Editd anti arrhythmic

ANTI-ARRHYTHMICANTI-ARRHYTHMICDRUGSDRUGS

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

Cardiac Arrhythmias:

- 25% treated with digitalis

- 50% anesthetized patients

- 80% patients with AMI

reduced cardiac output

drugs or nonpharmacologic:

- pacemaker, cardioversion, catheter ablation, surgery

ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS

ELECTRO-PHYSIOLOGY

OF

NORMAL

CARDIAC

RHYTHM

SA node

AV node

ATRIA

His-Purkinje System

VENTRICLES


IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY

Transmembrane potential of cardiac cells is determined by the concentrations of the ff. ions:– Sodium, Potassium, Calcium

The movement of these ions produces currents that form the basis of the cardiac action potential


PHASES OF ACTION POTENTIAL

Phase 0

>Rapid depolarization

>Opening fast Na+

channels→ Na+ rushes in →depolarization

Phase 1

>Limited depolarization

>Inactivation of fast

Na+ 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

>Rapid repolarization

>Na+ gates closed

>K+ efflux

>Inactivation of slow Ca++ channels

Phase 4

>Resting Membrane Potential

>High K+ efflux

>Ca++ influx


MECHANISMS OF ARRHYTHMIA

ARRHYTHMIA – absence of rhythm

DYSRRHYTHMIA – abnormal rhythm

ARRHYTHMIAS result from:

1. Disturbance in Impulse Formation

2. Disturbance in Impulse Conduction Block results from severely depressed conduction Re-entry or circus movement / daughter impulse


FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS:

1. Ischemia pH & electrolyte abnormalities 80% – 90% asstd with MI

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

3. Excessive discharge or sensitivity to autonomic transmitters

4. Excessive exposure to foreign chemicals & toxic substances

20% - 50% asstd with General Anesthesia 10% - 20% asstd with Digitalis toxicity


Supraventricular:

- Atrial Tachycardia

- Paroxysmal Tachycardia

- Multifocal Atrial Tachycardia

- Atrial Fibrillation

- Atrial Flutter

Ventricular:- Wolff-Parkinson-

White (preexcitation syndrome)

- Ventricular Tachycardia

- Ventricular Fibrillation- Premature Ventricular

Contraction

ARRHYTHMIAS:


CLASS I: Sodium Channel Blocking Drugs IA - lengthen AP duration

- Intermediate interaction with Na+ channels

- Quinidine, Procainamide, Disopyramide IB - shorten AP duration

- rapid interaction with Na+ channels- Lidocaine, Mexiletene, Tocainide, Phenytoin

IC - no effect or minimal AP duration - slow interaction with Na+ channels- Flecainide, Propafenone, Moricizine


Increase AV nodal conduction Increase PR interval Prolong AV refractoriness Reduce adrenergic activity Propranolol, Esmolol, Metoprolol,

Sotalol

CLASS II: BETA-BLOCKING AGENTS


Prolong effective refractory period by prolonging Action Potential – Amiodarone - Ibutilide – Bretylium - Dofetilide– Sotalol

CLASS III: POTASSIUM CHANNEL BLOCKERS


CLASS IV: CALCIUM CHANNEL BLOCKERS

Blocks cardiac calcium currents

→ slow conduction

→ increase refractory period

*esp. in Ca++ dependent tissues (i.e. AV node)

Verapamil, Diltiazem, Bepridil


Miscellaneous: ADENOSINE → inhibits AV conduction &

increases AV refractory period

DIGITALIS → Indirectly alters autonomic outflow

MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels

POTASSIUM → normalize K+ gradients


Depress pacemaker rate Depress conduction & excitability Slows repolarization & lengthens AP duration

→ due to K+ channel blockade with reduction of repolarizing outward current → reduce maximum reentry frequency → slows tachycardia

(+) alpha adrenergic blocking properties → vasodilatation & reflex ↑ SA node rate

CLASS I: Sodium Channel Blocking Drugs

CLASS IA: QUINIDINE


CLASS I: SODIUM CHANNEL BLOCKERS

Pharmacokinetics:– Oral → rapid GI absorption – 80% plasma protein binding – 20% excreted unchanged in the urine → enhanced

by acidity– t½ = 6 hours– Parenteral → hypotension

Dosage: 0.2 to 0.6 gm 2-4X a day

CLASS IA: QUINIDINE



Therapeutic Uses:– Atrial flutter & fibrillation– Ventricular tachycardia– IV treatment of malaria

Drug Interaction:– Increases digoxin plasma levels

CLASS IA: QUINIDINE



Toxicity:– Antimuscarinic actions → inh. vagal effects– Quinidine syncope (lightheadedness, fainting)– Ppt. arrhythmia or asystole– Depress contractility & ↓ BP– Widening QRS duration– Diarrhea, nausea, vomiting– Cinchonism (HA, dizziness, tinnitus)– Rare: rashes, fever, hepatitis, thrombocytopenia,etc

CLASS IA: QUINIDINE


Less effective in suppressing abnormal ectopic pacemaker activity

More effective Na+ channel blockers in depolarized cells

Less prominent antimuscarinic action

(+) ganglionic blocking properties → ↓PVR → hypotension (severe if rapid IV or with severe LV dysfunction)


CLASS IA: PROCAINAMIDE


PHARMACOKINETICS:

Oral, IV, IM N-acetylprocainamide (NAPA) → major

metabolite Metabolism: hepatic Elimination: renal t½ = 3 to 4 hrs.




Dosage:

Loading IV – 12 mg/kg at 0.3 mg/kg/min or less rapidly

Maintenance – 2 to 5 mg/min

Therapeutic Use:

2nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI




Toxicity:

- ppt. new arrhythmias- LE-like syndrome- pleuritis, pericarditis, parenchymal pulmonary disease- ↑ ANA- nausea, DHA, rash, fever, hepatitis, agranulocytosis




More marked cardiac antimuscarinic effects than quinidine → slows AV conduction

Pharmacokinetics:

- oral administration

- extensive protein binding

- t½ = 6 to 8 hrs


CLASS IA: DISOPYRAMIDE


Dosage: 150 mg TID up to 1 gm/day Therapeutic Use: Ventricular arrhythmias Toxicity:

- negative inotropic action (HF without prior myocardial dysfunction)

- Urinary retention, dry mouth, blurred vision, constipation, worsening glaucoma


CLASS IA: DISOPYRAMIDE


Approved only in serious ventricular arrhythmias Broad spectrum of action on the Very effective Na+ channel blocker but low affinity

for activated channels Markedly lengthens AP by blocking also K+

channels Weak Ca++ channel blocker Noncompetetive inhibitor of beta adrenoceptors Powerful inhibitor of abnormal automaticity


CLASS IA: AMIODARONE


Slows sinus rate & AV conduction Markedly prolongs the QT interval Prolongs QRS duration ↑ atrial, AV nodal & ventricular refractory

periods Antianginal effects – due to noncompetetive α

& β blocking property and block Ca++ influx in vascular sm.m.

Perivascular dilatation - α blocking property and Ca++ channel-inhibiting effects




Pharmacokinetics:

> t½ = 13 to 103 days

> effective plasma conc: 1-2 μg/ml Dosage: - Loading – 0.8 to 1.2 g daily

- Maintenance – 200 to 400 mg daily Drug Interaction: reduce clearance of warfarin,

theophylline, quinidine, procainamide, flecainide Therapeutic Use: Supraventricular & Ventricular

arrhythmias




Toxicity:- 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 only Arrhythmias asstd with MI Potent abnormal cardiac activity suppressor Rapidly act exclusively on Na+ channels Shorten AP, prolonged diastole → extends time

available for recovery Suppresses electrical activity of DEPOLARIZED,

ARRHYTHMOGENIC tissues only


CLASS IB: LIDOCAINE


Pharmacokinetics:- Extensive first-pass hepatic metabolism

- t½ = 1 to 2 hrs Dosages: loading- 150 to 200 mg

maintenance- 2-4 mg Drug Interaction:

propranolol, cimetidine – reduce clearance Therapeutic Use:

DOC for suppression of recurrences of ventricular tachycardia & fibrillation in the first few days after AMI.


CLASS IB: LIDOCAINE


Toxicity:– Ppt. SA nodal standstill or worsen impaired

conduction– Exacerbates ventricular arrhythmias– Hypotension in HF– Neurologic: paresthesias, tremor, nausea,

lightheadedness, hearing disturbances, slurred speech, convulsions


CLASS IB: LIDOCAINE


Congeners of lidocaine Oral route - resistant to first-pass hepatic

metabolism Tptic use: ventricular arrhythmias Elimination t½ = 8 to 20 hrs Dosage: Mexiletene – 600 to 1200 mg/day

Tocainide – 800 to 2400 mg/day S/E: tremors, blurred vision, lethargy, nausea,

rash, fever, agranulocytosis


CLASS IB: TOCAINIDE & MEXILETENE


Anti-convulsant with anti-arrhythmic properties Suppresses ectopic pacemaker activity Useful in digitalis-induced arrhythmia Extensive, saturable first-pass hepatic metabolism Highly protein bound Toxicity: ataxia, nystagmus, mental confusion,

serious dermatological & BM reactions, hypotension, gingival hyperplasia

D/I: Quinidine, Mexiletene, Digitoxin, Estrogen, Theophyllin, Vitamin D


CLASS IB: PHENYTOIN


Potent blocker of Na+ & K+ channels No antimuscarinic effects Used in patients with supraventricular

arrhythmias Effective in PVC’s Hepatic metabolism & renal elimination Dosage: 100 to 200 mg bid


CLASS IC: FLECAINIDE


(+) weak β-blocking activity Potency ≈ flecainide Average elim. t½ = 5 to 7 hrs. Dosage: 450 – 900 mg TID Tptic use: supraventricular arrhythmias Adv. effects: metallic taste, constipation,

arrhythmia exacerbation


CLASS IC: PROPAFENONE


Antiarrhythmic phenothiazine derivative Used in ventricular arrhythmias Potent Na+ channel blocker Donot prolong AP duration Dosage: 200 to 300 mg orally tid Adv. effects: dizziness, nausea


CLASS IC: MORICIZINE


↑ AV nodal conduction time (↑ PR 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 automaticity

Reduces HR, decrease IC Ca2+ overload & inhibit after depolarization automaticity

Prevent recurrent infarction & sudden death in patients recovering from AMI

CLASS II: BETA ADRENOCEPTOR BLOCKERS


“membrane stabilizing effect” Exert Na+ channel blocking effect at high doses Acebutolol, metoprolol, propranolol, labetalol,

pindolol “intrinsic sympathetic activity”

Less antiarrhythmic effect Acebutolol, celiprolol, carteolol, labetalol, pindolol

Therapeutic indications: Supraventricular & ventricular arrhythmias hypertension



Propranolol – (+) MSA Acebutolol – as effective as quinidine in

suppressing ventricular ectopic beats

Esmolol - short acting hence used primarily for intra-operative & other acute arrhythmias

Sotalol – has K+ channel blocking actions (class III)


Specific agents:


Drugs that prolong effective refractory period by prolonging action potential

Prolong AP by blocking K+ channels in cardiac muscle (↑ inward current through Na+ & Ca++ channels)

Quinidine & Amiodarone → prolong AP duration Bretylium & Sotalol → prolong AP duration &

refractory period Ibutilide & Dofetilide → “pure” class III agents Reverse use-dependence



Antihypertensive Interferes with neuronal release of

catecholamines With direct antiarrhythmic properties Lengthens ventricular AP duration & effective

refractory period Markedly ↑ strength of electrical stimulation

needed to induce V.fib. & delays onset of fibrillation after acute coronary ligation

(+) inotropic action


BRETYLIUM


Intravenous administration Dosage: 5 mg/kg Tptic Use: ventricular fibrillation In emergency setting, during attempted

resuscitation from ventricular fibrillation when lidocaine & cardioversion have failed

S/E: postural hypotension***ppt. ventricular arrhythmianausea & vomiting


BRETYLIUM


Nonselective beta-blocker that also slows repolarization & prolongs AP duration

Effective antiarrhythmic agent Used in supraventricular & ventricular

arrhythmias in pediatric age group Renal excretion Dosage: 80 – 320 mg bid Toxicity: torsades de pointes

beta-blockade symptoms


SOTALOL


Slows repolarization Prolong cardiac action potentials MOA: > enhance inward Na+ current

> by blocking Ikr- > both

routes: Oral, IV (1 mg over 10min) Clin. Uses: atrial flutter, atrial fibrillation Toxicity: Torsades de pointes


IBUTILIDE


A potential Ikr- blocker Dosage: 250-500 ug bid Clin. Uses: Atrial flutter & fibrillation Renal excretion Toxicity: Torsade de pointes


DOFETILIDE


Blocks both activated & inactivated calcium channels

Prolongs AV nodal conduction & effective refractory period

Suppress both early & delayed afterdepolarizations

May antagonize slow responses in severely depolarized tissues

Peripheral vasodilatation → HPN & vasospastic disorders


VERAPAMIL


Oral administration → 20% bioavailability t½ = 7 hrs Liver metabolism Dosage:

IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/minOral: 120-640 mg daily, divided in 3-4 doses

Tptic use: SVT, AF, atrial fib, ventricular arrhythmias Toxicity: AV block, can ppt. sinus arrest

constipation, lassitude, nervousness, peripheral edema


VERAPAMIL


Similar efficacy to verapamil in supraventricular arrhythmias & rate control in atrial fibrillation

Bepridil AP & QT prolonging action→ ventricular

arrhythmias but may ppt. torsade de pointes Rarely used → primarily to control refractory

angina


DILTIAZEM & BEPRIDIL


Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone

Results in decreased conduction time & increased refractory period in the AV node

MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

DIGITALIS


A nucleoside that occurs naturally in the body t½ ≈ 10 seconds MOA: enhances K+ conductance & inhibits

cAMP-induced Ca++ influx → results in marked hyperpolarization & suppression of Ca++-dependent AP

IV bolus: directly inhibits AV nodal conduction & ↑ AV nodal refractory period


ADENOSINE


DOC for prompt conversion of paroxysmal SVT to sinus rhythm due to its high efficacy & very short duration of action

Dosage: 6-12 mg IV bolus D/I:

theophylline, caffeine – adenosine receptor blockers

Dipyridamole – adenosine uptake inhibitor Toxicity: flushing, SOB or chest burning, atrial

fibrillation, headache, hypotension, nausea, paresthesia


ADENOSINE


Effective in patients with recurrent episodes of torsades de pointes (MgSO4 1 to 2 g IV) & in digitalis-induced arrhythmia

MOA: unknown → influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channels


MAGNESIUM


Therapy directed toward normalizing K+ gradients & pools in the body

Effects of increasing serum K+:1. resting potential depolarizing action2. membrane potential stabilizing action

Hypokalemia: ↑ risk of early & delayed afterdepolarization ↑ ectopic pacemaker activity esp if (+) digitalis

Hyperkalemia: Depression of ectopic pacemakers Slowing of conduction



POTASSIUM

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Editd anti arrhythmic