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1、CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS,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,Automa
2、ticity,Reentry-induced dysrhythmia,Classification of Antiarrhythmic Agents,IA Quinidine IC Flecainide Procainamide Propafenone Disopyramide Encainide IB Lidocaine I? Moricizine Mexiletine Tocainide,Classification of Antiarrhythmic Agents,II Beta-adrenergic blockers III Amiodarone Ibutilide Dronedaro
3、ne Dofetilide Sotalol Bretylium IV Calcium channel blockers Diltiazem & Verapamil,Classification of Antiarrhythmic Agents,Digoxin Adenosine,Generic Brandname Disopyramide Norpace Mexiletine Mexitil Flecainide Tambocor Propafenone Rythmol Amiodarone Cordarone, Pacerone Dronedarone Multaq Esmolol Brev
4、ibloc Sotalol Betapace, Sorine Ibutilide Corvert Dofetilide Tikosyn Digoxin Lanoxin, Digitek Adenosine Adenocard,Type Ix,Type Ia,Type Ib,Type Ic,Ias create a double block,Ibs take away the block,What about Ics? - They have no effect on action potential duration,Type II & IV,Type III,CLINICAL INDICAT
5、IONS,Medication Ventricular Atrial QuinidinePO,SR,IV X X Procainamide IV X X DisopyramidePO,SR X X LidocaineIV X - MexiletinePO X - FlecainidePO X! X PropafenonePO,SR X X,CLINICAL INDICATIONS,Medication Ventricular Atrial Beta-blockersPO,SR,IV E AV AmiodaronePO,IV X X DronedaronePO - X SotalolPO,IV
6、X X/AV DofetilidePO ? X IbutilideIV ? AF/Fl Calcium channel blockersPO,SR,IV E? AV,CLINICAL INDICATIONS,Medication Ventricular Atrial DigoxinPO,IV - AV AdenosineIV - PSVT,Quinidine,Type IA antiarrhythmic Indicated for atrial fibrillation and ventricular tachycardias,Quinidine,Adverse Effects GI irri
7、tation 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
8、 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% hepatical
9、ly 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
10、 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,Disopyramid
11、e,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
12、 concentration,Concentration at Steady State,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 p
13、atients “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,Disopyr
14、amide,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
15、 into therapy Lidocaine reduces its own rate of metabolism,Lidocaine,Toxicity most often manifested by: Nausea Dizziness Drowsiness Confusion Tremors Facial numbness Paresthesias Peripheral numbness Altered speech Seizures,Lidocaine,Dosing 1.0-1.5 mg/kg IVP over 1-2 min; repeat every 5-10 min with 0
16、.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 H
17、alf-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,F
18、lecainide,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 Gastroi
19、ntestinal 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 Clearance decreases w/ higher doses Hepatic elimination Active metabolites Extensive (90%) &
20、 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 elimina
21、ted 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
22、 hours,Amiodarone,Type III antiarrhythmic agent Contains alpha- & beta-receptor blocking properties as well as sodium-, potassium-, & calcium- channel blocking properties Indicated for ventricular & atrial dysrhythmias,Amiodarone,Large volume of distribution Half-life: 30 - 100 days Metabolized prim
23、arily by CYP 3A4 Active metabolite: N-desethylamiodarone Half-life: 60 days,Amiodarone,Toxicities CNS Liver Cornea deposits GI Thyroid Optic neuropathy Skin Bradycardia Photosensitivity Pulmonary fibrosis Baseline labs Thyroid (recheck every 6 mths) Liver (recheck every 6 mths) Pulmonary (annual CXR
24、) 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 O
25、ral 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 repeat as needed to a total of 2.2 gm in 24 hours,A Sampling of Drug Interactions,Warfarin Digoxin Metoprolol Quinidine Procainamide Disopyramide,Flecainid
26、e Theophylline Phenytoin Simvastatin Cyclosporine 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 Ac
27、ute 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
28、 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 1
29、0 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 Mainte
30、nance Proarrhythmic Torsade de pointes Need “certification” to prescribe & dispense,Dofetilide,To become “certified” to dispense dofetilide, visit: www.TIKOSYN.com Click on the prompt that allows you to become a Confirmed Prescriber and follow the instructions,Dofetilide,Clearance Hepatic CYP 3A4 Re
31、nal Renal tubular secretion,Dofetilide,Drug Interaction Precautions CYP 3A4 inhibitors Erythro, Clarithro, Grapefruit, Conazoles, SSRIs Cationic renal secretion inhibitors Triamterene, Metformin, Amiloride QT-prolonging medications,Dofetilide,Contraindications QTc 440 msec ( 500 msec w/ VCD) CrCl 20
32、 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)
33、 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 up
34、on 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 500 mcg BID 40 - 60 mL/min 250 mcg BID 20 - 39 mL/min 125 mcg BID,Dofetilide,Check QTc 2-3 hours after 1s
35、t 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 Improv
36、es 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
37、 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: 12 mcg/L,Digoxin General Facts,Half-life: 36 hours or longer Long distribution phase (6-12 hours) Primarily renal elimination Important Drug interactions Ve
38、rapamil Quinidine Amiodarone Propafenone Effects reversed with Digibind & Digifab Digibind/fab use impacts digoxin levels,Drug Distribution,Cp,Time,12 h,Digoxin Adverse Effects,Gastrointestinal Dysrhythmias Central nervous system Visual,DIGOXIN TOXICITY Precipitating Factors,Hypokalemia Hypomagnesem
39、ia Hypercalcemia Hypothyroidism Amyloidosis,DIGOXIN DRUG INTERACTIONS,Increased concentrations Quinidine Ranolazine Verapamil Carvedilol Amiodarone Cyclosporine Dronedarone PPIs Propafenone Macrolides Decreased concentrations Acarbose/Miglitol Bile acid sequestrants,Adenosine,Rapid IV push (6 mg ove
40、r 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 Chest discomfort Shortness of breath Asystole Effects potentiated by dipyridamole & CBZ DO NOT use in heart transplant patients,Adenosine,The effec
41、ts of adenosine are antagonized by methylxanthines Theophylline Caffeine,MEDICATION COMPARISON,Medication Efficacy Side Effects Toxicity Quinidine 2 Mod Mod Disopyramide* 1.5 High Low Mexiletine 1 Mod Low Flecainide* 2o V. Low Low Propafenone* 2? Low-Mod Low Amiodarone 4 High V. High Sotalol* 2.5 Lo
42、w-Mod Low *Negative Inotrope oProarrhythmia risk ?Has potential for proarrhythmia?,TORSADE DE POINTES Cardiovascular Agents,Type IA Quinidine Procainamide Disopyramide Type III Sotalol Dronedarone Ibutilide Dofetilide Ranolazine,TORSADE DE POINTES Antimicrobials,Pentamidine Macrolides Erythromycin &
43、 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 Disc
44、ontinued 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,