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Kimto Oche Emmanuel

Comprehensive classification of Anti-arrhythmic drugs.

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CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS BY KIMTO OCHE EMMANUEL CARDIOLOGY 1 UNIT INTERNAL MEDICINE JOS UNIVERSITY TEACHING HOSPITAL (JUTH) 6/2/2023 1
OUTLINE • BACKGROUND Introduction Brief history Timeline Epidemiology Relevant studies • AETIOLOGY • CLASSIFICATION OF ARRHYTHMIA • MECHANISMS OF CARDIAC ARRHYTHMIA • CLINICAL FEATURES • INVESTIGATIONS • CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS • OTHER TREATMENT MODALITIES • CONCLUSION • REFERENCES 6/2/2023 2
INTRODUCTION • Cardiac arrhythmias are a frequent problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction Arrhythmia is defined as an abnormality of the cardiac rate, rhythm or both 6/2/2023 3
TIMELINE 6/2/2023 4
6/2/2023 5
6/2/2023 6
Relevant Studies • The Cardiac Arrhythmia Suppression Trial I - CAST-I "Mortality and morbidity in patients receiving encainide, flecainide, or placebo". The New England Journal of Medicine. 1991. 324(12):781-788 “Among patients with recent MI and increased ventricular ectopy, use of antiarrhythmics suppresses ventricular ectopy, but increases mortality.” 6/2/2023 7
… • The Cardiac Arrhythmia Suppression Trial II - CAST-II "As with the antiarrhythmic agents used in CAST (flecainide and encainide), the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful." 6/2/2023 8
… • Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (Pilot) - CAMIAT “Amiodarone reduces the incidence of ventricular fibrillation or arrhythmic death among survivors of acute myocardial infarction with frequent or repetitive VPDs. Amiodarone, in moderate loading and maintenance dosages with adjustments in response to plasma levels, VPD suppressions, and side effects, results in effective VPD suppression and acceptable levels of toxicity.” 6/2/2023 9
… • Sudden Cardiac Death in Heart Failure Trial - SCD- HeFT “Among patients with NYHA class II or III CHF and reduced LVEF, treatment with an ICD was associated with a reduction in all-cause mortality compared with placebo, but there was no difference between amiodarone and placebo. The ICD was programmed for VF treatment only 6/2/2023 10
… • On long-term follow-up, there was potentially some attenuation in benefit beyond 6 years, although the crossover rate to the ICD arm was >50%. Benefit was highest among patients with ischemic cardiomyopathy and NYHA class II symptoms.” 6/2/2023 11
… • Multicenter Automatic Defibrillator Implantation Trial II - MADIT-II Moss AJ, et al. "Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction". The New England Journal of Medicine. 2002. 346(12):877-883. “In post-MI patients with systolic dysfunction (EF ≤30%), prophylactic ICD reduced all-cause mortality compared to standard medical therapy.” 6/2/2023 12
AETIOLOGY Cardiac • Ischemic Heart Disease • Rheumatic Heart Disease • Cardiac failure • Dilated CM • Hypertrophic CM • EMF • Infiltrative Heart Disease • Myocarditis Non-cardiac • Hormonal (↑catecolamines, thyroxine, ↓thyroxine). • Metabolic (Ca, K, acid/base, hypothermia) • Hypoxia • Drugs (digoxin. TCA, caffeine, sympatho-memetics/lytics) • Toxins (alcohol, diphtheria toxin) • Trauma • Electrocution • Others (fear, iatrogenic) 6/2/2023 13
CLASSIFICATION OF ARRHYTHMIAS 6/2/2023 14
100 60 Normal range 150 Simple tachyarrhythmia 200 Paroxysmal TA 350 Atrial flutter . 500 Atrial fibrillation 40 Mild bradyarrhythmias 20 moderate BA Severe BA 6/2/2023 15
ARRHYTHMIAS Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia SVT 6/2/2023 16
Impulse generation and transmission 6/2/2023 17
Pacemaker AP Phase 4: pacemaker potential Na influx, K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Phase 0: upstroke: Due to Ca++ influx Phase 3: repolarization: Due to K+ efflux Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously 6/2/2023 18
+30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+ Na+ Resting open Inactivated Phase zero depolarization Early repolarization Plateau phase Rapid Repolarization phase Phase 4 depolarization Myocardiac AP 6/2/2023 19
Depolarization & Repolarization waves seen in ECG 6/2/2023 20
ECG… • P wave: atrial depolarization • PR-Interval reflects AV nodal conduction time • QRS DURATION reflects conduction time in ventricles • T-wave: ventricular repolarization • QT interval is a measure of ventricular APD 6/2/2023 21
MECHANISMS OF CARDIAC ARRHYTHMIA • Abnormal impulse generation: • Depressed automaticity • Enhanced automaticity • Triggered activity (after depolarization): • Delayed after depolarization • Early after depolarization • Abnormal impulse conduction: • Conduction block • Re-entry phenomenon • Accessory tract pathways 6/2/2023 22
CLINICAL FEATURES 6/2/2023 23
INVESTIGATIONS Non-Cardiac • Eectrolyte Urea and Creatinine and Uric Acid (E/U/Cr + U.A) • Thyroid Function Test (TFT) • Liver Function Test (LFT) • Full Blood Count and Erythrocyte Sedimentation Rate (FBC + ESR) • Fasting Blood Sugar (FLS) • Fasting Lipid Profile (FP) Cardiac • Electrocardiogram (ECG) • 24hour Holter monitor • Event recorder • Echocardiogram • Implantable loop recorder • Stress test • Tilt table test • Electrophysiological testing and mapping 6/2/2023 24
CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS 6/2/2023 25
… • Vaughan-wiliams-singh classification (1969) • Sicilian-gambit classification (1991) • Modernized oxford classification (2018) • Classification based on clinical use (…) 6/2/2023 26
6/2/2023 27
6/2/2023 28
MODERNIZED OXFORD CLASSIFICATION • It now introduces new classes incorporating additional targets, including: • Class 0: ion channels involved in automaticity • Class V: mechanically sensitive ion channels • Class VI: connexins controlling electrotonic cell coupling • Class VII: molecules underlying longer term signalling processes affecting structural remodeling 6/2/2023 29
CLASSIFICATION BASED ON CLINICAL USE • Drugs used for supraventricular arrhythmias – Adenosine, Verapamil, Diltiazem • Drugs used for ventricular arrhythmias – Lignocaine, Mexelitine, Bretylium • Drugs used for supraventricular as well as ventricular arrhythmias – Amiodarone, - blockers, Disopyramide, Procainamide 6/2/2023 30
VAUGHAN-WILLIAMS-SINGH Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV - 80m V II I III IV Class I: block Na+ channels Ia (Quinidine, Procainamide, Disopyramide) (1-10s) Ib (Lignocaine) (<1s) Ic (Flecainide) (>10s) Class II: ß-adrenoceptor antagonists (Atenolol, Sotalol) Class III: prolong action potential and prolong refractory period (Amiodarone, Dofetilide, Sotalol) Class IV: Ca2+ channel antagonists (Verapamil, Diltiazem) 6/2/2023 31
NA+ CHANNEL BLOCKER • Bind to and block Na+ channels (and K+ also) • Act on initial rapid depolarization (slowing effect) • Local Anaesthetic (higher concentration): block nerve conduction • Do not alter resting membrane potential (Membrane Stabilisers) 6/2/2023 32
… • At times, post repolarization refractoriness • Bind preferentially to the open channel state • Use dependence: The more the channel is in use, the more drug is bound 6/2/2023 33
IA IB IC Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS 6/2/2023 34
… • IA: Ʈrecovery moderate (1-10sec) Prolong APD • IB: Ʈrecovery fast (<1sec) Shorten APD in some heart tissues • IC: Ʈrecovery slow(>10sec) Minimal effect on APD 6/2/2023 35
Class IA 6/2/2023 36
Quinidine • Historically first antiarrhythmic drug used • In 18th century, the bark of the cinchona plant was used to treat “rebellious palpitations” Pharmacological effects threshold for excitability automaticity prolongs AP 6/2/2023 37
… Formulation: It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree Dosage: Orals and injectables Tablet (sulfate):100 to 600 mg/dose orally every 4 to 6 hours; begin at 200 mg/dose and titrate to desired effect (maximum daily dose: 3 to 4 g) Extended Release: 324 to 648 mg (gluconate) orally every 8 to 12 hours or 300 to 600 mg (sulfate) orally every 8 to 12 hours 6/2/2023 38
… IV: 800 mg of quinidine gluconate diluted to 50 mL and given at a rate not to exceed 1 mL/min Clinical Pharmacokinetics • well absorbed • 80% bound to plasma proteins (albumin) • extensive hepatic oxidative metabolism 6/2/2023 39
… Uses • To maintain sinus rhythm in patients with atrial flutter or atrial fibrillation • To prevent recurrence of ventricular tachycardia or VF 6/2/2023 40
… Adverse Effects: Non cardiac • Diarrhea, thrombocytopenia • Cinchonism and skin rashes Cardiac • Marked QT-interval prolongation and Torsades de pointes (2-8% ) • Hypotension and tachycardia 6/2/2023 41
… Drug interactions • Metabolized by CYP450 • Increases Digoxin levels • Cardiac depression with beta blockers • Inhibits CYP2D6 6/2/2023 42
Disopyramide • Exerts electrophysiologic effects very similar to those of Quinidine • Better tolerated than Quinidine • Exert prominent anticholinergic actions • Negative ionotropic action 6/2/2023 43
… • Formulation: made up of Disopyramide phosphate • Dose: Mainly orals 400-800 mg/day. The recommended dose for most adults is 600 mg/day Patients < 50 kg may be given 400 mg/day Immediate-release form: The dose is divided and administered every 6 hours Extended-release form: The dose is divided and administered every 12 hours 6/2/2023 44
… Adverse effects: • Precipitation of glaucoma • Constipation, dry mouth • Urinary retention 6/2/2023 45
Procainamide • Lesser vagolytic action, depression of contractility and fall in BP • Metabolized by acetylation to N-acetyl Procainamide which can block K+ channels • Does not alter plasma Digoxin levels 6/2/2023 46
… • Formulation: 4-amino-N-2-(diethylamino)ethyl-benzamide • Dosage: Orals and injectables • IV: Loading dose: 15 to 18 mg/kg administered as slow infusion over 25 to 30 minutes or 100 mg/dose at a rate not to exceed 50 mg/minute repeated every 5 minutes as needed to a total dose of 1 gram. Maintenance dose: 1 to 4 mg/minute by continuous infusion • IM: 50 mg/kg divided into fractional amounts of 1/8 to 1/4 and injected every 3 to 6 hours or 0.5 to 1 gram every 4 to 8 hours 6/2/2023 47
… • Orals: Immediate-release: 250 mg orally every 3 hours Sustained-release: 500 mg every 6 hours Twice daily formulation: 1000 mg every 12 hours 6/2/2023 48
… • Cardiac adverse effects like Quinidine • Can cause SLE not recommended >6 months • Use: Monomorphic VT, WPW Syndrome 6/2/2023 49
Class IB drugs Lignocaine, Phenytoin, Mexiletine Block sodium channels and shorten repolarization 6/2/2023 50
Class IB 6/2/2023 51
Lignocaine • Blocks inactivated sodium channels more than open state • Relatively selective for partially depolarized cells • Selectively acts on diseased myocardium • Rapid onset and shorter duration of action • Useful in ventricular arrhythmias and Digitalis induced ventricular arrhythmias 6/2/2023 52
• Formulation: Lidocaine hydrochloride • Dosage: Mainly injectable • Initial dose: 50 to 100 mg IV bolus once over 2 to 3 minutes; may repeat after 5 minutes if necessary not to exceed up to 300 mg in a 1-hour period Following bolus administration: 1 to 4 mg/min continuous IV infusion 6/2/2023 53
… Pharmacokinetics: • High first pass metabolism • Metabolism dependent on hepatic blood flow • T ½ = 8min – distributive, 2hrs – elimination • Propranolol decreases half life of Lignocaine • Dose= 50-100mg bolus followed by 20-40mg every 10-20min IV 6/2/2023 54
… Adverse effects • Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings • Rarely convulsions, blurred vision, nystagmus • Least cardiotoxic 6/2/2023 55
• Local anaesthetic • Inactive orally • Given IV for antiarrhythmic action • Na+ channel blockade which occurs • Only in inactive state of Na+ channels • CNS side effects in high doses • Action lasts only for 15 min • Inhibits Purkinje fibres and ventricles but • No action on AVN and SAN so • Effective in Ventricular arrhythmias only 6/2/2023 56
Mexiletine • Oral analogue of Lignocaine • No first pass metabolism in liver • Uses: – Chronic treatment of ventricular arrhythmias associated with previous MI – Unlabelled use in diabetic neuropathy 6/2/2023 57
… • Formulation: Mexiletine hydrochloride • Dosage: mainly orals • Initial dose: 200 mg orally every 8 hours A minimum of 2-3 days between dose adjustments is recommended Dose may be adjusted in 50 or 100 mg increments up or down • The dose should not exceed 1200 mg/day 6/2/2023 58
… • Tremor is early sign of Mexiletine toxicity • Hypotension • Bradycardia, • Widened QRS, • Dizziness and • Nystagmus 6/2/2023 59
Class IC drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers • Risk of cardiac arrest and sudden death-so not used commonly • May be used in severe ventricular arrhythmias 6/2/2023 60
Class IC 6/2/2023 61
Propafenone • Structural similarity with Propranolol and has - blocking action • Undergoes variable first pass metabolism • Reserve drug for ventricular arrhythmias, re-entrant tachycardia involving accessory pathway 6/2/2023 62
… • Formulation: Propafenone hydrochloride • Dosage: Mainly orals Initial dose: 150 mg orally every 8 hours; may increase dose after at least 3 to 4 days to 225 mg orally every 8 hours; if additional therapeutic effect is needed, may increase dose to 300 mg orally every 8 hours Maximum dose: 900 mg/day 6/2/2023 63
… Adverse effects: • Metallic taste • Constipation • Pro-arrhythmic 6/2/2023 64
Class II: Beta blockers • -receptor stimulation: • ↑ Automaticity • ↑ AV conduction velocity • ↓ Refractory period • -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors 6/2/2023 65
… • Depress phase 4 depolarization of pacemaker cells • Slow sinus as well as AV nodal conduction: ↓HR, ↑PR • ↑ERP, prolong AP Duration by ↓AV conduction • Reduce myocardial oxygen demand • Well tolerated and Safer 6/2/2023 66
β Adrenergic Stimulation β Blockers ↑ magnitude of Ca2+ current & slows its inactivation ↓ Intracellular Ca2+ overload ↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate ↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity Epinephrine induces hypokalemia (β2 action) Propranolol blocks this action 6/2/2023 67
Use in arrhythmia • Control supraventricular arrhythmias, Atrial flutter, fibrillation and PSVT • Treat tachyarrhythmias caused by: -Hyperthyroidism, Pheochromocytoma and during anaesthesia with halothane 6/2/2023 68
… • Digitalis induced tachyarrythmias • Prophylactic in post-MI • Ventricular arrhythmias in prolonged QT syndrome 6/2/2023 69
Esmolol • β1 selective agent • Very short elimination t1/2: 9 mins • Metabolized by RBC esterases • Rate control of rapidly conducted AF Uses: • Arrythmia associated with anaesthesia • Supraventricular tachycardia 6/2/2023 70
… • Formulation: Esmolol hydrochloride • Dosage: Mainly injectibles Optional loading dose (500 mcg/kg IV over 1 minute), then 50 mcg/kg/min IV for 4 minutes; if the response is adequate, the infusion may be maintained at 50 mcg/kg/min Maintenance dose: 25 to 200 mcg/kg/min IV -Maximum dose: 200 mcg/kg/min IV -Duration: Maintenance infusions may be continued for up to 48 hours 6/2/2023 71
Class III drugs ↑APD & ↑RP by blocking the K+ channels 6/2/2023 72
Vm (mV) -80mV 0mV ↑ APD Block IK 6/2/2023 73
Amiodarone • Iodine containing long acting drug • Mechanism of action: (Multiple actions) – Prolongs APD by blocking K+ channels – blocks inactivated sodium channels – β blocking action , Blocks Ca2+ channels – ↓ Conduction, ↓ectopic automaticity 6/2/2023 74
… • Formulation: (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]- 2,6-diiodophenoxy}ethyl)diethylamine • Dosage: Both Injectibles and orals • IV: Initial dose: 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen: -Loading infusions: 150 mg over the first 10 minutes (15 mg/min), followed by 360 mg over the next 6 hours (1 mg/min) -Maintenance infusion: 540 mg over the remaining 18 hours (0.5 mg/min) Maximum dose: Initial infusion rate: 30 mg/min 6/2/2023 75
… • Oral Loading dose: 800 to 1600 mg orally per day for 1 to 3 weeks Adjustment dose: 600 to 800 mg orally per day for 1 month, then switch to maintenance dose Maintenance dose: 400 mg orally per day Maximum dose: 600mg/day 6/2/2023 76
• Pharmacokinetics: – Variable absorption 35-65% – Slow onset 2days to several weeks – Duration of action: weeks to months • Dose: – Loading dose: 150mg over 10min – Then 1mg/min for 6 hrs – Then maintenance infusion of 0.5mg/min for 24 hr … 6/2/2023 77
… • Uses: – Can be used for both supraventricular and ventricular tachycardia • Adverse effects: – Cardiac: heart block, QT prolongation, bradycardia, cardiac failure, hypotension – Pulmonary: pneumonitis leading to pulmonary fibrosis 6/2/2023 78
… – Bluish discoloration of skin – Corneal microdeposits – GIT disturbances, hepatotoxicity – Blocks peripheral conversion of T4 to T3 can cause hypothyroidism or hyperthyroidism 6/2/2023 79
• Antiarrhythmic • Multiple actions • Iodine containing • Orally used mainly • Duration of action is very long (t ½ = 3-8 weeks) • APD & ERP increases • Resistant AF, VT, Recurrent VF are indications • On prolonged use- pulmonary fibrosis • Neuropathy may occur • Eye: corneal microdeposits may occur 6/2/2023 80
• Bretylium: – Adrenergic neuron blocker used in resistant ventricular arrhythmias • Sotalol: – Beta blocker • Dofetilide, Ibutilide: – Selective K+ channel blocker, less adverse events – use in AF to convert or maintain sinus rhythm – May cause QT prolongation 6/2/2023 81
Newer class III drugs • Dronedarone • Vernakalant • Azimilide • Tedisamil 6/2/2023 82
Calcium channel blockers (Class IV) • Inhibit the inward movement of calcium ↓ contractility, automaticity, and AV conduction. • Verapamil and Diltiazem 6/2/2023 83
Verapamil • Formulation: Verapamil hydrochloride • Dosage: Mainly Orals -Chronic atrial fibrillation in digitalized patients: 240 to 320 mg/day orally in 3 or 4 divided doses -Prophylaxis of paroxysmal supraventricular tachycardia (PSVT) in non-digitalized patients: 240 to 480 mg/day orally in 3 or 4 divided doses • Maximum dose: 480mg/day 6/2/2023 84
… • Uses: – Terminate PSVT – Control ventricular rate in atrial flutter or fibrillation • Drug interactions: – Displaces Digoxin from binding sites – ↓Renal clearance of Digoxin 6/2/2023 85
Other anti-arrhythmics • Adenosine • Atropine • Digitalis • Magnesium Sulphate 6/2/2023 86
Adenosine Purine nucleoside having short and rapid action  IV suppresses automaticity, AV conduction and dilates coronaries  Drug of choice for PSVT  Has very short half life Adverse effects: Nausea, dyspnea, flushing and headache 6/2/2023 87
Drugs Of Choice 6/2/2023 88
6/2/2023 89
6/2/2023 90
OTHER TREATMENT MODALITIES Electrical Devices: • Permanent pacemaker • Implantable cardioverter-defibrillator • Biventricular pacemakers and defibrillators 6/2/2023 91
… Invasive Therapies: • Electrical cardioversion • Catheter ablation • Pulmonary vein isolation 6/2/2023 92
… Surgery • MAZE procedure 6/2/2023 93
6/2/2023 94
CONCLUSION • Since arrhythmia is associated with high morbidity and mortality, it is expedient to know what drug to use in what situation so as to reduce these unfavourable outcomes 6/2/2023 95
REFERENCES • Kumar and Clark, Textbook of Clinical Medicine • Katzung, Textbook of Pharmacology • Medical school lecture notes • Sideshare notes • https://en.wikipedia.org/wiki/Cardiac_Arrhythmia_Suppression_Trial • https://www.nigeriamedj.com/article.asp?issn=0300- 1652;year=2015;volume=56;issue=6;spage=429;epage=432;aulast=Okeahialam • [Agents Used in Cardiac Arrhythmias -(Robert D. Harvey; Augustus O. Grant)] • https://www.mayoclinic.org/tests-procedures/maze-procedure/pyc- 20384973#:~:text=Maze%20is%20a%20surgical%20procedure,to%20make%20several%20precise %20incisions. 6/2/2023 96

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CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS - Copy.pptx

  • 1. CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS BY KIMTO OCHE EMMANUEL CARDIOLOGY 1 UNIT INTERNAL MEDICINE JOS UNIVERSITY TEACHING HOSPITAL (JUTH) 6/2/2023 1
  • 2. OUTLINE • BACKGROUND Introduction Brief history Timeline Epidemiology Relevant studies • AETIOLOGY • CLASSIFICATION OF ARRHYTHMIA • MECHANISMS OF CARDIAC ARRHYTHMIA • CLINICAL FEATURES • INVESTIGATIONS • CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS • OTHER TREATMENT MODALITIES • CONCLUSION • REFERENCES 6/2/2023 2
  • 3. INTRODUCTION • Cardiac arrhythmias are a frequent problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction Arrhythmia is defined as an abnormality of the cardiac rate, rhythm or both 6/2/2023 3
  • 7. Relevant Studies • The Cardiac Arrhythmia Suppression Trial I - CAST-I "Mortality and morbidity in patients receiving encainide, flecainide, or placebo". The New England Journal of Medicine. 1991. 324(12):781-788 “Among patients with recent MI and increased ventricular ectopy, use of antiarrhythmics suppresses ventricular ectopy, but increases mortality.” 6/2/2023 7
  • 8. … • The Cardiac Arrhythmia Suppression Trial II - CAST-II "As with the antiarrhythmic agents used in CAST (flecainide and encainide), the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful." 6/2/2023 8
  • 9. … • Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (Pilot) - CAMIAT “Amiodarone reduces the incidence of ventricular fibrillation or arrhythmic death among survivors of acute myocardial infarction with frequent or repetitive VPDs. Amiodarone, in moderate loading and maintenance dosages with adjustments in response to plasma levels, VPD suppressions, and side effects, results in effective VPD suppression and acceptable levels of toxicity.” 6/2/2023 9
  • 10. … • Sudden Cardiac Death in Heart Failure Trial - SCD- HeFT “Among patients with NYHA class II or III CHF and reduced LVEF, treatment with an ICD was associated with a reduction in all-cause mortality compared with placebo, but there was no difference between amiodarone and placebo. The ICD was programmed for VF treatment only 6/2/2023 10
  • 11. … • On long-term follow-up, there was potentially some attenuation in benefit beyond 6 years, although the crossover rate to the ICD arm was >50%. Benefit was highest among patients with ischemic cardiomyopathy and NYHA class II symptoms.” 6/2/2023 11
  • 12. … • Multicenter Automatic Defibrillator Implantation Trial II - MADIT-II Moss AJ, et al. "Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction". The New England Journal of Medicine. 2002. 346(12):877-883. “In post-MI patients with systolic dysfunction (EF ≤30%), prophylactic ICD reduced all-cause mortality compared to standard medical therapy.” 6/2/2023 12
  • 13. AETIOLOGY Cardiac • Ischemic Heart Disease • Rheumatic Heart Disease • Cardiac failure • Dilated CM • Hypertrophic CM • EMF • Infiltrative Heart Disease • Myocarditis Non-cardiac • Hormonal (↑catecolamines, thyroxine, ↓thyroxine). • Metabolic (Ca, K, acid/base, hypothermia) • Hypoxia • Drugs (digoxin. TCA, caffeine, sympatho-memetics/lytics) • Toxins (alcohol, diphtheria toxin) • Trauma • Electrocution • Others (fear, iatrogenic) 6/2/2023 13
  • 15. 100 60 Normal range 150 Simple tachyarrhythmia 200 Paroxysmal TA 350 Atrial flutter . 500 Atrial fibrillation 40 Mild bradyarrhythmias 20 moderate BA Severe BA 6/2/2023 15
  • 16. ARRHYTHMIAS Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia SVT 6/2/2023 16
  • 17. Impulse generation and transmission 6/2/2023 17
  • 18. Pacemaker AP Phase 4: pacemaker potential Na influx, K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Phase 0: upstroke: Due to Ca++ influx Phase 3: repolarization: Due to K+ efflux Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously 6/2/2023 18
  • 19. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+ Na+ Resting open Inactivated Phase zero depolarization Early repolarization Plateau phase Rapid Repolarization phase Phase 4 depolarization Myocardiac AP 6/2/2023 19
  • 21. ECG… • P wave: atrial depolarization • PR-Interval reflects AV nodal conduction time • QRS DURATION reflects conduction time in ventricles • T-wave: ventricular repolarization • QT interval is a measure of ventricular APD 6/2/2023 21
  • 22. MECHANISMS OF CARDIAC ARRHYTHMIA • Abnormal impulse generation: • Depressed automaticity • Enhanced automaticity • Triggered activity (after depolarization): • Delayed after depolarization • Early after depolarization • Abnormal impulse conduction: • Conduction block • Re-entry phenomenon • Accessory tract pathways 6/2/2023 22
  • 24. INVESTIGATIONS Non-Cardiac • Eectrolyte Urea and Creatinine and Uric Acid (E/U/Cr + U.A) • Thyroid Function Test (TFT) • Liver Function Test (LFT) • Full Blood Count and Erythrocyte Sedimentation Rate (FBC + ESR) • Fasting Blood Sugar (FLS) • Fasting Lipid Profile (FP) Cardiac • Electrocardiogram (ECG) • 24hour Holter monitor • Event recorder • Echocardiogram • Implantable loop recorder • Stress test • Tilt table test • Electrophysiological testing and mapping 6/2/2023 24
  • 26. … • Vaughan-wiliams-singh classification (1969) • Sicilian-gambit classification (1991) • Modernized oxford classification (2018) • Classification based on clinical use (…) 6/2/2023 26
  • 29. MODERNIZED OXFORD CLASSIFICATION • It now introduces new classes incorporating additional targets, including: • Class 0: ion channels involved in automaticity • Class V: mechanically sensitive ion channels • Class VI: connexins controlling electrotonic cell coupling • Class VII: molecules underlying longer term signalling processes affecting structural remodeling 6/2/2023 29
  • 30. CLASSIFICATION BASED ON CLINICAL USE • Drugs used for supraventricular arrhythmias – Adenosine, Verapamil, Diltiazem • Drugs used for ventricular arrhythmias – Lignocaine, Mexelitine, Bretylium • Drugs used for supraventricular as well as ventricular arrhythmias – Amiodarone, - blockers, Disopyramide, Procainamide 6/2/2023 30
  • 31. VAUGHAN-WILLIAMS-SINGH Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV - 80m V II I III IV Class I: block Na+ channels Ia (Quinidine, Procainamide, Disopyramide) (1-10s) Ib (Lignocaine) (<1s) Ic (Flecainide) (>10s) Class II: ß-adrenoceptor antagonists (Atenolol, Sotalol) Class III: prolong action potential and prolong refractory period (Amiodarone, Dofetilide, Sotalol) Class IV: Ca2+ channel antagonists (Verapamil, Diltiazem) 6/2/2023 31
  • 32. NA+ CHANNEL BLOCKER • Bind to and block Na+ channels (and K+ also) • Act on initial rapid depolarization (slowing effect) • Local Anaesthetic (higher concentration): block nerve conduction • Do not alter resting membrane potential (Membrane Stabilisers) 6/2/2023 32
  • 33. … • At times, post repolarization refractoriness • Bind preferentially to the open channel state • Use dependence: The more the channel is in use, the more drug is bound 6/2/2023 33
  • 34. IA IB IC Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS 6/2/2023 34
  • 35. … • IA: ĆŽrecovery moderate (1-10sec) Prolong APD • IB: ĆŽrecovery fast (<1sec) Shorten APD in some heart tissues • IC: ĆŽrecovery slow(>10sec) Minimal effect on APD 6/2/2023 35
  • 37. Quinidine • Historically first antiarrhythmic drug used • In 18th century, the bark of the cinchona plant was used to treat “rebellious palpitations” Pharmacological effects threshold for excitability automaticity prolongs AP 6/2/2023 37
  • 38. … Formulation: It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree Dosage: Orals and injectables Tablet (sulfate):100 to 600 mg/dose orally every 4 to 6 hours; begin at 200 mg/dose and titrate to desired effect (maximum daily dose: 3 to 4 g) Extended Release: 324 to 648 mg (gluconate) orally every 8 to 12 hours or 300 to 600 mg (sulfate) orally every 8 to 12 hours 6/2/2023 38
  • 39. … IV: 800 mg of quinidine gluconate diluted to 50 mL and given at a rate not to exceed 1 mL/min Clinical Pharmacokinetics • well absorbed • 80% bound to plasma proteins (albumin) • extensive hepatic oxidative metabolism 6/2/2023 39
  • 40. … Uses • To maintain sinus rhythm in patients with atrial flutter or atrial fibrillation • To prevent recurrence of ventricular tachycardia or VF 6/2/2023 40
  • 41. … Adverse Effects: Non cardiac • Diarrhea, thrombocytopenia • Cinchonism and skin rashes Cardiac • Marked QT-interval prolongation and Torsades de pointes (2-8% ) • Hypotension and tachycardia 6/2/2023 41
  • 42. … Drug interactions • Metabolized by CYP450 • Increases Digoxin levels • Cardiac depression with beta blockers • Inhibits CYP2D6 6/2/2023 42
  • 43. Disopyramide • Exerts electrophysiologic effects very similar to those of Quinidine • Better tolerated than Quinidine • Exert prominent anticholinergic actions • Negative ionotropic action 6/2/2023 43
  • 44. … • Formulation: made up of Disopyramide phosphate • Dose: Mainly orals 400-800 mg/day. The recommended dose for most adults is 600 mg/day Patients < 50 kg may be given 400 mg/day Immediate-release form: The dose is divided and administered every 6 hours Extended-release form: The dose is divided and administered every 12 hours 6/2/2023 44
  • 45. … Adverse effects: • Precipitation of glaucoma • Constipation, dry mouth • Urinary retention 6/2/2023 45
  • 46. Procainamide • Lesser vagolytic action, depression of contractility and fall in BP • Metabolized by acetylation to N-acetyl Procainamide which can block K+ channels • Does not alter plasma Digoxin levels 6/2/2023 46
  • 47. … • Formulation: 4-amino-N-2-(diethylamino)ethyl-benzamide • Dosage: Orals and injectables • IV: Loading dose: 15 to 18 mg/kg administered as slow infusion over 25 to 30 minutes or 100 mg/dose at a rate not to exceed 50 mg/minute repeated every 5 minutes as needed to a total dose of 1 gram. Maintenance dose: 1 to 4 mg/minute by continuous infusion • IM: 50 mg/kg divided into fractional amounts of 1/8 to 1/4 and injected every 3 to 6 hours or 0.5 to 1 gram every 4 to 8 hours 6/2/2023 47
  • 48. … • Orals: Immediate-release: 250 mg orally every 3 hours Sustained-release: 500 mg every 6 hours Twice daily formulation: 1000 mg every 12 hours 6/2/2023 48
  • 49. … • Cardiac adverse effects like Quinidine • Can cause SLE not recommended >6 months • Use: Monomorphic VT, WPW Syndrome 6/2/2023 49
  • 50. Class IB drugs Lignocaine, Phenytoin, Mexiletine Block sodium channels and shorten repolarization 6/2/2023 50
  • 52. Lignocaine • Blocks inactivated sodium channels more than open state • Relatively selective for partially depolarized cells • Selectively acts on diseased myocardium • Rapid onset and shorter duration of action • Useful in ventricular arrhythmias and Digitalis induced ventricular arrhythmias 6/2/2023 52
  • 53. • Formulation: Lidocaine hydrochloride • Dosage: Mainly injectable • Initial dose: 50 to 100 mg IV bolus once over 2 to 3 minutes; may repeat after 5 minutes if necessary not to exceed up to 300 mg in a 1-hour period Following bolus administration: 1 to 4 mg/min continuous IV infusion 6/2/2023 53
  • 54. … Pharmacokinetics: • High first pass metabolism • Metabolism dependent on hepatic blood flow • T ½ = 8min – distributive, 2hrs – elimination • Propranolol decreases half life of Lignocaine • Dose= 50-100mg bolus followed by 20-40mg every 10-20min IV 6/2/2023 54
  • 55. … Adverse effects • Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings • Rarely convulsions, blurred vision, nystagmus • Least cardiotoxic 6/2/2023 55
  • 56. • Local anaesthetic • Inactive orally • Given IV for antiarrhythmic action • Na+ channel blockade which occurs • Only in inactive state of Na+ channels • CNS side effects in high doses • Action lasts only for 15 min • Inhibits Purkinje fibres and ventricles but • No action on AVN and SAN so • Effective in Ventricular arrhythmias only 6/2/2023 56
  • 57. Mexiletine • Oral analogue of Lignocaine • No first pass metabolism in liver • Uses: – Chronic treatment of ventricular arrhythmias associated with previous MI – Unlabelled use in diabetic neuropathy 6/2/2023 57
  • 58. … • Formulation: Mexiletine hydrochloride • Dosage: mainly orals • Initial dose: 200 mg orally every 8 hours A minimum of 2-3 days between dose adjustments is recommended Dose may be adjusted in 50 or 100 mg increments up or down • The dose should not exceed 1200 mg/day 6/2/2023 58
  • 59. … • Tremor is early sign of Mexiletine toxicity • Hypotension • Bradycardia, • Widened QRS, • Dizziness and • Nystagmus 6/2/2023 59
  • 60. Class IC drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers • Risk of cardiac arrest and sudden death-so not used commonly • May be used in severe ventricular arrhythmias 6/2/2023 60
  • 62. Propafenone • Structural similarity with Propranolol and has - blocking action • Undergoes variable first pass metabolism • Reserve drug for ventricular arrhythmias, re-entrant tachycardia involving accessory pathway 6/2/2023 62
  • 63. … • Formulation: Propafenone hydrochloride • Dosage: Mainly orals Initial dose: 150 mg orally every 8 hours; may increase dose after at least 3 to 4 days to 225 mg orally every 8 hours; if additional therapeutic effect is needed, may increase dose to 300 mg orally every 8 hours Maximum dose: 900 mg/day 6/2/2023 63
  • 64. … Adverse effects: • Metallic taste • Constipation • Pro-arrhythmic 6/2/2023 64
  • 65. Class II: Beta blockers • -receptor stimulation: • ↑ Automaticity • ↑ AV conduction velocity • ↓ Refractory period • -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors 6/2/2023 65
  • 66. … • Depress phase 4 depolarization of pacemaker cells • Slow sinus as well as AV nodal conduction: ↓HR, ↑PR • ↑ERP, prolong AP Duration by ↓AV conduction • Reduce myocardial oxygen demand • Well tolerated and Safer 6/2/2023 66
  • 67. β Adrenergic Stimulation β Blockers ↑ magnitude of Ca2+ current & slows its inactivation ↓ Intracellular Ca2+ overload ↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate ↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity Epinephrine induces hypokalemia (β2 action) Propranolol blocks this action 6/2/2023 67
  • 68. Use in arrhythmia • Control supraventricular arrhythmias, Atrial flutter, fibrillation and PSVT • Treat tachyarrhythmias caused by: -Hyperthyroidism, Pheochromocytoma and during anaesthesia with halothane 6/2/2023 68
  • 69. … • Digitalis induced tachyarrythmias • Prophylactic in post-MI • Ventricular arrhythmias in prolonged QT syndrome 6/2/2023 69
  • 70. Esmolol • β1 selective agent • Very short elimination t1/2: 9 mins • Metabolized by RBC esterases • Rate control of rapidly conducted AF Uses: • Arrythmia associated with anaesthesia • Supraventricular tachycardia 6/2/2023 70
  • 71. … • Formulation: Esmolol hydrochloride • Dosage: Mainly injectibles Optional loading dose (500 mcg/kg IV over 1 minute), then 50 mcg/kg/min IV for 4 minutes; if the response is adequate, the infusion may be maintained at 50 mcg/kg/min Maintenance dose: 25 to 200 mcg/kg/min IV -Maximum dose: 200 mcg/kg/min IV -Duration: Maintenance infusions may be continued for up to 48 hours 6/2/2023 71
  • 72. Class III drugs ↑APD & ↑RP by blocking the K+ channels 6/2/2023 72
  • 74. Amiodarone • Iodine containing long acting drug • Mechanism of action: (Multiple actions) – Prolongs APD by blocking K+ channels – blocks inactivated sodium channels – β blocking action , Blocks Ca2+ channels – ↓ Conduction, ↓ectopic automaticity 6/2/2023 74
  • 75. … • Formulation: (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]- 2,6-diiodophenoxy}ethyl)diethylamine • Dosage: Both Injectibles and orals • IV: Initial dose: 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen: -Loading infusions: 150 mg over the first 10 minutes (15 mg/min), followed by 360 mg over the next 6 hours (1 mg/min) -Maintenance infusion: 540 mg over the remaining 18 hours (0.5 mg/min) Maximum dose: Initial infusion rate: 30 mg/min 6/2/2023 75
  • 76. … • Oral Loading dose: 800 to 1600 mg orally per day for 1 to 3 weeks Adjustment dose: 600 to 800 mg orally per day for 1 month, then switch to maintenance dose Maintenance dose: 400 mg orally per day Maximum dose: 600mg/day 6/2/2023 76
  • 77. • Pharmacokinetics: – Variable absorption 35-65% – Slow onset 2days to several weeks – Duration of action: weeks to months • Dose: – Loading dose: 150mg over 10min – Then 1mg/min for 6 hrs – Then maintenance infusion of 0.5mg/min for 24 hr … 6/2/2023 77
  • 78. … • Uses: – Can be used for both supraventricular and ventricular tachycardia • Adverse effects: – Cardiac: heart block, QT prolongation, bradycardia, cardiac failure, hypotension – Pulmonary: pneumonitis leading to pulmonary fibrosis 6/2/2023 78
  • 79. … – Bluish discoloration of skin – Corneal microdeposits – GIT disturbances, hepatotoxicity – Blocks peripheral conversion of T4 to T3 can cause hypothyroidism or hyperthyroidism 6/2/2023 79
  • 80. • Antiarrhythmic • Multiple actions • Iodine containing • Orally used mainly • Duration of action is very long (t ½ = 3-8 weeks) • APD & ERP increases • Resistant AF, VT, Recurrent VF are indications • On prolonged use- pulmonary fibrosis • Neuropathy may occur • Eye: corneal microdeposits may occur 6/2/2023 80
  • 81. • Bretylium: – Adrenergic neuron blocker used in resistant ventricular arrhythmias • Sotalol: – Beta blocker • Dofetilide, Ibutilide: – Selective K+ channel blocker, less adverse events – use in AF to convert or maintain sinus rhythm – May cause QT prolongation 6/2/2023 81
  • 82. Newer class III drugs • Dronedarone • Vernakalant • Azimilide • Tedisamil 6/2/2023 82
  • 83. Calcium channel blockers (Class IV) • Inhibit the inward movement of calcium ↓ contractility, automaticity, and AV conduction. • Verapamil and Diltiazem 6/2/2023 83
  • 84. Verapamil • Formulation: Verapamil hydrochloride • Dosage: Mainly Orals -Chronic atrial fibrillation in digitalized patients: 240 to 320 mg/day orally in 3 or 4 divided doses -Prophylaxis of paroxysmal supraventricular tachycardia (PSVT) in non-digitalized patients: 240 to 480 mg/day orally in 3 or 4 divided doses • Maximum dose: 480mg/day 6/2/2023 84
  • 85. … • Uses: – Terminate PSVT – Control ventricular rate in atrial flutter or fibrillation • Drug interactions: – Displaces Digoxin from binding sites – ↓Renal clearance of Digoxin 6/2/2023 85
  • 86. Other anti-arrhythmics • Adenosine • Atropine • Digitalis • Magnesium Sulphate 6/2/2023 86
  • 87. Adenosine Purine nucleoside having short and rapid action  IV suppresses automaticity, AV conduction and dilates coronaries  Drug of choice for PSVT  Has very short half life Adverse effects: Nausea, dyspnea, flushing and headache 6/2/2023 87
  • 91. OTHER TREATMENT MODALITIES Electrical Devices: • Permanent pacemaker • Implantable cardioverter-defibrillator • Biventricular pacemakers and defibrillators 6/2/2023 91
  • 92. … Invasive Therapies: • Electrical cardioversion • Catheter ablation • Pulmonary vein isolation 6/2/2023 92
  • 95. CONCLUSION • Since arrhythmia is associated with high morbidity and mortality, it is expedient to know what drug to use in what situation so as to reduce these unfavourable outcomes 6/2/2023 95
  • 96. REFERENCES • Kumar and Clark, Textbook of Clinical Medicine • Katzung, Textbook of Pharmacology • Medical school lecture notes • Sideshare notes • https://en.wikipedia.org/wiki/Cardiac_Arrhythmia_Suppression_Trial • https://www.nigeriamedj.com/article.asp?issn=0300- 1652;year=2015;volume=56;issue=6;spage=429;epage=432;aulast=Okeahialam • [Agents Used in Cardiac Arrhythmias -(Robert D. Harvey; Augustus O. Grant)] • https://www.mayoclinic.org/tests-procedures/maze-procedure/pyc- 20384973#:~:text=Maze%20is%20a%20surgical%20procedure,to%20make%20several%20precise %20incisions. 6/2/2023 96

Hinweis der Redaktion

  1. RMP IS -90 MV Cardiac bounded by a lipoprotein membrane which has receptor channels crossing it WHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering it Intracellular negativity starts diminishing When such depolarisation reaches a threshold potential, the sodium channels open abruptly Na enters cell in large quantities CELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MV Phase 0: rapid depolarisation…fast selective inflow of na ions During latter part, ca ions also enter the cell via na channels Frther in phase 1 and 2 ca ions enter thru slow ca channels THE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATE The ca which enters the cell in dis manner causes release of ca from sarcoplasmic reticulumraising the conc of ca within the cells This intracellular free ca interacts with actin myocin system and causes contraction of heart Afetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIME Phase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATION Phase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITY FROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASE Phase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pump RMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERS The cycle is then repeated Inactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mv Cardiac sodium channel protein shows 3 different conformations Depolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeability Brief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarising stimulUs Very large influx of na accounts for phase 0 depolarisation Clusure of inactivation gates result Remain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period.. Cardiac calcium channels are L type Phase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves.. Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium 2 types of main potassium currents involved in phase 3 : ikr and iks Certain potassium channels are open at rest also…”inward rectifier” channels In addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and and na-ca exchange pump Normally na ions concentrated extracellularly and vice versa for k cions Thus have a tendency odf diffusion along concentration gradient This diffusion is opposed by na k pump This pump operates contimuously and does not switch on and off during action potential of cardiac cells
  2. ↓ Automaticity ↓ Excitability ↓ Conduction velocity Refractory period Direct action : prolonged in all cardiac tissues Vagolytic action : Atria: ↑ AV node : ↓ Ventricles : unaltered Over all : ↑ atrial , ↑ ventricular, ↓ AV node Contractility BP ECG Extracardiac Depresses skeletal muscle Quinine like antimalarial , antipyretic and oxytocic action
  3. Prominent cardiac depressant and antivagal action Use: second line drug for preventing recurrences of ventricular arrhythmia No affect on sinus rate due to opposing actions Can also cause mental depression, erectile dysfunction, and hypotension
  4. 50 % EXCRETED UNCHANGED IN URINE Also discuss about procaine
  5. Class Ib drug blocks sodium channels more in inactivated state than open state but do not delay the channel recovery, they do not depress AV conduction or prolong APD Even shorten Than with long APD ( Na + channels remain inactivated for long period of time Normal ventricular fibres are minmally affected , depolarized damaged fibres are significantly depressed Brevity of AP and lack of lidocaine effect on channel recovery may explain its inefficacy in atrial arrhythmias No significant hemodynamic effect No significant autonomic actions
  6. IV preparation must not contain preservative, symapthomimetic or vasoconstrictor 1-3 mg/min infusion Clinical Pharmacokinetics High first pass metabolism half-life 1–2 hours a loading dose of 150–200 mg administered over about 15 minutes should be followed by a maintenance infusion of 2–4 mg/min
  7. 400 mg loading dose then 200 mg 8 hrly Contraindicated in patients with AV block as it may accelerate AV block 450- 750 mg of Mexiletine orally per day provides significant relief in diabetic neuropathy
  8. Can precipitate CHF by depressing AV CONDUCTION and ALSO CAN CAUSE bronchospasm. Dose = 200 mg tds Morcizine has properties of all 3 classes but as it prolongs QRS it has been placed along with class Ic drugs
  9. Beta receptor stimulation causes increased automaticity, steeper phase 4, Increased AV conduction velocity and decreased refractory period Beta adrenergic blockers competitively block catecholamine induced stimulation of cardiac beta receptors
  10. Slow sinus as well as AV nodal conduction which results in decrease in HR and increase PR atrial depolarization, QT and QRS are not significantly altered.
  11. Propranolol, Acebutolol and Esmolol have been approved for antiarrhythmic use
  12. Class III drugs block outward K+ channels during phase III of action potential These drugs prolong the duration of action potential without affecting phase 0 of action potential or resting membrane potential they instead prolong ERP
  13. HENCE IT DECREASES HEART RATE AS WELL AS AV conduction, better efficacy with lower risk of development of Torsades de pointes
  14. Many drug interactions
  15. Bretylium became obsolete because of poor bioavailability and development of tolerance, reintroduced as anti-arrhythmic for parenteral use. Main adverse effect is postural hypotension, nausea and vomiting. Long term use may result in swelling of parotid gland particularly at meal time. It is contraindicated in digitalis induced arrhythmias and cardiogenic shock
  16. Dronaderone: Amiodarone like drug without iodine atoms so no pulmonary or thyroid toxicity. Has shorter half life 1-2 days compared to months Vernakalant mixed sodium and potassium channel blocker Azimilide: blocks rapid and slow components of potassium channels low incidence of torsades de pointes Tedisamil:
  17. Timeline of findings from landmark trials in atrial fibrillation management, including treatment of concomitant conditions and prevention (green), anticoagulation (blue), rate control therapy (orange), rhythm control therapy (red), and atrial fibrillation surgery (purple).