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  • Resting intracellular voltage of myocardial cell is –90mV (high intracellular K maintained by Na/K pump)
  • Sinoatrial node located at junction of superior vena cava and the right atrium.
  • Narrow originate in atria or AV node Broad originate from ventricles or from atria or AV node wirh aberrant concuction to the ventricles (LBBB or RBBB)
  • Re-entry is when tisue that is usually refractory is reactivated. Occurs if there is a ring of tissue that does not conduct normally. Usually the two paths of action potentials meet and die out, but if they do not meet then a circuit is set up. Abnormal pacemaker activity can occur if myocardial cells are damaged eg ischaemic heart disease also via catecholamine overactivity Delayed after-depolarisation occurs when in cardiac tissue that usually has to wait for the initiation of an action potential from pacemaker tissue, the cardiac cell automatically depolarises. This leads to a repetitive discharge (triggers ectopic beats -‘R on T phenomenon’) (related to extent of inward Ca current) caused by cardiac glycosides eg digoxin Re-entry (partial conduction block eg accessory pathways linking atria and ventricles eg Wolff-Parkinson-White syndrome) halted by drugs that prolong the refractory period
  • Multiple micro re-entry circuits within (often diseased) atrial tissue. Chaotic ventricular rhythm
  • Digoxin-specific binding (Fab) fragment, antibody to digoxin, neutralises digoxin in the plasma
  • Transcript

    • 1. Anti-arrhythmic drugs
    • 2. Content
      • Physiology of normal cardiac rhythm
      • Definition and mechanisms of arrhythmias
      • Classification of drugs to treat arrhythmias
      • Important anti-arrhythmic drugs (mechanism and pharmacological characteristics)
      • Arrhythmias in clinical practice
    • 3. Physiology of cardiac rate and rhythm
      • Cardiac myocytes are electrically excitable
      • Resting intracellular voltage of myocardial cells is negative -90mV (SA node is -40mV)
      • Resting state - K + inside and Na + outside cell (Na + /K + pump)
      • Action potential occurs when Na + enters the cell and sets up a depolarising current
      • Stimulation of a single muscle fibre causes electrical activity to spread across the myocardium
    • 4. Phases of action potential of cardiac cells
      • Phase 0 rapid depolarisation (inflow of Na +)
      • Phase 1 partial repolarisation (inward Na + current deactivated, outflow of K + )
      • Phase 2 plateau (slow inward calcium current)
      • Phase 3 repolarisation (calcium current inactivates, K + outflow)
      • Phase 4 pacemaker potential (Slow Na + inflow, slowing of K + outflow) ‘autorhythmicity’
      • Refractory period (phases 1-3)
      Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV -80mV II I III IV
    • 5. Sinus rhythm
      • Sinoatrial node is cardiac pacemaker
      • Normal sinus rhythm 60-100 beats/min
      • Depolarisation triggers depolarisation of atrial myocardium (‘forest fire’)
      • Conducts more slowly through AV node
      • Conducts rapidly through His bundles and Purkinje fibres
    • 6. Sinus rhythm
      • Sinoatrial rate controlled by autonomic nervous system
      • Parasympathetic system predominates (M2 muscarinic receptors)
      • Sympathetic system (ß1 receptors)
        • Increased heart rate (positive chronotropic effect)
        • Increased automaticity
        • Facilitation of conduction of AV node
    • 7. ECG
      • Recording of electrical activity of the heart
      • Net sum of depolarisation and repolarisation potentials of all myocardial cells
      • P-QRS-T pattern
      • P - atrial depolarisation
      • QRS - ventricular depolarisation
      • T - ventricular repolarisation
    • 8. Definition of arrhythmia
      • Cardiac arrhythmia is an abnormality of the heart rhythm
      • Bradycardia – heart rate slow (<60 beats/min)
      • Tachycardia – heart rate fast (>100 beats/min)
    • 9. Clinical classification of arrhythmias
      • Heart rate (increased/decreased)
      • Heart rhythm (regular/irregular)
      • Site of origin (supraventricular / ventricular)
      • Complexes on ECG (narrow/broad)
    • 10. Mechanisms of arrhythmia production
      • Re-entry (refractory tissue reactivated due to conduction block, causes abnormal continuous circuit. eg accessory pathways linking atria and ventricles in Wolff-Parkinson-White syndrome)
      • Abnormal pacemaker activity in non-conducting/conducting tissue (eg ischaemia)
      • Delayed after-depolarisation (automatic depolarisation of cardiac cell triggers ectopic beats, can be caused by drugs eg digoxin)
    • 11. Vaughan Williams classification of antiarrhythmic drugs
      • Class I : block sodium channels
        • Ia (quinidine, procainamide, disopyramide)  AP
        • Ib (lignocaine)  AP
        • Ic (flecainide)  AP
      • Class II : ß-adrenoceptor antagonists (atenolol, sotalol)
      • Class III : prolong action potential and prolong refractory period (suppress re-entrant rhythms) (amiodarone, sotalol)
      • Class IV : Calcium channel antagonists. Impair impulse propagation in nodal and damaged areas (verapamil)
      Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV -80mV II I III IV
    • 12. Management of arrhythmias
      • Acute management (clinical assessment of patient and diagnosis)
      • Prophylaxis
      • Non-pharmacological
      • Pharmacological (some antiarrhythmics are also proarrhythmic)
    • 13. Non-pharmacological treatment
      • Acute
        • Vagal manoeuvres
        • DC cardioversion
      • Prophylaxis
        • Radiofrequency ablation
        • Implantable defibrillator
      • Pacing (external, temporary, permanent)
    • 14. Pharmacological treatment-Lignocaine (Lidocaine)
      • Class Ib (blocks Na + channels, reduces AP duration)
      • Ventricular arrhythmias (acute Rx)
      • IV infusion only (2 hour half life, high first pass metabolism)
      • Hepatic metabolism (inhibited by cimetidine, propranolol)
      • SE mainly CNS - drowsiness, disorientation, convulsions, hypotension
    • 15. Flecainide
      • Class Ic (block Na + channels, no change to AP)
      • Slows conduction in all cardiac cells
      • Acute Rx /prophylaxis
      • Supraventricular tachycardias
      • Paroxysmal atrial fibrillation
      • Ventricular tachycardias
      • Oral/IV
      • Long acting (T1/2 14 hours)
      • Hepatic metabolism, urinary elimination
    • 16. Flecainide
      • CAST (Cardiac Arrhythmia Suppression Trial) 1989 – increased mortality post MI (VF arrest)
      • SE- cardiac failure, ventricular arrhythmias, blurred vision, abdominal discomfort, nausea, paraesthesia, dizzyness, tremor, metallic taste
    • 17. Amiodarone
      • Class III - increases refractory period and AP
      • Major effect acutely is depression of AV node
      • Acute Rx/prophylaxis
      • Atrial and ventricular arrhythmias
      • Oral or IV (central line)
      • Loading and maintenance doses
      • T1/2 54 days
      • Large volume of distribution
      • Accumulates
      • Hepatic metabolism- biliary and intestinal excretion
    • 18. Amiodarone – adverse effects
      • Photosensitive rashes
      • Grey/blue discolouration of skin
      • Thyroid abnormalities 2%
      • Pulmonary fibrosis
      • Corneal deposits
      • CNS/GI disturbance
      • Pro-arrhythmic effects (torsade de pointe)
      • Heart block
      • Nightmares 25%
      • Abnormal LFT 20%
      • Interacts with digoxin, warfarin (reduces clearance)
    • 19. Adenosine
      • Not in Vaughan Williams class
      • Purine nucleotide (activates adenosine receptors)
      • Slows AV nodal conduction
      • Acute Rx
      • Termination of SVT/ diagnosis of VT
      • Given IV only (rapid bolus)
      • T1/2 < 2seconds
    • 20. Adenosine- adverse effects
      • Feeling of impending doom!
      • Flushing, dyspnoea, chest pain, transient arrhythmias
      • Contraindicated in asthma, heart block
    • 21. Verapamil
      • Class IV (calcium channel blocker)
      • Prolongs conduction and refractoriness in AV node, slows rate of conduction of SA node
      • Acute Rx /prophylaxis
      • Used IV/oral
      • Do not use IV verapamil with ß- blocker (heart block)
      • T1/2 6-8 hours
    • 22. Verapamil- adverse effects
      • Heart failure
      • Constipation
      • Bradycardia
      • Nausea
    • 23. Digoxin
      • Not in Vaughan Williams class
      • Cardiac glycoside (digitalis, foxglove)
      • Act on Na/K-ATPase of cell membrane (inhibits Na + /K + pump, increases intracellular Na + and calcium)/ increases vagal activity
      • Increase cardiac contraction and slows AV conduction by increasing AV node refractory period
    • 24. Digoxin
      • Atrial fibrillation or flutter (controls ventricular rate)
      • Acute Rx/prophylaxis
      • Oral/IV
      • Loading and maintenance doses
      • T1/2 36 hours
      • Excreted by kidneys
      • Narrow therapeutic index
      • Therapeutic drug monitoring
      • Reduce dose in elderly/renal impairment
    • 25. Atrial fibrillation                                                                                                                                                       
    • 26. Digoxin – adverse effects
      • Arrhythmias, heart block, anorexia, nausea, diarrhoea, xanthopsia, gynaecomastia, confusion, agitation
      • AE potentiated by hypokalaemia and hypomagnesaemia
      • Overdose –Digibind (digoxin binding antibody fragments), phenytoin for ventricular arrhythmias, pacing, atropine
    • 27. Clinical cases
    • 28. 36 year old woman with asthma has ‘thumping in chest’
    • 29. 76 year old man with breathlessness
    • 30. 54 year woman collapses 24 hours post MI
    • 31. 60 year old man with recurrent blackouts
    • 32. Summary
      • Anti-arrhythmic drugs are classified by their effect on the cardiac action potential
      • Not all drugs fit this classification
      • In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient
      • Anti-arrhythmic drugs are efficacious but may have serious adverse effects
      • Not all arrhythmias are treated with drug therapy alone
    • 33. Any questions?