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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 classificationImportant pharmacotherapeutic issues related to antiarrhythmic useThe causes&treatment of torsade de pointes,Automaticit
2、y,Reentry-induced dysrhythmia,Classification of Antiarrhythmic Agents,IAQuinidineICFlecainideProcainamidePropafenoneDisopyramideEncainideIBLidocaineI?MoricizineMexiletineTocainide,Classification of Antiarrhythmic Agents,IIBeta-adrenergic blockersIIIAmiodaroneIbutilideDronedarone DofetilideSotalol Br
3、etylium IVCalcium channel blockers Diltiazem&Verapamil,Classification of Antiarrhythmic Agents,DigoxinAdenosine,GenericBrandnameDisopyramideNorpaceMexiletineMexitilFlecainideTambocorPropafenoneRythmolAmiodaroneCordarone,PaceroneDronedaroneMultaqEsmololBreviblocSotalolBetapace,SorineIbutilideCorvertD
4、ofetilideTikosynDigoxinLanoxin,Digitek AdenosineAdenocard,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 INDICATIONS,Medication VentricularAtrialQuinidinePO,SR,IVX XProcai
5、namideIVX XDisopyramidePO,SRX XLidocaineIVX-MexiletinePOX-FlecainidePOX!XPropafenonePO,SRX X,CLINICAL INDICATIONS,Medication Ventricular AtrialBeta-blockersPO,SR,IV E AV AmiodaronePO,IV X XDronedaronePO-XSotalolPO,IV X X/AVDofetilidePO?XIbutilideIV?AF/FlCalcium channel blockersPO,SR,IV E?AV,CLINICAL
6、 INDICATIONS,Medication VentricularAtrialDigoxinPO,IV-AVAdenosineIV-PSVT,Quinidine,Type IA antiarrhythmicIndicated for atrial fibrillation and ventricular tachycardias,Quinidine,Adverse EffectsGI irritationBitter tasteHepatitis&other hepatic conditionsRash&drug feverThrombocytopeniaCinchonismTinnitu
7、sBlurred visionHeadachesDizziness,Quinidine,Different salts Sulfate(83%)PO,SRGluconate(62%)SR,IVHepatically eliminated(t1/2 6-8 hr)Increases digoxin&warfarin levelsIV dosage form hemodynamic instabilitySome concern when IV verapamil or diltiazem is given to a patient on quinidine,Procainamide,Type I
8、A antiarrhythmicIndicated for acute conversion of ventricular&atrial dysrhythmias,Procainamide,Short half-life(3 hours)6-h&12-h SR dosage forms once existed50%hepatically metabolized,mostly to NAPA(fast/slow acetylators)NAPA(as w/50%of PA)is renally eliminatedCauses drug-induced SLE,Procainamide,Adv
9、erse EffectsGastrointestinalCNSFeverRashBlood dyscrasias Some negative inotropic propertiesHypotension w/rapid IV infusions,Procainamide,DosingAcute:17 mg/kg 20 mg/min(50 mg/min,if urgent)Infusion:1-4 mg/min(depends on renal fxn)MetabolismNAPA produced(a renally eliminated active metabolite of proca
10、inamide)Toxicity if NAPA levels exceed 20 mg/L,Disopyramide,Type IA antiarrhythmicIndicated in atrial and ventricular arrhythmias,Disopyramide,Concentration-dependent plasma protein bindingAn increase in dosage rate results in an increase in the percentage of disopyramide that is unboundIncreased un
11、bound drug allows for enhanced clearanceAs a result,increasing the dosage rate results in a less than proportional increase in total drug concentration,Concentration at Steady State,Dosage Rate,Disopyramide,Therefore,total drug concentrations have a limited role in assisting on how much to adjust th
12、e dosage of disopyramide due to its concentration-dependent plasma protein bindingTotal drug concentrations can be used to document a patients“effective”drug concentration once efficacy has been demonstrated,Disopyramide,Adverse EffectsGastrointestinalNegative inotropeAnticholinergic adverse effects
13、Dry mouthBlurred visionConstipationUrinary hesitation,Disopyramide,Elimination50%hepatic50%renalHalf-life7 hours,Disopyramide,Used in neurocardiogenic syncope&hypertrophic heartsAnticholinergic propertiesNegative inotropic properties,Lidocaine,Type IB antiarrhythmicIndicated in acute treatment and p
14、revention of ventricular dysrhythmias,Lidocaine,Half LifeInitially,1.5 hours;but increases to 3.0 hours 2-3 days into therapyLidocaine reduces its own rate of metabolism,Lidocaine,Toxicity most often manifested by:NauseaDizzinessDrowsinessConfusionTremorsFacial numbnessParesthesiasPeripheral numbnes
15、sAltered speechSeizures,Lidocaine,Dosing1.0-1.5 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 doseTypical maintenance dose:1.0-4.0 mg/minUse lower rate with CHF,Mexiletine,Type IB antiarrhythmicOnly indicated to prevent ventricular arrhythmias,Mexilet
16、ine,Adverse EffectsExtremely GI irritatingAltered CNS functioningHepatically metabolizedHalf-life:6-12 hours,Flecainide,Type IC antiarrhythmicSince it is very proarrhythmic:Generally used only for atrial dysrhythmias,Flecainide,Very proarrhythmic in patients with:CADCHFVentricular dysrhythmiasUsed p
17、rimarily in atrial fibrillation when concerns for proarrhythmias are not present,Flecainide,Adverse EffectsGastrointestinalCNSNegative inotropePharmacokineticsMostly hepatic clearance(60%);some renal(30%)Half-life:20 hours,Propafenone,Type IC with some beta-blocking propertiesPrimarily used for atri
18、al dysrhythmiasRarely,ventricular,Propafenone,Adverse EffectsGastrointestinalCNSNegative inotropeMetallic taste,Propafenone,Non-linear absorption&eliminationBioavailability increases w/higher dosesIR and SR dosages are NOT bioequivalentSR has reduced bioavailabilityClearance decreases w/higher doses
19、Hepatic eliminationActive metabolitesExtensive(90%)&Slow(10%)metabolizersIncreases digoxin levels,Sotalol,Non-selective beta-blocker with type III antiarrhythmic activityUsed to acutely treat and prevent atrial&ventricular dysrhythmias,Sotalol,Renally eliminatedNegative inotropeBeta-blocker concerns
20、Torsade de pointes,Sotalol,Renally eliminatedNegative inotropeBeta-blocker concernsTorsade de pointesDo not initiate if QT 450 msecDesire QT 500 msec for first 3 daysDesire QT 520 msec thereafter,Sotalol,Now available parenterallyIndicationsVentricular tachyarrhythmiasAtrial fibrillation/flutter75 m
21、g IV=80 mg poGive dose over 5 hours,Amiodarone,Type III antiarrhythmic agentContains alpha-&beta-receptor blocking properties as well as sodium-,potassium-,&calcium-channel blocking propertiesIndicated for ventricular&atrial dysrhythmias,Amiodarone,Large volume of distributionHalf-life:30-100 daysMe
22、tabolized primarily by CYP 3A4Active metabolite:N-desethylamiodaroneHalf-life:60 days,Amiodarone,ToxicitiesCNSLiverCornea depositsGIThyroidOptic neuropathySkinBradycardiaPhotosensitivity Pulmonary fibrosisBaseline labsThyroid(recheck every 6 mths)Liver(recheck every 6 mths)Pulmonary(annual CXR)Arch
23、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 protocol15 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 dailyOral bioavailabili
24、ty:50%,Amiodarone,General IV load150 mg over 10 minutes1 mg/min x 6 hours0.5 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,WarfarinDigoxinMetoprololQuinidineProcainamideDisopyramide,FlecainideTheophyllinePhenytoinSimv
25、astatinCyclosporineMethotrexate,Dronedarone,A“less toxic”amiodaroneHalf-life:13-19 hoursOnly FDA-approved for atrial fibrillation/flutterNot as effective as amiodarone,Dronedarone,GI irritationProlongs QT interval Negative inotropeContraindicated in:NYHA IVAcute CHF exacerbations,Dronedarone,Metabol
26、ized by CYP 3A4Inhibits CYPs 3A4&2D6 and P-gpIncreases digoxin levelsDosing:400 mg BID,Ibutilide,PharmacologyType III antiarrhythmicIndicated for acute conversion of atrial flutter a/o fibrillationProarrhythmicMore so in patients w/CHF If ibutilide fails to convert,it may at least enhance the respon
27、se to electrocardioversion,Ibutilide,Monitor for proarrhythmias,including torsade de pointes,for 4-6 hours after dosing and until QT is not prolongedHepatically clearedHalf-life:6 hours,Ibutilide,Approved Dosing1 mg(0.01 mg/kg 60 kg)over 10 min;repeat,if needed,after 10 minPreload with magnesium(?)A
28、lternative Method of Dosing2 mg(placed in 50 cc D5W)over 30 minutesStop infusion when patient convertsPreload with magnesium(?),Dofetilide,Oral“relative”to ibutilideIndicated for atrial fibrillation/flutterConversionMaintenanceProarrhythmicTorsade de pointesNeed“certification”to prescribe&dispense,D
29、ofetilide,To become“certified”to dispense dofetilide,visit:www.TIKOSYN.com Click on the prompt that allows you to become a Confirmed Prescriberand follow the instructions,Dofetilide,ClearanceHepaticCYP 3A4RenalRenal tubular secretion,Dofetilide,Drug Interaction Precautions CYP 3A4 inhibitorsErythro,
30、Clarithro,Grapefruit,Conazoles,SSRIsCationic renal secretion inhibitorsTriamterene,Metformin,AmilorideQT-prolonging medications,Dofetilide,ContraindicationsQTc 440 msec(500 msec w/VCD)CrCl 20 mL/minDrugsCimetidineTrimethoprim(incl.Bactrim)VerapamilKetoconazoleProchlorperazineMegestrolHCTZ,Dofetilide
31、,Generally,wait three half-lives after stopping previous antiarrhythmic before starting dofetilideWith 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 th
32、erapy:Hospitalization for 3 daysContinuous EKG monitoringDetermine baseline CrCl&QTcConfirm that patient has method of obtaining medication from a“certified”pharmacy upon dischargeIf patient cannot immediately obtain dofetilide upon discharge,assure that patient can obtain 7-day“bridge”therapy from
33、the hospital,Dofetilide,Starting dosesCrCl Dose 60 mL/min500 mcg BID40-60 mL/min250 mcg BID20-39 mL/min125 mcg BID,Dofetilide,Check QTc 2-3 hours after 1st doseDecrease future doses by 50%if:QTc increased by 15%from baseline QTc 500 msec(550 msec if VCD),Dofetilide,With each subsequent dose,check QT
34、c 2-3 hours after administration Discontinue dofetilide if QTc 500 msec(550 msec if VCD),Digoxin in CHF,Loading dose not essential for CHFImproves CHF morbidity,but not mortalityDrug levels for CHF:0.7-0.9 ng/mL,Digoxin,Vagolytic effects slow heart rate and conduction through AV nodeUsed to slow the
35、 ventricular rate of atrial fibrillationUsed to interrupt reentry in PSVT,Digoxin,Loading dose About 0.0125 mg/kg of LBWGive 50%now,then two doses of 25%;each separated by 4-6 hoursSevere renal failure reduces the Vd;thus,a smaller loading dose is requiredTherapeutic range:12 mcg/L,Digoxin General F
36、acts,Half-life:36 hours or longerLong distribution phase(6-12 hours)Primarily renal eliminationImportant Drug interactionsVerapamilQuinidine AmiodaronePropafenoneEffects reversed with Digibind&DigifabDigibind/fab use impacts digoxin levels,Drug Distribution,Cp,Time,12 h,DigoxinAdverse Effects,Gastro
37、intestinalDysrhythmiasCentral nervous system Visual,DIGOXIN TOXICITYPrecipitating Factors,HypokalemiaHypomagnesemiaHypercalcemiaHypothyroidismAmyloidosis,DIGOXIN DRUG INTERACTIONS,Increased concentrationsQuinidineRanolazineVerapamilCarvedilolAmiodaroneCyclosporineDronedaronePPIsPropafenoneMacrolides
38、Decreased concentrationsAcarbose/MiglitolBile acid sequestrants,Adenosine,Rapid IV push(6 mg over 1-2 sec)When using IV line,flush with salineIf no effect after 1-2 min,give 12 mg;may repeat 12 mg dose onceShort-term adverse effects:FlushingChest discomfortShortness of breathAsystoleEffects potentia
39、ted by dipyridamole&CBZDO NOT use in heart transplant patients,Adenosine,The effects of adenosine are antagonized by methylxanthinesTheophyllineCaffeine,MEDICATION COMPARISON,Medication Efficacy Side Effects ToxicityQuinidine2ModModDisopyramide*1.5HighLowMexiletine1ModLowFlecainide*2oV.LowLowPropafe
40、none*2?Low-ModLowAmiodarone4HighV.HighSotalol*2.5Low-ModLow*Negative Inotrope oProarrhythmia risk?Has potential for proarrhythmia?,TORSADE DE POINTES Cardiovascular Agents,Type IA QuinidineProcainamideDisopyramideType IIISotalolDronedaroneIbutilideDofetilideRanolazine,TORSADE DE POINTESAntimicrobial
41、s,PentamidineMacrolidesErythromycin&ClarithromycinKetolidesTelithromycinFluoroquinolonesMoxifloxacin,TORSADE DE POINTESNon-Cardiovascular Agents,AntipsychoticsAntidepressantsVasopressinTacrolimusDroperidolTamoxifen,MethadoneChloral hydrateTriptansCyclobenzaprineApomorphineVardenafilPosaconazole,TORS
42、ADE DE POINTESDiscontinued Agents,Terfenadine/AstemizoleCisaprideGatifloxacin/Grepafloxacin/SparfloxacinProbucolBepridil,TORSADE DE POINTES Treatment,Discontinue causative medicationCorrect hypokalemia&hypomagnesemiaGive magnesium 1-2 grams IVTo prevent subsequent episodes,increase heart rate until cause of TdP is corrected and/or cleared from the bodyTemporary pacemakerIsoproterenolCardioversion is only indicated when patient becomes hemodynamically compromised,
