Drugs used in Cardiac Arrhythmias

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Drugs used in Cardiac Arrhythmias

• Dr.V.V.Gouripur

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What is an arrhythmia?

• The rhythm of the heart is normally generated and
  regulated by pacemaker cells within the
  sinoatrial (SA) node, which is located within the
  wall of the right atrium. 
• SA nodal pacemaker activity normally governs the
  rhythm of the atria and ventricles. 
• Normal rhythm is very regular, with minimal
  cyclical fluctuation.  Furthermore, atrial
  contraction is always followed by ventricular
  contraction in the normal heart.
• When this rhythm becomes irregular, too fast
  (tachycardia) or too slow (bradycardia), or the
  frequency of the atrial and ventricular beats are
  different, this is called an arrhythmia. 
• The term "dysrhythmia" is sometimes used and has
  a similar meaning.

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arrhythmia

• Def'n
• 1. an abnormality of rate, regularity, or site of
  origin of the cardiac impulse, or
• 2. a disturbance in conduction that causes an
  alteration of the normal sequence of
• activation of the atria and ventricles
• NB these may arise from abnormal impulse
  generation, altered conduction, or both

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• Normal Cardiac excitation requires
• a pacemaker (normally the SA node) and
• follower cells
• Conducting fibers
• Myocardium.
• Between the atria and ventricle is the AV node
  which acts as a filter to prevent too frequent
  activation of the ventricles by supraventricular
  tachyarrhythmias.

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1. Action potentials and conduction in the
   conducting tissue, atria and ventricles occur due
   to entry of extracellular sodium through fast Na
   channels.
2. SA and AV nodes do not use fast Na channels.
   Instead they rely solely on Ca channels for
   action potentials and conduction.
3. SA node is the dominant pacemaker because it
   beats at a rate faster than the AV node

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• 4. Each SA nodal beat is accompanied by one wave
  of activation affecting the atria, AV node,
  Bundle branches, Purkinje fibers and myocardium.
• 5. The heart then rests during diastole before
  the next sinus beat occurs.

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The normal cardiac action potential in non
conducting tissues (e.g. ventricles)

• Phase 0-Due to opening of fast Na channels (when
  the threshold potential ( -70mV) is reached)
• There is a massive influx of Na into the muscle
  cell, causing a rapid depolarisation
• Phase 1- Partial repolarisation-Due to closure
  of the Na channels
• Phase 2-Plateau phase-Due to opening of slow Ca2
  channels

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• Phase 3- Repolarisation-Due to closure of the
  Ca2 channels and opening of the K channels,
  causing a massive loss ofK out of the cell
• Phase 4-Pacemaker potential
• This phase is unimportant in non conducting
  heart tissues.
• In conducting tissues (SA and AV nodes) the
  pacemaker potential gradually depolarises during
  diastole to reach the threshold potential,
  resulting in a spike

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• Conducting tissues always fire action potentials,
  at varying frequencies (they have intrinsic
  firing capacity). The SA node fires the fastest
  and so assumes the role of the pacemaker.
• Non conducting tissues need a jump start
  impulse from the conducting tissues in order to
  depolarise (i.e. they are not capable of
  intrinsically firing, unless under pathological
  conditions)

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Mechanism of Arrhythmia

• Enhanced automaticity
• Triggered automaticity (normal action potential
  is interrupted or followed by an abnormal
  depolarization)
• Reentry (abnormal impulse conduction)

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• Sometimes the normal wave of activation gets
  fractionated, giving rise to multiple beats
  before the next sinus beat comes.
• This is called reentry

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Re-entry
Purkinje fibre
Damage e.g. thrombotic clot causes muscle to
become ischaemic
Ventricular muscle
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Re-entry

• Caused by unidirectional block, usually in
  diseased tissues
• Probably the cause of many arrhythmias
• Can occur in atria, ventricles and nodal tissue
• APs conducted only one-way, but conduction is
  slower
• Causes a constant loop of APs re-exciting
  repeatedly (Circus Rhythm)
• The tissue begins to beat independently of input

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Re-entry

• Reentry can occur in any part of the heart.
• It can be stopped by making the unidirectionally
  blocked tissue become bidirectionally blocked.
• It can also be blocked by converting
  unidirectional conduction into bidirectional
  conduction.
• i) This can be done with drugs that block Na
  channels directly or indirectly.

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• Two special cases of reentry in the AV node are
• Paroxysmal supraventricular tachycardia - cause
  not clear is often short lasting

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• The other special cause of reentry in the AV node
  is
• Wolf Parkinson White Syndrome where the normal
  slowly conducting AV node is straddled by a fast
  conducting Accessory fibre which resembles atrial
  tissue.

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ECTOPIC PACEMAKER

• SPONTANEOUS PACEMAKER (Purkinje Fiber)
• TRIGGERED AUTOMATICITY
• Delayed afterdepolarisation
• Early afterdepolarisation

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ECTOPIC PACEMAKER

• DELAYED AFTERDEPOLARISATION
• Abnormal Oscillatory Ca Release from SR
• Caused by Ca Overload
• Elevated Cytosolic Ca Causes Increased Membrane
  Conductance to Cations
• This leads to Oscillatory Depolarization of Cell
  Membrane

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ECTOPIC PACEMAKER

• EARLY AFTERDEPOLARIZATION
• Sometimes caused by prolonged action potential
  duration
• Due to oscillatory fluctuation of delayed K
  channels
• May also be due to oscillatory inactivation of
  calcium channels

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What causes arrhythmias?

• coronary artery disease-When cardiac cells lack
  oxygen, they become depolarized, which lead to
  altered impulse formation and/or altered impulse
  conduction.
• Changes in cardiac structure that accompany heart
  failure (e.g., dilated or hypertrophied cardiac
  chambers), can also precipitate arrhythmias. 
• Finally, many different types of drugs
  (including antiarrhythmic drugs) as well as
  electrolyte disturbances (primarily K and Ca)
  can precipitate arrhythmias.

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Types of Arrhythmias(caused by the described
mechanisms)

• Atrial flutter atria beat rapidly at 250-350
  beats per min
• Supraventricular paroxysmal tachycardia no more
  than 200 beats per min. Trivial compared to the
  other types
• Atrial fibrillation 350-600 beats per min.
  Irregular, uncoordinated contractions,
  fragmentary, ventricles beat at one fifth the
  rate of the atria, but not regularly. If chronic,
  then the condition is serious
• Ventricular fibrillation immediate cause of
  death in many fatal causes of MI and
  electrocution. Ventricles pump too fast. Use
  electric paddles in order to disrupt contraction
  pattern and re-instate normal rhythm
• Ventricular tachycardia leads to a series of
  rapid contractions called ventricular
  extrasystole

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Clinical symptoms

• palpitation or fluttering sensation in the
  chest. 
• a skipped beat -forceful contraction and a
  thumping sensation in the chest. .)
• Patients may experience dyspnea (shortness of
  breath), syncope (fainting), fatigue,, chest pain
  or cardiac arrest.

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Treatment

• Reassurance is important. Most cardiac
  arrhythmias cause no symptoms, have no
  hemodynamic importance, and have no prognostic
  significance but may cause anxiety in a patient
  who becomes aware of them.
• In rare cases, a precipitating factor may be
  identified and modified (eg, excessive intake of
  caffeine or alcohol).

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Drug treatment

• Antiarrhythmic drug therapy is the mainstay of
  management for most important arrhythmias.

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Classification of Antiarrhythmic Drugs based on
Drug Action( Table1)
CLASS ACTION DRUGS
I. Sodium Channel Blockers
1A. Moderate phase 0 depression and slowed conduction (2) prolong repolarization Quinidine, Procainamide, Disopyramide
1B. Minimal phase 0 depression and slow conduction (0-1) shorten repolarization Lidocaine
1C. Marked phase 0 depression and slow conduction (4) little effect on repolarization Flecainide
II. Beta-Adrenergic Blockers Propranolol, esmolol
III. K Channel Blockers (prolong repolarization) Amiodarone, Sotalol, Ibutilide
IV. Calcium Channel Blockade Verapamil, Diltiazem
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Mechanism of Action of Antiarrhythmic Drugs

• Stop Automaticity
• Increase Membrane Threshold for Activation
• Cause Membrane Hyperpolarization

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Mechanism of Action of Antiarrhythmic Drugs

• Stop Reentry
• Convert Unidirectional Block to Bidirectional
  Block
• Abolish Unidirectional Block

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Mechanism of Action of Antiarrhythmic Drugs

• Improve Ventricular Function
• Slow ventricular rate
• Increase ventricular filling
• Increase cardiac output

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Class I Na Channel Blockers

• Binds to Na channels and prevent conduction of
  ions
• Bind preferentially to the open channel state
  (i.e. use-dependent)
• The more the channel is used, the more drug is
  bound

Na CHANNEL BLOCKERS
REST
REFRACTORY
OPEN

• Useful in conditions where channels open
  frequently
• Sub-classified into 3 groups Ia, Ib and Ic

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Quinidine (class Ia)

• This broad-spectrum drug is effective for the
  suppression of VEBs and VT and for the control of
  narrow QRS tachycardias, including atrial flutter
  and fibrillation.
• It is one of the few drugs that may convert AF to
  sinus rhythm.
• Elimination half-life (t1/2) is 6 to 7 h.
• If an initial test dose of quinidine sulfate is
  tolerated, the maintenance dosage is usually 200
  to 400 mg po q 4 to 6 h.
• Dosing should be adjusted so that QRS duration is
  lt 140 msec and QT is lt 550 msec.

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Procainamide (class Ia)

• The main metabolite, N-acetyl procainamide, also
  has antiarrhythmic effects and contributes to
  procainamide's efficacy and toxicity.
• It can be given cautiously IV as 100 mg over 1 to
  2 min repeated q 5 min to a usual maximum total
  dose of 600 mg (rarely up to 1 g) while
  monitoring BP and ECG.
• Oral procainamide has a short elimination t1/2 (lt
  4 h), requiring frequent dosing or use of
  sustained-release preparations. The usual oral
  dosage is 250 to 625 mg q 3 or 4 h..

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Adverse reactions

• QRS widening by 25 and QT prolongation to 550
  msec suggest toxicity.
• Almost all patients receiving long-term therapy
  (gt 12 mo) develop serologic abnormalities
  (notably a positive antinuclear factor test), and
  
• up to 40 have symptoms and signs of
  hypersensitivity (arthralgia, fever, pleural
  effusions

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Disopyramide

• It has an elimination t1/2 of 5 to 7 h.
• Oral dosing is usually 100 or 150 mg q 6 h.
  Parenteral dosing, not available.
• Disopyramide has powerful anticholinergic
  effects that play only a minor role in arrhythmia
  management but are responsible for urinary
  retention and glaucoma
• less serious ADR (eg, dry mouth, problems of
  accommodation, bowel upset, may contribute to
  noncompliance.
• Bradycardia may occur

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Qunidine adverse reactions

• About 30 of patients develop.
• GI problems (diarrhea, colic, flatulence) are
  most common, but fever, thrombocytopenia, and
  liver function abnormalities also occur.
• Quinidine syncope is a potentially dangerous
  idiosyncratic and unpredictable effect caused by
  torsade de pointes

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TYPE 1A AGENTSProcainamide

• Depresses hemodynamics
• Effective against atrial ventricular
  arrhythmia
• Paradoxical tachycardia

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PROCAINAMIDE

• Prolongation of QRS complex
• Paradoxical tachycardia - prevented by
  prophylactic digoxin
• Syncope - due to Torsade de pointes
• SLE-like Syndrome
• reversible not associated with nephropathy
• Procainamide not good for therapy gt 6 months
• greater toxicity in fast acetylators
• Bone marrow depression

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TYPE 1B AGENTS Lidocaine Mexiletine Tocainide

• Suppress automaticity
• Shorten action potential duration
• Prolong refractory period
• Decrease conduction (especially in ischemic
  therefore more depressed tissue)
• Lesser hemodynamic depression than with
  Procainamide

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Lidocaine

• . It produces minimal myocardial depression and
  has little effect on the sinus node, atria, or
  atrioventricular node but acts powerfully on
  His-Purkinje's and ventricular myocardial tissue.
• It can suppress the ventricular arrhythmias that
  complicate MI (VEBs, VT) and reduce the incidence
  of primary ventricular fibrillation (VF) when
  given prophylactically in early acute MI.

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• It is used only parenterally. The usual regimen
  is 100 mg IV over 2 min followed by 50 mg IV 5
  min later if the arrhythmia has not reverted. An
  infusion of 4 mg/min (2 mg/min in patients gt 65
  yr) should then be started. If it is continued
  for gt 12 h, toxic levels may be reached.
• Adverse effects
• neurologic (tremor, convulsions) rather than
  cardiac.
• Drowsiness, delirium, and paresthesias may occur
  with too-rapid administration.
• Mexiletine, similar to lidocaine, has few
  cardiovascular adverse effects, but GI (nausea,
  vomiting) and CNS (tremor, convulsions) effects
  may limit its acceptability.

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• Class Ic drugs are among the most powerful
  antiarrhythmics but have been associated with a
  significant risk of proarrhythmia and depression
  of cardiac contractility

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LIDOCAINE

• Lidocaine is effective mainly in ventricular
  tachyarrhythmias
• Lidocaine is useless orally
• extensive first pass metabolism in the liver
• metabolite is proconvulsant not antiarrhythmic
• Hence Lidocaine given IV

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LIDOCAINE

• Useless in any supraventricular arrhythmia
• Half life of lidocaine
• distribution phase is 9 min
• elimination phase is 100 min
• Therefore it is given as a bolus combined with
  infusion initially as well as with each increase
  in dose

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LIDOCAINE

• Lidocaine is ideal in life-threatening
  situations
• Effective
• Rapid action
• Short duration
• Toxicity
• Cardiac depression
• CNS stimulation, tinnitus, convulsion, post-ictal
  depression

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TYPE 1C AGENTPropafenone Flecainide
Encainide

• Block sodium entry and beta receptors
• Minimal change in action potential duration
• Suppress automaticity
• Very useful in WPW syndrome
• Decrease cardiac contractility (dont give is
  cardiac mechanical function is poor)
• Metallic taste on prolonged use

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TYPE 2 AGENTS (b blockers)Propranolol
Metoprolol Esmolol

• Suppress automaticity (decreased sympathetics)
• Shorten action potential duration
• Decrease conduction in SA AV nodes

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Class III - Drugs that prolong repolarisation

• Prolonging the cardiac AP by increasing the
  refractory period
• Also have interactions with the ANS
• Have a diverse pharmacology which is poorly
  understood
• Examples are bretyllium and amiodarone
• Numerous side effects e.g. hepatic injury,
  hypotension
• Bretyllium only used for life-threatening
  ventricular arrhythmias, amiodarone for recurrent
  ventricular fibrillation

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Class IV Ca2 channel blockers

• Verapamil, diltiazem, nifedipine
• Block Ca2 channels in the plasma membrane
  especially L-type channels)
• Reduce slow inward current and force of
  contraction
• Also slow conduction of AV node due to calcium
  channel blockade
• Verapamil used in acute paroxysmal tachycardia

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Classification of arrhythmias and drugs of choice

• Atrial fibrillation and flutter?
• ?Digoxin is the drug of choice to slow
  ventricular response?
• ?Alternative drugs that are widely used include
  verapamil and propanolol?
• ?Digoxin, verapamil, and possibly beta-blockers
  may be hazardous in patients with
  Wolf-Parkinson-White syndrome (catheter ablation
  of extra-nodal pathways in WPW is successful)?
• ?Subclass IA drugs (quinidine, procainamide,
  disopyramide) have been used for long-term
  suppression, but preliminary studies indicate
  higher mortality than placebo?
• ?Class III (amiodarone) and Subclass IC
  (flecainide, encainide, and propafenone) are also
  effective for suppression, but may be associated
  with higher mortality than no drug therapy?

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Supraventricular tachycardia

• ?Vagotonic maneuvers (carotid massage, Valsalva
  maneuver, gagging) may be effective?
• ?Adenosine (short-lived) or verapamil (i.v.) are
  the drugs of choice for termination?
• ?Verapamil is contraindicated in patients with
  congestive heart failure, those receiving i.v.
  beta-blockers, and should be used with caution in
  patients taking oral quinidine?
• ?Esmolol (a beta-blocker) or digoxin are
  alternatives for termination?
• ?Cardioversion or atrial pacing may be necessary
  for some patients?
• ?Long-term suppression (possible increase in
  mortality) Subclass IA, IC, Class II, Class IV,
  and digoxin??

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Ventricular PVCs or non-sustained ventricular
tachycardia

• No drug therapy for asymptomatic patients??A
  beta-blocker for patients with symptoms (syncope,
  dizziness)?
• data indicates higher mortality with encainide
  and flecainide than placebo?
• Sustained ventricular tachycardia
• Cardioversion (safest and most effective therapy)
  is preferred by most cardiologists in ventricular
  tachycardia causing hemodynamic compromise?
• ?Lidocaine is drug of choice for acute
  treatment??Alternative drugs are procainamide and
  bretylium?
• ?Long-term suppression Class II, Class III,
  Subclass IA, and mexiletine (Class IB)?

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Ventricular fibrillation

• Defibrillation (with CPR) is the treatment of
  choice
• Drugs are used for prevention of recurrence?
• Lidocaine is the drug of choice??Procainamide,
  amioradone, bretylium are alternatives?

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Cardiac glycoside-induced ventricular
tachyarrhythmias

• ?Lidocaine is drug of choice?
• ?Phenytoin, procainamide, or a beta-blocker are
  alternatives?
• ?Digibind should be used in life-threatening
  cases?
• ?Avoid cardioversion and bretylium except for
  ventricular fibrillation or sustained ventricular
  tachycardia?
• ?Beta-blockers and procainamide can make heart
  block worse?

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• THE END