Antiarrhythmic treatment by amiodarone: present state and future

UNIVERSITY OF DEBRECEN FACULTY OF MEDICINE DEPARTMENT OF PHARMACOLOGY AND PHARMACOTHERAPY Antiarrhythmic Treatment by Amiodaron: Present State and Future M.D. THESIS BY Thordur Gunnar Thorvaldsson APPROVED BY Zoltán Szilvássy, M.D., Ph.D., D.Sc. József András Szentmiklósi, M.D., Ph.D Professor and Chairman of Pharmacology Associate Professor and Supervisor DEBRECEN 2019 DECLARATION I, the undersigned Thordur Gunnar Thorvaldsson, a student of the Faculty of General Medicine of Debrecen University, being fully aware of my legal liability, do thereby declare and certify with my signature that my thesis, entitled Antiarrhythmic Treatment by Amiodarone: Present State and Future is my own original work and that the printed and electronic literature referred to in it was used in accordance with the international rules of copyright. I understand that in the case of a thesis, it is considered plagiarism when: ● quoting word for word without quotation marks and referring to literature without proper citation. ● referring to content without citing the literature. ● presenting previously published ideas of other authors as one’s own. I, the undersigned, declare that I have been informed of the concept of plagiarism. I understand that in case of plagiarism, my thesis will be rejected. Debrecen 29.05.2019 _________________________________________________________ signature Table of Contents Abstract ................................................................................................................................................... 1 Abbreviations .......................................................................................................................................... 2 Introduction ............................................................................................................................................. 3 Cardiac Rhythm and its Action Potential ................................................................................................ 4 Regulation by the autonomic nervous system ..................................................................................... 5 Arrhythmias ............................................................................................................................................. 7 Atrial Fibrillation and its Treatment With Amiodarone ........................................................................ 10 Amiodarone in cardiopulmonary resuscitation (CPR) ...................................................................... 13 Classification of Antiarrhythmic Drugs ................................................................................................ 15 Therapeutic drug monitoring of all classes of antiarrhythmic drugs ................................................. 19 The History of Amiodarone .................................................................................................................. 20 Pharmacology of Amiodarone ............................................................................................................... 22 Chemistry and structure ..................................................................................................................... 23 Pharmacokinetics of amiodarone ...................................................................................................... 23 Hemodynamic effects of amiodarone ................................................................................................ 24 Amiodarone interactions with other drugs ........................................................................................ 24 Dosage Regimen and Differences Between Oral and Intravenous Use of Amiodarone ....................... 26 Oral amiodarone ................................................................................................................................ 26 Intravenous amiodarone .................................................................................................................... 27 Transition from IV to oral therapy .................................................................................................... 28 Side Effects Caused by Amiodarone ..................................................................................................... 30 Ocular changes .................................................................................................................................. 31 Amiodarone dermatopathies .............................................................................................................. 32 Hepatotoxicity side effects of amiodarone ........................................................................................ 32 Gastrointestinal side effects ............................................................................................................... 33 Neurological side effects ................................................................................................................... 33 Amiodarone Pulmonary side effects ................................................................................................. 33 Amiodarone and thyroid side effects ................................................................................................. 35 Amiodarone induced hypothyroidism (AIH) .................................................................................... 36 Amiodarone induced hyperthyroidism (AIT) .................................................................................... 37 Frequency of long-term side effects using oral amiodarone ............................................................. 38 Monitoring and Follow-up on Patients Being Treated with Amiodarone ............................................. 39 Dronedarone, Amiodarone’s Little Brother .......................................................................................... 40 Future of Amiodarone and Other Antiarrhythmics ............................................................................... 41 Vernakalant, a new drug under development .................................................................................... 42 Use of Amiodarone in Children ............................................................................................................ 42 Conclusion ............................................................................................................................................. 44 Acknowledgements ............................................................................................................................... 45 Bibliography .......................................................................................................................................... 46 1 Abstract Cardiac arrhythmias are one of the most common disorders affecting people today. Various medications and surgical interventions are used to manage and treat cardiac arrhythmias. Among these cardiac arrhythmias is atrial fibrillation (AF) one of the most common. The cardiac conduction system uses electrical impulses to control the speed and rhythm of each heartbeat. Normally, each heartbeat starts in the right atrium in the sinoatrial (SA) node. Action potentials generated by the SA node’s pacemaker cells spread to the walls of the atria and cause their contraction and continue to the atrioventricular (AV) node. AF is a form of supraventricular tachyarrhythmia, which is characterized by uncoordinated atrial activation that leads to a decline in the mechanical function of the atria in the heart. AF is the most common rhythm disturbance in adults. It can be paroxysmal, persistent or permanent. The first registration of AF was recorded by Willem Einthoven in 1906 with his development of electrocardiography. AF affects about 4.5-6 million people in Europe, about 6 million in China and more than 2 million in the USA. More than 60 percent of these patients have symptoms. Most severe complications caused by AF are stroke and thromboembolism. Antiarrhythmic agents are classified by the Vaughan Williams classification according to their effect on the cardio myocyte AP. Among these is the drug amiodarone. Amiodarone is a class III antiarrhythmic agent that expresses it efficacy on all the phases of the action potential. Thus, it became very popular to treat arrhythmic patients with amiodarone. Amiodarone is extracted from khellin – an extract from the Ammi visnaga plant found in Afrika. It was when the Argentinian physician Mauricio Rosenbaum started to use amiodarone to treat his patients with supraventricular and ventricular arrhythmias that the popularity of amiodarone started to expand. Amiodarone is an iodinated benzofurane (highly liposoluble) derivative. Its chemical formula is C25H29I2NO3. It is a highly iodine rich compound. It can seep into all tissues but is found highly in adipose tissue. The lipophilicity of amiodarone is one of the main reasons it can cause vast side effects. Amiodarone side effects are ocular, dermatological, hepatic, pulmonic and thymotic to name but a few. Due to this fact it has been a priority of many pharmacist and doctors to discover a new drug with fewer side effects, but which have the same or similar efficacy as amiodarone. These drugs are dronedarone and vernakalant. Dronedarone is a derivative of amiodarone but does not contain iodine. These drugs are effective and classed as class III drugs like amiodarone, but though their side effect are less they do not show as good efficacy as amiodarone. With better tools and better knowhow of surgical and ICD devices, cardiac pathologies such as AF can be treated quite well. However, amiodarone’s role in modern medicine is still of utmost importance to further treat and manage the whole spectrum of arrhythmias where other drugs show less efficacy of treating such pathologies. 2 Abbreviations ACh - acetylcholine ACLS - advanced cardiac life support AERP - atrial effective refractory period Afib - atrial fibrillation AF - atrial fibrillation AIH – amiodarone induced hypothyroidism AIT – amiodarone induced thyroid toxicity APB – atrial premature beat APD - action potential duration AV - atrioventricular node BNP - brain natriuretic peptide Ca2+ - calcium ion cAMP - cyclic adenosine monophosphate CPR - cardiopulmonary resuscitation CRP - C reactive protein CV - conduction velocity ICD - Implantable Cardiodefibrilator INR - international normalized ratio If - funny channel K+ - potassium ion Na+ - sodium ion NOAC - new oral anticoagulant ROSC - return of spontaneous circulation SA - sinoatrial node SCA – sudden cardiac arrest TDM = Therapeutic Drug Monitoring 3 Introduction Within the field of medicine, the definition of arrhythmia is that heartbeats may be too slow (bradycardia = less than 60 beats per minute), too rapid (tachycardia = greater than 100 beats per minute), too irregular (fibrillations), or too early (premature contraction). Cardiac arrhythmias are one of the most common disorders or illnesses affecting people today. Various drugs, medications and surgical interventions are used to manage and treat cardiac arrhythmias. In this thesis, the aetiology, epidemiology, signs and symptoms of arrhythmias will be briefly explained as well as the classifications of various anti-arrhythmic medications and their classes. The main emphasis, however, is going to be on the drug amiodarone and Class III of antiarrhythmic drugs, the pharmacokinetics of amiodarone and its function, and the future of amiodarone. Amiodarone has multiple actions. Besides blocking K+ channels, amiodarone also blocks Na+ channels, Ca2+ channels and even some − and −receptors. The main purpose of this thesis is to make it easier for future medical doctors to understand the main function of amiodarone, its usage, its benefits, its functions as a clinical diagnostic tool, its therapeutic monitoring, and its side effects. 4 Cardiac Rhythm and its Action Potential The cardiac conduction system uses electrical impulses to control the speed and rhythm of each heartbeat. Normally, each heartbeat starts in the right atrium in the sinoatrial (SA) node. Action potentials generated by the SA node’s pacemaker cells spread to the walls of the atria and cause their contraction and continue to the atrioventricular (AV) node. After a delay, the electrical signal diverges and is conducted through the left and right bundle of His to the respective Purkinje-fibres for each side of the heart, leading to the contraction of the ventricles. This is a continuous loop and is repeated with each heartbeat. The SA node is not, however, the only region of the heart capable of cyclically generating action potentials; it is merely the dominant one that overrides the others. The AV node and the bundle of His are also capable of automaticity when it is not driven by the SA node. In the pacemaker cells, the resting membrane potential is negative. An action potential begins with the voltage becoming more positive. In this, a non-specific cation channel (If = funny channel) has the most important role. It is a voltage-dependent ion channel, which opens during Figure 1: Comparison of the ionic currents underlying SA node and ventricular myocyte action potentials. The constant leak of Na+ from SA node pacemaker cells leads to a continuously depolarising baseline. This ultimately opens voltage gated ion channels leading to an action potential. In ventricular myocytes, the membrane potential is stable until the depolarising stimulus arrives, again causing voltage gated ion channels to open. Note that the ionic currents underlying the action potential in each case are different: Ca2+ for SA node cells and Na+ for ventricular cells (Vander et al., 2001). 5 membrane hyperpolarisation. Through this, Na+ leaks into the cells slowly. This slow depolarising baseline drift is the key to automaticity (spontaneous diastolic depolarisation). After this, two sets of voltage gated Ca2+ channels contribute to the upstroke of the action potential. The first channel to come into play is the T-type Ca2+ channel, which opens at a specific level of membrane depolarisation. These open transiently (thus T-type), providing the initial depolarising kick to fire the action potential proper, which is mediated by the opening of L-type (L for long-lasting) Ca2+channels. After a brief delay, the L-type calcium channels close and the voltage gated K+ channels open. The increased K+ current that follows in response will drive membrane potential back down again. This hyperpolarisation opens the Na+ leak channels, thus starting the process again (Vander et al., 2001, pp. 390-406). The action potential in ventricular myocytes differs from the SA nodal action potential. Ventricular myocytes have no capacity for generating action potentials, and their resting membrane potential rests at a stable level until an action potential arrives from the bundle of His. Fast Na+ channels open, rapidly depolarising the cell (Phase 0). This initiates the ventricular action potential, which is followed by an early repolarisation phase (Phase 1), because of the opening of the early, transient K+ channels. At this point, voltage gated L–type Ca2+ channels open and an increase in Ca2+ entry and contraction of the myocyte occur (Phase 2 - Plato phase). When these calcium channels close and the late, rapid K+ channels open, the membrane potential decreases. It is called repolarisation (Phase 3), and it brings the membrane potential back to its resting level (Phase 4). As in skeletal muscles, there is a refractory period during which ventricular myocytes cannot sustain an action potential due to the inactivation of Na+ channels. Regulation by the autonomic nervous system The sympathetic nervous system increase heart rate (positive chronotropy) by decreasing the time to produce an action potential in the SA node. It also increases the conduction velocity and the power of the muscle contractions. A hormone called noradrenaline is released, which binds to, and activates, receptors on the pacemaker cell membrane known as β1 adrenoceptors. This activates a protein called a Gs-protein (s for stimulatory). Activation of the G-protein leads to increased levels of cAMP in the cell (via the cAMP pathway). cAMP binds to the so-called funny channels, increasing the sodium current and therefore increasing the rate of depolarization during the pacemaker potential. The increased cAMP also increases the opening time of L -type calcium channels, increasing the Ca2+ current through the channel. 6 The parasympathetic nervous system decreases heart rate (negative chronotropy) by increasing the time taken to produce an action potential in the SA node. The Vagus nerve travels to the sinoatrial node, releases a molecule called acetylcholine (ACh), which binds to a receptor located on the outside of the pacemaker cell, called an M2 muscarinic receptor. This activates a Gi-protein (I for inhibitory) which activates a special set of potassium channels, increasing potassium flow out of the cell and decreasing membrane potential, meaning that the pacemaker cells take longer to reach their threshold value. The Gi-protein also inhibits the cAMP pathway and inhibits funny channels and L-type calcium channels. These are important details when it comes to the complex mechanism of amiodarone. Amiodarone inhibits K+ channels, which results in slower repolarization of the cells. It also inhibits Na+ channels when the heart rate is elevated and causes slower depolarization and conduction velocity in a frequency-dependent manner. L-type Ca2+ channels are also inhibited, and with chronic use of amiodarone, inhibition of αand βadrenergic receptors is detected because of down-regulation of these receptors. This explains why amiodarone is an effective drug in a wide range of conditions when the normal heart rhythm is disturbed. 13 rate is only 34 percent. Also, the mortality rate results are significantly better with catheter ablation (8 percent versus 18 percent) (Di Biase et al., 2016). Amiodarone in cardiopulmonary resuscitation (CPR) The American Heart Association and the European Resuscitation Council guidelines recommend the administration of amiodarone for sustained ventricular fibrillation (VF) and ventricular tachycardia (VT) refractory to CPR and defibrillation in sudden cardiac arrests. However, it is a weak recommendation. I was based on clinical trials that compared placebo and amiodarone and showed that amiodarone improved the rate of return of spontaneous circulation (ROSC) but not the survival to hospital discharge and neurological outcome. In 2017 the European Resuscitation Council guideline was updated, and although there is no clear evidence that amiodarone is useful in improving the outcome of CPR, it is still part of the algorithm. In future updates of the guidelines, a further revision of amiodarone’s role can be expected, which may remove or replace amiodarone in cardiac arrest guidelines (Pozner et al., 2019). The up-to-date algorithm of advanced cardia life support (ACLS) is shown on page 14. 14 Figure 4: Adult cardiac arrest algorithm (Pozner et al., 2019). 15 Classification of Antiarrhythmic Drugs Antiarrhythmic agents/drugs are generally classified according to the Vaughan Williams into five main classes. The Vaughan Williams classification was introduced in 1979 by Miles Vaughan Williams. Vaughan Williams was the tutor of Bramah N. Singh, who later contributed to the development of the classification system so now it is sometimes called the Singh– Vaughan Williams classification. Dr. Bramah Singh later became one of the discoverers of amiodarone’s antiarrhythmic effect. The classification of antiarrhythmic drugs is based on the effects of individual drugs on the conduction velocity (a Na+ channel-dependent effect) and action potential duration (a K+ channel dependent effect) (Dudley & Cunney, 2004). The classification of antiarrhythmic drugs by V. Williams was originally based on the effects each drug had on the action potential. Subsequent modifications and enhancements to the system included the molecular targets such as specific ion channels and beta-adrenergic receptors. The latest advances in the classification add extra classes and subclasses to the original four-system classification from the Singh-Vaughan Williams classification. For example, the new Class 0 is a pacemaker channel blocker – ivradabine, and others are experimental or for theoretical targets like Class VI is a gap junction blocker. This new and modified version of the V. Williams classification has proven to be useful, even though it is a somewhat simplified version of the electrophysiological events that occur. As pointed out above, the classification has five classes from 0-V. These will be briefly described here below, while a summary and the names of individual drugs are shown in Table 1. • Class 0 – A new class that modulates the pacemaker channel HCN4, which affects the pacemaker current If. The drug ivabradine slows the heart rate (Lei, Wu, Terrar, & Huang, 2018). • Class I – Acts by modulating or blocking the Na+ channels by inhibiting the phase 0 of depolarization. Class I is subclassified into three subclasses: class Ia, class Ib and class Ic. These subgroups have been put in because their mechanism and duration of action are different, due to the fact that their drug binding to and dissociation from channel receptors are variable (Makielski, MD & Eckhardt, MD, 2019). o Class Ia drugs are intermediate regarding speed of binding and dissociation from binding sites. 16 o Class Ib have the most rapid binding and dissociation from binding sites. o Class Ic have the slowest binding and dissociation from binding sites. • Class II – Drugs in this class act by inhibiting sympathetic activity, primarily by causing beta blockade, commonly known as beta blockers. They can also have a mild inhibitory effect on the sodium channels (Podrid, Fuchs, & Candinas, 1990). It blocks catecholamine and beta blockers also slow the rate of discharge of the sinus and ectopic pacemakers, which in turn increases the effective refractory period of the AV node (Frishman & Silverman, 1979). Commonly, most beta blockers end with the suffix -olol. • Class III – Drugs in Class III block the potassium channels to inhibit IKr, IKs, IK1, and IKUR, thereby prolonging repolarization, the APD, and the refractory period. The relative potency of these drugs for specific potassium currents may account for atrial selectivity; for example, IKUR is only known to be in the atria. Blockage of ventricular potassium currents is manifested on the surface ECG by prolongation of the QT interval, providing the substrate for torsades de pointes, a polymorphic ventricular tachycardia. Amiodarone and dronedarone are exceptions with very little proarrhythmic activity, perhaps because of a balance of offsetting actions. Additionally, there are more atrial-specific agents such as vernakalant that block primarily IKUR (Makielski & Lee, 2019). • Class IV – Drugs in this class are Ca2+ channel blockers. Verapamil and diltiazem (the most commonly used drugs in this class) can slow the sinus rate, increase the refractoriness and prolong the conduction through the AV node. They can also prolong the PR interval and depress the left ventricular function. • Classes V and VI – These are newer classes of the V. Williams classification. Drugs in class V are mechanosensitive channel blockers and class VI are gap junction blockers. Drugs in these classes are still open and under investigation. Thus, these classes are still under construction and allow for further extension of the V. Williams classification. Figure 5 below demonstrates the action and effect of each phase of the cardiac myocyte action potential. 17 Additionally, Table 2 demonstrates the cardiac effect of common anti-arrhythmic drugs. It shows their names and when they became approved, their channel effects and what ECG changes should be expected. Figure 5: This figure gives the reader an idea where and at what phase the classes of antiarrhythmic agenst affect the cardio action potential and its effect on the ECG (Wikipedia, antiarrhythmic agent, 2019). 18 Table 1: Names of anitarrhythmic drugs and their places in the Vaughan Williams classification (Makielski & Lee, 2019). 19 Therapeutic drug monitoring of all classes of antiarrhythmic drugs Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics and have as a common action the blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the β-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol, amiodarone and dronedarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity. As will be discussed later, many of amiodarone’s side effects are dose dependent. Amiodarone and its metabolites are found in higher concentration in tissues compared with plasma. There is some evidence that plasma concentration above 0,5 µg ml seems to be required for efficacy. However, in the literature there is no convincing data showing a correlation between actual plasma concentrations and antiarrhythmic effect (Rotmensch et al., 1984). While serious toxicity seems to be more likely at concentration above 2,5 µg ml, its incidence is more reliably correlated with measures of total drug usage, suggesting the importance of accumulation in target tissue over time (Jürgens et al., 2003). Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. Table 2: The cardiac effects of various antiarrhythmic agents (Zimetbaum, 2012). 20 TDM is very useful for monitoring the administration (and particularly the safety) of both these agents. Therapeutic drug monitoring has played an extremely important role in the development and clinical application of many agents used to treat cardiac rhythm disturbances. This is particularly true of the Class I agents and of perhexiline and digoxin. TDM has been less important in monitoring the use of β-adrenoceptor blockers and Class IV drugs and has played only a limited role in the use of amiodarone, where there is some value in monitoring for compliance and toxicity. TDM of digoxin and perhexiline will remain important to the practicing cardiologist. There are several new, pure Class III antiarrhythmic agents under development, some of which will definitely require TDM if they come into wide-spread clinical use (Jürgens et al., 2003). The History of Amiodarone On its release for human use in 1962, amiodarone was initially marketed as a kind of super or wonder drug. It was kind of stated that it “always works and has no side effects.” However, subsequent clinical trials revealed this not to be the case. In fact, amiodarone side effects are almost certain and can even be very severe and lifethreatening. In 1946, the Russian physiologist Gleb Von Anrep was observing the medical properties of khellin. Khellin is obtained from a plant extract of Khella or Ammi visnaga, which is a very common plant in NorthAfrica. Anrep became very curious about this plant and its properties when he noticed that one of his technicians had been cured from anginal symptoms after taking khellin. From this it led to the isolation of the active compound from the Khella plant by European pharmaceutical industries (Anrep et al., 1946). By 1961 the Belgian company Labaz had started to manufacture amiodarone and worked on preparations derived from khellin. It soon became very popular in Europe as a treatment for angina pectoris. A doctoral candidate at that time at Oxford University, Bramah Figure 6: Ammi Visnaga, or Khella plant, from where Khelin is extrated. 21 Singh, was researching antiarrhythmic properties and whether amiodarone, later also the drug sotalol, had any antiarrhythmic properties. He determined a new class of antiarrhythmic agents (what later came to be known as class III antiarrhythmic agents, as stated previously) (B N Singh & Vaughan Williams, 1970). Barah Singh showed initially with his studies that amiodarone could prolong the AP and the refractory period by its interaction among other functions with K+ channels. It was when the Argentinian physician Mauricio Rosenbaum started to use amiodarone to treat his patients with supraventricular and ventricular arrhythmias that the popularity of amiodarone started to expand. Rosenbaum had demonstrated impressive results on his patients (Rosenbaum et al., 1976). Because of Rosenbaum’s paper and results, developed from Singh’s theories, physicians in the US began to prescribe amiodarone to their patients with life-threatening arrhythmias that did not respond to any other drugs on the market. The FDA permitted amiodarone to be used on a compassionate-use basis. Physician in the US obtained the drug from Canada and Europe through the compassionate-use basis by the FDA, but the drug remained unapproved. It has been estimated that during this time more than 10,000 US patients were being treated with amiodarone (Fogoros, 2018). Many physicians started to do trials on their own and began reporting various weird side effects - ocular, skin, pulmonary, hepatic and thyroid. Amiodarone was the most potent at suppressing arrythmias than any other drug. As serious side effects such as the difficult thyroid disorders and life-threatening pulmonary toxicity began to be reported, the FDA became reluctant to approve the drug. However, the FDA had no other choice but to approve the drug when European manufacturers of amiodarone threatened to cut off US supply, because they had been supplying the drug for free to thousands and thousands of Americans for more than five years. So, in December 1985 amiodarone became FDA-approved without vast, FDA-sanctioned, randomized clinical trials. This history of amiodarone makes it one of the very few drugs approved by the FDA without randomized clinical trials. The FDA knew about the recently discovered toxicity, and approved amiodarone only for life-threatening arrhythmias for which no other treatment was feasible. The FDA noted it needed a black-box warning regarding its side effects and urged manufactures to conduct randomized clinical trials to gain formal approval for indications such ad atrial fibrillation, noting that these trials would teach us a lot about true incidences and seriousness of the drug’s side effects. Those trial where never done, and during that time the patent on the 22 drug was running out, opening the market for generic manufacturers. Thus amiodarone became restricted by the FDA again, and the use of amiodarone for atrial fibrillation (the most common reason it is prescribed) remains off-label in the US (Fogoros, 2018). Amiodarone has been available in Europe since 1961. It was initially used and developed for the treatment of angina pectoris. I was not until after 1975 that it was recognized that amiodarone had unique antiarrhythmic properties. It is specifically unique in converting acuteor chronic A. fib to sinus rhythm. Amiodarone is a class III antiarrhythmic drug (potassium channel blockers). It has a wide range of action and shares its action within all the classes of antiarrhythmic drugs. Its mechanism of action is that amiodarone blocks potassium channels in cardiac muscle cells and also enhances the inward current of sodium channels. Therefore, amiodarone prolongs the action potential. To phrase it differently: it prolongs the Q – T interval on the electrocardiogram (ECG) tracing. Amiodarone is on the WHO list of essential medicines (WHO Model List of Essential Medicines, 2017). It has been approved in Europe and by the FDA for use in VT and V.fib. It has not been approved by the FDA for use in A.fib, but it is in Europe. It is a good cardio converter of tachycardias to sinus rhythm and for use in patients with ICD to minimize shocks. Amiodarone is highly effective in both supraventricular and ventricular arrhythmias. For further information, amiodarone is manufactured by Pfizer pharmaceuticals. Amiodarone can either be oral tablets or injectable medications. The brand names are Cordarone, Nextrone and Pacerone. Pharmacology of Amiodarone To be able to understand amiodarone’s therapeutic possibilities, side effects and function, it is vital for us as physicians and medical doctors who might end up prescribing amiodarone to our future patients to understand its structure, mechanism of action, pharmacokinetics and drug interactions. 29 been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. - Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function. For amiodarone there is no need for any specific renal and/or hepatic dose adjustments. To summarize the oral and IV amiodarone therapy, there are some difference in their function and availability. IV is more rapid in action than oral therapy to turn arrhythmic patients towards sinus rhythm. However, to maintain that sinus rhythm, and when the patient is stable, oral therapy should be introduced as quickly as possible. The image here below show a dosage guidelines summary for amiodarone for quick revision. Figure 10: Dosage guidelines for Amiodarone therapy (Siddoway, 2003). . 30 Side Effects Caused by Amiodarone Since amiodarone was first accepted as a treatment for patients with supraventricular and ventricular arrhythmias, clinicians, physicians and pharmacologist have noted and reported side effects and adverse effects related to the drug. Many of the effects are related to dosage of the drug, while others are related to the chemical structure and metabolism of amiodarone. From the vast literature, studies and clinical trials, adverse effects/side effects of amiodarone are in general observed in 75 percent of patients, of which 18 percent and up to 37 percent need to suspend the use of the drug (Zaidel, 2019). It has been shown that unwanted effects seen in patients taking amiodarone can be divided into two broad groups. One group of effects is dosage related, while the other group of effects is both dosageand duration-dependent (Harris et al., 1983). Toxic effects of amiodarone can be divided into three groups: cardiac toxic effects, non-cardiac toxic effects and thyroid toxicity. i) Cardiac toxic effects: bradycardia, heart block in patients with sinus or AV nodal diseases. ii) Non-cardiac toxic effects: amiodarone accumulates in tissues, e.g. heart, lung, liver and skin. Of these, pulmonary accumulation can lead to fatal pulmonary fibrosis. Amiodarone can cause abnormal hepatic tears and hepatitis. In skin it can cause photodermatitis and grey/purple skin discoloration in sun-exposed areas. Ocular effects occur. iii) Thyroid toxicity: amiodarone blocks the peripheral conversion of T4 to T3, so it may result in either hypoor hyperthyroidism. The following table below is reconstructed from the article by R.G. Trohman et al., 2018, and shows the percentages of the most common and severe side effects caused by amiodarone and long-term amiodarone therapy. 31 Ocular changes The main ocular changes are in the form of microdeposits as reported by ophthalmologist and occur in almost 100 percent of patients during first 1-2 months of treatment with amiodarone. This is, however, not a reason for discontinuing the drug. Microdeposits will resolve on their own after 3-4 months. The microdeposits are usually not symptomatic. However, the development of blurred vision, photophobia and blue/green halos occur seldom but are a reason for giving up treatment with the drug (Shukla, Jowett, Thompson, & Pohl, 1994). Table 3: Side effects and toxicity caused by amiodarone (Trohman et al., 2018). 32 Amiodarone dermatopathies Patients that are treated with amiodarone mainly experience two types of skin reaction. In approximately 75 percent of dermatopathies reported is photosensitivity. Intense sunburn during mild sun exposure over summer months, erythema, swelling. It varies between patients if they experience any skin reaction in the beginning of therapy or after long-term usage. It has been reported that patients who have been taking amiodarone (600mg/day for more than 2 years) can develop grey/purple pigmentation as can be seen in Figure 9. In these patients that develop alterations in their skin colour, they have had high plasma concentration of amiodarone (>3,1 mg/l) and desethyl amiodarone (3,2 mg/l). Biopsies have been taken from the affected skin areas and shown an increase in the deposits of lipofuscin. It has also been reported that melanin is reduced in the affected skin areas (Harris et al., 1983). It has also been hypothesised in a journal article by Harris et al. that photosensitivity comes prior to elastic degeneration, lipofuscin deposition and skin discoloration. Hepatotoxicity side effects of amiodarone A rise in serum aminotransferase concentrations occurs in approximately 25 percent (range 15 to 50 percent) of patients soon after amiodarone therapy has begun (Lewis et al., 1989). The patients are usually asymptomatic, but the drug should be discontinued if there is more than a twofold elevation (Goldschlager et al., 2007). Symptomatic hepatitis occurs in less than 3 percent of patients; potential complications include cirrhosis and hepatic failure. As a result, it is recommended that liver function tests be monitored at baseline and every six months. Jaundice is an unusual side effect that may be due to intrahepatic cholestasis. Serum bilirubin concentrations may first increase or continue to increase for a period of time after the drug is discontinued. These findings are consistent with the long half-life of amiodarone (25 to 100 days). Figure 11: Slate-gray facial pigmentation in a patient who has taken amiodarone for more than 2 years (Harris et al., 1983). . 33 The histopathologic features of amiodarone-induced hepatotoxicity include Mallory bodies, steatosis, intralobular inflammatory infiltrates, fibrosis, and phospholipidosis. These changes are like those in alcoholic liver disease. The presence of phospholipid-laden lysosomal lamellar bodies on electron microscopy may help distinguish amiodarone hepatotoxicity from alcoholic liver disease (Giardina et al., 2019). Gastrointestinal side effects Gastrointestinal side effects associated with amiodarone therapy include nausea, vomiting, anorexia, diarrhoea, and constipation. They have been described in up to 30 percent of patients (see table of adverse reaction), mostly during the initial loading phase of therapy. In the metaanalysis of trials of chronic low-dose amiodarone therapy, gastrointestinal side effects were not significantly more frequent than with placebo (Giardina et al., 2019). Neurological side effects Neurologic toxicity may take many forms, including tremor, ataxia, peripheral neuropathy with paraesthesias, and sleep disturbances. These effects, which have been described in 3 to 30 percent of patients, appear to be dose-related, being more common during initial loading or in patients requiring higher doses. In the meta-analysis of trials of chronic lowdose amiodarone therapy (mean dose 150 to 330 mg/day), neurologic side effects were much less common than reported in early studies that utilized higher doses of amiodarone, but still significantly more frequent than with placebo (4.6 versus 1.9 percent, OR 2.0, 95 percent CI 1.1-3.7). A retrospective study of 707 patients in Olmsted County treated with amiodarone arrived at a similar conclusion (Goldschlager et al., 2007; Orr et al., 2009; Vorperian et al., 1997) Amiodarone Pulmonary side effects Amiodarone therapy can lead to several forms of pulmonary toxicity, including interstitial pneumonitis (the most common presentation), eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar haemorrhage (DAH), pulmonary nodules and masses, but rarely pleural effusions. The incidence of pulmonary toxicity from amiodarone is not precisely known; it is estimated to be 1 to 5 percent. Pulmonary side effects 34 caused by amiodarone are dose dependent. The higher the dose, the more likely patients are to develop pulmonary side effects. Risk factors for amiodarone-induced pulmonary toxicity include a daily dose of ≥400 mg/day, duration of therapy exceeding two months, patient age >60 years, pre-existing lung disease, surgery, and pulmonary angiography. If pulmonary side effects develop, the primary therapy is to cease amiodarone therapy altogether. Interstitial pneumonitis due to amiodarone toxicity is characterized by the insidious onset of non-productive cough and/or dyspnoea. Fever, pleuritic pain, weight loss, and malaise can also occur. The onset of symptoms is usually 6 to 12 months of amiodarone therapy but may occur within two months or after several years of treatment. The chest radiograph typically reveals new focal or diffuse reticular or ground glass opacities. Highresolution computed tomography (HRCT) of the chest and upper abdomen usually shows ground glass and reticular opacities and increased attenuation in the lungs, liver, and spleen (Figure 12). Pulmonary function tests typically show restriction and a reduced diffusing capacity (DLCO). A clinical diagnosis of amiodaroneinduced interstitial pneumonitis can often be made when the clinical features are consistent; other possibilities (e.g. infection, heart failure) have been excluded; and the patient improves with drug cessation and, possibly, a trial of glucocorticoid therapy. Lung biopsy is usually deferred unless the diagnosis remains uncertain after a trial of drug cessation. In addition to cessation of amiodarone, for most patients with more than mild symptoms of interstitial pneumonitis due to amiodarone, systemic glucocorticoid therapy is recommended. The usual dose is the equivalent of oral prednisone 40 to 60 mg/day. Due to the long elimination Figure 12: HRCT showing extensive and severe bilateral ground glass opacities due to long-term therpy by amiodarone (Sweidan et al., 2016) . 35 half-life (approximately 45 days) of amiodarone, pulmonary toxicity may initially progress despite drug discontinuation and may recur upon glucocorticoid withdrawal (Chan et al., 2019; Colby et al., 2017; Sweidan et al., 2016). Other types of pneumonia can develop, as mentioned above in this chapter, but detailed discussion will not be included here as these are very rare complications and do not often occur. Amiodarone and thyroid side effects Amiodarone effects on the thyroid gland are today well known and studies have shown and proven that it causes either hypoor hyperthyroidism. These side effects can be divided into intrinsic effects resulting from inherent properties of the compound and iodineinduced effects that are solely due to the pharmacological effects caused by iodine overload. These effects are summarized in Figure 13. As stated above, amiodarone is a very iodinerich compound (37.3 percent of its molecular weight is iodine). Amiodarone itself even has structural similarity to the thyroid hormone. Even low dose oral therapy (200 mg daily) can elevate daily iodine intake by 50-100 times (Martino et al., 2001). It has been stated in the past that incidences of amiodarone-induced thyroid dysfunction ranged between 2 to 24 percent (Albert, Alves, & Rose, 1987). In more recent reviews of the literature it is said that hypothyroidism occurs in 5-10 percent and hyperthyroidism occurs in approximately 0.9-10 percent of amiodarone patients. Due to this fact, amiodarone side effects have been shown to be in many cases dose-related and that also correlates with thyroid side effects. Recently it has been shown that lower amiodarone dose therapy (152-330mg daily) reduces thyroid side effects significantly and incidences of thyroid dysfunction are 3.7 percent (Trohman et al., 2018) The structure of amiodarone, however, is such that is contains 75mg of organic iodine (I) per 200mg of active dose. During biotransformation, the drug is de-iodinated and studies have estimated that in a dose of 200mg of amiodarone some 6 mg of free iodine are released (Wiersingal & Trip, 1986). Figure 13: Mechanism by which amiodarone affects thyroid hormone metabolism (TH=thyroid hormone) (Basaria & Cooper, 2005). 36 Amiodarone induced hypothyroidism (AIH) As noted previously, amiodarone is iodine rich. Large amounts of amiodarone released during the amiodarone metabolism inhibit the thyroid hormone biosynthesis and release the so-called Wolff-Chaikoff effect (Harjai et al., 1997; Vorperian et al. , 1997). The Wolff-Chaikoff effect is known as an autoregulatory phenomenon which inhibits organification in the thyroid gland, the formation of thyroid hormone inside the thyroid follicle, and release of thyroid hormones into the blood stream. Acute Wolff-Chaikoff effect lasts for a few days, and through the socalled escape from Wollff-Chaikoff effect the levels of intrathyroidal iodide and normal synthesis of T4 and T3 returns to normal. Amiodarone induced hypothyroidism usually resolves in 2-4 months after cessation of the amiodarone therapy. However, persistent AIH despite withdrawal is in direct correlation with underlying autoimmune thyroid diseases such as Hashimoto thyroiditis. AIH is slightly more frequents in females, with female to male ratio of 1.5:1 (Trohman et al., 2018). Hypothyroidism may develop as early as within two weeks or as late as after 39 months after the amiodarone therapy has been initiated. Although IV administration has twice more bioavailability than oral therapy, according to the latest literature it is unlikely that short administration of IV amiodarone can induce AIH. It is more likely that it is due to long term oral therapy. AIH patients usually show very vague signs and symptoms. These symptoms are like those seen in patients with spontaneous hypothyroidism: cool, pale, dry skin, fatigue, cold intolerance, slow speech and mental sluggishness are common. Slow movement, dyspnoea on exertion and decreased exercise capacity caused by hypothyroidism may be difficult to distinguish from baseline or normal progressive cardiopulmonary abnormalities. For the management of patients who develop AIH and due to the high degree of efficacy, amiodarone is often the only antiarrhythmic option for the patient and administration is usually continued with levothyroxine (L-T4) replacement. T4 is thus the drug of choice in these conditions, especially in patients with cardiac problems, because it requires once-daily administration and is not associated with spikes in serum thyroid hormones. It needs to be kept in mind that it is advisable to keep the serum Thyroid hormone in the upper half of the normal range of TSH (Trohman et al., 2018). 37 Amiodarone induced hyperthyroidism (AIT) There are two types of AIT. In type I, there is increased synthesis of thyroid hormone, whereas in type II there is excess release of T4 and T3 due to a destructive thyroiditis. However, it is often difficult to distinguish between the two types and some patients may have elements of both. The 24-hour radioiodine uptake is typically not able to distinguish between types I and II AIT, because the high levels of ingested iodine with amiodarone result in 24-hour uptakes of less than 1 percent in most patients with either type I or type II AIT. Technetium-99m (99mTc)- sestamibi imaging, where available, or colour flow Doppler sonography (CFDS) may be the best ways of distinguishing between the two types of AIT. In patients who develop AIT and to whom amiodarone was prescribed for life-threatening ventricular arrhythmias, it is suggested continuing the amiodarone therapy and treating the hyperthyroidism as well. If the amiodarone was not prescribed for life-threatening ventricular arrhythmias, the literature suggests discontinuing the drug. In the case of type I AIT amiodarone should not be stopped until the hyperthyroid symptoms are well under control with thionamides therapy. Type I AIT is hyperthyroidism with increased synthesis of T4 and T3; the excess iodine provides increased substrate, resulting in enhanced thyroid hormone production. It is suggested to use thionamides as first-line drug to treat type I AIT. Higher than average doses of thionamides are usually needed (30 to 40 mg of methimazole or 450 to 600 mg propylthiouracil (PTU) daily). Perchlorate or lithium are sometimes added to speed recovery; however, perchlorate is not available in the United States. In addition, perchlorate has been associated, albeit rarely, with aplastic anaemia. Type II AIT is a destructive thyroiditis that results in the release of excess T4 and T3, but not increased synthesis. It is typically seen in patients without underlying thyroid disease and is caused by a direct toxic effect of amiodarone on the thyroid gland. The hyperthyroid phase may last from several weeks to several months and is often followed by a hypothyroid phase and then recovery. For the treatment and management of type II AIT, it is recommended to give glucocorticoids as first line treatment, commonly prednisone 40 to 60 mg/day is given and therapy continued for 1-2 months, before tapering. If the mechanism of amiodarone-induced hyperthyroidism is uncertain, it is recommended to consider a mixture between type I and type II AIT. The mainstay therapy in these cases is a combination of prednisone 40 mg/day and methimazole 40 mg/day. If there is a rapid response, 38 type II AIT can be suggested and methimazole can be tapered or stopped. Poor response suggests type I AIT (Basaria et al., 2005; Ross, n.d.; Trohman et al., 2018). The following algorithm by Trohman et al. 2018 gives a good overview of the thyroid followup and treatment. Frequency of long-term side effects using oral amiodarone A study by Greene et al. focuses on the long-term side effects on 70 patients who were treated with oral amiodarone. They were given a 1200 mg/day loading dose for 7 days and 600 mg/day after that for at least 6-12months on average with a follow-up after 6 months. Side effects occurred in 93 percent of the patients and 19 percent of the patients needed to discontinue their medication. 56 patients had gastrointestinal side effects, most commonly constipation. All patients except one developed corneal microdeposits. Cardiovascular side effects were Figure 14: Algorithm showing the thyroid follow-up and treatment suggested for patients recieving amiodarone (Trohman et al., 2018). 45 Acknowledgements I would like to express my gratitude to my supervisor, József András Szentmiklósi, M.D., Ph.D, for his time, support, positivity and guidance. Without his encouragement this task would have been an insurmountable challenge. I would like to thank all members of the department of pharmacology and pharmacotherapy, notably the head of the department Professor Zoltan Szilvassy. My deepest thanks to my parents, Asdis O. Vatnsdal and Thorvaldur H. Thordarson, for never ceasing to believe in me and encouraging me to follow my dream of becoming a doctor. 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