 March 2024 | archive-date=5 December 2023 | archive-url=https://web.archive.org/web/20231205075036/https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%20967/amiodarone | url-status=live }}</ref><ref>{{cite journal|doi=10.2165/00003088-198917020-00005 |title=Pharmacokinetic Drug Interactions with Amiodarone |date=1989 |journal=Clinical Pharmacokinetics |volume=17 |issue=2 |pages=130–140 |pmid=2673606 | vauthors = Lesko L }}</ref><ref name="pmid29489285">{{cite book|pmid=29489285|id={{NCBIBook|NBK482154}} |date=2024 |title=Amiodarone | vauthors = Florek JB, Lucas A, Girzadas D }}</ref>

The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.<ref name="pmid14677664"/>

The metabolism of amiodarone is inhibited by [[grapefruit]] juice, leading to elevated [[blood plasma|serum]] levels of amiodarone.{{medical citation needed|date=March 2024}}

On 8 August 2008, the [[Food and Drug Administration|US Food and Drug Administration]] (FDA) issued a warning of the risk of [[rhabdomyolysis]], which can lead to [[kidney failure]] or death, when [[simvastatin]] is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20&nbsp;mg. This drug combination, especially with higher doses of simvastatin, should be avoided.<ref name="FDA-Simvastin-2008">{{cite web |url=https://www.fda.gov/cder/drug/infopage/simvastatin_amiodarone/default.htm |title=Information on Simvastatin/Amiodarone |website=[[Food and Drug Administration]] |access-date=21 September 2008| archive-url= https://web.archive.org/web/20080921230357/https://www.fda.gov/Cder/drug/infopage/simvastatin_amiodarone/default.htm| archive-date= 21 September 2008 | url-status= live}}</ref>

Amiodarone is extensively metabolized in the liver. The primary metabolic pathway of amiodarone is by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C8.<ref name="FDA-2010"/><ref name="pmid29489285"/> The metabolism of amiodaron can be characterized by two phases:

* phase I metabolism, when amiodarone undergoes oxidative processes mainly mediated by CYP3A4 and to a lesser extent by CYP2C8; these reactions result in the formation of several active metabolites, including desethylamiodarone (DEA) and di-desethylamiodarone (DDEA); DEA is the most abundant metabolite and exhibits similar pharmacological effects as amiodarone;{{medical citation needed|date=March 2024}}

* phase II metabolism, when both amiodarone and its major metabolite DEA can undergo conjugation reactions with glucuronic acid;t his process increases water solubility of these compounds for their efficient elimination from the body.{{medical citation needed|date=March 2024}}

Amiodarone has an exceptionally long half-life due to a combination of several factors:<ref name="pmid32166725"/>

* high lipid solubility, given that amiodarone has high lipid solubility, which allows it to distribute throughout various tissues in the body rapidly; the extensive tissue distribution of amiodarone contributes to a large volume of distribution that leads to slow clearance from plasma compartments;

* extensive tissue binding, so that amiodarone extensively binds to different tissues, including fat deposits, muscles, heart tissue, and other organs; this binding creates reservoirs where drug release can occur slowly over time, resulting in an extended duration of action even after stopping the therapy;

* enterohepatic recycling, meaning that amiodarone undergoes enterohepatic recycling, where it is reabsorbed from the intestines after being excreted into bile, which contributes to its prolonged presence.<ref name="pmid33658939">{{cite journal |vauthors=Shleghm MR, Mircioiu C, Voicu VA, Mircioiu I, Anuta V |title=Estimation of the In Vivo Release of Amiodarone From the Pharmacokinetics of Its Active Metabolite and Correlation With Its In Vitro Release |journal=Front Pharmacol |volume=11 |pages=621667 |date=2020 |pmid=33658939 |pmc=7917713 |doi=10.3389/fphar.2020.621667 |doi-access=free}}</ref>

=== Excretion ===

Excretion is primarily via the liver and the bile duct with almost no elimination via the kidney and it is not dialyzable.<ref name="DailyMed-Pacerone-2022" /> Elimination half-life average of 58 days (ranging from 25 to 100 days [Remington: The Science and Practice of Pharmacy 21st edition]) for amiodarone and 36 days for the active metabolite, desethylamiodarone (DEA).<ref name="DailyMed-Pacerone-2022" /> There is 10-50% transfer of amiodarone and DEA in the placenta as well as a presence in breast milk.<ref name="DailyMed-Pacerone-2022" /> Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs),<ref name="DailyMed-Pacerone-2022" /> therefore, if an individual was taking amiodarone on a chronic basis if it is stopped it will remain in the system for weeks to months.<ref name="DailyMed-Pacerone-2022" />

Whereas amiodarone is primarily eliminated from the body through hepatic metabolism and biliary excretion, a very small portion of amiodarone and its metabolites are excreted unchanged in urine or feces.<ref name="FDA-2010"/><ref name="pmid29489285"/>

The liver plays a significant role in the elimination of amiodarone. After being extensively metabolized by cytochrome P450 enzymes, particularly [[CYP3A4]] and [[CYP2C8]], amiodarone is transported into bile via multidrug-resistant protein 2 (MRP2) transporter. Bile containing amiodarone and its metabolites is then released into the gastrointestinal tract.{{medical citation needed|date=March 2024}}

Some of these compounds can be reabsorbed back into systemic circulation through enterohepatic recirculation, where they may undergo additional rounds of metabolism before eventually being excreted again into bile.{{medical citation needed|date=March 2024}}

Although renal excretion contributes only minimally to the elimination of amiodarone, dose adjustment based on kidney function is generally not necessary. This is because most patients with normal renal function can adequately clear the drug through hepatic metabolism and biliary elimination pathways.<ref name="pmid32166725"/>

==Pharmacology==

Amiodarone is categorized as a class III [[antiarrhythmic agent]], and prolongs phase 3 of the [[cardiac action potential]], the repolarization phase where there is normally decreased calcium permeability and increased potassium permeability. It has numerous other effects, however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV.{{medical citation needed|date=March 2024}}

Amiodarone is a blocker of [[voltage gated potassium channel|voltage gated potassium]] ([[KCNH2]]) and [[voltage gated calcium channel]]s ([[CACNA2D2]]).<ref>{{cite web|url=https://www.drugbank.ca/drugs/DB01118|publisher=Drugbank|title=Amiodarone|access-date=28 May 2019|archive-date=23 May 2019|archive-url=https://web.archive.org/web/20190523212530/https://www.drugbank.ca/drugs/DB01118|url-status=live}}</ref>

Amiodarone slows the conduction rate and prolongs the refractory period of the SA and AV nodes.<ref name = harris>{{cite book| veditors = Harris L, Williams RR |title=Amiodarone: pharmacology, pharmacokinetics, toxicology, clinical effects|date=1986|publisher=Médecine et sciences internationales|location=Paris|isbn=978-2-86439-125-8|page=12}}</ref> It also prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibers without exhibiting any effects on the conduction rate.<ref name = harris/> Amiodarone has been shown to prolong the myocardial cell action potential duration and refractory period and is a non-competitive β-adrenergic inhibitor.<ref>{{cite web|title=FDA Drug Label|url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=11249|url-status=live|archive-url=https://web.archive.org/web/20170327171522/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=11249|archive-date=27 March 2017}}</ref>

It also shows [[beta blocker]]-like and [[calcium channel blocker]]-like actions on the [[SA node|SA]] and [[AV node]]s, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the [[cardiac action potential]], via sodium-channel effects. It is suggested that amiodarone may also exacerbate the phenotype associated with Long QT-3 syndrome causing mutations such as ∆KPQ. This effect is due to a combination of blocking the peak sodium current, but also contributing to an increased persistent sodium current.<ref name=pmid26973526 >{{cite journal | vauthors = Ghovanloo MR, Abdelsayed M, Ruben PC | title = Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels | journal = Frontiers in Pharmacology | volume = 7 | pages = 39 | year = 2016 | pmid = 26973526 | pmc = 4771766 | doi = 10.3389/fphar.2016.00039 | doi-access = free }}</ref>

Amiodarone chemically resembles [[thyroxine]] (thyroid hormone), and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions.<ref>{{cite book | veditors = Brunton LL, Lazo JS, Parker K |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |publisher=McGraw-Hill |location=New York |year=2005 | isbn=0-07-142280-3|title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }}{{page needed|date=July 2022}}</ref>

The mechanisms of action of amiodarone include blocking potassium ion channels (prolonging repolarization), blocking sodium ion channels, and antagonizing alpha- and beta-adrenergic receptors.<ref name="pmid32166725"/>

The action of amiodarone can be characterized by the following effects:<ref name="pmid32166725"/>

* potassium channel blockade, since amiodarone blocks potassium channels involved in cardiac repolarization during phase 3 of the action potential, so that this blockade prolongs the duration of cardiac action potentials, resulting in an increased refractory period and decreased excitability;<ref name="pmid32166725"/>

* sodium channel blockade, characterized by inhibiting sodium ion influx through voltage-gated sodium channels, so that amiodarone reduces the conduction velocity of electrical impulses in cardiac tissue that leads to a slowed heart rate and improved rhythm control;<ref name="pmid32166725"/>

* calcium channel blockade, by inhibiting L-type calcium channels in myocardial cells, decreasing intracellular calcium concentration during ventricular contraction;<ref name="pmid32166725"/>

* noncompetitive adrenergic receptor antagonism, meaning that amiodarone has both alpha- and beta-adrenergic receptor antagonistic effects, which help reduce sympathetic stimulation on the heart.<ref name="pmid32166725"/>

==History==

The original observation that amiodarone's progenitor molecule, [[khellin]], had cardioactive properties, was made by the Russian physiologist [[Anrep effect|Gleb von Anrep]] while working in Cairo in 1946.<ref>{{cite journal | vauthors = Anrep GV, Barsoum GS, Kenawy MR, Misrahy G | title = Ammi Visnaga in the Treatment of the Anginal Syndrome | journal = British Heart Journal | volume = 8 | issue = 4 | pages = 171–177 | date = October 1946 | pmid = 18610042 | pmc = 503580 | doi = 10.1136/hrt.8.4.171 }}</ref> Khellin is obtained from a plant extract of [[Khella]] or ''[[Ammi visnaga]]'', a common plant in north Africa. Anrep noticed that one of his technicians had been cured of anginal symptoms after taking khellin, then used for various, non-cardiac ailments. This led to efforts by European pharmaceutical industries to isolate an active compound.{{citation needed|date=February 2012}} Amiodarone was initially developed in 1961 at the Labaz company, [[Belgium]], by chemists Tondeur and Binon, who were working on preparations derived from khellin. It became popular in Europe as a treatment for [[angina pectoris]].<ref>{{cite journal | vauthors = Deltour G, Binon F, Tondeur R, Goldenberg C, Henaux F, Sion R, Deray E, Charlier R | title = [Studies in the benzofuran series. VI. Coronary-dilating activity of alkylated and aminoalkylated derivatives of 3-benzoylbenzofuran] | language = fr | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 139 | pages = 247–254 | date = September 1962 | pmid = 14026835 }}</ref><ref>{{cite journal | vauthors = Charlier R, Deltour G, Tondeur R, Binon F | title = [Studies in the benzofuran series. VII. Preliminary pharmacological study of 2-butyl-3-(3,5-diiodo-4-beta-N-diethylaminoethoxybenzoyl)-benzofuran] | language = fr | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 139 | pages = 255–264 | date = September 1962 | pmid = 14020244 }}</ref><ref name="Books-LLC-Antiarrhythmic-Agents">{{cite book|isbn=978-1-156-39374-1|title=Antiarrhythmic Agents|publisher=Books LLC}}</ref>

As a doctoral candidate at Oxford University, Bramah Singh determined that amiodarone and [[sotalol]] had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents).<ref>{{cite journal | vauthors = Singh BN, Vaughan Williams EM | title = The effect of amiodarone, a new anti-anginal drug, on cardiac muscle | journal = British Journal of Pharmacology | volume = 39 | issue = 4 | pages = 657–667 | date = August 1970 | pmid = 5485142 | pmc = 1702721 | doi = 10.1111/j.1476-5381.1970.tb09891.x }}</ref> Today the mechanisms of action of amiodarone and sotalol have been investigated in more detail. Both drugs have been demonstrated to prolong the duration of the [[action potential]], prolonging the refractory period, by interacting among other cellular functions with [[K+ channels]].<ref name="Books-LLC-Antiarrhythmic-Agents"/>

Based on Singh's work, the [[Argentina|Argentinian]] physician Mauricio Rosenbaum began using amiodarone to treat his patients who have supraventricular and ventricular arrhythmias, with impressive results. Based on papers written by Rosenbaum developing Singh's theories, physicians in the [[United States]] began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s.<ref>{{cite journal | vauthors = Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, Lázzari JO, Elizari MV | title = Clinical efficacy of amiodarone as an antiarrhythmic agent | journal = The American Journal of Cardiology | volume = 38 | issue = 7 | pages = 934–944 | date = December 1976 | pmid = 793369 | doi = 10.1016/0002-9149(76)90807-9 }}</ref><ref>{{cite journal | vauthors = Rosenbaum MB, Chiale PA, Haedo A, Lázzari JO, Elizari MV | title = Ten years of experience with amiodarone | journal = American Heart Journal | volume = 106 | issue = 4 Pt 2 | pages = 957–964 | date = October 1983 | pmid = 6613843 | doi = 10.1016/0002-8703(83)90022-4 }}</ref>

The US [[Food and Drug Administration]] (FDA) was reluctant to officially approve the use of amiodarone since initial reports had shown an increased incidence of serious pulmonary side effects of the drug. In the mid-1980s, the European pharmaceutical companies began putting pressure on the FDA to approve amiodarone by threatening to cut the supply to American physicians if it was not approved. In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias.<ref name="DailyMed-2018" /><ref>{{cite web|title=Drug Approval Package: Cordarone (Amiodarone Hydrochloride) Tablets. NDA #018972|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/18-972_Cardarone.cfm|publisher=U.S. Food and Drug Administration|access-date=6 February 2014|url-status=live|archive-url=https://web.archive.org/web/20140221092003/http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/18-972_Cardarone.cfm|archive-date=21 February 2014}}</ref>

=== Name ===

Amiodarone may be an acronym{{Citation needed|date=May 2021}} for its IUPAC name (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethyl'''<u>am</u>'''ino)ethoxy]-3,5-di<u>'''iod'''</u>o'''<u>phen</u>'''yl]methan'''<u>one</u>''',<ref>{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/amiodarone#section=3D-Conformer|title=Compound summary for CID 2157|publisher=pubchem.ncbi.nil.nih.gov|url-status=live|archive-url=https://web.archive.org/web/20160324044226/https://pubchem.ncbi.nlm.nih.gov/compound/amiodarone#section=3D-Conformer|archive-date=24 March 2016}}</ref> where '''<u>[[Aryl|ar]]</u>''' is a placeholder for phenyl. This is partially supported by [[dronedarone]] which is noniodinated benzofuran derivative of amiodarone, where the <u>'''ar'''</u>ylmethan'''<u>one</u>''' is conserved.{{Citation needed|date=May 2021}}

==Dosing==

Amiodarone is available in oral and intravenous formulations.

Orally, it is available under the brand names Pacerone (produced by [[Upsher-Smith Laboratories|Upsher-Smith Laboratories, Inc.]]) and Cordarone (produced by Wyeth-Ayerst Laboratories).<ref name="DailyMed-Pacerone-2022" /><ref name="DailyMed-2018" /> It is also available under the brand name Aratac (produced by Alphapharm Pty Ltd) in Australia and New Zealand, and further in Australia under the brands Cardinorm and Rithmik as well as a number of generic brands. Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.). In South America, it is known as Atlansil and is produced by Roemmers.

In India, amiodarone is marketed (produced by Cipla Pharmaceutical) under the brand name Tachyra. It is also available in intravenous ampules and vials.

The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated. When administered orally, the [[bioavailability]] of amiodarone is quite variable. Absorption ranges from 22 to 95%, with better absorption when it is given with food.<ref name="pmid14677664"/>

== References ==

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