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Download Antiarrhythmic Agents - University of Toledo
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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS Vincent F. Mauro, PharmD, FCCP Professor of Clinical Pharmacy and Adjunct Professor of Medicine The University of Toledo GOALS To have a better understanding of: The EPS properties of antiarrhythmics according to their Vaughan-Williams classification Important pharmacotherapeutic issues related to antiarrhythmic use The causes & treatment of torsade de pointes Automaticity Reentry-induced dysrhythmia Classification of Antiarrhythmic Agents IA Quinidine Procainamide Disopyramide IC Flecainide Propafenone Encainide IB Lidocaine Mexiletine Tocainide I? Moricizine Classification of Antiarrhythmic Agents II Beta-adrenergic blockers III Amiodarone Dronedarone Sotalol IV Calcium channel blockers Ibutilide Dofetilide Bretylium Diltiazem & Verapamil Classification of Antiarrhythmic Agents Digoxin Adenosine Generic Brandname Disopyramide Mexiletine Flecainide Propafenone Amiodarone Dronedarone Esmolol Sotalol Ibutilide Dofetilide Digoxin Adenosine Norpace Mexitil Tambocor Rythmol Cordarone, Pacerone Multaq Brevibloc Betapace, Sorine Corvert Tikosyn Lanoxin, Digitek Adenocard Type Ix Type Ia Type Ib Type Ic Ia’s create a double block Ib’s take away the block What about Ic’s? - They have no effect on action potential duration Type II & IV Type III CLINICAL INDICATIONS Medication Ventricular Atrial QuinidinePO,SR,IV Procainamide IV DisopyramidePO,SR X X X X X X LidocaineIV MexiletinePO X X - FlecainidePO PropafenonePO,SR X!! X X X CLINICAL INDICATIONS Medication Ventricular Atrial Beta-blockersPO,SR,IV E AV AmiodaronePO,IV DronedaronePO SotalolPO,IV DofetilidePO IbutilideIV X X ? ? X X X/AV X AF/Fl Calcium channel blockersPO,SR,IV E? AV CLINICAL INDICATIONS Medication DigoxinPO,IV AdenosineIV Ventricular - Atrial AV PSVT Quinidine • • Type IA antiarrhythmic Indicated for atrial fibrillation and ventricular tachycardias Quinidine Adverse Effects • GI irritation • Bitter taste • Hepatitis & other hepatic conditions • Rash & drug fever • Thrombocytopenia • Cinchonism • • • • Tinnitus Blurred vision Headaches Dizziness Quinidine • Different salts • • • • • • Sulfate (83%)PO,SR Gluconate (62%)SR,IV Hepatically eliminated (t1/2 ~6-8 hr) Increases digoxin & warfarin levels IV dosage form – hemodynamic instability Some concern when IV verapamil or diltiazem is given to a patient on quinidine Procainamide Type IA antiarrhythmic Indicated for acute conversion of ventricular & atrial dysrhythmias Procainamide • • • • • Short half-life (~3 hours) 6-h & 12-h SR dosage forms once existed 50% hepatically metabolized, mostly to NAPA (fast/slow acetylators) NAPA (as w/ 50% of PA) is renally eliminated Causes drug-induced SLE Procainamide Adverse Effects • Gastrointestinal • CNS • Fever • Rash • Blood dyscrasias • Some negative inotropic properties • Hypotension w/ rapid IV infusions Procainamide Dosing Acute: 17 mg/kg @ 20 mg/min (50 mg/min, if urgent) Infusion: 1-4 mg/min (depends on renal fxn) Metabolism NAPA produced (a renally eliminated active metabolite of procainamide) Toxicity if NAPA levels exceed 20 mg/L Disopyramide • • Type IA antiarrhythmic Indicated in atrial and ventricular arrhythmias Disopyramide • • • • Concentration-dependent plasma protein binding An increase in dosage rate results in an increase in the percentage of disopyramide that is unbound Increased unbound drug allows for enhanced clearance As a result, increasing the dosage rate results in a less than proportional increase in total drug concentration Dosage Rate Disopyramide • Therefore, total drug concentrations have a limited role in assisting on how much to adjust the dosage of disopyramide due to its concentration-dependent plasma protein binding • Total drug concentrations can be used to document a patient’s “effective” drug concentration once efficacy has been demonstrated Disopyramide Adverse Effects • Gastrointestinal • Negative inotrope • Anticholinergic adverse effects • • • • Dry mouth Blurred vision Constipation Urinary hesitation Disopyramide • Elimination • • • ~50% hepatic ~50% renal Half-life • ~7 hours Disopyramide • Used in neurocardiogenic syncope & hypertrophic hearts • • Anticholinergic properties Negative inotropic properties Lidocaine • • Type IB antiarrhythmic Indicated in acute treatment and prevention of ventricular dysrhythmias Lidocaine Half Life Initially, 1.5 hours; but increases to 3.0 hours 2-3 days into therapy Lidocaine reduces its own rate of metabolism Lidocaine Toxicity most often manifested by: Nausea Drowsiness Dizziness Confusion Tremors Paresthesias Altered speech Facial numbness Peripheral numbness Seizures Lidocaine Dosing 1.0-1.5 mg/kg IVP over 1-2 min; repeat every 5-10 min with 0.5-0.75 mg/kg, as needed, until 3 mg/kg total dose Typical maintenance dose: 1.0-4.0 mg/min Use lower rate with CHF Mexiletine • • Type IB antiarrhythmic Only indicated to prevent ventricular arrhythmias Mexiletine Adverse Effects • Extremely GI irritating • Altered CNS functioning • Hepatically metabolized • Half-life: 6-12 hours Flecainide • Type IC antiarrhythmic • Since it is very proarrhythmic: • Generally used only for atrial dysrhythmias Flecainide • Very proarrhythmic in patients with: • CAD • CHF • Ventricular dysrhythmias • Used primarily in atrial fibrillation when concerns for proarrhythmias are not present Flecainide Adverse Effects • • • Gastrointestinal CNS Negative inotrope Pharmacokinetics • • Mostly hepatic clearance (60%); some renal (30%) Half-life: ~20 hours Propafenone • • Type IC with some beta-blocking properties Primarily used for atrial dysrhythmias • Rarely, ventricular Propafenone Adverse Effects • Gastrointestinal • CNS • Negative inotrope • Metallic taste Propafenone • Non-linear absorption & elimination • Bioavailability increases w/ higher doses • IR and SR dosages are NOT bioequivalent • SR has reduced bioavailability • • Hepatic elimination • • • Clearance decreases w/ higher doses Active metabolites Extensive (90%) & Slow (10%) metabolizers Increases digoxin levels Sotalol • • Non-selective beta-blocker with type III antiarrhythmic activity Used to acutely treat and prevent atrial & ventricular dysrhythmias Sotalol • Renally eliminated Negative inotrope Beta-blocker concerns • Torsade de pointes • • Sotalol • Renally eliminated Negative inotrope Beta-blocker concerns • Torsade de pointes • • • • • Do not initiate if QT > 450 msec Desire QT < 500 msec for first 3 days Desire QT < 520 msec thereafter Sotalol Now available parenterally • Indications • • • • Ventricular tachyarrhythmias Atrial fibrillation/flutter 75 mg IV = 80 mg po Give dose over 5 hours Amiodarone Type III antiarrhythmic agent Contains alpha- & beta-receptor blocking properties as well as sodium-, potassium-, & calciumchannel blocking properties Indicated for ventricular & atrial dysrhythmias Amiodarone Large volume of distribution Half-life: 30 - 100 days Metabolized primarily by CYP 3A4 Active metabolite: N-desethylamiodarone Half-life: ~60 days Amiodarone Toxicities CNS GI Skin Liver Thyroid Bradycardia Cornea deposits Optic neuropathy Photosensitivity Pulmonary fibrosis Baseline labs Thyroid (recheck every 6 mths) Liver (recheck every 6 mths) Pulmonary (annual CXR) Arch Intern Med 2000;160:1741-8 Amiodarone An allergy to iodine (but not contrast dye) is a contraindication to using amiodarone Amiodarone An oral dosing protocol 15 mg/kg/day x 1 week (~400 mg TID) 10 mg/kg/day x 2 weeks (~400 mg BID) 5 mg/kg/day (~400 mg QD) Eventually reduce to 100-200 mg daily Oral bioavailability: ~50% Amiodarone General IV load 150 mg over 10 minutes 1 mg/min x 6 hours 0.5 mg/min x 18 hours or longer Monitor heart rate & blood pressure Ventricular fibrillation 300 mg IVP; may repeat w/ 150 mg IVP Ventricular tachycardia 150 mg over 10 min; repeat as needed to a total of 2.2 gm in 24 hours A Sampling of Drug Interactions Warfarin Flecainide Digoxin Theophylline Metoprolol Phenytoin Quinidine Simvastatin Procainamide Cyclosporine Disopyramide Methotrexate Dronedarone A “less toxic” amiodarone Half-life: 13-19 hours Only FDA-approved for atrial fibrillation/flutter Not as effective as amiodarone Dronedarone GI irritation Prolongs QT interval Negative inotrope Contraindicated in: NYHA IV Acute CHF exacerbations Dronedarone Metabolized by CYP 3A4 Inhibits CYPs 3A4 & 2D6 and P-gp Increases digoxin levels Dosing: 400 mg BID Ibutilide Pharmacology Type III antiarrhythmic Indicated for acute conversion of atrial flutter a/o fibrillation Proarrhythmic More so in patients w/ CHF If ibutilide fails to convert, it may at least enhance the response to electrocardioversion Ibutilide Monitor for proarrhythmias, including torsade de pointes, for 4-6 hours after dosing and until QT is not prolonged Hepatically cleared Half-life: ~6 hours Ibutilide Approved Dosing 1 mg (0.01 mg/kg < 60 kg) over 10 min; repeat, if needed, after 10 min Preload with magnesium (?) Alternative Method of Dosing 2 mg (placed in 50 cc D5W) over 30 minutes Stop infusion when patient converts Preload with magnesium (?) Dofetilide Oral “relative” to ibutilide Indicated for atrial fibrillation/flutter Conversion Maintenance Proarrhythmic Torsade de pointes Need “certification” to prescribe & dispense Dofetilide become “certified” to dispense dofetilide, visit: www.TIKOSYN.com To Click on the prompt that allows you to become a Confirmed Prescriber and follow the instructions Dofetilide Clearance Hepatic CYP 3A4 Renal Renal tubular secretion Dofetilide Drug Interaction Precautions CYP 3A4 inhibitors Erythro, Cationic Clarithro, Grapefruit, Conazoles, SSRIs renal secretion inhibitors Triamterene, Metformin, Amiloride QT-prolonging medications Dofetilide Contraindications QTc > 440 msec (> 500 msec w/ VCD) CrCl < 20 mL/min Drugs Cimetidine Trimethoprim (incl. Bactrim) Verapamil Ketoconazole Prochlorperazine Megestrol HCTZ Dofetilide Generally, wait three half-lives after stopping previous antiarrhythmic before starting dofetilide With amiodarone, wait three months (or until amiodarone concentration < 0.3 mcg/mL) Wait 48 hours after stopping dofetilide before starting another antiarrhythmic Dofetilide Considerations when initiating therapy: Hospitalization for 3 days Continuous EKG monitoring Determine baseline CrCl & QTc Confirm that patient has method of obtaining medication from a “certified” pharmacy upon discharge If patient cannot immediately obtain dofetilide upon discharge, assure that patient can obtain 7-day “bridge” therapy from the hospital Dofetilide Starting doses CrCl Dose > 60 mL/min 40 - 60 mL/min 20 - 39 mL/min 500 mcg BID 250 mcg BID 125 mcg BID Dofetilide Check QTc 2-3 hours after 1st dose Decrease future doses by 50% if: QTc increased by 15% from baseline QTc > 500 msec (> 550 msec if VCD) Dofetilide With each subsequent dose, check QTc 2-3 hours after administration Discontinue dofetilide if QTc > 500 msec (> 550 msec if VCD) Digoxin in CHF • • • Loading dose not essential for CHF Improves CHF morbidity, but not mortality Drug levels for CHF: 0.7-0.9 ng/mL Digoxin • Vagolytic effects slow heart rate and conduction through AV node • Used to slow the ventricular rate of atrial fibrillation Used to interrupt reentry in PSVT • Digoxin • Loading dose • • • • About 0.0125 mg/kg of LBW Give 50% now, then two doses of 25%; each separated by 4-6 hours Severe renal failure reduces the Vd; thus, a smaller loading dose is required Therapeutic range: 1–2 mcg/L Digoxin – General Facts • • • • Half-life: 36 hours or longer Long distribution phase (6-12 hours) Primarily renal elimination Important Drug interactions • • • • • Verapamil Quinidine Amiodarone Propafenone Effects reversed with Digibind & Digifab • Digibind/fab use impacts digoxin levels Drug Distribution Cp 12 h Time Digoxin Adverse Effects Gastrointestinal Dysrhythmias Central nervous system Visual DIGOXIN TOXICITY Precipitating Factors Hypokalemia Hypomagnesemia Hypercalcemia Hypothyroidism Amyloidosis DIGOXIN DRUG INTERACTIONS Increased concentrations Quinidine Verapamil Amiodarone Dronedarone Propafenone Ranolazine Carvedilol Cyclosporine PPI’s Macrolides Decreased concentrations Acarbose/Miglitol Bile acid sequestrants Adenosine Rapid IV push (6 mg over 1-2 sec) When using IV line, flush with saline If no effect after 1-2 min, give 12 mg; may repeat 12 mg dose once Short-term adverse effects: Flushing Shortness of breath Chest discomfort Asystole Effects potentiated by dipyridamole & CBZ DO NOT use in heart transplant patients Adenosine The effects of adenosine are antagonized by methylxanthines Theophylline Caffeine MEDICATION COMPARISON Medication Quinidine Disopyramide* Mexiletine Flecainide* Propafenone* Amiodarone Sotalol* *Negative Efficacy 2 1.5 1 2o 2? 4 2.5 Inotrope oProarrhythmia risk ?Has potential for proarrhythmia? Side Effects Mod High Mod V. Low Low-Mod High Low-Mod Toxicity Mod Low Low Low Low V. High Low TORSADE DE POINTES Cardiovascular Agents Type IA Quinidine Procainamide Disopyramide Type III Sotalol Dronedarone Ibutilide Dofetilide Ranolazine TORSADE DE POINTES Antimicrobials Pentamidine Macrolides Erythromycin & Clarithromycin Ketolides Telithromycin Fluoroquinolones Moxifloxacin TORSADE DE POINTES Non-Cardiovascular Agents Antipsychotics Antidepressants Vasopressin Tacrolimus Droperidol Tamoxifen Methadone Chloral hydrate Triptans Cyclobenzaprine Apomorphine Vardenafil Posaconazole TORSADE DE POINTES Discontinued Agents Terfenadine/Astemizole Cisapride Gatifloxacin/Grepafloxacin/Sparfloxacin Probucol Bepridil TORSADE DE POINTES Treatment Discontinue causative medication Correct hypokalemia & hypomagnesemia Give magnesium 1-2 grams IV To prevent subsequent episodes, increase heart rate until cause of TdP is corrected and/or cleared from the body Temporary pacemaker Isoproterenol Cardioversion is only indicated when patient becomes hemodynamically compromised
