Pacerone - General Information
An antianginal and antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting Na,K-activated myocardial adenosine triphosphatase. There is a resulting decrease in heart rate and in vascular resistance. [PubChem]
Pharmacology of Pacerone
Pacerone belongs to a class of drugs called Vaughan-Williams Class III antiarrhythmic agents. It is used in the treatment of a wide range of cardiac tachyarhthmias, including both ventricular and supraventricular (atrial) arrhythmias. After intravenous administration in man, amiodarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. Pacerone prolongs phase 3 of the cardiac action potential. It has numerous other effects however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV. Pacerone shows beta blocker-like and calcium channel blocker-like actions on the SA and AV nodes, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the cardiac action potential, via sodium-channel effects.
Pacerone for patients
Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochromes P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, chiefly with the oral formulation, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone.
Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Reported examples include the following:
Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.
Histamine H2 antagonists:
Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.
Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, resulting in increased plasma levels of amiodarone. Grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone.
Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. Reported examples of this interaction include the following:
Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.
HMG-CoA Reductase Inhibitors:
Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.
Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On administration of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well.
Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to oral amiodarone, the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of oral amiodarone. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
Antihypertensives: Amiodarone should be used with caution in patients receiving ß-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.
Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely.
Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:
Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
Other substances, including herbal preparations:
St. Johnís Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. Johnís Wort in patients receiving amiodarone could result in reduced amiodarone levels.
Other reported interactions with amiodarone:
Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.
Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.
Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t1/2.
Disopyramide increases QT prolongation which could cause arrhythmia.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.
Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil.
Volatile Anesthetic Agents:
In addition to the interactions noted above, chronic (> 2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.
Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with Cordarone I.V., as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.
Cordarone I.V. is contraindicated in patients with known hypersensitivity to any of the components of Cordarone I.V., including iodine, or in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available.
Additional information about Pacerone
Pacerone Indication: Intravenously, for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Orally, for the treatment of life-threatening recurrent ventricular arrhythmias such as recurrent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia.
Mechanism Of Action: The antiarrhythmic effect of amiodarone may be due to at least two major actions. It prolongs the myocardial cell-action potential (phase 3) duration and refractory period and acts as a noncompetitive a- and b-adrenergic inhibitor.
Drug Interactions: Amprenavir The protease inhibitor increases the effect and toxicity of amiodarone
Anisindione Increases the anitcoagulant effect
Atazanavir Increased risk of cardiotoxicity/arrhythmias
Atomoxetine The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
Cisapride Increased risk of cardiotoxicity and arrhythmias
Clarithromycin Increased risk of cardiotoxicity and arrhythmias
Cyclosporine Increases the effect and toxicity of cyclosporine
Dicumarol Increases the anticoagulant effect
Digoxin Increases the effect of digoxin
Dihydroquinidine barbiturate Increases the effect of quinidine
Diltiazem Increased risk of cardiotoxicity and arrhythmias
Erythromycin Increased risk of cardiotoxicity and arrhythmias
Ethotoin Increases the effect of hydantoin
Fentanyl Possible bradycardia, hypotension
Flecainide Increases the effect and toxicity of flecainide
Fosamprenavir The protease inhibitor increases the effect and toxicity of amiodarone
Fosphenytoin Increases the effect of hydantoin
Gatifloxacin Increased risk of cardiotoxicity and arrhythmias
Grepafloxacin Increased risk of cardiotoxicity and arrhythmias
Indinavir Indinavir increases the effect and toxicity of amiodarone
Levofloxacin Increased risk of cardiotoxicity and arrhythmias
Mephenytoin Increases the effect of hydantoin
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Moxifloxacin Increased risk of cardiotoxicity and arrhythmias
Nelfinavir Nelfinavirincreases the effect and toxicity of amiodarone
Acenocoumarol Increases the anticoagulant effect
Phenytoin Increases the effect of hydantoin
Procainamide Increases serum levels and toxicity of procainamide
Quinidine Increases the effect of quinidine
Quinidine barbiturate Increases the effect of qiunidine
Ranolazine Possible additive effect on QT prolongation
Rifampin Rifampin decreases the effect of amiodarone
Ritonavir Ritonavir increases the effect and toxicity of amiodarone
Saquinavir The protease inhibitor increases the effect and toxicity of amiodarone
Simvastatin Increased risk of rhabdomyolysis
Sparfloxacin Increased risk of cardiotoxicity and arrhythmias
Telithromycin Increased risk of cardiotoxicity and arrhythmias
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Vardenafil Increased risk of cardiotoxicity and arrhythmias
Warfarin Increases the anticoagulant effect
Ziprasidone Increased risk of cardiotoxicity and arrhythmias
Iohexol Increased risk of cardiotoxicity and arrhythmias
Food Interactions: Take without regard to meals.
Grapefruit can significantly increase serum levels of this product.
Grapefruit and grapefruit juice should be avoided throughout treatment.
Generic Name: Amiodarone
Synonyms: Amiodarona [INN-Spanish]; Amiodarone Base; Amiodarone HCL; Amiodarone Hydrochloride; Amiodaronum [INN-Latin]
Drug Category: Vasodilator Agents; Enzyme Inhibitors; Anti-Arrhythmia Agents
Drug Type: Small Molecule; Approved; Investigational
Absorption: Slow and variable (about 20 to 55% of an oral dose is absorbed).
Toxicity (Overdose): Intravenous, mouse: LD50 = 178 mg/kg. Some side effects have a significant mortality rate: specifically, hepatitis, exacerbation of asthma and congestive failure, and pneumonitis.
Protein Binding: >96%
Biotransformation: Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can effect the metabolism of numerous other drugs. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.
Half Life: 58 days (range 15-142 days)
Dosage Forms of Pacerone: Solution Intravenous
Chemical IUPAC Name: (2-butyl-1-benzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodophenyl]methanone
Chemical Formula: C25H29I2NO3
Amiodarone on Wikipedia: https://en.wikipedia.org/wiki/Amiodarone
Organisms Affected: Humans and other mammals