anti arrhythmic

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ANTIANTI- -ARRHYTHMICARRHYTHMICDRUGSDRUGS

Ma. Janetth B. Serrano, M.D.,DPBA



ANTI ± ARRHYTHMIC DRUGS

Cardiac Arrhythmias:

- 25% treated with digitalis

- 50% anesthetized patients

- 80% patients with AMI

reduced cardiac output

drugs or nonpharmacologic :

- pacemaker, cardioversion, catheter

ablation, surgery



ELECTRO- PHYSIOLOGY

OF

N ORMAL

CARDIAC

RHYTHM

SA node


AV node

ATRIA

His-Purkinje System

VENTRICLES



IO N IC B ASIS OF MEM BRA N E ELECTRICAL ACTIVITY

T ransmembrane potential of cardiac cellsis determined by the concentrations of the ff. ions: ±

Sodium, Potassium, CalciumT he movement of these ions producescurrents that form the basis of the cardiacaction potential




PHASES OF ACTIO N POTE N TIAL

Phase 0>R apid depolarization>O pening fast Na+channels Na+ rushes

in depolarization


Phase 1

>Limited depolarization>Inactivation of fastNa+ channels Na+ion conc equalizes> K+ efflux & Cl- influx

Phase 2

>Plateau Stage>Cell less permeable to Na+>Ca++ influx through slow

Ca++ channels>K+ begins to leave cell

Phase 3>R apid repolarization>Na+ gates closed>K+ efflux>Inactivation of slow

Ca++ channels

Phase 4>R esting Membrane Potential>High K+ efflux>Ca++ influx



FACTORS PRECIPITATI N G CARDIAC ARRHYTHMIAS :

1. Ischemiap H & electrolyte abnormalities80% ± 9 0% asstd with MI

2. Excessive myocardial fiber stretch/ scarred/diseased cardiac tissue

3. Excessive discharge or sensitivity to autonomictransmitters4. Excessive exposure to foreign chemicals & toxic

substances20% - 50% asstd with General Anesthesia10% - 20% asstd with Digitalis toxicity




Supraventricular:- Atrial T achycardia- Paroxysmal

T achycardia

- Multifocal AtrialT achycardia- Atrial Fibrillation- Atrial Flutter

V entricular:- W olff-Parkinson-

W hite (preexcitationsyndrome)

- Ventricular T achycardia

- Ventricular Fibrillation- Premature Ventricular

Contraction

ANTI ± ARHYTHMIC DRUGS

ARRHYTHMIAS :



CLASS I: Sodium Channel Blocking Drugs

IA - lengthen AP duration- Intermediate interaction with Na+ channels- Q uinidine, P rocainamide, D isopyramide

IB - shorten AP duration- rapid interaction with Na+ channels- L idocaine, M exiletene, T ocainide, P henytoin

IC - no effect or minimal AP duration- slow interaction with Na+ channels- F lecainide, P ropafenone, M oricizine




Increase AV nodal conductionIncrease P R intervalProlong AV refractorinessReduce adrenergic activityP ropranolol, E smolol, M etoprolol,S otalol

CLASS II: BE T A-B LO CKING AGEN T S




Prolong effective refractory period byprolonging Action Potential ± A miodarone - Ib utilide

± Bretylium - D ofetilide ± S otalol


CLASS III: P OT ASSIUM C HANNE L BLO CKERS




Miscellaneous:ADE N OSI N E inhibits AV conduction &

increases AV refractory period

MAG N ESIUM Na+/ K+ A T Pase, Na+, K+,Ca++ channels

POTASSIUM normalize K+ gradients




Depress pacemaker rateDepress conduction & excitabilitySlows repolarization & lengthens AP duration

due to K+ channel blockade with reduction of

repolarizing outward current reduce maximumreentry frequency slows tachycardia(+) alpha adrenergic blocking properties vasodilatation & reflex SA node rate

ANTI ± ARRHYTHMIC DRUGS ANTI ± ARRHYTHMIC DRUGS

CLASS I: Sodium Channel Blocking Drugs

CLASS IA : Q UI N IDI N E



CLASS I: S ODIUM C HANNE L BLO CKERS

P harmacokinetics: ± Oral rapid GI absorption

± 80% plasma protein binding ± 20% excreted unchanged in the urine

enhanced by acidity ± t½ = 6 hours ± Parenteral hypotension

D osage: 0.2 to 0.6 gm 2-4X a day






T herapeutic U ses: ± Atrial flutter & fibrillation ± Ventricular tachycardia ± IV treatment of malaria

D rug I nteraction: ± Increases digoxin plasma levels






T oxicity: ± Antimuscarinic actions inh. vagal effects ± Quinidine syncope (lightheadedness, fainting) ± Ppt. arrhythmia or asystole ± Depress contractility & BP ± W idening Q RS duration ± Diarrhea , nausea, vomiting ± Cinchonism ( HA, dizziness, tinnitus) ± Rare: rashes, fever, hepatitis, thrombocytopenia,etc





Less effective in suppressing abnormal ectopicpacemaker activity

More effective Na+ channel blockers indepolarized cells

Less prominent antimuscarinic action

(+) ganglionic blocking properties PV Rhypotension (severe if rapid IV or with severe LVdysfunction)



CLASS IA : PROCAI N AMIDE



PHARMACOKI N ETICS :

Oral, IV, IMN-acetylprocainamide (NAPA) major

metaboliteMetabolism: hepaticElimination: renalt½ = 3 to 4 hrs.






D osage:Loading IV ± 1 2 mg/kg at 0.3 mg/kg/min or lessrapidlyMaintenance ± 2 to 5 mg/min

T herapeutic U se:2nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI






T oxicity:- ppt. new arrhythmias- LE-like syndrome

- pleuritis, pericarditis, parenchymalpulmonary disease- ANA- nausea, D HA, rash, fever, hepatitis,

agranulocytosis






More marked cardiac antimuscarinic effectsthan quinidine slows AV conduction

P harmacokinetics:- oral administration- extensive protein binding- t½ = 6 to 8 hrs



CLASS IA : DISOPYRAMIDE



D osage : 1 50 mg T ID up to 1 gm/dayT herapeutic U se : Ventricular arrhythmiasT oxicity:

- negative inotropic action ( HF withoutprior myocardial dysfunction)- Urinary retention, dry mouth, blurredvision, constipation, worsening glaucoma



CLASS IA : DISOPYRAMIDE



Approved only in serious ventricular arrhythmiasBroad spectrum of action on theVery effective Na+ channel blocker but low affinityfor activated channelsMarkedly lengthens AP by blocking also K+channelsW eak Ca++ channel blocker Noncompetetive inhibitor of beta adrenoceptorsPowerful inhibitor of abnormal automaticity



CLASS IA : AMIODARO N E



Slows sinus rate & AV conductionMarkedly prolongs the Q T intervalProlongs Q RS duration

atrial, AV nodal & ventricular refractoryperiods

Antianginal effects ± due to noncompetetive & blocking property and block Ca++influx in vascular sm.m.

Perivascular dilatation - blocking propertyand Ca++ channel-inhibiting effects






P harmacokinetics:> t½ = 13 to 1 03 days> effective plasma conc: 1- 2 g/ml

D osage: - Loading ± 0.8 to 1. 2 g daily

- Maintenance ± 200 to 4 00 mg dailyD rug I nteraction: reduce clearance of warfarin,theophylline, quinidine, procainamide, flecainideT herapeutic U se: Supraventricular & Ventricular

arrhythmias






T oxicity:

- fatal pulmonary fibrosis- yellowish-brown microcrystals corneal deposits- photodermatitis- grayish blue discoloration

- paresthesias, tremor, ataxia & headaches- hypo - / hyperthyroidism- Symptomatic bradycardia or heart block- Ppt. heart failure- Constipation, hepatocellular necrosis, inflam¶n, fibrosis,

hypotension






Intravenous route onlyArrhythmias asstd with MIPotent abnormal cardiac activity suppressor Rapidly act exclusively on Na+ channels

Shorten AP, prolonged diastole extends timeavailable for recoverySuppresses electrical activity of DEP OL ARIZED,ARRHY T HMOGENIC tissues only



CLASS I B: LIDOCAI N E



Pharmacokinetics:- Extensive first-pass hepatic metabolism- t½ = 1 to 2 hrs

Dosages: loading- 1 50 to 200 mgmaintenance- 2-4 mg

Drug Interaction:propranolol, cimetidine ± reduce clearance

T herapeutic Use:DOC for suppression of recurrences of ventricular tachycardia & fibrillation in the firstfew days after AMI.






T oxicity: ± Ppt. SA nodal standstill or worsen impaired

conduction ± Exacerbates ventricular arrhythmias

± Hypotension in HF ± Neurologic: paresthesias, tremor, nausea,

lightheadedness, hearing disturbances,slurred speech, convulsions






Congeners of lidocaineOral route - resistant to first-pass hepaticmetabolismT ptic use: ventricular arrhythmiasElimination t½ = 8 to 20 hrs

Dosage: Mexiletene ± 6 00 to 1 200 mg/dayT ocainide ± 8 00 to 2400 mg/day

S/E: tremors, blurred vision, lethargy, nausea,rash, fever, agranulocytosis



CLASS I B: TOCAI N IDE & MEXILETE N E



Anti-convulsant with anti-arrhythmic propertiesSuppresses ectopic pacemaker activityUseful in digitalis-induced arrhythmiaExtensive, saturable first-pass hepatic metabolismHighly protein boundT oxicity: ataxia, nystagmus, mental confusion,

serious dermatological & BM reactions,hypotension, gingival hyperplasia

D/I: Quinidine, Mexiletene, Digitoxin, Estrogen,T heophyllin, Vitamin D



CLASS I B: PHE N YTOI N



Potent blocker of Na+ & K+ channelsNo antimuscarinic effectsUsed in patients with supraventricular arrhythmiasEffective in PVC¶sHepatic metabolism & renal eliminationDosage: 1 00 to 200 mg bid



CLASS IC : FLECAI N IDE



(+) weak -blocking activityPotency § flecainideAverage elim. t½ = 5 to 7 hrs.Dosage: 4 50 ± 9 00 mg T IDT ptic use: supraventricular arrhythmiasAdv. effects: metallic taste, constipation,arrhythmia exacerbation



CLASS IC : PROPAFE N O N E



Antiarrhythmic phenothiazine derivativeUsed in ventricular arrhythmiasPotent Na+ channel blocker

Donot prolong AP durationDosage: 200 to 3 00 mg orally tidAdv. effects: dizziness, nausea



CLASS IC : MORICIZI N E



AV nodal conduction time ( P R interval)

Prolong AV nodal refractoriness ± Useful in terminating reentrant arrhythmias that

involve the AV node & in controlling ventricular response in AF & A.fib.

Depresses phase 4 slows recovery of cells, slows

conduction & decrease automaticityReduces HR , decrease IC Ca 2+ overload & inhibit after depolarization automaticityPrevent recurrent infarction & sudden death inpatients recovering from AMI


CLASS II: BE TA AD REN OCEP T OR BLO CKERS



³ membrane stabilizing effect´Exert Na+ channel blocking effect at high dosesAcebutolol, metoprolol, propranolol, labetalol,pindolol

³ intrinsic sympathetic activity´

Less antiarrhythmic effectAcebutolol, celiprolol, carteolol, labetalol, pindolol

T herapeutic indications:Supraventricular & ventricular arrhythmias

hypertension





P ropranolol ± (+) MSAA ce b utolol ± as effective as quinidine in

suppressing ventricular ectopicbeats

E smolol - short acting hence usedprimarily for intra-operative &other acute arrhythmias

S otalol ± has K+ channel blockingactions (class III)



Specific agents:



Antihypertensive

Interferes with neuronal release of catecholaminesW ith direct antiarrhythmic propertiesLengthens ventricular AP duration & effective

refractory periodMarkedly strength of electrical stimulationneeded to induce V.fib. & delays onset of fibrillation after acute coronary ligation

(+) inotropic action


CLASS III: P OTASSIUM C HANNE L BLO CKERS

BRETYLIUM



Intravenous administrationDosage: 5 mg/kgT ptic Use: ventricular fibrillationIn emergency setting, during attemptedresuscitation from ventricular fibrillation whenlidocaine & cardioversion have failedS/E: postural hypotension***

ppt. ventricular arrhythmianausea & vomiting



BRETYLIUM



Nonselective beta-blocker that also slowsrepolarization & prolongs AP durationEffective antiarrhythmic agentUsed in supraventricular & ventricular arrhythmias in pediatric age groupRenal excretionDosage: 8 0 ± 3 20 mg bidT oxicity: torsades de pointes

beta-blockade symptoms



SOTALOL



Slows repolarizationProlong cardiac action potentialsMOA: > enhance inward Na+ current

> by blocking I kr-

> bothroutes: Oral, IV (1 mg over 1 0min)Clin. Uses: atrial flutter, atrial fibrillationT oxicity: T orsades de pointes



I BUTILIDE



A potential I kr- blocker Dosage: 250 -500 ug bidClin. Uses: Atrial flutter & fibrillation

Renal excretionT oxicity: T orsade de pointes



DOFETILIDE



Oral administration 20% bioavailabilityt½ = 7 hrsLiver metabolismDosage:IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min

Oral: 1 20 -64 0 mg daily, divided in 3-4 dosesT ptic use: SV T , AF, atrial fib, ventricular arrhythmiasT oxicity: AV block, can ppt. sinus arrest

constipation, lassitude, nervousness,peripheral edema


CLASS IV: CA LCIUM C HANNE L BLO CKERS

VERAPAMIL



Similar efficacy to verapamil insupraventricular arrhythmias & ratecontrol in atrial fibrillationBepridil

AP & Q T prolonging action ventricular arrhythmias but may ppt. torsade de pointesRarely used primarily to control refractoryangina


CLASS IV: CA LCIUM C HANNE L BLO CKERS

DILTIAZEM & B EPRIDIL



Indirectly alters autonomic outflow byincreasing parasympathetic tone &decreasing sympathetic tone

Results in decreased conduction time &increased refractory period in the AVnode


MISCE LLANE OUS AN T IARRHY T HMIC AGEN T S:

DIGITALIS



A nucleoside that occurs naturally in the bodyt½ § 1 0 secondsMOA: enhances K+ conductance & inhibitscAMP-induced Ca++ influx results in marked

hyperpolarization & suppression of Ca++-dependent APIV bolus: directly inhibits AV nodal conduction &

AV nodal refractory period



ADE N OSI N E



DOC for prompt conversion of paroxysmal SV T to sinus rhythm due to its high efficacy & veryshort duration of actionDosage: 6-1 2 mg IV bolusD/I:

theophylline, caffeine ± adenosine receptor blockersDipyridamole ± adenosine uptake inhibitor

T oxicity: flushing, S OB or chest burning, atrialfibrillation, headache, hypotension, nausea,paresthesia



ADE N OSI N E



Effective in patients with recurrentepisodes of torsades de pointes (MgS O 4 1to 2 g IV) & in digitalis-induced arrhythmiaMOA: unknown influence Na+/ K+

AT Pase, Na+ channels, certain K+ andCa++ channels



MAG N ESIUM



T herapy directed toward normalizing K+ gradients &pools in the bodyEffects of increasing serum K+:1. resting potential depolarizing action2. membrane potential stabilizing action

Hypokalemia:

risk of early & delayed afterdepolarizationectopic pacemaker activity esp if (+) digitalis

Hyperkalemia:Depression of ectopic pacemakersSlowing of conduction



POTASSIUM

anti arrhythmic

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