ANTI-ARRHYTHMIC DRUGS

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ANTI-ARRHYTHMICDRUGS

• Ma. Janetth B. Serrano, M.D.,DPBA

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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

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ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC
RHYTHM
ANTI ARRHYTHMIC DRUGS

• SA node

ATRIA
AV node
His-Purkinje System
VENTRICLES
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IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY
ANTI ARRHYTHMIC DRUGS

• 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

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PHASES OF ACTION POTENTIAL
ANTI ARRHYTHMIC DRUGS
Phase 2 gtPlateau Stage gtCell less permeable to
Na gtCa influx through slow Ca channels gtK
begins to leave cell
Phase 1 gtLimited depolarization gtInactivation of
fast Na channels? Na ion conc equalizes gt? K
efflux Cl- influx
Phase 3 gtRapid repolarization gtNa gates
closed gtK efflux gtInactivation of slow Ca
channels

• Phase 0
• gtRapid depolarization
• gtOpening fast Na
• channels? Na rushes in ?depolarization

Phase 4 gtResting Membrane Potential gtHigh K
efflux gtCa influx
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MECHANISMS OF ARRHYTHMIA
ANTI ARRHYTHMIC DRUGS

• ARRHYTHMIA absence of rhythm
• DYSRRHYTHMIA abnormal rhythm

ARRHYTHMIAS result from

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

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FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS
ANTI ARRHYTHMIC DRUGS

• 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

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ANTI ARHYTHMIC DRUGS
ARRHYTHMIAS

• Ventricular
• Wolff-Parkinson-White (preexcitation syndrome)
• Ventricular Tachycardia
• Ventricular Fibrillation
• Premature Ventricular Contraction

• Supraventricular
• - Atrial Tachycardia
• - Paroxysmal Tachycardia
• Multifocal Atrial Tachycardia
• - Atrial Fibrillation
• - Atrial Flutter

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CLASS I Sodium Channel Blocking Drugs
ANTI ARRHYTHMIC 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

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CLASS II BETA-BLOCKING AGENTS
ANTI ARRHYTHMIC DRUGS

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

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CLASS III POTASSIUM CHANNEL BLOCKERS
ANTI ARRHYTHMIC DRUGS
ANTI ARRHYTHMIC DRUGS

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

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CLASS IV CALCIUM CHANNEL BLOCKERS
ANTI ARRHYTHMIC DRUGS
ANTI ARRHYTHMIC DRUGS

• Blocks cardiac calcium currents
• ? slow conduction
• ? increase refractory period
• esp. in Ca dependent tissues (i.e. AV node)
• Verapamil, Diltiazem, Bepridil

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Miscellaneous
ANTI ARRHYTHMIC DRUGS

• ADENOSINE ? inhibits AV conduction
  increases AV refractory period
• MAGNESIUM ? Na/K ATPase, Na, K, Ca
  channels
• POTASSIUM ? normalize K gradients

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ANTI ARRHYTHMIC DRUGS
ANTI ARRHYTHMIC DRUGS
CLASS I Sodium Channel Blocking Drugs
CLASS IA QUINIDINE

• 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

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CLASS I SODIUM CHANNEL BLOCKERS
ANTI ARRHYTHMIC DRUGS
CLASS IA QUINIDINE

• 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

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ANTI ARRHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA QUINIDINE

• Therapeutic Uses
• Atrial flutter fibrillation
• Ventricular tachycardia
• IV treatment of malaria
• Drug Interaction
• Increases digoxin plasma levels

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ANTI ARRHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA PROCAINAMIDE

• 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)

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA PROCAINAMIDE

• PHARMACOKINETICS
• Oral, IV, IM
• N-acetylprocainamide (NAPA) ? major metabolite
• Metabolism hepatic
• Elimination renal
• t½ 3 to 4 hrs.

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA PROCAINAMIDE

• 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA PROCAINAMIDE

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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA DISOPYRAMIDE

• More marked cardiac antimuscarinic effects than
  quinidine ? slows AV conduction
• Pharmacokinetics
• - oral administration
• - extensive protein binding
• - t½ 6 to 8 hrs

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA AMIODARONE

• 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
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 a
  ß blocking property and block Ca influx in
  vascular sm.m.
• Perivascular dilatation - a blocking property
  and Ca channel-inhibiting effects

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA AMIODARONE

• Pharmacokinetics
• gt t½ 13 to 103 days
• gt 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IA AMIODARONE

• 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,
  inflamn, fibrosis, hypotension

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IB LIDOCAINE

• 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
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.

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IB TOCAINIDE MEXILETENE

• 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IB PHENYTOIN

• 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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IC FLECAINIDE

• Potent blocker of Na K channels
• No antimuscarinic effects
• Used in patients with supraventricular
  arrhythmias
• Effective in PVCs
• Hepatic metabolism renal elimination
• Dosage 100 to 200 mg bid

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IC PROPAFENONE

• () weak ß-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

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ANTI ARHYTHMIC DRUGS
CLASS I SODIUM CHANNEL BLOCKERS
CLASS IC MORICIZINE

• 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

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ANTI ARHYTHMIC DRUGS
CLASS II BETA ADRENOCEPTOR BLOCKERS

• ? 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

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ANTI ARHYTHMIC DRUGS
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

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ANTI ARHYTHMIC DRUGS
CLASS II BETA ADRENOCEPTOR BLOCKERS
Specific agents

• 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)

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS

• 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

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS
BRETYLIUM

• 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

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS
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 arrhythmia
• nausea vomiting

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS
SOTALOL

• 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

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS
IBUTILIDE

• Slows repolarization
• Prolong cardiac action potentials
• MOA gt enhance inward Na current
• gt by blocking Ikr-
• gt both
• routes Oral, IV (1 mg over 10min)
• Clin. Uses atrial flutter, atrial fibrillation
• Toxicity Torsades de pointes

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ANTI ARHYTHMIC DRUGS
CLASS III POTASSIUM CHANNEL BLOCKERS
DOFETILIDE

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

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ANTI ARHYTHMIC DRUGS
CLASS IV CALCIUM CHANNEL BLOCKERS
VERAPAMIL

• 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

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ANTI ARHYTHMIC DRUGS
CLASS IV CALCIUM CHANNEL BLOCKERS
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/min
• Oral 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

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ANTI ARHYTHMIC DRUGS
CLASS IV CALCIUM CHANNEL BLOCKERS
DILTIAZEM BEPRIDIL

• 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

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ANTI ARHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS
DIGITALIS

• Indirectly alters autonomic outflow by increasing
  parasympathetic tone decreasing sympathetic
  tone
• Results in decreased conduction time increased
  refractory period in the AV node

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ANTI ARHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS
ADENOSINE

• 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

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ANTI ARHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS
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

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ANTI ARHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS
MAGNESIUM

• 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

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ANTI ARHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS
POTASSIUM

• Therapy directed toward normalizing K gradients
  pools in the body
• Effects of increasing serum K
• 1. resting potential depolarizing action
• 2. membrane potential stabilizing action
• Hypokalemia
• ? risk of early delayed afterdepolarization
• ? ectopic pacemaker activity esp if () digitalis
• Hyperkalemia
• Depression of ectopic pacemakers
• Slowing of conduction