Cardiovascular

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• Cardiovascular
• pharmacology

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PROF.AZZA ELMedany

• Department of pharmacology

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Antiarrhythmic Drugs
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Objectives

• At the end of lectures the students should know
• Classification of anti-arrhythmic drugs
• Characters of each class
• Examples of drugs in each class
• Pharmacological effects , therapeutic uses , side
  effects of individual drugs

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• CARDIAC CONDUCTION SYSTEM
• - S.A. node
• - Inter-nodal pathways
• - A.V. node
• - Bundle of His and branches
• - Purkinje fibres

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• WHAT IS ARRHYTHMIA?
• An Abnormality in the
• Heart rate ......... high
  tachycardia
• low
  bradycardia
• Regularity ..... extrasystoles
• Site of origin ... ectopic pacemakers
• Disturbance in conduction

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Circus Movement
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Therapeutic uses of anti-arrhythmic drugs

• The ultimate goal of anti-arrhythmic drugs
  therapy is to restore normal rhythm conduction
• When it is not possible to revert to normal sinus
  rhythm , drugs are used to prevent more serious
  lethal arrhythmias.

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• CLASSIFICATION
• OF
• ANTIARRHYTHMIC DRUGS
• According to Vaughan-Williams

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• CLASS 1 Na channel blockers
• CLASS II
• ß- adrenoceptor blockers
• CLASS III
• drugs that prolong action potential duration
• ( k channel blockers )
• CLASS IV
• Calcium channel blockers

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• Miscellaneous
• Adenosine
• Electrolyte supplement ( magnesium, potassium)
• Digitalis
• Atropine

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CLASS 1

• Sodium channels blockers , this result in
• a decreased rate of depolarization (
  phase 0).
• Suppression of action potential generation
  

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• Act on non-nodal tissues ( atria,
  ventricles, purkinje tissues ) which are
  depending on sodium ion to start depolarization
  
• All class 1 have local anesthetic effect that
  slow conduction in atrial ventricular tissues

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T-Ca2 kanál
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•  CLASS 1
• SUBCLASSIFIED INTO
• Class (1A)
• Class (1B)
• Class (1C)

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Other actions of Class ( 1A)

• Potassium channel blocking effect
• Prolong the action potential duration
• Prolong Effective refractory period
  (ERP)
• ECG change
• Prolong QT interval

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• Anticholinergic actions
• ( indirect effect increase AV conduction
  decrease AV conduction time that can precipitate
  lethal arrhythmias )
• Negative inotropic effect

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Clinical uses of Class 1A

• Atrial flutter or fibrillation
• These drugs should not be used alone for
  treatment of AF or AF because the ventricular
  rate may dramatically increase
• Ventricular tachycardia or fibrillation

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• Examples of Class 1A
• Quinidine
• Has a adrenergic blocking effect

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• Side effects of quinidine
• GIT
• diarrhea
• CARDIAC
• Torsade de pointes
• ( quinidine syncope )
• Hypotension

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Torsade de pointes
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• Adverse effects ( continue)
• Anticholinergic adverse effects
• dry mouth , dry skin , constipation
• Cinchonism
• ( ringing in the ears , diarrhea)

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• QUINIDINE
• GIVEN ORALLY ....rarely given I.V. because
• of toxicity .

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• 2 PROCAINAMIDE
• As compared to quinidine
• less toxic on the heart...
• can be given I.V. ( common route)
• More effective in ventricular than in
• atrial arrhythmias
• less depressant on cardiac contractility
• Weak anticholinergic or a-blocking actions

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• PROCAINAMIDE
• Clinical uses
• Second drug of choice ( after lidocaine ) for
  treatment of ventricular tachycardia after acute
  myocardial infarction

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•  ADVERSE EFFECTS
• lupus erythematosus-like syndrome
• Hypotension
• Torsade de pointes
• Hallucination psychosis

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• CLASS 1 B
• Shorten action potential duration
• and effective refractory period of
  Purkinje ventriclular cells
• e.g. lidocaine
• mexiletine

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• LIDOCAINE
• Clinical uses
• Very effective for suppressing arrhythmias
  due to ischemia, digitalis toxicity
• First drug of choice for emergency treatment of
  ventricular tachycardia following
• cardiac surgery or acute myocardial
  infarction

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Pharmacokinetics of lidocaine

• - Given I.V. bolus or slow infusion
• Not given orally because of its extensive first
  pass hepatic metabolism , only 3 of orally
  administered lidocaine appears in plasma.
• T1/2 2 hours

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• ADVERSE EFFECTS
• Neurological such as
• Convulsions , tremors

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• MEXILETINE
• Given Orally
• Clinical uses
• Chronic treatment of ventricular arrhythmia
• digitalis-induced arrhythmias
• Adverse effects
• Gastric upset
• Neurological manifestation
• t1/2 long ( 10 hr)

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CLASS 1C

• Slow conduction in all cardiac tissues.
• Depress cardiac contractility
• ( negative inotropic effect )
• No prominent effect on the duration of the
  action potential
• e.g. Flecainide ,Propafenone
  

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Clinical uses of class 1C

• Paroxysmal atrial flutter or fibrillation
• Life threatening ventricular arrhythmias
• ( Are used in arrhythmias not responding to
  other therapy)

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Side effects

• Significant risk of
• Heart failure
• Proarrhythmias
• These drugs may increase mortality when
  administered to patients surviving myocardial
  infarction

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• CLASS 11
• ß- Adrenergic receptor Antagonists
• blocking ß1- receptors in the heart ? reduce the
  sympathetic effect on the heart causing
• - decrease automaticity of S.A. node and
• ectopic pacemakers
• - slow conduction of the A.V node
• - Heart rate
• - Contractility

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• CLINICAL USES
• Atrial arrhythmias associated with emotion,
• exercise
• Digitalis-induced arrhythmias
• Drugs of choice to Prevent ventricular
  fibrillation following myocardial infarction.
• e.g. Propranolol
• Esmolol

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Class III

• Potassium channels blocking drugs
• Prolong the action potential duration effective
  refractory period .
• (Prolong phase 3 )

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• AMIODARONE
• Main effect is to prolong action potential
  duration and refractory period
• Has an additional actions of classes 1,
  11 1V
• Has an a and ß-adrenoceptor blocking effects

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• Clinical uses of amiodarone
• Treatment of recurrent ventricular tachycardia
  Fibrillation
• It is restricted for life-threatening
  arrhythmias.

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• ADVERSE EFFECTS
• Bradycardia heart block, heart failure
• pulmonary fibrosis ,interstitial
  pneumonitis
• hyper- or hypothyroidism
• Skin deposits causes photodermatitis ,
  gray-blue skin rash.

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• (CONTiNUE)
• Peripheral neuropathy
• constipation
• corneal opacities
• Hypotension

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• Pharmacokinetics of Amiodarone
• extremely long t1/2 13 - 103 DAYS
• Drug Interactions
• reduce renal clearance of several drugs

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Ibutilide

• Given by a rapid I.V. infusion
• Used for acute ( rapid ) conversion of atrial
  flutter or atrial fibrillation to normal sinus
  rhythm.
• Adverse effect
• QT interval prolongation ( precipitates
  torsade de pointes ).

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Class 1V calcium channel blockers

• e.g. Verapamil, Diltiazem
• Site of action is A.V.N S.A.N .
• Inhibits calcium entry through L-type calcium in
  the myocardium and depress AV nodal transmission.
  

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• Clinical uses of calcium channel blockers
• Atrial flutter - fibrillation
• Av nodal reentry
• NOT effective in ventricular arrhythmias

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Side effects

• Sinus arrest or complete AV nodal blockade in the
  presence of ß-adrenergic receptor blockers

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Miscellaneous Group

• e.g. ADENOSINE

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• ADENOSINE
• - Naturally occurring nucleoside
• half-life less than 10 sec.
• Mechanism In cardiac tissues
• Binds to type 1 (A1) receptors which are coupled
  to Gi- proteins , activation of this pathway
  causing
• Opening of potassium channels
• (hyperpolarization)

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• Decrease cAMP which inhibits L-type
• calcium channels (? calcium influx )
• causing decrease AV nodal conduction

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• Adenosine increases the vagal tone of
• the AV node ? decrease conduction
• velocity in Av node

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• Clinical uses of adenosine
• Drug of first choice for terminating an
• Episode of
• paroxysmal supraventricular tachycardia
• given 6 mg I.V. bolus followed by 12 mg if
• necessary

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• Adverse effects
• Flushing headache
• Dyspnea and chest pain
• Hypotension

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• BRADYARRHYTHMIAS
• ATROPINE
• sinus bradycardia after myocardial infarction
  and in heart block
• severe heart block isoprenaline may be
  combined with atropine

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• NONPHARMACOLOGIC THERAPY OF ARRHYTHMIAS (CONTD)
  
• Implantable Cardiac Defibrillator (ICD)
• can automatically detect and treat fatal
• arrhythmias such as ventricular fibrillation
  

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Thank you