pharmacology of antiarrhythmics and vasoactive substancesphillip l. coule, m.d. medical college of...

Pharmacology of Antiarrhythmics and Pharmacology of Antiarrhythmics and Vasoactive SubstancesVasoactive Substances

Phillip L. Coule, M.D.Phillip L. Coule, M.D.Medical College of Medical College of

GeorgiaGeorgiaDepartment of Department of

Emergency MedicineEmergency Medicine

Please give proper credit to the Please give proper credit to the author of this work:author of this work:

Phillip L. Coule, M.D.Phillip L. Coule, M.D.and the EMS Resource Center at and the EMS Resource Center at the Medical College of Georgiathe Medical College of Georgiahttp://www.mcg.http://www.mcg.eduedu//somsom//emergemerg

Phillip L. Coule, M.D. Medical College of Georgia Emergency MediPhillip L. Coule, M.D. Medical College of Georgia Emergency Medicinecine

ObjectivesObjectives

■■ Overview of Antiarrhythmic and Vasoactive Overview of Antiarrhythmic and Vasoactive MedicationsMedications•• actionsactions•• pharmacokineticspharmacokinetics•• indicationsindications•• dosing and Administrationdosing and Administration•• adverse effectsadverse effects

■■ Classification of AntiarrhythmicsClassification of Antiarrhythmics■■ Cardiac Arrest MedicationsCardiac Arrest Medications


Antiarrhythmic ClassificationAntiarrhythmic Classification

■■ Class I Class I -- Fast Channel BlockersFast Channel Blockers•• Ia Ia -- Quinidine, Disopyramide, Quinidine, Disopyramide,

ProcainamideProcainamide•• Ib Ib -- Lidocaine, Phenytoin, Mexilitine, Lidocaine, Phenytoin, Mexilitine,

TocainindeTocaininde•• Ic Ic -- Ecainide, Flecainide, Propafenone, Ecainide, Flecainide, Propafenone,

Indecainide, MoricizineIndecainide, Moricizine


Antiarrhythmic Classification Antiarrhythmic Classification

■■ Class II Class II -- Beta BlockersBeta Blockers•• Propanolol, Acebutolol, Atenolol, Betaxolol, Propanolol, Acebutolol, Atenolol, Betaxolol,

Bisoprolol, Esmolol, Labetalol, Metoprolol, Bisoprolol, Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, TimololSotalol, Timolol


Antiarrhythmic ClassificationAntiarrhythmic Classification

■■ Class IIIClass III•• Bretylium, Amiodarone, SotalolBretylium, Amiodarone, Sotalol

■■ Class IV Class IV -- Calcium Channel BlockersCalcium Channel Blockers•• Verapamil, DiltiazemVerapamil, Diltiazem

■■ Unclassified Unclassified -- Digoxin, Adenosine, MgDigoxin, Adenosine, Mg


Procainamide Procainamide -- ActionsActions

■■ Suppresses automaticity Suppresses automaticity •• decreasing the rate and amplitude of decreasing the rate and amplitude of

phase 4 diastolic depolarizationphase 4 diastolic depolarization•• prolongs action potential durationprolongs action potential duration•• reduces the speed of impulse conductionreduces the speed of impulse conduction•• suppresses fibrillatory activity in the atria suppresses fibrillatory activity in the atria

and ventriclesand ventricles■■ Dose dependant anticholinergic activityDose dependant anticholinergic activity


Procainamide Procainamide -- ActionsActions

■■ Negative InotropeNegative Inotrope•• more pronounced in ischemic myocardiummore pronounced in ischemic myocardium

■■ Hypotension in high dosesHypotension in high doses•• vasodilatation of peripheral vasculaturevasodilatation of peripheral vasculature


ProcainamideProcainamide-- PharmacokineticsPharmacokinetics

■■ OnsetOnset•• 5 5 -- 10 minutes IV10 minutes IV•• 15 15 -- 60 minutes IM60 minutes IM

■■ Half LifeHalf Life•• 2.5 to 4.7 hrs in normal renal function2.5 to 4.7 hrs in normal renal function•• increased in CHF, Renal Failureincreased in CHF, Renal Failure

■■ Metabolized to NMetabolized to N--acetyl Procainamideacetyl Procainamide•• NAPANAPA


Procainamide Procainamide -- IndicationsIndications

■■ Ventricular arrhythmiasVentricular arrhythmias•• Stable Ventricular TachycardiaStable Ventricular Tachycardia•• Premature Ventricular ContractionsPremature Ventricular Contractions•• Ventricular Fibrillation / Pulseless VTVentricular Fibrillation / Pulseless VT

■■ Supraventricular tachyarrhythmiasSupraventricular tachyarrhythmias•• PSVT, PAT, paroxysmal AV junctionalPSVT, PAT, paroxysmal AV junctional•• Atrial flutter and fibrillationAtrial flutter and fibrillation


ProcainamideProcainamide-- ContraindicationsContraindications

■■ AV block AV block •• Second or third degreeSecond or third degree

■■ Long QT intervalLong QT interval■■ Torsade de pointesTorsade de pointes■■ Caution Caution

•• SLE, CHF, hepatic or renal diseaseSLE, CHF, hepatic or renal disease


Procainamide Procainamide -- AdministrationAdministration

■■ Continuous infusion safer than bolusContinuous infusion safer than bolus■■ Infusion of 20 Infusion of 20 -- 30 mg/min until30 mg/min until

•• control of arrhythmiacontrol of arrhythmia•• hypotensionhypotension•• QRS widens by > 50%QRS widens by > 50%•• QT interval prolongationQT interval prolongation•• Total of 17 mg/kg has been administeredTotal of 17 mg/kg has been administered


Procainamide Procainamide -- AdministrationAdministration

■■ Once ectopy is suppressedOnce ectopy is suppressed•• maintenance drip of 1 to 4 mg/minmaintenance drip of 1 to 4 mg/min

■■ Lower doses for CHF and renal failureLower doses for CHF and renal failure


Procainamide Procainamide -- Adverse EffectsAdverse Effects

■■ Myocardial DepressionMyocardial Depression•• prolonged QRS, QT, AV conduction, VF prolonged QRS, QT, AV conduction, VF

and Torsade de pointesand Torsade de pointes■■ HypotensionHypotension

•• High doses or rapidly administeredHigh doses or rapidly administered■■ HypersensitivityHypersensitivity

•• angioedema, bronchoconstriction, vascular angioedema, bronchoconstriction, vascular collapse, febrile episodes, respiratory collapse, febrile episodes, respiratory arrestarrest


Lidocaine Lidocaine -- ActionsActions

■■ Class IB antiarrhythmicClass IB antiarrhythmic•• blocks fast sodium channelsblocks fast sodium channels•• decreases slope of phase 4decreases slope of phase 4•• decreased automaticity in the Hisdecreased automaticity in the His--purkinje purkinje

systemsystem•• action potential duration and effective action potential duration and effective

refractory period of Hisrefractory period of His--purkinje increasedpurkinje increased•• Acts preferentially on ischemic tissueActs preferentially on ischemic tissue


Lidocaine Lidocaine -- ActionsActions

■■ ContinuedContinued•• Causes little or no effect on AV conductionCauses little or no effect on AV conduction•• Elevates vElevates v--fib thresholdfib threshold•• Supresses ventricular ectopySupresses ventricular ectopy•• negligible effect negligible effect

–– autonomic nervous system autonomic nervous system –– myocardial contractility myocardial contractility –– peripheral vascular toneperipheral vascular tone


Lidocaine Lidocaine --PharmacokineticsPharmacokinetics

■■ Onset of ActionOnset of Action•• 30 to 60 seconds IV30 to 60 seconds IV•• 10 minutes IM10 minutes IM

■■ Bolus administration necessaryBolus administration necessary•• infusion alone will not reach therapeutic infusion alone will not reach therapeutic

levels for 30 min to several hrs.levels for 30 min to several hrs.■■ First pass metabolismFirst pass metabolism

•• No PO formNo PO form


Lidocaine Lidocaine -- PharmacokineticsPharmacokinetics

■■ HalfHalf--Life (elimination)Life (elimination)•• 80 to 108 minutes 80 to 108 minutes

–– healthy patientshealthy patients•• 7 hrs 7 hrs

–– in patients with CHF, liver diseasein patients with CHF, liver disease

■■ Therapeutic LevelsTherapeutic Levels•• 1.5 to 6 ug/ml1.5 to 6 ug/ml•• >5 ug/ml may cause CNS toxicity>5 ug/ml may cause CNS toxicity


Lidocaine Lidocaine -- IndicationsIndications

■■ Drug of Choice Drug of Choice •• ventricular arrhythmiasventricular arrhythmias•• ventricular ectopyventricular ectopy

–– frequent multifocal PVC’s (>6/min)frequent multifocal PVC’s (>6/min)–– PVC couplets, salvosPVC couplets, salvos–– long runs of VTlong runs of VT–– Not used for chronic PVC’s when asymptomaticNot used for chronic PVC’s when asymptomatic

■■ Prophylactic use Prophylactic use •• No longer recommendedNo longer recommended


Lidocaine Lidocaine -- AdministrationAdministration

■■ Initial Dose IVInitial Dose IV•• Ventricular EctopyVentricular Ectopy

–– 1 mg/kg bolus1 mg/kg bolus–– additional doses of 0.5 mg/kg q 5additional doses of 0.5 mg/kg q 5--10 min10 min

•• Ventricular FibrillationVentricular Fibrillation–– 1.5 mg/kg1.5 mg/kg

■■ Total Dose IVTotal Dose IV•• 3 mg/kg3 mg/kg


Lidocaine Lidocaine -- AdministrationAdministration

■■ EndotrachealEndotracheal•• If IV not availableIf IV not available•• 2 to 2 2 to 2 1/21/2 times the dose diluted to total times the dose diluted to total

volume of 10 cc’svolume of 10 cc’s■■ IMIM

•• 300 mg of 10% solution, deltoid vastus 300 mg of 10% solution, deltoid vastus lateralis lateralis

•• AutoAuto-- injectors availableinjectors available


Lidocaine Lidocaine -- Adverse EffectsAdverse Effects

■■ CNS side effectsCNS side effects■■ Abrupt change in mental statusAbrupt change in mental status■■ Plasma levels greater than 9 ug/mlPlasma levels greater than 9 ug/ml

•• psychosis, seizures, respiratory depressionpsychosis, seizures, respiratory depression■■ ContraindicatedContraindicated

•• SA or AV blocksSA or AV blocks•• Known hypersensitivityKnown hypersensitivity


Beta Blockers Beta Blockers -- ActionsActions

■■ Block effects of catacholamines on Beta Block effects of catacholamines on Beta receptorsreceptors

■■ Selective Beta blockersSelective Beta blockers•• metoprolol metoprolol •• acebutololacebutolol•• atenololatenolol•• esmololesmolol•• metoprololmetoprolol


Beta Blockers Beta Blockers -- ActionsActions

■■ NegativeNegative•• ChronotropicChronotropic

–– slows sinus rateslows sinus rate–– depresses AV conductiondepresses AV conduction–– Decreases cardiac outputDecreases cardiac output

•• InotropicInotropic■■ VasodilatationVasodilatation


Beta BlockersBeta Blockers-- PharmacokineticsPharmacokinetics

■■ OnsetOnset•• rapid rapid -- within 1 minute IVwithin 1 minute IV

■■ Half Life Half Life •• 1 to 26 hours1 to 26 hours•• Excretion is renal and GIExcretion is renal and GI

■■ Dose adjustment necessary for renal Dose adjustment necessary for renal failure for some beta blockers failure for some beta blockers


Beta Blockers Beta Blockers -- AdministrationAdministration

■■ MetoprololMetoprolol•• 5 mg IV push5 mg IV push•• selective B1selective B1•• Half life of 3Half life of 3--7 hrs7 hrs

■■ EsmololEsmolol•• ultraultra--short half life of 9 minutesshort half life of 9 minutes•• 2525--50 ug/kg/min50 ug/kg/min•• load of 500 ug/kg not necessaryload of 500 ug/kg not necessary


Beta Blockers Beta Blockers -- Adverse EffectsAdverse Effects

■■ Similar for most Beta blockersSimilar for most Beta blockers•• nausea, vomiting, light headedness, nausea, vomiting, light headedness,

mental depression, bradycardia, mental depression, bradycardia, hypotension, bronchospasmhypotension, bronchospasm

■■ ContraindicatedContraindicated•• > first degree heart block> first degree heart block•• CHF or cardiogenic shockCHF or cardiogenic shock•• Caution with calcium channel blockersCaution with calcium channel blockers


Bretylium Bretylium -- ActionsActions

■■ Class IIIClass III■■ Biphasic EffectsBiphasic Effects

•• Norepinephrine releaseNorepinephrine release–– effects last 20 minuteseffects last 20 minutes

•• Blocks release of norepinephrineBlocks release of norepinephrine–– 45 to 60 minutes after administration45 to 60 minutes after administration

•• Affects phase 3 (repolarization) prolongs Affects phase 3 (repolarization) prolongs refractoriness refractoriness -- antifibrillatoryantifibrillatory


Bretylium Bretylium -- IndicationsIndications

■■ VFVF•• refractory VF, after epinephrine, lidocainerefractory VF, after epinephrine, lidocaine

■■ VTVT•• refractory VT with a pulse, after lidocaine refractory VT with a pulse, after lidocaine

and procainamideand procainamide■■ Wide Complex Tachycardia UnknownWide Complex Tachycardia Unknown

•• after lidocaine and adenosineafter lidocaine and adenosine


Bretylium Bretylium -- AdministrationAdministration

■■ VF or Pulseless VTVF or Pulseless VT•• 5 mg/kg rapid IV push5 mg/kg rapid IV push•• repeat at 10 mg/kg in 15 to 30 minutesrepeat at 10 mg/kg in 15 to 30 minutes•• maximum is 35 mg/kgmaximum is 35 mg/kg

■■ VT / ventricular arrhythmiasVT / ventricular arrhythmias•• 5 5 -- 10 mg.kg over 8 to 10 minutes10 mg.kg over 8 to 10 minutes

■■ Maintenance of 1Maintenance of 1--2 mg/min2 mg/min


Diltiazem Diltiazem -- ActionsActions

■■ Class IV Class IV -- Calcium Channel BlockerCalcium Channel Blocker•• decreases conduction velocity in diseased decreases conduction velocity in diseased

tissuetissue•• prolongs refractory period in AV nodeprolongs refractory period in AV node•• slows discharge from SA nodeslows discharge from SA node•• minimal effect on normal tissue minimal effect on normal tissue •• Interrupts reentrant pathway in PSVTInterrupts reentrant pathway in PSVT


Diltiazem Diltiazem -- IndicationsIndications

■■ Rapid Conversion of PSVTRapid Conversion of PSVT•• as effective as adenosine and verapamilas effective as adenosine and verapamil

■■ Slowing of rate in ASlowing of rate in A--Fib or AFib or A--flutterflutter■■ HypertensionHypertension


Diltiazem Diltiazem -- AdministrationAdministration

■■ PSVT, APSVT, A--fib, Afib, A--flutterflutter•• .25 mg/kg (average 20 mg) over 2 minutes.25 mg/kg (average 20 mg) over 2 minutes•• Second bolus of .35 mg/kgSecond bolus of .35 mg/kg

■■ Maintenance InfusionMaintenance Infusion•• 55--15 mg/hr15 mg/hr


Diltiazem Diltiazem -- Adverse EffectsAdverse Effects

■■ CardiovascularCardiovascular•• angina, bradycardia, asystole, CHF, AV angina, bradycardia, asystole, CHF, AV

block, BBB, flushing, hypotensionblock, BBB, flushing, hypotension■■ NonNon--cardiovascularcardiovascular

•• headache, dizziness, constipation, rashheadache, dizziness, constipation, rash


Adenosine Adenosine -- ActionsActions

■■ Endogenous NucleosideEndogenous Nucleoside•• produced by dephosphorylation of ATPproduced by dephosphorylation of ATP

■■ Negative Chronotropic effects on SA Negative Chronotropic effects on SA and AV nodeand AV node•• Does not alter accessory pathwaysDoes not alter accessory pathways•• blockade of the AV nodeblockade of the AV node•• potent vasodilator potent vasodilator -- no effects due to no effects due to

metabolismmetabolism


Adenosine Adenosine -- PharmacokineticsPharmacokinetics

■■ OnsetOnset•• 30 seconds30 seconds

■■ Duration Duration •• 60 to 90 seconds60 to 90 seconds

■■ HalfHalf--life life •• less than 7 secondsless than 7 seconds


Adenosine Adenosine -- IndicationsIndications

■■ Emergency management of PSVTEmergency management of PSVT•• involving the AV nodeinvolving the AV node

■■ DiagnosticDiagnostic•• Wide complex tachycardia of uncertain Wide complex tachycardia of uncertain

originorigin•• detection of accessory pathwaysdetection of accessory pathways


Adenosine Adenosine -- AdministrationAdministration

■■ 6 mg Rapid IV push (over 16 mg Rapid IV push (over 1--2 seconds)2 seconds)•• most proximal portmost proximal port•• followed by 20 ml saline flushfollowed by 20 ml saline flush•• elevate the extremity after boluselevate the extremity after bolus

■■ Repeat DosingRepeat Dosing•• 12 mg rapid IV push if heart rate not 12 mg rapid IV push if heart rate not

decreased in 2 minutesdecreased in 2 minutes


Adenosine Adenosine -- Adverse EffectsAdverse Effects

■■ Minor and well toleratedMinor and well tolerated•• less than 1 minuteless than 1 minute•• dyspnea, cough, syncope, vertigo, dyspnea, cough, syncope, vertigo,

parasthesiasparasthesias■■ Higher dosesHigher doses

•• DipyramidoleDipyramidole•• CarbamazepineCarbamazepine•• Asthmatics, excessive coffee drinkersAsthmatics, excessive coffee drinkers


Magnesium Magnesium -- ActionsActions

■■ DirectlyDirectly•• Na, K+, ATPase pumpNa, K+, ATPase pump

■■ IndirectlyIndirectly•• calcium channel blocking activitycalcium channel blocking activity

■■ EffectsEffects•• Increases membrane potentialIncreases membrane potential•• prolongs AV conductionprolongs AV conduction•• Corrects hypomagnesemia/hypokalemiaCorrects hypomagnesemia/hypokalemia


Magnesium Magnesium -- IndicationsIndications

■■ Intractable VF/VTIntractable VF/VT■■ Torsade de pointesTorsade de pointes■■ May be usefulMay be useful

•• PVC’s, MAT, PSVT, digoxin toxicityPVC’s, MAT, PSVT, digoxin toxicity


Magnesium Magnesium -- AdministrationAdministration

■■ IV Loading doseIV Loading dose•• 1 to 2 grams in 501 to 2 grams in 50--100 cc of D5W over 1 to 100 cc of D5W over 1 to

2 minutes2 minutes■■ Acute MIAcute MI

•• 8 to 12 grams per day in acute MI8 to 12 grams per day in acute MI


Vasoactive MedicationsVasoactive Medications

■■ EpinephrineEpinephrine■■ DopamineDopamine■■ NorepinephrineNorepinephrine■■ AtropineAtropine■■ NitroglycerinNitroglycerin


Epinephrine Epinephrine -- OverviewOverview

■■ Nonselective alpha and beta agonistNonselective alpha and beta agonist•• increased heart rate, SVR, ventricular increased heart rate, SVR, ventricular

contractilitycontractility■■ Onset Onset

•• 1 to 2 minutes1 to 2 minutes■■ Duration of action Duration of action

•• 2 to 10 minutes2 to 10 minutes


Epinephrine Epinephrine -- ContinuedContinued

■■ IndicationsIndications•• Cardiac ArrestCardiac Arrest•• Bronchospasm Bronchospasm •• Anaphylaxis / hypersensitivity reactionsAnaphylaxis / hypersensitivity reactions

■■ AdministrationAdministration•• Cardiac ArrestCardiac Arrest

–– 1 mg IV push every 3 1 mg IV push every 3 -- 5 minutes5 minutes–– escalating and high dose optionsescalating and high dose options


Epinephrine Epinephrine -- ContinuedContinued

•• EndotrachealEndotracheal–– 2 to 2.5 the IV dose diluted to 10 cc2 to 2.5 the IV dose diluted to 10 cc

■■ Adverse EffectsAdverse Effects•• may increase myocardial oxygen may increase myocardial oxygen

consumptionconsumption


Dopamine Dopamine -- OverviewOverview

■■ ActionsActions•• acts on dopaminergic, alpha and beta acts on dopaminergic, alpha and beta

receptorsreceptors■■ Low DoseLow Dose

•• dilatation of renal, mesenteric, coronary, dilatation of renal, mesenteric, coronary, and intracerebral vascular bedsand intracerebral vascular beds

•• improves organ perfusion and increases improves organ perfusion and increases urine outputurine output


Dopamine Dopamine -- ContinuedContinued

■■ Moderate Dose 2 Moderate Dose 2 -- 10 ug/kg/min10 ug/kg/min•• mostly beta effects mostly beta effects

–– inotropic, chronotropic on heartinotropic, chronotropic on heart–– increased cardiac outputincreased cardiac output

■■ High Dose >10 ug/kg/minHigh Dose >10 ug/kg/min•• Alpha effects predominateAlpha effects predominate

–– increased peripheral resistanceincreased peripheral resistance–– decreased blood flow to kidneydecreased blood flow to kidney


Norepinephrine Norepinephrine -- OverviewOverview

■■ Endogenous CatacholamineEndogenous Catacholamine•• powerful alpha agonistpowerful alpha agonist•• potent vasoconstrictorpotent vasoconstrictor

■■ Onset Onset •• 1 to 3 minutes1 to 3 minutes

■■ IndicationsIndications•• severe hypotension refractory to fluids and severe hypotension refractory to fluids and

other pressor agentsother pressor agents


Norepinephrine Norepinephrine -- ContinuedContinued

■■ Specific UsesSpecific Uses•• Septic ShockSeptic Shock•• refractory hypotension due to AMIrefractory hypotension due to AMI

■■ DosingDosing•• 0.5 to 1 ug/kg/min0.5 to 1 ug/kg/min

–– increase by 1 to 2 ug/kg/min every 3increase by 1 to 2 ug/kg/min every 3--5 min 5 min –– goal is systolic BP of 80 to 100 goal is systolic BP of 80 to 100


Norepinephrine Norepinephrine -- ContinuedContinued

■■ Adverse EffectsAdverse Effects•• ventricular irritabilityventricular irritability•• cardiac depressioncardiac depression•• decreased renal blood flowdecreased renal blood flow•• reflex bradycardiareflex bradycardia•• acute hypertensionacute hypertension

–– MAOI, TCA’sMAOI, TCA’s•• Extravasation necrosisExtravasation necrosis

–– pentolamine 5pentolamine 5--10 mg/10 cc subcutaneous10 mg/10 cc subcutaneous


Atropine OverviewAtropine Overview

■■ Antimuscarinic AgentAntimuscarinic Agent•• parasympatholytic / vagolyticparasympatholytic / vagolytic

–– increases SA node automaticity by blocking increases SA node automaticity by blocking vagus nervevagus nerve

■■ IndicationsIndications•• hemodynamically unstable bradycardiashemodynamically unstable bradycardias•• PEA, Asystole, bradyasystolic rhythmsPEA, Asystole, bradyasystolic rhythms•• anticholinergic propertiesanticholinergic properties


Atropine ContinuedAtropine Continued

■■ DoseDose•• 0.5 to 1 mg IV0.5 to 1 mg IV

■■ EndotrachealEndotracheal•• 1 to 2 mg IV (10 cc volume)1 to 2 mg IV (10 cc volume)

■■ Adverse effectsAdverse effects•• increased MVO2increased MVO2•• undesirable tachycardiaundesirable tachycardia•• precipitate ventricular arrhythmiasprecipitate ventricular arrhythmias


SummarySummary

■■ Pharmacology of antiarrhythmic and Pharmacology of antiarrhythmic and vasoactive medicationsvasoactive medications•• ActionsActions•• PharmacokineticsPharmacokinetics•• IndicationsIndications•• AdministrationAdministration•• Adverse EffectsAdverse Effects

pharmacology of antiarrhythmics and vasoactive substancesphillip l. coule, m.d. medical college of...

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