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Antiarrhythmic drugs - drdhriti

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A PowerPoint Presentation on Basics of Arrhythmic Disorders and their Drug therapy suitable for study by Undergraduate MBBS Students of Pharmacology

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Antiarrhythmic drugs - drdhriti

  1. 1. Antiarrhythmic Drugs Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Introduction • Irregularity in Cardiac Rhythm • Bradyarrhythmia: Failure of impulse generation resulting in slow heart rates • Heart Block: Results from failure of impulse to propagate normally from atrium to ventricle – usually defect in AV node or His-Purkinje system • Tachyarrhythmias: Abnormally rapid heart rhythms – Common clinical condition – Treated by Antiarrhythmic Drugs - Drugs used to prevent or treat irregularities of Cardiac Rhythm
  3. 3. Causes of Arrhythmia • Root causes: When the normal sequence of impulse generation and propagation is perturbed
  4. 4. Arrhythmias – pacemaker acticity • Enhanced Automaticity: Pacemaker cells or ordinary fibres – Results due to patholgical increase in phase 4 slope - accelerated pacemaker rate – May result from current of Injury – Physiology: ACh reduces such pacemaker rate – by decreasing phase 4 and hyperpolarization – Ventricular wall cells (WMCs) may also show such pace maker activity – due to ischaemia
  5. 5. Triggered Activity • A normal AP interrupted/followed by a abnormal depolarization (a triggering rhythm) Delayed After Depolarization: Caused by Digoxin toxicity, Myocardial Ischaemia or Adrenergic stress or Heart failure – due to Ca++ overload Early After Depolarization: Due to interruption in phase 3 repolarization Causes: Slow heart rate, Hypokalaemia and drugs prolonging QT interval – quinidine, sotalol, procainamide etc. (block IK channel) Torsades de pointes: due to marked prolongation of APD – polymorphic ventricular tachycardia – long QT interval and frequent changing of QRS
  6. 6. Reentry • One of the causes of the most arrhythmias • Normally, impulses propagate in synchronized manners • But, here one impulse reenters and re-excites areas of heart more than once – no need for new impulse generation • Re-entering of impulses may be 1. Anatomically defined reentry – Circus movement type 2. Functionally defined reentry - Microentry circuit
  7. 7. Functionally defined reentry Ventricular fibrilation Atrial fibrillation
  8. 8. Anatomically defined reentry – Accessory pathway (WPW syndrome) Wolf-Parkinson-White Syndrome AV nodal reentry, Atrial flutter and PSVT
  9. 9. Fractionation of Impulse • Increased Vagal activity – Atrial ERP brief and inhomogenous • Premature impulses get conducted by fibres having short ERP – then to the fibres with longer ERP and so on • Asynchronous activation of atrial fibres – inhomogenicity – Atrial fibrilation etc.
  10. 10. Arrhythmia Conditions - Clinically • Extrasystole: premature beats due to abnormal automaticity/after depolarization – AES, VES or AV nodal ES • Paroxysmal Supraventricular Tachycardia (PSVT): Sudden onset of atrial tachycardia 150-200/minute (1:1), reentry phenomenon (AV node) • Atrial Flutter: 200-350/minute (2:1 to 4:1 AV block), reentrant circuit in right atrium • Atrial Fibrillation: Asynchronous activation of atrial fibres 350- 550/min with irregular 100 to 160 ventricular beats – due to electrophysiological inhomogenicity of atrial muscles (bag of worms) • Ventricular tachycardia: 4 or more consecutive extrasystole of ventricles – monomorphic or polymorphic • Ventricular Fibrillation: rapid irregular contractions – fatal (MI, electrocution) • Torsades de pointes: polymorphic ventricular tachycardia, rapid asynchronous complexes, rise and fall in baseline of ECG • Atrio-ventricular Block (A-V Block): vagal influence or ischaemia - 1st, 2nd and 3rd degree – slowed conduction, drop beat and no
  11. 11. Atria and Ventricular arrhythmia - Animation Ventricular arrhythmia Atrial arrhythmia
  12. 12. Vaugham-Williams classification • Class I – Na+ Channel Blockers – 1a: quinidine, procainamide, disopyramide – 1b: lignocaine, mexilitine, phenytoin, propafenone – 1c: Propafenone, Flecainide, Encainide, Moricizine • Class II – Beta-adrenergic Blockers - Propranolol, Sotalol, Esmolol and Acebutalol • Class III – K+ channel blockers: Amiodarone, Ibutilide, Dofetilide, Sotalol (II + III action) and bretylium • Class IV – Ca++ channel blockers: Verapamil, diltiazem and bepridil
  13. 13. Ionic Basis of Action Potential in Heart
  14. 14. Class I - antiarrhythmics Class I antiarrhythmics: are further classified to Ia, Ib and Ic – based on repolarization and potency of Na+ blockade – state dependant manner Lidocaine Phenytoin Flecainide Propafenone Na+ blockade: Ic>1a>1b ERP: 1a>2c>1b
  15. 15. Subclass – I A - quinidine, procainamide, disopyramide • Binds to Na+ channels in open state and prevent conduction of ions (Refractory – Rest – Open – Refractory) - Moderate sodium channel blockade in open state • Prolong refractoriness by blocking several types of potassium channel • Delayed Na channel recovery • Delayed AV conduction • Useful in conditions where Na+ channels open frequently – ectopic beats - atrial tachycardia and atrial fibrillation and ventricular arrhythmias • Abolish reentry – unidirectional block to bidirectional block • Electrophysiology changes: Lengthen action potential, slow rate of rise of phase 0, Prolong repolarization ---------------- also prolong AV node ERP - ECG changes: Prolong PR, QRS, QT
  16. 16. Subclass - IB • Lowest potency for Na+ channel blocker - inactivated state • Do not delay channel recovery • EP changes: Shorten action potential, Limited effect on rate of rise of phase 0, Shorten repolarization ------------- no ERP effect on AV node (shorten) • ECG: Shorten QT • Used in Treatment and prevention of ventricular tachycardia and fibrillation after Myocardial Infarction – lignocaine IV , e.g, lignocaine, mexilitine, phenytoin, propafenone
  17. 17. Subclass IC • Propafenone, Flecainide, Encainide, Moricizine • Marked Na+ channel blockade in open state – with longest recovery time • Refractory period of AV node is increased – marked delay in conduction • Electrophysiology changes: No effect on length of action potential, Markedly reduces rate of rise of phase 0 and ---------- marked delay in AV conduction with little effect on repolarization • ECG: markedly prolong PR and QRS complex • Prolong refractoriness by blocking outward-rectifying potassium channels • General reduction in excitability • Used in life threatening ventricular fibrillation since they have highest affinity to Na+ channels involving AV node - WPW syndrome and Paroxysmal atrial fibrillation
  18. 18. Individual Drugs
  19. 19. Antiarrhythmic - Quinidine • Dextroisomer of Quinine: N+ channel blocking and antivagal action • Actions:  Inhibition of Na channel – slanted O phase and Decreases phase 4  Prolongation of APD – due to K+ channel block  Increase in ERP – due to delay in Na+ and K+ channel recovery  Net result is delay in conductivity and increase in refractoriness  Fall in BP – direct cardiac depression  Other actions include – alpha blockade, decreased skeletal muscle contractility, uterine contractions, vomiting and diarrhoea etc.  Kinetics: well absorbed orally, half life – 10 Hrs  Uses:  Broad spectrum antiarrhythmic  Atrial fibrillation and flutter, prevention of PSVT and prevention of ventricular tachycardia  Adverse effects: Not used now for adverse effects like Proarrhythmia (torsades de pointes), sudden cardiac arrest or VF, cinchonism, angioedema, vascular collapse etc.  Available as 200, 300 mg tabs. And 300 mg/ml Injections
  20. 20. Procainamide • Procaine derivative (amide) • Identical action with quinidine except: – Minimal antivagal action – Lesser suppression of ectopic automaticity – Lesser depression of contractility and AV conduction – No alpha blocking action • Kinetics: – Absorbed orally and bioavailability is 80% – Metabolized in liver to N-acetyl-procainamide (NAPA) – blocks K channel and prolongs repolarization • Dosage – 250 mg tabs and 1gm/ml injections – Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 Hrs • Uses: Mainly for monomorphic VTs and to prevent recurrences • ADRs: Hypersensitivity, flushing, hypertension, torsedes de pointes and CNS symptoms – mental confusion, hallucinations and weakness
  21. 21. Antiarrhythmic – Lidocaine (Lignocaine) • Popular antiarrhythmic and also local anaesthetic (membrane stabilizing action) • Lowest potency for Na+ channel inactivated state – ECTOPIC Foci – Enhance phase – 4 depolarization in partially depolarized or stretched PF – After depolarization antagonized – no effect on SAN – Practically no action on Atrial fibres – Rate of 0 phase in AVN and ventricles – not affected – Reduction in APD in PF and ventricular myocardium • Actions: – Selective action on partially depolarized and cells with long APD – normal ventricular and conducting fibres – not affected – Suppression of automaticity in ectopic foci (reentry) – one way or two way block – Enhanced phase-4 depolarization in partially depolarized or stretched PF (APD long) – Little effects on cardiac contractility and arterial BP
  22. 22. Lidocaine – contd. • Kinetics: Ineffective orally, given IV lasts for 10-20 minutes. Therefore given as IV bolus 50-100 mg followed by 20-40 mg every 10-20 minutes. Half-life prolonged in CHF (coz. Vd decreases) and 70-80% metabolized by liver • Adverse effects: Neurological – drowsiness, paresthesia, blurred vision, nystagmus and fits etc. – No proarrhythmic effects – no cardiotoxicity • Uses: 50-100 mg bolus and 10-20 mg every 20 minutes – 1st line of drug in Arrhythmia following acute MI and cardiac surgery – Prevention of ventricular tachycardia – Digitalis toxicity – no AV block • LA lignocaine Vs Antiarrhythmic lignocaine ?
  23. 23. Beta blockers • Drugs used are beta-blockers: Propranolol, Sotalol, Esmolol and Acebutlol • Suppression of adrenergically mediated activity • Propranolol - Membrane stabilizing effect like quinidine on heart – high doses – clinical dose: cardiac adrenergic blockade • Clinical doses (antiarrhythmic effect) - Block beta-1 receptor in heart and decreases heart rate 1. Decrease in phase 4 depolarization and automaticity in SA node, AVN, PF and other ectopic foci (Adrenaline causes ventricular ES and fibrilation by increasing the phase 4 depolarization !!!) 2. Prolongation of ERP of AVN – impede AV conduction
  24. 24. Uses of Propranolol • Arrhythmias associated with increased sympathetic activity – sinus tachycardia, atrial extrasystoles provoked by emotion and exercise • Less effective in PSVT than adenosine and verapamil • Propranolol is used to treat sympathetically mediated arrhythmias - phaeochromocytoma and halothane anaesthesia – Sinus tachycardia, atrial and nodal extrasystole and nodal extrasystole provoked by exercise Does not abolish AF or Afl but decreases ventriculsar rate • Reduce mortality after MI – anti-ischaemic action • Esmolol IV – quickly terminates AF and fluttter and used in emergency control of arrhythmia due to anaesthetics
  25. 25. Class-III Antiarrhythmics • Class III drugs K channel blockers prolong repolarization (increase refractoriness) by blocking outward potassium conductance – Prolongation of Cardiac action potential – Increased ERP • Drugs – Amiodarone Ibutilide, dofetilide, sotalol (II + III action) and bretylium • Bretylium is used only in life threatening arrhythmias
  26. 26. Amiodarone Long acting and highly lipophillic and Iodine containing compound MOA: - multiple actions 1. Blocking of delayed rectifier K+ channel – prolongs APD 2. Weak class I (lidocaine like) – depresses conducton in partially depolarized and long APD 3. II (beta- blocker) – NC alpha and beta; and class IV actions 4. Also direct coronaray and peripheral vasodilator • Overall – Slowed conduction and supressed automaticity Kinetics: Incompletely and slowly absorbed – daily oral dose is given for several days for actions to develop, t1/2 = 3-8 weeks Dose: 400-600 mg/day p.o for many days followed by 100-200 mg/day as maintenance (100-300 mg slow IV)
  27. 27. Amiodarone Uses: • Most tachyarrhythmic conditions – ventricular and supraventricular • Recurrent VT and VF • WPW syndrome Adverse effects: • Photosensitization – skin pigmentation • Peripheral neuropathy – weak shoulder and pelvic muscles • Myocardial depression – bradycardia • Pulmonary alveolitis and fibrosis – kept below 200 mg • Corneal micro deposits – on long term use • Hypothyroidism, goitre – inhibition of T4 to T3 Drug Interactions: Digoxin and warfarin (reduced renal clearance)
  28. 28. Class IV - Antiarrhythmics • Three important classes: – Phenylalkylamines – hydrophillic Verapamil – Dihydropyridines – lipophilic Nifedepine – Benzothiazepines – hydrophilic Diltiazem • Verapamil and diltiazem: are useful in Arrhythmia • Relatively selective AV nodal L-type calcium channel blockers – depression of Ca++ mediated depolarization and delay recovery – Slows SA node automaticity – reduced phase 4 depolarization in SAN and PF – extinction of latent pacemakers and DAD – Prolongation of AVN ERP – reentry terminated – Negative ionotropic action
  29. 29. Class IV – contd. • Uses: Verapamil 1. PSVT: • For termination of attack – 5 mg IV over 2-3 minutes (reflex bradycardia) • For prevention of attack 60-120 mg orally tds 2. Reduce ventricular rate in Atrial fibrillation (AF) and Atrial flutter – with digitalis
  30. 30. Miscellaneous Agents Adenosine: • Endogenously produced important chemical mediator used in PSVT • MOA: – Activation of ACh sensitive K+ channel - membrane hyperpolarization of SA node (G-protein coupled adenosine receptor A1) – depression of SA node and also slowing of AV conduction – shortening of action potential in atrium and reduced excitability – Also indirectly reduces Ca++ current in AV node – depression of reentry in PSVT
  31. 31. Adenosine – contd. • Very short half life – 20-30 sec. - Uptake by RBCs and endothelial cells (5-AMP and inosine) • Administered intravenously – available as free base or ATP – 6 - 12 mg/ATP 10 - 20 mg given as a rapid intravenous bolus (administered over a 1-2 second period) – If the first dose does not result in elimination of the supraventricular tachycardia within 1-2 minutes - 12 mg should be given as a rapid intravenous bolus • ADR: chest tightness, dyspnoea, fall in BP and flushing etc.
  32. 32. When Antiarrhythmics ? • Asymptomatic and those which do not interfere haemodynamics – AES, VES, 1st degree block and bundle branch block – no need of treatment • Therapy needed: – Life threatening VT, TdP and VF – Causing breathlessness, hypotension and cardiac failure – Marked palpitation – PSVT, VT, AF and TdP – Myocardial infarction
  33. 33. Non-pharmacological treatment • Acute – Vagal manoeuvres – DC cardioversion • Prophylaxis – Radiofrequency ablation – Implantable defibrillator • Pacing (external, temporary, permanent)
  34. 34. The Pacemaker • Surgical implantation of electrical leads attached to a pulse generator 1) Leads via subclavian vein and advanced to the chambers on the vena cava (right) side of the heart 2) 2 leads - right atrium, and right ventricle 3) Pulse generator containing microcircuitry and battery are attached to leads and placed into a “pocket” under the skin near the clavicle 4) Pulse generator sends signal - to contract atria, then ventricles • Pulse generator - sense electrical activity - only deliver electrical impulses when needed. • Pacemakers : can only speed up a heart experiencing bradycardia, cannot alter a condition of tachycardia
  35. 35. Expected Questions ?? • Classification of anttiarrhythmic drugs • Lidocaine as antiarrhythmic agent • Amiodarone as antiarrhythmic agent • Role of Beta blockers (Propranolol) and Ca++ channel blockers (Verapamil) in Arrhythmia • Short Note: Adenosine

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