Antiarrhythmic Drugs Department of Pharmacology NEIGRIHMS, Shillong
Content <ul><li>Physiology of normal cardiac rhythm </li></ul><ul><li>Definition and mechanisms of arrhythmias </li></ul><...
Cardiac Physiology <ul><li>Recall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) ...
Cardiac Physiology – Myocardial Cells <ul><li>2 types  – Pacemaker and non pacemaker </li></ul><ul><ul><li>Pacemaker and c...
Cardiac Electrophysiology  <ul><li>A transmembrane electrical gradient (potential) is maintained, with the interior of the...
Cardiac Action Potential - WMCs
Cardiac Action Potential  <ul><li>Divided into five phases (0,1,2,3,4) </li></ul><ul><ul><li>Phase 4  - resting phase (res...
Cardiac Na+ channels
Cardiac Action Potential – contd. <ul><li>Phase 2 - plateau phase </li></ul><ul><ul><li>sustained by the balance between t...
Cardiac Action Potential – Pacemaker  Cells <ul><li>PCs - Slow, continuous depolarization during rest </li></ul><ul><li>Sl...
Cardiac Electrophysiology – contd. ECG (EKG)  showing  wave segments Contraction of atria Contraction of ventricles Repola...
The Normal EKG Right Arm Left Leg P Q R S T QT PR 0.12-0.2 s approx. 0.44 s Atrial muscle depolarization Ventricular muscl...
Cardiac arrhythmias
Cardiac Arrhythmias <ul><li>Cardiac dysrhythmia (arrhythmia) </li></ul><ul><ul><li>Large and heterogeneous group of condit...
Cardiac Arrhythmias – Clinical Classification <ul><li>Heart rate (increased / decreased) </li></ul><ul><ul><li>Tachycardia...
Normal Vs Atrial Arrhythmia <ul><li>Normal Rhythm </li></ul><ul><li>Atrial Rhythm </li></ul>
Ventricular Arrhythmia <ul><li>Ventricular arrhythmias are common in most people and are usually not a problem but… </li><...
Cardiac Arrhythmias - Mechanism <ul><li>Enhanced or ectopic pacemaker activity </li></ul><ul><ul><li>Catecholamine over ac...
After depolarization – EAD and DAD
Cardiac Arrhythmias - Reentry Phenomenon <ul><li>Probably the cause of most arrhythmias </li></ul><ul><li>Common abnormali...
Reentry Phenomenon – Functional reentry
Reentry Phenomenon – Accessory pathway (WPW syndrome)
Arrhythmia Conditions <ul><li>Extrasystole:  abnormal automaticity/after depolarization </li></ul><ul><li>Paroxysmal Supra...
Antiarrhythmic Drugs <ul><li>Biggest problem  – antiarrhythmics can cause arrhythmia! </li></ul><ul><ul><li>Example: Treat...
Antiarrhythmic Drugs <ul><li>Vaugham-Williams classification : </li></ul><ul><li>Class I – Na+ Channel Blockers </li></ul>...
Class I - antiarrhythmics Class IA  Class IB  Class IC Class I antiarrhythmics are further classified to  IA, IB and IC Qu...
Subclass – I A   <ul><li>Lengthen action potential </li></ul><ul><li>Slow rate of rise of phase 0 </li></ul><ul><li>Prolon...
<ul><li>Shorten action potential </li></ul><ul><li>Limited effect on rate of rise of phase 0 </li></ul><ul><li>Shorten rep...
Subclass – IC  <ul><li>No effect on length of action potential </li></ul><ul><li>Markedly reduces rate of rise of phase 0 ...
Antiarrhythmic Drugs - Quinidine <ul><li>Dextroisomer of Quinine: N+ channel blocking and antivagal action </li></ul><ul><...
Antiarrhythmic Drugs - Procainamide <ul><li>Procaine derivative (amide) </li></ul><ul><li>Identical action with quinidine ...
Antiarrhythmic Drugs - Lidocaine <ul><li>Popular antiarrhythmic and also local anaesthetic </li></ul><ul><li>Actions: </li...
Class II Antiarrhythmics <ul><li>They  act indirectly on Electrophysiology – by blocking beta-adrenergic receptor, prolong...
Class II – contd. <ul><li>Block beta-1 receptor in heart and decreases  heart rate </li></ul><ul><li>Adrenline causes   ve...
Class III  Antiarrhythmics <ul><li>Class III drugs K channel blockers prolong repolarization (increase refractoriness) by ...
Class III - Amiodarone <ul><li>MOA:  Long acting and highly lipophillic </li></ul><ul><li>Weak class I, II (beta- blocker)...
Amiodarone <ul><li>Adverse effects: </li></ul><ul><li>Photosensitization </li></ul><ul><li>Peripheral neuropathy </li></ul...
Class IV -  Antiarrhythmics <ul><li>Relatively selective AV nodal L-type calcium channel blockers – slow sinus rhythm, pro...
Class IV – contd. <ul><li>Uses:  Verapamil </li></ul><ul><ul><li>PSVT: </li></ul></ul><ul><ul><ul><li>For termination of a...
Miscellaneous Agents <ul><li>Compounds whose actions do not fit the standard four classes – digoxine, adenosine and alinil...
Adenosine – contd. <ul><li>Very short half life – 20-30 sec. - Uptake by RBCs and endothelial cells </li></ul><ul><li>Admi...
Summary <ul><li>Anti-arrhythmic drugs are classified by their effect on the cardiac action potential </li></ul><ul><li>An ...
Non-pharmacological treatment <ul><li>Acute </li></ul><ul><ul><li>Vagal manoeuvres </li></ul></ul><ul><ul><li>DC cardiover...
Pacemakers <ul><li>Surgical implantation of electrical leads attached to a pulse generator </li></ul><ul><ul><li>Leads are...
The Pacemaker
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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 Students of Pharmacology

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  • The gross electrical activities that can be observed in ecg are due to the action potentials generated in different cardiac tissues.
  • 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.
  • 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
  • Abnormal pacemaker activity can occur if myocardial cells are damaged eg ischaemic heart disease also via catecholamine overactivity
  • 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.
  • Atrial fibrillation - Atria remains dilated and quiver like bag of worms Torsades de pointes – polymorphic ventricular tachycardia
  • 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.
  • Antiarrhythmic drugs - drdhriti

    1. 1. Antiarrhythmic Drugs Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Content <ul><li>Physiology of normal cardiac rhythm </li></ul><ul><li>Definition and mechanisms of arrhythmias </li></ul><ul><li>Classification of drugs to treat arrhythmias </li></ul><ul><li>Important anti-arrhythmic drugs (mechanism and pharmacological characteristics) </li></ul><ul><li>Arrhythmias in clinical practice </li></ul>
    3. 3. Cardiac Physiology <ul><li>Recall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity </li></ul><ul><li>Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany  contract and hold contraction for certain length of time] </li></ul><ul><li>Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues </li></ul>
    4. 4. Cardiac Physiology – Myocardial Cells <ul><li>2 types – Pacemaker and non pacemaker </li></ul><ul><ul><li>Pacemaker and conducting cells – SAN, AVN, Bundle of His and Purkinje`s fibres </li></ul></ul><ul><ul><li>Non pacemaker – Working Myocardial Cell (WMC) or CMC </li></ul></ul><ul><li>Sinus rhythm means rhythm originates in SAN </li></ul><ul><li>Sinus tachycardia means tachycardia but rhythm originates in SAN – fever, exercise etc. </li></ul><ul><li>Tachycardia = heart rate > 100 per minute </li></ul><ul><li>Bradycardia = heart rate < 60 per min. </li></ul>
    5. 5. Cardiac Electrophysiology <ul><li>A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell </li></ul><ul><li>Caused by unequal distribution of ions inside vs. outside cell </li></ul><ul><ul><li>Na+ higher outside than inside cell </li></ul></ul><ul><ul><li>Ca+ much higher “ “ “ “ </li></ul></ul><ul><ul><li>K+ higher inside cell than outside </li></ul></ul><ul><li>Maintenance by ion selective channels, active pumps and exchangers </li></ul>
    6. 6. Cardiac Action Potential - WMCs
    7. 7. Cardiac Action Potential <ul><li>Divided into five phases (0,1,2,3,4) </li></ul><ul><ul><li>Phase 4 - resting phase (resting membrane potential) </li></ul></ul><ul><ul><ul><li>Phase cardiac cells remain in until stimulated </li></ul></ul></ul><ul><ul><ul><li>Associated with diastole portion of heart cycle </li></ul></ul></ul><ul><li>Addition of current into cardiac muscle (stimulation) causes </li></ul><ul><ul><li>Phase 0 – opening of fast Na channels and rapid depolarization </li></ul></ul><ul><ul><ul><li>Drives Na + into cell (inward current), changing membrane potential </li></ul></ul></ul><ul><ul><ul><li>Transient outward current due to movement of Cl - and K + </li></ul></ul></ul><ul><ul><li>Phase 1 – initial rapid repolarization </li></ul></ul><ul><ul><ul><li>Closure of the fast Na + channels </li></ul></ul></ul><ul><ul><ul><li>Phase 0 and 1 together correspond to the R and S waves of the ECG </li></ul></ul></ul>
    8. 8. Cardiac Na+ channels
    9. 9. Cardiac Action Potential – contd. <ul><li>Phase 2 - plateau phase </li></ul><ul><ul><li>sustained by the balance between the inward movement of Ca+ and outward movement of K+ </li></ul></ul><ul><ul><li>Has a long duration compared to other nerve and muscle tissue </li></ul></ul><ul><ul><li>Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) </li></ul></ul><ul><ul><li>Corresponds to ST segment of the ECG. </li></ul></ul><ul><li>Phase 3 – repolarization </li></ul><ul><ul><li>K+ channels remain open, </li></ul></ul><ul><ul><li>Allows K+ to build up outside the cell, causing the cell to repolarize </li></ul></ul><ul><ul><li>K + channels finally close when membrane potential reaches certain level </li></ul></ul><ul><ul><li>Corresponds to T wave on the ECG </li></ul></ul>
    10. 10. Cardiac Action Potential – Pacemaker Cells <ul><li>PCs - Slow, continuous depolarization during rest </li></ul><ul><li>Slow depolarization during 0 phase </li></ul><ul><li>Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization) </li></ul><ul><li>Funny current ( I f ) </li></ul>
    11. 11. Cardiac Electrophysiology – contd. ECG (EKG) showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles
    12. 12. The Normal EKG Right Arm Left Leg P Q R S T QT PR 0.12-0.2 s approx. 0.44 s Atrial muscle depolarization Ventricular muscle depolarization Ventricular muscle repolarization
    13. 13. Cardiac arrhythmias
    14. 14. Cardiac Arrhythmias <ul><li>Cardiac dysrhythmia (arrhythmia) </li></ul><ul><ul><li>Large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart </li></ul></ul><ul><ul><li>The hearts too fast or too slow, and may be regular or irregular </li></ul></ul><ul><ul><li>Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO) </li></ul></ul><ul><li>Result from disorders of impulse formation, conduction, or both </li></ul><ul><li>Causes of arrhythmias </li></ul><ul><ul><li>Cardiac ischemia </li></ul></ul><ul><ul><li>Excessive discharge or sensitivity to autonomic transmitters </li></ul></ul><ul><ul><li>Exposure to toxic substances </li></ul></ul><ul><ul><li>Unknown etiology </li></ul></ul>
    15. 15. Cardiac Arrhythmias – Clinical Classification <ul><li>Heart rate (increased / decreased) </li></ul><ul><ul><li>Tachycardia – heart rate fast (>100 beats/min) </li></ul></ul><ul><ul><li>Bradycardia – heart rate slow (<60 beats/min) </li></ul></ul><ul><li>Heart rhythm (regular/irregular) </li></ul><ul><li>Site of origin (supraventricular / ventricular) </li></ul><ul><li>Complexes on ECG (narrow/broad) </li></ul><ul><ul><li>PR interval, QRS complex, ST segment or QT complex etc </li></ul></ul>
    16. 16. Normal Vs Atrial Arrhythmia <ul><li>Normal Rhythm </li></ul><ul><li>Atrial Rhythm </li></ul>
    17. 17. Ventricular Arrhythmia <ul><li>Ventricular arrhythmias are common in most people and are usually not a problem but… </li></ul><ul><li>VA’s are most common cause of sudden death </li></ul><ul><li>Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA’s </li></ul><ul><li>Medications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death  treatment may be worse then the disease! </li></ul>
    18. 18. Cardiac Arrhythmias - Mechanism <ul><li>Enhanced or ectopic pacemaker activity </li></ul><ul><ul><li>Catecholamine over activity </li></ul></ul><ul><ul><li>Injury current in damaged myocardial cells, e.g. Myocardial ischemia </li></ul></ul><ul><li>Oscillatory After-depolarization </li></ul><ul><ul><li>EAD: depolarization at phase 3 interrupted and MP oscillates </li></ul></ul><ul><ul><li>DAD: Related to Ca++ current. After attaining RMP premature action potential develops, e.g. digitalis toxicity </li></ul></ul><ul><li>Reentry Phenomenon </li></ul>
    19. 19. After depolarization – EAD and DAD
    20. 20. Cardiac Arrhythmias - Reentry Phenomenon <ul><li>Probably the cause of most arrhythmias </li></ul><ul><li>Common abnormality of conduction also called “circus movement” </li></ul><ul><li>One impulse reenters and excites areas of heart more than once </li></ul><ul><li>Path of re-entering impulses may be </li></ul><ul><ul><li>small areas of heart (near AV node) </li></ul></ul><ul><ul><li>Large (atrial or ventricular wall) – atrial and ventricular fibrillation </li></ul></ul><ul><ul><li>Anatomically determined (WPW syndrome) – reentry circuit consists of atrial tissue, AV node, ventricular wall and accessory ventricular connection (a bypass tract) </li></ul></ul>
    21. 21. Reentry Phenomenon – Functional reentry
    22. 22. Reentry Phenomenon – Accessory pathway (WPW syndrome)
    23. 23. Arrhythmia Conditions <ul><li>Extrasystole: abnormal automaticity/after depolarization </li></ul><ul><li>Paroxysmal Supraventricular Tachycardia: 150-200/minute (1:1), reentry phenomenon (AV node) </li></ul><ul><li>Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right atrium </li></ul><ul><li>Atrial Fibrillation: 350-550/min, electrophysiological inhomogenicity of atrial muscles (bag of worms) </li></ul><ul><li>Ventricular tachycardia: 4 or more consecutive extrasystole of ventricles </li></ul><ul><li>Ventricular Fibrillation: rapid irregular contractions – fatal (MI, electrocution) </li></ul><ul><li>Torsades de pointes: polymorphic ventricular tachycardia, rapid asynchronous complexes, rise and fall in baseline of ECG </li></ul><ul><li>Atrio-ventricular Block (A-V Block): vagal influence or ischaemia - 1st, 2 nd and 3 rd degree </li></ul>
    24. 24. Antiarrhythmic Drugs <ul><li>Biggest problem – antiarrhythmics can cause arrhythmia! </li></ul><ul><ul><li>Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia </li></ul></ul><ul><ul><li>Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmics </li></ul></ul><ul><li>Mechanism of action: </li></ul><ul><ul><li>Sodium channel blockade </li></ul></ul><ul><ul><li>Blockade of sympathetic autonomic effects </li></ul></ul><ul><ul><li>Blockade of Effective Refractory Period (ERP) – increase ERP/APD ratio </li></ul></ul><ul><ul><li>Calcium Channel Blockade </li></ul></ul>
    25. 25. Antiarrhythmic Drugs <ul><li>Vaugham-Williams classification : </li></ul><ul><li>Class I – Na+ Channel Blockers </li></ul><ul><li>Class II - Beta-adrenergic Blockers </li></ul><ul><li>Class III – Prolong Repolarization </li></ul><ul><li>Class IV – Calcium Channel Blocker </li></ul>
    26. 26. Class I - antiarrhythmics Class IA Class IB Class IC Class I antiarrhythmics are further classified to IA, IB and IC Quinidine Procainamide Disopyramide Lidocaine Phenytoin Flecainide Propafenone
    27. 27. Subclass – I A <ul><li>Lengthen action potential </li></ul><ul><li>Slow rate of rise of phase 0 </li></ul><ul><li>Prolong repolarization </li></ul><ul><li>Prolong refractoriness by blocking several types of potassium channel </li></ul><ul><li>Prolong PR, QRS, QT </li></ul><ul><li>Moderate-marked sodium channel blockade in Open state </li></ul><ul><li>E.g, quinidine, procainamide, disopyramide </li></ul>
    28. 28. <ul><li>Shorten action potential </li></ul><ul><li>Limited effect on rate of rise of phase 0 </li></ul><ul><li>Shorten repolarization </li></ul><ul><li>Shorten QT </li></ul><ul><li>Raise fibrillation threshold in ventricular tissues </li></ul><ul><li>Mild-moderate sodium channel blockade </li></ul><ul><li>Little effect on refractoriness since there is essentially no blockade of potassium channels </li></ul><ul><li>E.g, lignocaine, mexilitine, phenytoin, propafenone </li></ul>Subclass - IB
    29. 29. Subclass – IC <ul><li>No effect on length of action potential </li></ul><ul><li>Markedly reduces rate of rise of phase 0 </li></ul><ul><li>Little effect on repolarization </li></ul><ul><li>Markedly prolongs PR and QRS </li></ul><ul><li>Refractory period of AV node is increased </li></ul><ul><li>Marked Na+ channel blockade </li></ul><ul><li>Prolong refractoriness by blocking outward-rectifying potassium channels </li></ul><ul><li>Used in life threatening ventricular fibrillation since they have highest affinity to Na+ channels </li></ul><ul><li>E.g, flecainide </li></ul>
    30. 30. Antiarrhythmic Drugs - Quinidine <ul><li>Dextroisomer of Quinine: N+ channel blocking and antivagal action </li></ul><ul><li>Actions: </li></ul><ul><ul><li>Inhibition of Na channel – slanted O phase and Decreases phase 4 </li></ul></ul><ul><ul><li>Net result is delay in conductivity and increase in refractoriness </li></ul></ul><ul><ul><li>Other actions include – alpha blockade, decreased skeletal muscle contractility, vomiting and diarrhoea etc </li></ul></ul><ul><li>Kinetics: well absorbed orally, half life – 10 Hrs </li></ul><ul><li>Uses: </li></ul><ul><ul><li>Broad spectrum antiarrhythmic </li></ul></ul><ul><ul><li>Atrial fibrillation and flutter, AF after direct current cardioversion to maintain sinus rhythm, prevention of PSVT and prevention of ventricular tachycardia </li></ul></ul><ul><li>Adverse effects: Not used now for adverse effects like Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism etc. </li></ul>
    31. 31. Antiarrhythmic Drugs - Procainamide <ul><li>Procaine derivative (amide) </li></ul><ul><li>Identical action with quinidine except: </li></ul><ul><ul><li>Minimal antivagal action </li></ul></ul><ul><ul><li>Lesser suppression of ectopic automaticity </li></ul></ul><ul><ul><li>Lesser depression of automaticity and AV conduction </li></ul></ul><ul><ul><li>No alpha blocking action </li></ul></ul><ul><li>Kinetics: </li></ul><ul><ul><li>Absorbed orally and bioavailability is 80% </li></ul></ul><ul><ul><li>Metabolized in liver to N-acetyl-procainamide (NAPA) – blocks K channel and prolongs repolarization </li></ul></ul><ul><li>Dosage – 250 mg tabs and 1gm/ml injections </li></ul><ul><ul><li>Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 Hrs </li></ul></ul><ul><li>Uses: Mainly for monomorphic VTs and to prevent recurrences </li></ul>
    32. 32. Antiarrhythmic Drugs - Lidocaine <ul><li>Popular antiarrhythmic and also local anaesthetic </li></ul><ul><li>Actions: </li></ul><ul><ul><li>Suppression of automaticity in ectopic foci </li></ul></ul><ul><ul><li>Slowing of O phase and shortening of phase 3 of CMC and PF </li></ul></ul><ul><ul><li>No action on SAN and AVN </li></ul></ul><ul><ul><li>Reduction in APD in ventricular myocardium </li></ul></ul><ul><ul><li>Suppression of reentry – ventricular </li></ul></ul><ul><li>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 </li></ul><ul><li>Adverse effects: Neurological – drowsiness, paresthesia, blurred vision, nystagmus and fits etc. </li></ul><ul><li>Uses: </li></ul><ul><ul><li>1 st line of drug in Arrhythmia following acute MI and cardiac surgery </li></ul></ul><ul><ul><li>Prevention of ventricular tachycardia </li></ul></ul><ul><ul><li>Digitalis toxicity </li></ul></ul>
    33. 33. Class II Antiarrhythmics <ul><li>They act indirectly on Electrophysiology – by blocking beta-adrenergic receptor, prolong PR interval, but no effects on QRS or QT interval – adrenergically mediated activity </li></ul><ul><li>Drugs used are beta-blockers: </li></ul><ul><li>Propranolol, Sotalol, Esmolol and Acebutlol </li></ul>
    34. 34. Class II – contd. <ul><li>Block beta-1 receptor in heart and decreases heart rate </li></ul><ul><li>Adrenline causes ventricular extrasystole and fibrillation by increasing the slope of phase 4 depolarization </li></ul><ul><ul><li>Also increases spontaneous firing of SA node </li></ul></ul><ul><li>AV conductions also needs sympathetic activity – Beta blockers prevent these activity </li></ul><ul><li>Uses: </li></ul><ul><ul><li>Reduce mortality after MI </li></ul></ul><ul><ul><li>Arrhythmias associated with increased sympathetic activity – sinus tachycardia, atrial extrasystoles provoked by emotion and exercise </li></ul></ul><ul><ul><li>Less effective in PSVT than adenosine and verapamil </li></ul></ul><ul><ul><li>Propranolol is used to treat sympathetically mediated arrhythmias - phaeochromocytoma and halothane anaesthesia </li></ul></ul>
    35. 35. Class III Antiarrhythmics <ul><li>Class III drugs K channel blockers prolong repolarization (increase refractoriness) by blocking outward potassium conductance </li></ul><ul><ul><li>Prolongation of Cardiac action potential </li></ul></ul><ul><ul><li>Also have interaction with the ANS </li></ul></ul><ul><ul><li>Diverse Pharmacology which is poorly understood </li></ul></ul><ul><li>Drugs – Ibutilide, dofetilide, sotalol (II + III action), amiodarone and bretylium </li></ul><ul><li>Bretylium is used only in life threatening arrhythmias </li></ul>
    36. 36. Class III - Amiodarone <ul><li>MOA: Long acting and highly lipophillic </li></ul><ul><li>Weak class I, II (beta- blocker) and class IV actions </li></ul><ul><li>Depresses automaticity of SA and AVN </li></ul><ul><li>Also non-competitive alpha and beta blocking property </li></ul><ul><li>Also direct coronray and peripheral vasodiltor </li></ul><ul><li>Kinetics: Incompletely and slowly absorbed – daily oral dose is give for several days for actions tto develop, t1/2 = 3-8 weeks </li></ul><ul><li>Dose: 400-600 mg/day p.o for many days followed by 100-200 mg/day as maintenance (100-300 mg slow IV) </li></ul><ul><li>Uses: </li></ul><ul><li>Most tachyarrhythmic conditions – ventricular and supraventricular </li></ul><ul><li>Recurrent VT and VF </li></ul><ul><li>WPW syndrome </li></ul>
    37. 37. Amiodarone <ul><li>Adverse effects: </li></ul><ul><li>Photosensitization </li></ul><ul><li>Peripheral neuropathy </li></ul><ul><li>Myocardial depression – bradycardia </li></ul><ul><li>Pulmonary alveolitis and fibrosis </li></ul><ul><li>Cornel micro deposits </li></ul><ul><li>hypothyroidism </li></ul>
    38. 38. Class IV - Antiarrhythmics <ul><li>Relatively selective AV nodal L-type calcium channel blockers – slow sinus rhythm, prolong PR interval, no effect on QRS complex </li></ul><ul><li>(Verapamil, diltiazem and bepridil) </li></ul><ul><li>Sinus Bradycardia – SA node and PF </li></ul><ul><li>AV block – no rentry </li></ul><ul><li>Negative ionotropic effect – interference with Ca++ mediated contraction </li></ul><ul><li>MOA: </li></ul><ul><ul><li>Block L-type channels – Phase 4 depolarization of SA and PF reduced </li></ul></ul><ul><ul><li>Reduce slow inward current and force of contraction </li></ul></ul><ul><ul><li>Also slow conduction of AV node due to calcium channel blockade </li></ul></ul>
    39. 39. Class IV – contd. <ul><li>Uses: Verapamil </li></ul><ul><ul><li>PSVT: </li></ul></ul><ul><ul><ul><li>For termination of attack – 5 mg IV over 2-3 minutes (reflex bradycardia) </li></ul></ul></ul><ul><ul><ul><li>For prevention of attack 60-120 mg orally tds </li></ul></ul></ul><ul><ul><li>Reduce ventricular rate in Atrial fibrillation (AF) </li></ul></ul>
    40. 40. Miscellaneous Agents <ul><li>Compounds whose actions do not fit the standard four classes – digoxine, adenosine and alinilide (a chloride channel blocker) </li></ul><ul><li>Adenosine: </li></ul><ul><li>Endogenously produced important chemical mediator used in PSVT </li></ul><ul><li>MOA: </li></ul><ul><ul><li>Activation of Ach sensitive K+ channel - membrane hyper polarization of SA node (G-protein coupled adenosine receptor) – depression of SA node and also slowing of AV conduction and shortening of action potential in atrium </li></ul></ul><ul><ul><li>Also indirectly reduces CA++ current in AV node – depression of reentry in PSVT </li></ul></ul>
    41. 41. Adenosine – contd. <ul><li>Very short half life – 20-30 sec. - Uptake by RBCs and endothelial cells </li></ul><ul><li>Administered intravenously </li></ul><ul><ul><li>6 mg given as a rapid intravenous bolus (administered over a 1-2 second period) </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><li>ADR: chest tightness, dyspnoea, fall in BP and flushing etc. </li></ul>
    42. 42. Summary <ul><li>Anti-arrhythmic drugs are classified by their effect on the cardiac action potential </li></ul><ul><li>An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissues to a greater extent than normal tissues of the heart </li></ul><ul><li>Many of the Na and Ca channel blockers have this property because they preferentially block sodium and calcium channels in the depolarized tissues </li></ul><ul><li>Most of the drugs exhibit mixed action </li></ul><ul><li>In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient </li></ul><ul><li>Anti-arrhythmic drugs are efficacious but may have serious adverse effects </li></ul><ul><li>Not all arrhythmias are treated with drug therapy alone </li></ul>
    43. 43. Non-pharmacological treatment <ul><li>Acute </li></ul><ul><ul><li>Vagal manoeuvres </li></ul></ul><ul><ul><li>DC cardioversion </li></ul></ul><ul><li>Prophylaxis </li></ul><ul><ul><li>Radiofrequency ablation </li></ul></ul><ul><ul><li>Implantable defibrillator </li></ul></ul><ul><li>Pacing (external, temporary, permanent) </li></ul>
    44. 44. Pacemakers <ul><li>Surgical implantation of electrical leads attached to a pulse generator </li></ul><ul><ul><li>Leads are inserted via subclavian vein and advanced to the chambers on the vena cava (right) side of the heart </li></ul></ul><ul><ul><li>Two leads used, one for right atrium, other for right ventricle </li></ul></ul><ul><ul><li>Pulse generator containing microcircuitry and battery are attached to leads and placed into a “pocket” under the skin near the clavicle </li></ul></ul><ul><ul><li>Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles </li></ul></ul><ul><li>Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed. </li></ul><ul><li>Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia </li></ul>
    45. 45. The Pacemaker
    46. 46. Thank You
    47. 47. Watch the Video
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