Pharmacological treatment of dysrhythmias.pdf

Treatment of Dysrhythmias Dr Samantha J. Pitt [email protected] Footer: Title of this talk? 1 Learning outcomes 1. Understand the Vaughan Williams classification of anti-dysrhythmic drugs 2. Recognise that some drugs are unclassified on this scheme 3. Know the mechanism of action, and uses...

Treatment of Dysrhythmias Dr Samantha J. Pitt [email protected] Footer: Title of this talk? 1 Learning outcomes 1. Understand the Vaughan Williams classification of anti-dysrhythmic drugs 2. Recognise that some drugs are unclassified on this scheme 3. Know the mechanism of action, and uses of the Class I group of drugs 4. Recognise the term ""use-dependent"" block 5. Understand the mechanism of action, and uses of the Class II group of drugs 6. Know the mechanism of action, and uses of the Class III group of drugs 7. Understand the mechanism of action, and uses of the Class IV group of drugs 8. Know the mechanisms of action, and uses of the unclassified drugs 2 Reminder – Basic Physiology 3 Reminder – Basic Physiology The spontaneous electrical discharge of the SAN is from the combined effect of: • Decrease in K+ outflow • “funny” Na+ current • Slow inward Ca2+ current 4 Reminder – Basic Physiology 5 Reminder – Basic Physiology 6 Reminder – Dysrhythmia Underlying Physiology Dysrhythmia (arrhythmia) describes conditions where the co-ordinated sequence of electrical activity in the heart is disrupted This could be due to: • Changes in the heart cells • Changes in the conduction of the impulse through the heart • Combinations of these 7 Reminder – Dysrhythmia Classification Dysrhythmias (arrhythmias) are broadly classified as: • Atrial (supraventricular) • Junctional (associated with the AV node) • Ventricular Site of the origin of the abnormality • Tachycardia or bradycardias 8 Reminder – Dysrhythmia General Classification Dysrhythmias (arrhythmias) arise from four broad categories of event: • Ectopic pacemaker activity • Delayed after-depolarisations • Circus re-entry • Heart block 9 Pharmacologic Management of Arrhythmias 10 Classes of Antidysrhythmic DrugsVaughan Williams system. • • • • • • • 1a: -Sodium channel blockers, disopyramide 1b: -Sodium channel blockers, lignocaine 1c: -Sodium channel blockers, flecainide 2: -b-adrenoreceptor blockers, sotalol 3: -Potassium channel block, amiodarone 4: -Calcium channel blockers, verapamil Unclassified: adenosine and digoxin 11 Class 1-Sodium Channel Blockers Drug binding domains of voltage-gated sodium channels 12 Class 1-Sodium Channel Blockers • Inhibit action potential propagation and they reduce the rate of cardiac depolarisation during phase 0. • Subdivision to class a, b and c is based on the properties of the drugs in binding to sodium channels in their various states such as open, refractory and resting. • Depolarisation switches channels from resting to open states- known as activation. Maintained depolarisation causes the channels to move to a refractory state - known as inactivation. • Cardiac myocytes must repolarise to reset the sodium channels back to resting state. • These drugs bind to the open and refractory states of the channels and so are viewed as use-dependent i.e. work more effectively if there is high activity and so are more effective against abnormal high frequency activity and not so much against normal beating rates. 13 Clinical use of class 1 antidysrhythmic drugs • Class 1a. Disopyramide (resembles quinidine) • Ventricular dysrhythmias, prevention of recurrent atrial fibrillation triggered by vagal over activity. • Class 1b. Lignocaine (given by IV) • Treatment and prevention of ventricular tachycardia and fibrillation during and immediately after MI. • Classs 1c. Flecainide. • Suppresses ventricular ectopic beats. Prevents paroxysmal atrial fibrillation and recurrent tachycardias associated with abnormal conducting pathways. 14 Class 2 drugs- b blockers. Signal transduction pathway of β adrenoceptors catecholamines 15 Class 2 drugs- b blockers. • Block b-1 receptors slow the heart and decrease cardiac output. • b-1 receptor activation increases the rate of depolarisation of the pacemaker cells so blocking them decreases this. • b-1 receptor activation enhances calcium entry in phase 2 of the cardiac action potential so blocking them reduces this. • b-blockers increase the refractory period of the AV node so prevent recurrent attacks of supraventricular tachycardias. • Basically increased sympathetic drive and influence tend to promote dysrhythmias and so attenuating their influence will slow the heart and decrease their occurrence. 16 Class 2 drugs- b blockers. • Sotalol, bisoprolol, atenolol. Clinical uses are to reduce mortality following MI and to prevent recurrence of tachycardias provoked by increased sympathetic activity. 17 Class 3 drugs – potassium channel blockers. • Amiodarone - prolongs the cardiac action potential by prolonging the refractory period. 18 Clinical uses of Class 3 drugs. • Amiodarone, tachycardia associated with the WolffParkinson-White syndrome. Wolff-Parkinson-White syndrome is a heart condition featuring episodes of an abnormally fast heart rate. Episodes can last for seconds, minutes, hours or (in rare cases) days. They may occur regularly, once or twice a week, or just once in a while. • Amiodarone is also effective in many other supreventricular and ventricular tachyarrhythmias. • Sotalol combines class 3 with class 2 actions. It is used in supraventricular dysrhythmias and suppresses ventricular ectopic beats and short runs of ventricular tachycardia. 19 Class 4 drugs – Calcium Channel Blockers. • Verapamil and diltiazem. • Blocks cardiac voltagegated L-type calcium channels. • Slow conduction through the SA and AV nodes where the conduction of the AP relies on the slow calcium currents. • They shorten the plateau of the cardiac AP and reduce the force of contraction of the heart. 20 Clinical Uses of class 4 drugs. • Verapamil is the main drug. • Used to prevent recurrence of supraventricular tachycardias (SVTs) • And to reduce the ventricular rate in patients with atrial fibrillation provided they do not have Wolff-Parkinson-White syndrome. • It is ineffective and dangerous in ventricular dysrhythmias. • Diltiazem is similar to verapamil but has more effect on smooth muscle calcium channels and has less bradychardia. 21 22 Unclassified - Adenosine • Produced endogenously with effects on breathing, cardiac and smooth muscle, vagal afferent nerves and platelets. • A1 receptor is responsible for the effect on the AV node. • These receptors are linked to the same cardiac potassium channels that are activated by ACh. and so it hyperpolarises cardiac conducting tissue and slows the heart rate. It decreases pacemaker activity. • Used to terminate SVTs. 23 Unclassified - Digoxin • Cardiac glycosides are a family of compounds that are derived from the foxglove plant (Digitalis purpurea). • Increase vagal efferent activity to the heart (by unknown mechansim) • This parasympathomimetic action of digoxin reduces sinoatrial firing rate (decreases heart rate) and reduces conduction velocity of electrical impulses through the atrioventricular node • Toxic concentrations disturb sinus rhythm. Inhibition of Na+/K+ pump cause depolarisation – ectopic beats 24 Should the Vaughan Williams Classification system be updated? Class 0: HCN (pacemaker) Channel Blockers Ivabradine: Stable angina and chronic heart failure with heart rate ≥70 bpm Class I: Voltage-gated Na+ Channel Blockers Class II: Beta Blockers Class III: K+ Channel Blockers Class IV: Ca2+ handling modulators To include intracellular Ca2+ channel blockers and SERCA activators (not FDA approved) flecainide- Catecholaminergic polymorphic ventricular tachycardia(CPVT) Class V: Mechanosensitive channel blockers –Not FDA approved Class VI: Gap junction (connexin-associated )channel blockers – Not FDA approved Class VII: Upstream target modulators Statins- Potential for use in atrial fibrillation. Angiotensin Converting Enzyme (ACE) inhibitors (prevent the body from producing AngII): captopril - Potential application in atrial fibrillation due to heart failure 25 Learning outcomes 1. Understand the Vaughan Williams classification of anti-dysrhythmic drugs 2. Recognise that some drugs are unclassified on this scheme 3. Know the mechanism of action, and uses of the Class I group of drugs 4. Recognise the term ""use-dependent"" block 5. Understand the mechanism of action, and uses of the Class II group of drugs 6. Know the mechanism of action, and uses of the Class III group of drugs 7. Understand the mechanism of action, and uses of the Class IV group of drugs 8. Know the mechanisms of action, and uses of the unclassified drugs 26 Suggested reading in addition to lecture notes: Medicine General Reading List Section 3:Drugs affecting major organs – The heart Rang et al: Rang & Dale’s Pharmacology, 9e. The Heart: Pages: 271-289 27