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Antiarrhythmic drugs - drdhriti
This document discusses antiarrhythmic drugs used to treat irregularities in cardiac rhythm. It covers various types of arrhythmias including bradyarrhythmias, tachyarrhythmias, and heart block. The causes of arrhythmias are discussed including enhanced automaticity, triggered activity, reentry, and fractionation of impulses. The Vaughan-Williams classification of antiarrhythmic drugs is presented along with details about specific drug classes and examples like quinidine, procainamide, lidocaine, and beta blockers. Mechanisms of action and ion channel effects are explained for different drug classes.
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Antiarrhythmic drugs - drdhriti
- 1. Antiarrhythmic Drugs Dr. D.K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
- 2. Introduction • Irregularity inCardiac 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. Causes of Arrhythmia •Root causes: When the normal sequence of impulse generation and propagation is perturbed
- 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. Triggered Activity • A normalAP 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. Reentry • One ofthe 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. Functionally defined reentry Ventricularfibrilation Atrial fibrillation
- 8. Anatomically defined reentry– Accessory pathway (WPW syndrome) Wolf-Parkinson-White Syndrome AV nodal reentry, Atrial flutter and PSVT
- 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. 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. Atria and Ventriculararrhythmia - Animation Ventricular arrhythmia Atrial arrhythmia
- 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. Ionic Basis ofAction Potential in Heart
- 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. Subclass – IA - 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. 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. 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.
- 19. Antiarrhythmic - Quinidine • Dextroisomerof 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. 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. 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. 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. Beta blockers • Drugsused 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. 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. Class-III Antiarrhythmics • Class IIIdrugs 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. Amiodarone Long acting andhighly 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. Amiodarone Uses: • Most tachyarrhythmicconditions – 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. 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. 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. Miscellaneous Agents Adenosine: • Endogenouslyproduced 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. 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. 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. Non-pharmacological treatment • Acute –Vagal manoeuvres – DC cardioversion • Prophylaxis – Radiofrequency ablation – Implantable defibrillator • Pacing (external, temporary, permanent)
- 34. The Pacemaker • Surgicalimplantation 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. 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
Editor's Notes
- #7 The gross electrical activities that can be observed in ecg are due to the action potentials generated in different cardiac tissues.
- #9 The fast sodium channel can be modeled as being controlled by a number of gates . Each gate (or gating variable) can attain a value between 1 (fully open) and 0 (fully closed). The product of all the gates denotes the percentage of channels available to conduct Na + . Following the model of Hodgkin and Huxley , the sodium channel contains three gates: m , h , and j . In the resting state, the m gate is closed (zero) and the h and j gates are open (one). Hence, the product denoting the percentage of conducting channels is also zero. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h and j gates close more slowly. For a brief period of time, all gates are open ( i.e. non-zero) and Na + can enter the cell following its electrochemical gradient . If, as above, the resting membrane potential is too positive, the h or j gates may be considerably less than one, such that the product of m , h and j becomes too small upon depolarization.
- #12 Electrical activities in different part of the cardiac tissues can be recorded externally over the skin by placing electrodes on both side of the heart – called ECG or EKG
- #19 Abnormal pacemaker activity can occur if myocardial cells are damaged eg ischaemic heart disease also via catecholamine overactivity
- #23 Ventricles can be excited with each sinus node depolarization. The will generally travel via AV node and accessory pathway if present. However accessory pathways have fast action tissues and AV node has slow action tissues. Thus in patients with WPW syndrome has premature atrial impulses and cannot excite accessory pathway as not enough threshold can be generated there but can excite AV node slowly and conducts the impulse. The impulse will pass down the ventricular wall and somewhere meets the accessory pathway which is by now may be no longer refractory and the impulse traverse back to the atrium and again reach the AV node and reenter ventricle.
- #24 Atrial fibrillation - Atria remains dilated and quiver like bag of worms Torsades de pointes – polymorphic ventricular tachycardia
- #25 Pharmacologically, minimum interval between the two propagating action potentials. It is closely related to AP duration (APD). An AP can be evoked in fast channel fibres before complete repolarization. Because Na+ channel recover in a voltage-dependent manner, above the threshold potential. In contrast, the Ca++ channels recover in time dependent manner.