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Pharmacotherapy of
Cardiac Arrhythmia
Dr. Vikas S. Sharma
Dept. Of Pharmacology
GMC, Nagpur
16.02.2016
Overview
• Electrophysiology of cardiac rhythm
• Mechanisms in cardiac arrhythmia
• Classification of anti-arrhythmic drug...
Electrophysiology of cardiac rhythm
Page 3 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma
16.02.2016
Fast & Slow channel AP
Page 4 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma
16.02.2016
Mechanism of Cardiac arrhythmias
• Abnormal impulse generation
• After-depolarization
• Delayed after-depolarization (DAD)...
Abnormal impulse generation
• Depressed automaticity SA node – escape beat & ↓ HR
• Enhanced automaticity SA node - ↑ HR
•...
Ectopic activity is encouraged by-
• Faster phase 4 depolarisation
• Less negative resting membrane
potential (RMP)
• More...
After depolarisation
Normal action potential (AP) triggers
extra-abnormal depolarisation
Abnormal Ca2+ influx into cardiac...
Page 9 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma
16.02.2016
Abnormal impulse conduction
A. Conduction block:
• Dropped beat or idioventricular rhythm
• Severely depressed conduction
...
B. Re-entry phenomenon:
• 80 – 90 % Clinical arrhythmia
• Re-entrant arrhythmias
Premature beat, paroxysmal supraventricul...
Circus movement of rhythm & accessory
tract pathway
Page 12 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sh...
Functional re-entry
• Functional obstacle and unidirectional conduction pathway
is created by a premature impulse
• On enc...
Fractionation of impulse
• When atrial ERP is brief and inhomogeneous, an impulse
generated early in diastole gets conduct...
Classification
I. Membrane stabilizing agents (Na+ channel blockers):
A. Quinidine, Procainamide, Disopyramide
B. Lidocain...
In addition
1. For PSVT : Adenosine, Digoxin
2. For A-V block : Sympathomimetics - Isoprenaline
Anticholinergics - Atropin...
Class I
• Division: interaction with cardiac Na+ channel &
effect on different phases of cardiac AP
Binds to Na+ channel m...
Class IA
• Mechanism of action (MoA):
• Extinguish ectopic pacemaker & abolish re-entry by
converting unidirectional block...
Quinidine
• Also has anti-vagal action
• Depresses myocardial contractility
• ECG - ↑ PR & QT interval & broaden QRS compl...
Procainamide
• Cardiac electrophysiological action is almost identical to
that of quinidine
• Differences are:
• Long term...
• Dose:
• Uses:
Abolition of arrhythmia:
500 mg iv loading dose (25 mg/min inj.) f/b 2 mg/kg/hr
Or
500 mg oral / im f/b 25...
Disopyramide
• Prominent cardiac depressant & anti-cholinergic action
• No interaction with digoxin
• Longer T1/2 (6-8 hrs...
Class IB
• Mechanism of action (MoA):
• Like quinidine, also abolish ventricular re-entry
tachycardia
• Block inactivated ...
Lidocaine
• Most prominent action –
• Inactive orally due to high first pass metabolism
• Action of IV bolus lasts only 10...
• T1/2:
Early distribution phase – 8 mins
Later elimination phase – 2 hrs
• Dose:
50-100 mg iv bolus f/b 20-40 mg every 10...
Mexiletine
• Local anaesthetic & orally active
• Automaticity in PF is ↓ by both ↓ phase 4 & ↑ threshold
voltage
• By ↓ ra...
• Dose:
100-250 mg iv over 10 mins, 1mg/min infusion
Oral 150-200 mg TDS with meals
• Use:
Post MI ventricular arrhythmia ...
Class IC
• Mechanism of action (MoA):
• High proarrhythmic potential when administered chronically
• Markedly ↓ rate of ph...
Flecainide
• Prototype drug which markedly delays Na+ channel recovery
• No consistent effect on APD & no β blocking activ...
Propafenone
• By blocking Na+ channels, depresses impulse
transmission & has profound effect on His-Purkinje as well
as ac...
• Side effects:
Proarrhythmic events
• Dose:
150 mg BD – 300 mg TDS
• Use:
Prophylaxis & treatment of ventricular arrhythm...
Class II
• Mechanism of action (MoA):
• Slows sinus & AV nodal conduction which result in ↓ in
HR & prolongation in PR int...
Propranolol
• Marked ↓ in slope of phase 4 depolarisation &
automaticity occur in SA node, PF & other ectopic foci
when sa...
• Uses:
Inappropriate sinus tachycardia
AES / VES, especially provoked by emotion or exercise
Prevent recurrences of PSVT
...
Esmolol
• Quick & short acting β1 blocker administered IV for
emergency control of ventricular rate in AF / AFL
• Terminat...
Sotalol
• Prominent class III action of prolonging repolarisation by
blocking cardiac inward rectifier K+ channel
• Non-se...
Class III
• Mechanism of action:
• Prolong ERP
• QT & PR interval are prolonged
• Tissue remains refractory even after ful...
Amiodarone
• Iodine containing, highly lipophilic, long acting
• Conduction is slowed & ectopic automaticity is markedly
d...
• Incompletely & slowly absorbed from GIT
On daily oral ingestion, action develops over several days
On IV injection, acti...
• Uses:
• Dose:
1. Resistant VT & recurrent VF
2. Maintain sinus rhythm in AF when other drugs have failed
3. Rapid termin...
Dronedarone
• Amiodarone like drug without iodine atoms
• Shorter t1/2 – 1-2 days
• Dose:
400 mg BD orally
• Use:
Prevent ...
Bretylium
• Given only in ICU facility for treating refractory life-
threatening ventricular tachycardia & fibrillation
• ...
Dofetilide
• Pure Class III drug
• Prolongs APD & ERP by selectively blocking rapid
components of delayed rectifier K+ cur...
Vernakalant
• Mixed Na+ & K+ channel blocker
• Prolong atrial ERP & slows conduction through AV node
• Association & disso...
Azimilide
• Blocks both slow & rapid components of K+ channels
• Low incidence of torsades de pointes
• Under trial to con...
Tedisamil
• Upcoming Class III drug
• Given by IV infusion
• For conversion of AF & AFL to sinus rhythm
Page 46 of 68 Phar...
Class IV
• Mechanism of action:
Blocks both activated & inactivated L-type Ca2+
channels in myocardium
↓ in rate of depola...
Verapamil
• Most prominent cardiac electrophysiological action
• Basic action is to depress Ca2+ mediated depolarization.
...
2. To control ventricular rate in AF or AFL:
Dose dependent (40–120 mg TDS oral) reduction in
ventricular rate in AF and A...
Diltiazem
• Alternative to verapamil – termination & prophylaxis of
PSVT
• For rapid control of ventricular rate in AF or ...
Adenosine
Stimulates adenosine receptors (A1)
Opens G-protein coupled K+ channel & inhibits SA
nodal, atrial & AV nodal co...
• very short t½ in blood (~10 sec)
• Advantages of adenosine for termination of PSVT are:
1. Efficacy equivalent to or bet...
• Main side effects:
Facial flushing, shortness of breath, bronchospasm,
nausea, metallic taste
• Other uses of adenosine:...
Atrial / Ventricular extrasystole
• Asymptomatic – no treatment required
• Symptomatic - β blocker
Page 54 of 68 Pharmacot...
Atrial fibrillation
• Definition:
Fast ectopic, irregular atrial activity (350-600 bpm)
• Ventricular rate ~ 100-150 bpm
•...
3. Rhythm control:
Electrical
Acute therapy – DC shock
Chronic therapy – Amiodarone
Pharmacological
Acute therapy – Amioda...
Acute AF (> 48 hours)
Transesophageal echocardiography
Yes No
Don’t cardiovert immediately Immediate cardioversion
Warfari...
Chronic AF (>6 months)
a. Rate control with β blocker, CCB & Digoxin
b. ↓ Risk of ischemic stroke
Aspirin / Warfarin based...
Atrial flutter
• Atrial rate 250-350 bpm
• Ventricular rate 75-175 bpm
• TOC – DC shock
• Recurrent atrial flutter:
A. Rad...
Wolf-Parkinson-White Syndrome
Tachycardia
• Termination:
Cardioversion, Radiofrequency ablation
• Maintenance:
1. Narrow Q...
PSVT
• An attack of PSVT can be terminated by reflex vagal
stimulation through
• Alternatively, or if it does not work, th...
Ventricular tachycardia
• Definition:
≥ 4 consecutive ventricular extrasystole of > 100 bpm
• Unstable VT:
Immediate DC sh...
Chronic ventricular tachycardia
• Nonsustained VT:
Suppression - Propranolol/amiodarone (oral)
• Sustained VT:
• Abolition...
Ventricular fibrillation
• Grossly irregular, rapid & fractionated activation of
ventricles resulting in inco-ordinated co...
Bradyarrhythmias
• Results from failure of impulse generation within SA node
or
failure of impulse conduction through AV n...
• Second degree A-V block: Some supraventricular
complexes are not conducted: drop beats
• Third degree A-V block: No supr...
• Sympathomimetics (isoprenaline): Overcome partial
heart block by facilitating A-V conduction and shortening
ERP of condu...
Summary
• Abnormal automaticity or impaired conduction or both
underlies cardiac arrhythmia
• Anti-arrhythmic drugs used t...
References
• Goodman & Gilman’s The Pharmacological Basis of
Therapeutics 12th
Edition
• Longo, Fauci, Kasper, Hauser, Jam...
16.02.2016
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Pharmacotherapy of cardiac arrhythmias

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Pharmacotherapy of cardiac arrhythmias

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Pharmacotherapy of cardiac arrhythmias

  1. 1. Pharmacotherapy of Cardiac Arrhythmia Dr. Vikas S. Sharma Dept. Of Pharmacology GMC, Nagpur 16.02.2016
  2. 2. Overview • Electrophysiology of cardiac rhythm • Mechanisms in cardiac arrhythmia • Classification of anti-arrhythmic drugs • Treatment of individual arrhythmias • Summary Page 2 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  3. 3. Electrophysiology of cardiac rhythm Page 3 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  4. 4. Fast & Slow channel AP Page 4 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  5. 5. Mechanism of Cardiac arrhythmias • Abnormal impulse generation • After-depolarization • Delayed after-depolarization (DAD) • Early after-depolarization (EAD) • Abnormal impulse conduction • Conduction block • Re-entry phenomenon (Circus movement of rhythm) • Accessory tract pathway Page 5 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  6. 6. Abnormal impulse generation • Depressed automaticity SA node – escape beat & ↓ HR • Enhanced automaticity SA node - ↑ HR • AV node , Purkinje fibres, atrial & ventricular cells: spontaneous diastolic depolarisation & repetitive firing – RMP - 60 mV AV nodal rhythm, idioventricular rhythm or ectopic beats Page 6 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  7. 7. Ectopic activity is encouraged by- • Faster phase 4 depolarisation • Less negative resting membrane potential (RMP) • More negative threshold potential Page 7 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  8. 8. After depolarisation Normal action potential (AP) triggers extra-abnormal depolarisation Abnormal Ca2+ influx into cardiac myocyte during or immediately after phase 3 of ventricular AP Page 8 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  9. 9. Page 9 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  10. 10. Abnormal impulse conduction A. Conduction block: • Dropped beat or idioventricular rhythm • Severely depressed conduction Page 10 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  11. 11. B. Re-entry phenomenon: • 80 – 90 % Clinical arrhythmia • Re-entrant arrhythmias Premature beat, paroxysmal supraventricular tachycardia (PSVT), atrial flutter (AFL) & ventricular fibrillation (VF) Page 11 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  12. 12. Circus movement of rhythm & accessory tract pathway Page 12 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  13. 13. Functional re-entry • Functional obstacle and unidirectional conduction pathway is created by a premature impulse • On encountering refractory tissue in one direction, wavefront travels through partially recovered fibres—gets markedly slowed and can set up small re-entry circuits which may constantly shift location Ventricular extrasystoles, polymorphic ventricular tachycardia, Atrial / Ventricular Fibrillation Page 13 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  14. 14. Fractionation of impulse • When atrial ERP is brief and inhomogeneous, an impulse generated early in diastole gets conducted irregularly over the atrium, slowly through fibres with longer ERP (partially recovered) and not at all through those still refractory • Asynchronous activation of atrial fibres→ atrial fibrillation Page 14 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  15. 15. Classification I. Membrane stabilizing agents (Na+ channel blockers): A. Quinidine, Procainamide, Disopyramide B. Lidocaine, Mexiletine C. Propafenone, Flecainide II. Antiadrenergic agents (β blockers): Propranolol, Esmolol, Sotalol III. Agents widening AP: Amiodarone, Dronedarone Dofetilide, Ibutilide IV. Calcium channel blockers: Verapamil, Diltiazem Page 15 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  16. 16. In addition 1. For PSVT : Adenosine, Digoxin 2. For A-V block : Sympathomimetics - Isoprenaline Anticholinergics - Atropine 3. Digitalis: AF, AFL and PSVT to control ventricular rate Page 16 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  17. 17. Class I • Division: interaction with cardiac Na+ channel & effect on different phases of cardiac AP Binds to Na+ channel more strongly when they are in activated or inactivated state USE DEPENDENCE Block high frequency excitation of myocardium without preventing heart from beating at normal frequency Page 17 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  18. 18. Class IA • Mechanism of action (MoA): • Extinguish ectopic pacemaker & abolish re-entry by converting unidirectional block into bidirectional block Blocks activated Na+ channels > inactivated channel & slow rate of dissociation (recovery time 1-10 sec) Page 18 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  19. 19. Quinidine • Also has anti-vagal action • Depresses myocardial contractility • ECG - ↑ PR & QT interval & broaden QRS complex • Side effect – • Rise in blood levels & toxicity of digoxin • Dose – 200-400 mg TDS orally Diarrhoea (MC) Quinidine syncope Cinchonism Page 19 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  20. 20. Procainamide • Cardiac electrophysiological action is almost identical to that of quinidine • Differences are: • Long term high dose therapy – SLE •Less effective in suppressing ectopic automaticity •Less marked depression of contractility & AV conduction •No anti-vagal action •No α blocking activity •Doesn’t alter plasma levels of digoxin Page 20 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  21. 21. • Dose: • Uses: Abolition of arrhythmia: 500 mg iv loading dose (25 mg/min inj.) f/b 2 mg/kg/hr Or 500 mg oral / im f/b 250-500 mg every 2 hrs Maintenance dose: 500 mg every 4-6 hrs To terminate VT & some supraventricular arrhythmia Many WPW reciprocal VTs respond & to prevent recurrence of VF Page 21 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  22. 22. Disopyramide • Prominent cardiac depressant & anti-cholinergic action • No interaction with digoxin • Longer T1/2 (6-8 hrs) • Side effects – anti-cholinergic are most prominent • Dose – 100-150 mg 6-8 hrly oral • Uses – 2nd line drug for prevention of recurrence of ventricular arrhythmia Page 22 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  23. 23. Class IB • Mechanism of action (MoA): • Like quinidine, also abolish ventricular re-entry tachycardia • Block inactivated > activated Na+ channels & rapid rate of association & dissociation • Do not delay channel recovery (recovery time < 1 sec) • Block Na+ channels more in diseased myocardium Page 23 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  24. 24. Lidocaine • Most prominent action – • Inactive orally due to high first pass metabolism • Action of IV bolus lasts only 10-20 mins 1. Suppression of automaticity in ectopic foci 2. ↓ APD in Purkinje Fibres (PF) & ventricular muscles Suppresses re-entrant ventricular arrhythmia either by abolishing 1 way block or producing 2 way block Page 24 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  25. 25. • T1/2: Early distribution phase – 8 mins Later elimination phase – 2 hrs • Dose: 50-100 mg iv bolus f/b 20-40 mg every 10-20 min (Max 300 mg in 1 hr) Or 1-3 mg/min infusion • S/E: Dose related neurological effects • No proarrhythmic potential & least cardiotoxic Page 25 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  26. 26. Mexiletine • Local anaesthetic & orally active • Automaticity in PF is ↓ by both ↓ phase 4 & ↑ threshold voltage • By ↓ rate of 0 phase depolarisation in ischemic PF, converts 1 way block into 2 way block • Tremors – early sign of toxicity Bradycardia, hypotension & accentuation of AV block – iv • T1/2 – 9-12 hrs Page 26 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  27. 27. • Dose: 100-250 mg iv over 10 mins, 1mg/min infusion Oral 150-200 mg TDS with meals • Use: Post MI ventricular arrhythmia as alternative to lidocaine Page 27 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  28. 28. Class IC • Mechanism of action (MoA): • High proarrhythmic potential when administered chronically • Markedly ↓ rate of phase 0 depolarisation in Purkinje & ventricular myocardial fibres • ↓ automaticity, ↓ AV conduction & contractility • Retard re-entry of retrograde & anterograde impulses • Prominent depressant action on normal heart as well Most potent Na+ channel blocker with more prominent action on open state & longest recovery time (> 10 sec) Page 28 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  29. 29. Flecainide • Prototype drug which markedly delays Na+ channel recovery • No consistent effect on APD & no β blocking activity • CAST study, ↑ mortality in patients recovering from MI • Provokes arrhythmias during chronic therapy Highest proarrhythmic potential Page 29 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  30. 30. Propafenone • By blocking Na+ channels, depresses impulse transmission & has profound effect on His-Purkinje as well as accessory pathway conduction • Anterograde & retrograde conduction in bypass tract of WPW syndrome is retarded • Prolongs APD & has β blocking property – can precipitate CHF & bronchospasm • Bioavailability & T1/2 differ considerably among individuals Page 30 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  31. 31. • Side effects: Proarrhythmic events • Dose: 150 mg BD – 300 mg TDS • Use: Prophylaxis & treatment of ventricular arrhythmias, re- entrant tachycardia involving AV node / accessory pathway & to maintain sinus rhythm in AF ↑ ventricular rate in atrial flutter by slowing atrial rate & allowing 1:1 AV transmission Page 31 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  32. 32. Class II • Mechanism of action (MoA): • Slows sinus & AV nodal conduction which result in ↓ in HR & prolongation in PR interval • QT & QRS interval are not altered significantly β blockers that competitively block catecholamine induced stimulation of cardiac β receptors & depress phase 4 depolarisation of pacemaker cells Page 32 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  33. 33. Propranolol • Marked ↓ in slope of phase 4 depolarisation & automaticity occur in SA node, PF & other ectopic foci when same has ↑ under adrenergic influence • ECG: Prolonged PR interval • Dose: Rapid action: Slow iv infusion 1-3 mg/min in 50 ml of 5% glucose solution (max 5 mg) Oral: 40-80 mg TDS For resistant ventricular arrhythmias - ~1000 mg Page 33 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  34. 34. • Uses: Inappropriate sinus tachycardia AES / VES, especially provoked by emotion or exercise Prevent recurrences of PSVT Recurrence of VT Terminate torsades de pointes Page 34 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  35. 35. Esmolol • Quick & short acting β1 blocker administered IV for emergency control of ventricular rate in AF / AFL • Terminate supraventricular tachycardia • Sympathetically mediated arrhythmias seen in pheochromocytoma & anaesthesia with halothane • Dose: Loading dose of 0.5 mg/kg in 1 min followed by 0.05–0.2 mg/kg/min i.v. infusion. Page 35 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  36. 36. Sotalol • Prominent class III action of prolonging repolarisation by blocking cardiac inward rectifier K+ channel • Non-selective β blocker & effect is exhibited at doses below than that required for prolongation of APD Both Class II & III action • Limitation: Prolongation of APD & QT, risk of dose dependent torsade de pointes • Dose: 80 mg BD orally Page 36 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  37. 37. Class III • Mechanism of action: • Prolong ERP • QT & PR interval are prolonged • Tissue remains refractory even after full repolarisation Re-entrant arrhythmias are terminated Prolongation of repolarisation by blocking outward K+ channel during phase 3 of AP Page 37 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  38. 38. Amiodarone • Iodine containing, highly lipophilic, long acting • Conduction is slowed & ectopic automaticity is markedly depressed, but that of SA node is only slightly affected • Despite prolongation of APD, arrhythmia provoking potential of amiodarone is low Blocks Na+ channels Mild β blocking activity Ca2+ blocking action Page 38 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  39. 39. • Incompletely & slowly absorbed from GIT On daily oral ingestion, action develops over several days On IV injection, action develops rapidly • Duration of action is exceptionally long; t1/2 – 3-8 weeks • Side effects: 1. Pulmonary alveolitis & fibrosis – most serious 2. Hypotension, bradycardia & myocardial depression – on IV injection & after drug accumulation 3. Corneal microdeposits 4. Photosensitisation & sun burn like pigmentation Page 39 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  40. 40. • Uses: • Dose: 1. Resistant VT & recurrent VF 2. Maintain sinus rhythm in AF when other drugs have failed 3. Rapid termination of VT & VF and supraventricular arrhythmia – IV injection 4. WPW tachyarrhythmia is terminated by suppression of both normal & aberrant pathway 1. Orally 400–600 mg/day for few weeks, followed by 100–200 mg OD for maintenance therapy 2. Loading dose – 150 mg IV rapid infusion over 10 min f/b slow infusion of 1 mg/min for 6 hrs then maintenance infusion of 0.5 mg/min for 24 hrs Page 40 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  41. 41. Dronedarone • Amiodarone like drug without iodine atoms • Shorter t1/2 – 1-2 days • Dose: 400 mg BD orally • Use: Prevent recurrence in patients with persistent AF Page 41 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  42. 42. Bretylium • Given only in ICU facility for treating refractory life- threatening ventricular tachycardia & fibrillation • Also known as Chemical / Pharmacological defibrillator • Ventricular fibrillation: 5 mg/kg by rapid IV inj. & repeated every 15-30 mins • Side effects: Postural hypotension Page 42 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  43. 43. Dofetilide • Pure Class III drug • Prolongs APD & ERP by selectively blocking rapid components of delayed rectifier K+ current • Converts AF / AFL to sinus rhythm in ~30%; but more effective in maintaining sinus rhythm in converted patients • Dose: 0.5 mg BD orally Page 43 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  44. 44. Vernakalant • Mixed Na+ & K+ channel blocker • Prolong atrial ERP & slows conduction through AV node • Association & dissociation with Na+ channels is faster, thus more effective in myocytes firing more rapidly • Use: Treatment of AF • Dose: IV infusion 3 mg/kg over 10 min then 2 mg/kg over 15 min Page 44 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  45. 45. Azimilide • Blocks both slow & rapid components of K+ channels • Low incidence of torsades de pointes • Under trial to convert AF into sinus rhythm Page 45 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  46. 46. Tedisamil • Upcoming Class III drug • Given by IV infusion • For conversion of AF & AFL to sinus rhythm Page 46 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  47. 47. Class IV • Mechanism of action: Blocks both activated & inactivated L-type Ca2+ channels in myocardium ↓ in rate of depolarisation (phase 4) in SA & AV node & slowed conduction through AV node ↑ in PR interval & ERP Page 47 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  48. 48. Verapamil • Most prominent cardiac electrophysiological action • Basic action is to depress Ca2+ mediated depolarization. This suppresses automaticity and re-entry dependent on slow channel response • Most consistent action - prolongation of A-V nodal ERP • Uses: 1. PSVT – Terminate attack:- 5 mg IV over 2-3 min Prevent recurrence:- 60-120 mg TDS orally Page 48 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  49. 49. 2. To control ventricular rate in AF or AFL: Dose dependent (40–120 mg TDS oral) reduction in ventricular rate in AF and AFl, and is a first line drug Injected i.v. for emergency control of ventricular rate in AF and AFL (5-10 mg/hr IV infusion) 3. Re-entrant supraventricular and nodal arrhythmias are susceptible to verapamil, but it is contraindicated in broad QRS complex WPW tachycardia Page 49 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  50. 50. Diltiazem • Alternative to verapamil – termination & prophylaxis of PSVT • For rapid control of ventricular rate in AF or AFL - i.v. diltiazem is preferred over verapamil, because • Dose: 5-15 mg/hr continuous infusion till adequate response 1. more easily titrated to the target heart rate 2. causes less hypotension or myocardial depression 3. used even in the presence of mild-to-moderate CHF Page 50 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  51. 51. Adenosine Stimulates adenosine receptors (A1) Opens G-protein coupled K+ channel & inhibits SA nodal, atrial & AV nodal conduction • Terminates re-entrant circuit through AV node & restores normal sinus rhythm in PSVT • Administered by rapid i.v. injection (over 1–3 sec) either as the free base (6–12 mg) or as ATP (10–20 mg), terminates within 30 sec. >90% episodes of PSVT involving A-V node Page 51 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  52. 52. • very short t½ in blood (~10 sec) • Advantages of adenosine for termination of PSVT are: 1. Efficacy equivalent to or better than verapamil. 2. Action lasts < 1 min; adverse effects are transient. 3. No haemodynamic deterioration; can be given to patients with hypotension, CHF or on β blockers 4. Safe in wide QRS tachycardia 5. Effective in patients not responding to verapamil Page 52 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  53. 53. • Main side effects: Facial flushing, shortness of breath, bronchospasm, nausea, metallic taste • Other uses of adenosine: (a) Diagnosis of tachycardia dependent on A-V node (b) To induce brief coronary vasodilatation during certain diagnostic/interventional procedures (c) To produce controlled hypotension during surgery Page 53 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  54. 54. Atrial / Ventricular extrasystole • Asymptomatic – no treatment required • Symptomatic - β blocker Page 54 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  55. 55. Atrial fibrillation • Definition: Fast ectopic, irregular atrial activity (350-600 bpm) • Ventricular rate ~ 100-150 bpm • Treatment: 1. Underlying heart disease – find out cause 2. Rate control – 70-100 bpm β blocker:- esmolol Acute therapy CCB:- verapamil Digoxin Chronic therapy Page 55 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  56. 56. 3. Rhythm control: Electrical Acute therapy – DC shock Chronic therapy – Amiodarone Pharmacological Acute therapy – Amiodarone IV Chronic therapy – Amiodarone Propafenone Page 56 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  57. 57. Acute AF (> 48 hours) Transesophageal echocardiography Yes No Don’t cardiovert immediately Immediate cardioversion Warfarin for 3 weeks Cardioversion Warfarin for 4 weeks Page 57 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  58. 58. Chronic AF (>6 months) a. Rate control with β blocker, CCB & Digoxin b. ↓ Risk of ischemic stroke Aspirin / Warfarin based on CHADS 2 score If score ≥2 – warfarin <2 – aspirin Page 58 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  59. 59. Atrial flutter • Atrial rate 250-350 bpm • Ventricular rate 75-175 bpm • TOC – DC shock • Recurrent atrial flutter: A. Radiofrequency ablation (Elective procedure) B. Digoxin Atrial flutter Atrial fibrillation Page 59 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  60. 60. Wolf-Parkinson-White Syndrome Tachycardia • Termination: Cardioversion, Radiofrequency ablation • Maintenance: 1. Narrow QRS - Propafenone/procainamide 2. Wide QRS - Propafenone + verapamil / propranolol or Amiodarone / sotalol Page 60 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  61. 61. PSVT • An attack of PSVT can be terminated by reflex vagal stimulation through • Alternatively, or if it does not work, the drug of choice is adenosine (i.v.). Other alternatives are i.v. injection of verapamil / diltiazem / esmolol. • Prevent recurrences - oral therapy with verapamil, diltiazem or propranolol alone or combined with digoxin TOC – Radiofrequency ablation 1. Valsalva maneuver, 2. Splashing ice cold water on face, 3. Hyperflexion (head between knees), etc. Page 61 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  62. 62. Ventricular tachycardia • Definition: ≥ 4 consecutive ventricular extrasystole of > 100 bpm • Unstable VT: Immediate DC shock Amiodarone (DOC) / Lidocaine / procainamide (IV) • Prevention of recurrence / sudden cardiac death: Best method – Intracardiac defibrillator Alternative – Amiodarone / Propranolol / Propafenone Page 62 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  63. 63. Chronic ventricular tachycardia • Nonsustained VT: Suppression - Propranolol/amiodarone (oral) • Sustained VT: • Abolition - i.v. Amiodarone + propranolol or cardioversion or propafenone / lidocaine (i.v.) • Maintenance therapy - Amiodarone/sotalol (prevention of VF/arrest) Implantable defibrillator Page 63 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  64. 64. Ventricular fibrillation • Grossly irregular, rapid & fractionated activation of ventricles resulting in inco-ordinated contraction of its fibres with loss of pumping action • Termination: Defibrillation + amiodarone (i.v.) • Recurrence prevention: Amiodarone (oral) / propranolol Page 64 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  65. 65. Bradyarrhythmias • Results from failure of impulse generation within SA node or failure of impulse conduction through AV node • Atrio-ventricular (A-V) block is due to depression of impulse conduction through A-V node and bundle of His, mostly due to vagal influence or ischaemia. • First degree A-V block: Slowed conduction resulting in prolonged P-R interval Page 65 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  66. 66. • Second degree A-V block: Some supraventricular complexes are not conducted: drop beats • Third degree A-V block: No supraventricular complexes are conducted; ventricle generates its own impulse; complete heart block • Definitive treatment - pacing with cardiac pacemaker • Drugs are of value only for acute/transient A-V block and as an interim measure. • Atropine: When A-V block is due to vagal overactivity, it can be improved by atropine 0.6–1.2 mg i.m. Page 66 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  67. 67. • Sympathomimetics (isoprenaline): Overcome partial heart block by facilitating A-V conduction and shortening ERP of conducting tissues. Also used in complete (3rd degree) heart block to maintain a sufficient idioventricular rate till external pacemaker can be implanted Page 67 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  68. 68. Summary • Abnormal automaticity or impaired conduction or both underlies cardiac arrhythmia • Anti-arrhythmic drugs used to prevent or treat irregularities of cardiac rate & rhythm • Anti-arrhythmic drugs themselves, may cause arrhythmias by altering electrophysiological properties of cardiac fibres • Asymptomatic atrial / ventricular extrasystole need not be treated • Ventricular arrhythmias are most important cause of sudden cardiac death. Therefore, should be monitored & treated in intensive coronary care unit Page 68 of 68 Pharmacotherapy of cardiac arrhythmias – Dr. Vikas S. Sharma 16.02.2016
  69. 69. References • Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th Edition • Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. Harrisons’s Principles of Internal Medicine. 19th Edition • Rang & Dales’s Pharmacology 7th Edition • H. L. Sharma & K. K. Sharma’s Principles of Pharmacology 2nd Edition • Lippincott Illustrated Reviews: Pharmacology 6th Edition
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