Basic and Clinical Pharmacology

C14 AGENTS USED IN CARDIAC ARRHTHYMIAS

ANITA Q. SANGALANG, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

 Cardiac arrhythmias commonly occur in the presence of preexisting heart disease

 Most common cause of death in patients who have had a myocardial infarction
 Most serious manifestation of digitalis toxicity
 Often associated with
o Anesthesia
o Hyperthyroidism
o Electrolyte disorders

CARDIAC FUNCTION
 Generation of an impulse in the SA node
 Conduction through the atrial muscle through the AV node, through the purkinje
conduction system to the ventricular muscle
 Requires normal action potential (dependent on sodium, calcium and potassium channel
activity)
 Any rhythm that is not a normal sinus rhythm (NSR) is an arrhythmia
 2 major mechanisms for arrhythmia
1) abnormal automaticity
2) abnormal reentrant conduction

 Examples of arrhythmia
o Atrial flutter
o Atrial fibrillation (AF)
o AV nodal reentry
o Premature ventricular beats (PVBs)
o Ventricular tachycardia (VT)
o Ventricular fibrillation (VF)
 Torsade de pointes
o Ventricular arrhythmia
o Often induced by antiarrhythmic and other drugs

 Cellular action potentials

 Ion fluxes through voltage-gated channels and carrier mechanisms
 Sodium current (INA)
 Dominates the upstroke of the action potential (phase O)
 Most important determinant of conduction of the action potential (AP)
 Cellular action potentials
o Ion fluxes through voltage-gated channels and carrier mechanisms
 Sodium current (INA)
o Dominates the upstroke of the action potential (phase O)
o Most important determinant of conduction of the action potential (AP)
 Calcium current (ICA)
o Plateau of the AP (phase 2) is dominated by (ICA)
 Potassium current (IK)
o Rapid repolarization (phase 3)

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 ACTION POTENTIAL PHASES
0: Upstroke
1: Early-fast repolarization
2: Plateau
3: Repolarization
4: Diastole

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 P WAVE - atrial depolarization
QRS - ventricular muscle depolarization
T WAVE - ventricular repolarization
PR INTERVAL - conduction time from atrium to ventricle
QRS - intraventricular conduction time
QT interval - duration of ventricular AP

 Refractory period of the cardiac cell

o Function of how rapidly sodium channels recover from inactivation
o Depends on
o Membrane potential
o Extracellular potassium concentration
o Actions of drugs that bind to the sodium channel
 Sodium pump and sodium-calcium exchanger are critical for the maintenance of the ion
gradients on which Na+, Ca2+ and K+ currents depend
 Antiarrhythmic drugs act on
o One or more of the 3 major currents (INA, ICA, IK)
o Second messenger systems that modulate these currents

DRUG CLASSIFICATION
 Based on the channel or receptor involved
Class I. Sodium channel blockers
Class II. Beta adrenoceptor blockers

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 Class III. Potassium channel blockers
Class IV. Calcium channel blockers
Miscellaneous group includes adenosine, digitalis, potassium ion, and
magnesium ion

CLASS I ANTIARRHYTHMICS (LOCAL ANESTHETICS)

 Subdivided on the basis of their effects on AP duration

 CLASS IA
o Prolong the AP
o Procainamide
 CLASS IB
o Shorten the AP in some cardiac tissues
o Lidocaine
 CLASS IC
o No effect on AP duration
o Flecainide

 Slow or block conduction (especially in depolarized cells)

 Slow or abolish abnormal pacemakers wherever these processes depend on sodium
channels
 Bind to their receptors much more readily when the channel is open or inactivated than
when it is fully repolarized and recovered from its previous activity
 Block channels in abnormal tissues more effectively than channels in normal tissue
 Use dependent or state dependent (they selectively depress tissue that is frequently
depolarizing (i.e., fast tachycardia) or relatively depolarized during rest (e.g., hypoxia)

 Affect both atrial and ventricular arrhythmias

 Block INA slow conduction velocity in the atria, purkinje and ventricular cells increased
QRS duration
 Procainamide
o Used in all types of arrhythmias (both atrial and ventricular)
o Used in arrhythmias during the acute phase of myocardial infarction
o Causes hypotension (IV) and a reversible syndrome similar to lupus erythematosus
(LE)
 Quinidine and disopyramide have similar effects
 Quinidine
o Reduces the clearance of digoxin and may increase serum concentration
significantly
o Causes
o Cinchonism (headache, vertigo and tinnitus)
o Cardiac depression
o GI upset
o Autoimmune reactions
 Amiodarone
o Classified as CLASS III
o Has typical class IA actions
o Has the greatest AP-prolonging effect
o Disopyramide
o Marked antimuscarinic (atropine-like) effects

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 o May precipitate heart failure
 All class IA drugs may precipitate new arrhythmias
 Torsade de pointes is particularly associated with quinidine and other drugs that prolong
AP duration except amiodarone
 Hyperkalemia exacerbates cardiac toxicity of class I drugs
 Treated with sodium lactate to reverse drug-induced arrhythmias and pressor
sympathomimetics to reverse drug- induced hypotension

CLASS IB
 Selectively affects ischemic or depolarized Purkinje and ventricular tissue and has little
effect on atrial tissue reduces AP duration
 Slows recovery of sodium channels from inactivation,
 Does not shorten ERP
 Little effect on normal cardiac muscle
 Little effect on the ECG

 Lidocaine
o Prototype IB drug
o Useful in acute ventricular arrhythmias
o Usually given IV but intramuscular (IM) is possible
o Never given orally because of very high first-pass effect and the metabolites are
cardiotoxic
 Mexiletine and tocainide
o Have similar effects with lidocaine
o Given orally
o Tocainide may cause agranulocytosis
 Phenytoin
o An anticonvulsant and not a true local anesthetic
o Sometimes classified with the class IB
o Can be used to reversed digitalis- induced arrhythmias
o Resembles lidocaine in lacking significant effect on the ECG
o Rarely cause typical local anesthetic toxicity
o CNS stimulation including convulsions
o Cardiovascular depression (minor)
o Allergy (rashes; anaphylaxis)
o They may also precipitate arrhythmias but is less common
o Hyperkalemia increases cardiac toxicity

CLASS IC
 These drugs have no effect on AP ventricular duration or QT interval
 Powerful depressants of the sodium current increase the QRS duration
 Can markedly slow down atrial and ventricular conduction velocity
 Cause local anesthetic-like CNS toxicity
 Hyperkalemia increases the cardiac toxicity
 Flecainide
o Used only for refractory ventricular tachycardias that tend to progress to ventricular
fibrillation at unpredictable times ”sudden death”
o For intractable supraventricular arrhythmias
 Encainide, moricizine and propafenone are also members of these class
o More likely to exacerbate arrhythmias (proarrhythmic effect)

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 o Restricted to use in arrhythmias that fail to respond to other drugs

CLASS II ANTIARRHYTHMICS (BETA BLOCKERS)

Propranolol and Esmolol

 Cardiac beta adrenoceptor blockade and reduction in cAMP reduction of sodium and
calcium currents and suppression of abnormal pacemakers
 AV node is particularly sensitive
 Prolongs PR interval
 Used as prophylactic drugs in patients who have had MI
 Protective effect for 2 years or longer after the MI

 Esmolol
o Very short-acting
o Given IV
 Toxicities are the same in patients with arrhythmias as in patients with other conditions
 More prone to beta-blocker induced depression of CO but with proper use, it reduces
chronic heart failure and reduces the incidence of potentially fatal arrhythmias in this
condition

CLASS III ANTIARRHYTHMICS (POTASSIUM IK CHANNEL BLOCKERS)

 Causes blockade of IK potassium channels (repolarization) prolong AP duration increase
ERP increase QT interval
 Produces this effect in most cardiac cells, seen in ECG as increase QT
 Sotalol and Ibutilide are prototypes
 Sotalol
o Chiral compound (2 optical isomers)
o One isomer is an effective beta-blocker
o Both isomers have antiarrhythmic effect
o More commonly used and is available by the oral route
o May precipitate torsade de pointes as well as signs of excessive beta-blockade like
sinus bradycardia or asthma
 Dofetilide
o Newer drug
o Recommended for atrial flutter and fibrillation together with ibutilide
o Most important toxicity is induction of torsade de pointes
 Bretylium
o An older drug that combines sympathoplegia and K-channel blocking effect
o Used only in the treatment of refractory post-myocardial infarction arrhythmias
o May precipitate new arrhythmias or marked hypotension
 Amiodarone
Effective in most a of arrhythmias
 Most efficacious of all the drugs
 Broad spectrum, it blocks sodium, calcium, and potassium channels and beta
adrenoceptors
 Because of its toxicities, it is used mainly for arrhythmias resistant to other drugs
 Causes microcrystalline deposits in the cornea and skin, thyroid dysfunction (hyper or
hypothyroidism), paresthesias, tremor, and pulmonary fibrosis
 Rarely causes new arrhythmias

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CLASS IV ANTIARRHYTHMICS (CALCIUM CHANNEL BLOCKERS)
 Cause a state- and use-dependent selective depression of calcium current in tissues
that require the participation of L-type calcium channels ----- decreased conduction
velocity ------ increased ERP ----- increased PR interval
 Effective for converting AV nodal reentry (nodal tachycardia) to normal sinus rhythm
 Major use in the prevention of nodal arrhythmias in patient prone to recurrence
 Orally active
 Verapamil
o Also available in IV form
o Most important toxicity is excessive pharmacologic effect (cardiac contractility, AV
conduction and BP are significantly depressed)
 Diltiazem
o Effective but is not approved for this purpose

 Nifedipine
o Not useful because they evoke compensatory mechanism to the heart

MISCELLANEOUS ANTIARRHYTHMICS DRUGS

 ADENOSINE
o Normal component of the body
o When given in high doses, as IV bolus, slows or completely blocks conduction in the
AV node
o Very low toxicity
o Drug of choice for AV nodal arrhythmia
o Toxicity includes
 Flushing and hypotension (short duration of action 15 sec)
 Chest pain and dyspnea
 Does not limit its use
 DIGITALIS
o Slows AV conduction to protect the ventricles from excessively high rates
o Treatment of rapid atrial or AV nodal arrhythmias
 POTASSIUM ION
o Depresses ectopic pacemakers including those caused by digitalis toxicity
 MAGNESIUM ION
o Similar depressive effects on digitalis-induced toxicity
o Effective in some cases of torsade de pointes
 IVABRADINE
o The localized expression of the “funny” current If in the SA node and its important
role in pacemaker activity provide an attractive therapeutic target for heart rate
control
o Selective blocker of If
o It slows pacemaker activity by decreasing diastolic depolarization of sinus node cells
o It is an open channel blocker that shows use-dependent block
o Unlike other heart rate-lowering agents such as β blockers, it reduces heart rate
without affecting myocardial contractility, ventricular repolarization, or intracardiac
conduction

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  RANOLAZINE
o Originally developed as an antianginal agent
o Antiarrhythmic properties that are dependent on the blockade of multiple ion
channels.
+
o Blocks the early INa and the late component of the Na current, INaL, the latter
having a tenfold higher sensitivity to the drug.
o Antiarrhythmic proper- ties in both atrial and ventricular arrhythmias.
o It prevents the induction of and may terminate atrial fibrillation
 VERNAKALANT
o Multi-ion channel blocker, placing it in several classes of antiarrhythmic action
o It causes frequency- and voltage- dependent block of the early and late components
of the sodium current
o The muscarinic potassium current IKACh, which is constitutively activated in atrial
fibrillation, is blocked

NONPHARMACOLOGIC TREATMENT OF ARRHYTHMIAS

 External defibrillation
 Implanted defibrillators
 Implanted pacemakers
 Radiofrequency ablation of arrhythmogenic foci via a catheter

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