Cardiac Arrhythmias

1. Cardiac Arrhythmias

2. Types of cardiac arrhythmias: • Bradyarrhythmias • Tachyarrhythmias • Bradyarrhythmias: treat with atropine, pacing • Tachyarrhythmias can occur due to: • Enhanced automaticity • Afterdepolarization and triggered activity • Re-entry

3. Tachyarrhythmias: • Enhanced automaticity: • In tissues undergoing spontaneous depolarization • -stimulation, hypokalemia, mechanical stretch of cardiac muscle • Automatic behaviour in tissues that normally lack spontaneous pacemaker activity e.g. ventricular ischaemia depolarizes ventricular cells and can cause abnormal rhythm • Afterdepolarization: • EAD: when APD is markedly prolonged • Occur in phase 3 • May be due to inwards Na+ or Ca2+ current • Excessive prolongation of APD- torsades de pointes syndrome

4. EAD DAD

5. Torsades de pointes: polymorphic ventricular tachycardia along with prolonged QT interval • DAD: precipitating conditions are intracellular or sarcoplasmic Ca2+ overload, adrenergic stress, digitalis intoxication, heart failure • If afterdepolarizations reach a threshold, an AP is genererated which is called ‘triggered beat’ • DAD occur when the HR is fast, EAD occur when the HR is slow • Re-entry: when a cardiac impulse travels in a path such as to return to and reactivate its original site and self perpetuate rapid reactivation independent of normal sinus node conduction

6. Requirements for re-entry rhythm: • slowing or conduction failure due to either an anatomic or functional barrier • Anatomic barrier- Wolff-Parkinson-White syndrome • Functional barrier- ischaemia, differences in refractoriness • Presence of an anatomically defined circuit • Heterogenecity in refractoriness among regions in the circuit • Slow conduction in one part of the circuit

7. What are channels? – they are macromolecular complexes consisting of a pore forming  subunit,  subunits and accessory proteins • They are: • Transmembrane proteins • Consist of a voltage sensitive domain • A selectivity filter • A conducting pore and, • An inactivating particle • In response to changes in membrane voltage, the channel changes conformation so as to allow or prevent the flow of ions through it along their concentration gradient

9. K+ (Transient) K+ (delayed rectifier) Ca2+ Ca2+ Na+ Na+ Na+K+ATPase K+

10. K+ channel blocker -blocker, CCB Na+ channel blocker

11. Ca2+ channel blocker & -blocker

12. How can drugs slow the cardiac rhythm? • Decreasing phase 4 slope • Increase in threshold potential for excitation • Increase in maximum diastolic potential • Increase in APD • Fast response tissues • Slow response tissues

13. Na+ channel blocker: • Na+ channel block depends on: • HR • Membrane potential • Drug specific physiochemical characteristic-  recovery • Blockade of Na+ channels results in: • Threshold for excitability is increased (more current) • Increase in pacing and defibrillation threshold • Decrease conduction velocity in fast response tissues • Increase QRS interval • Some drugs tend to prolong PR interval- flecainide (possibly Ca2+ channel blockade)

14. Some sodium channel blockers shorten the PR interval (quinidine; vagolytic effect) • APD unaffected or shortened • Increase in threshold for excitation also decreases automaticity • Can also inhibit DAD/EAD • Delays conduction so can block re-entry • In some cases, it can exacerbate re-entry by delaying conduction • Shift voltage dependence of recovery of sodium channels from inactivated state to more negative potentials and so increases refractoriness • Net effect- whether it will suppress or exacerbate re-entry arrhythmia depends on its effect on both factors- conduction velocity and refractoriness

15. Most Na+ channel blockers bind to either open or inactivated state and have very little affinity for channels in closed state, drug binds to channels during systole & dissociates during diastole • ADRs: • Decrease in conduction rate in atrial flutter- slows rate of flutter and increases HR due to decrease in AV blockade • Especially common with quinidine due to its vagolytic property; also seen with flecainide and propafenone • Cases of ventricular tachycardia due to re-entrant rhythm following MI may worsen due to slowing of conduction rate • Slowing of conduction allows the re-entrant rhythm to persist within the circuit so that complicated arrhythmias can occur • Several Na+ channel blockers have been reported to exacerbate neuromuscular paralysis by d-tubocurarine

16. K+ Channel blockers: • Prolong APD (QT interval) and reduces automaticity • Increase in APD also increases refractoriness • Effective in treating re-entrant arrhythmias • Reduce energy requirement for defibrillation • Inhibit ventricular arrhythmias in cases of myocardial ischemia • Many K+ channel blockers also have  blocking activity also like sotalol • Disproportionate prolongation of APD can result in torsaides de pointes, specially when basal HR is slow

17. CCBs: • Major effect on nodal tissues • Verapamil, diltiazem and bepridil cause slowing of HR, nifedipine and other dihydropyridines reflexly increase HR • Decrease AV nodal conduction so PR interval increases • AV nodal block occurs due to decremental conduction and increase in AV nodal refractoriness • DAD leading to ventricular tachycardia respond to verapamil • Verapamil and diltiazem are recommended for treatment of PSVT • Bepridil increases APD in many tissues and can exert antiarrhythmic action in atria and ventricles but it use is associated with increased incidence of torsades de pointes- rarely used