תרופות אנטיאריתמיות Antiarrhythmic Drugs. Prof. Amos Katz Cardiology Department
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1 תרופות אנטיאריתמיות Antiarrhythmic Drugs 0 mv קורס למת מחים, קיסריה נובמבר -80mv 2010 Prof. Amos Katz פרו פ ע מוס כץ Cardiology Department המערך הקרדיולוגי
2 נוש אי ה ו רא ה Pharmacology Pharmacodynamics Pharmacokinetics Use Dependency Classification Vaughn Williams Special Situation ICD / PM AF Model Brugada syndrome Pregnancy Sicilian Gambit Adverse effects: Cardiovascular Proarrhythmia Exacerbation of CHF Noncardiovascular
3 Pharmacodynamics Principles The effect of the drug on the patients
4 כלל י AA drugs cross the cell membrane and interact with receptors in the membrane channels when the latter are in the Rested Activated Inactivated Different association and dissociation rate constants Voltage and time dependent When the drug is bound to a receptor ionic channel can not conduct, even in the activated
5 USE-DEPENDENCE AA that exert inhibitory effects on the upstroke of the action potential At rapid rates of stimulation After longer periods of stimulation Depression of V max, is greater after the channel has been "used" (i.e., after action potential depolarization) Interaction of the AA with Open Inactive Little interaction with the resting channels class IB exhibit fast kinetics class IC drugs have slow kinetics class IA drugs intermediate With increased diastole time - slower rate a greater proportion of receptors become drug free
6 REVERSE USE-DEPENDENCE Exert greater effects at slow rates than at fast rates Particularly true for drugs that lengthen repolarization The QT interval becomes prolonged more at slow than fast rates This effect is opposite to what the ideal antiarrhythmic - precipitating torsades de pointes.
7 Use Dependency Use Dependency Open block Reverse use dependency Use dependency Closed block CL (msec) APD prolongation (msec)
8 Dronedarone a non reverse-use dependent effect on action potential duration Dronedarone 100mg/kg/day 80 p< vs. Control Amiodarone 100mg/kg/day APD90, msec Action potential duration Control AP duration longer than control at higher heart rates Frequency of Stim, Hz (Representing increased heart rate) On rabbit atrial APD90 (Action Potential Duration at 90% repolarisation). Sun W, et al. J Cardiovasc Pharmacol. May 2002;39(5):
9 Pharmacokinetics Principles Absorption, Distribution, Elimination
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11 CLACIFICATION
12 סווג של תרופות אנטיאריתמיות Vaughn Williams Class I Na Channel blockers Ia I b I c Class II - Beta Blockers Class III K channel blockers Class IV Ca Channel blockers Digoxin Adenosine
13 The Sicilian Gambit A New Approach to the Classification of Antiarrhythmic Drugs Based on Their Action on Arrhythmogenic Mechanisms Circulation 1991;84:1831
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15 Dronedarone
16 Mechanisms of Action of Antiarrhythmic Drugs Class I a b c C > A > B
17 Ia Ib Ic
18 Quinidine Quinidine: a valuable medication joins the list of endangered species Sami Viskin Europace 2007 Brugada syndrome congenital short QT syndrome Idiopathic VF AF? ICD?
19 Effects of Ito blockers 4-AP and quinidine on pinacidil-induced phase 2 reentry and VT in arterially perfused RV wedge preparation Yan, G.-X. et al. Circulation 1999;100: Copyright 1999 American Heart Association
20 Lidocaine Slows conduction: blocks the fast Na + channels rapid heart rate high K +, ischemia Decreases refractoriness Blocks Na + entry during the plateau phase of AP. APs of longer duration have greater window currents. Lido Therefore, APs of greater duration are preferentially shortened.
21 Mechanisms of Action of Antiarrhythmic Drugs Class II
22 Mechanisms of Action of Antiarrhythmic Drugs Class III
23 Class III Drugs that prolong repolarization Amiodarone Sotalol Dofetilide Ibutilide Azimelide Dronedarone
24 Dronedarone Displays Important Differences to Amiodarone Blocks Multiple K + Channels Na + Channel Blockade Sympathetic Blockade Ca 2+ Channel Blockade Overall Effects Slows heart rate Slows ventricular rate in atrial fibrillation Prolongs APD and QT/QTc Similar electrophysiological and antifibrillatory effects in ventricles and atria Reduces effect of EAD in M-cells and PF Reduces intrinsic and drug-induced heterogeneity of myocardial refractoriness Negligible proarrhythmia and may be anti-torsadogenic potential Elimination half-life 1-2 days Anti-ischemic and Antifibrillatory LVEF: Not Much Influence Pulmonary Fibrosis Unusually Long Plasma Half-life Thyroid Hormone Effects Shared Properties Amiodarone-specific properties, not shared with dronedarone Doggrell SA, Hancox JC, Expert Opin Investig Drugs 2004;13: Kathofer et al. Cardiovasc Drug Rev 2005;23(3):
25 Dronedarone has Key Structural Differences to Amiodarone Dronedarone O (CH 2 ) 3 CH 3 CH 3 SO 2 HN O(CH 2 ) 3 N (CH 2 ) 3 CH 3 O (CH 2 ) 3 CH 3 O (CH 2 ) 3 CH 3 I O(CH 2 ) 2 N CH 2 CH 3 Amiodarone O I CH 2 CH 3 Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):
26 Dronedarone is a Multichannel Blocker Dronedarone Possesses Electrophysiologic Characteristics of all Four Vaughan Williams Classes Outward currents Ikr: rapidly activating delayed rectifier potassium current (ventricle) Iks: slowly activating delayed rectifier potassium current (ventricle) Ito: transient outward current Ik(Ach): muscarinic receptor-operated K+ current (atrium) Inward currents Fast sodium currents Calcium channel antagonist Gautier P, et al. J Cardiovasc Pharmacol. 2003;41(2): Doggrell SA, Hancox JC, Expert Opin Investig Drugs 2004;13:
27 Dronedarone possesses a very low proarrhythmic profile Dronedarone induces a homogenous effect on ventricular repolarisation Dronedarone effect on action potential duration shows no reverse-use dependency Dronedarone suppresses early afterdepolarisation induces by pure class III agents Sicouri S, Fund Clin Pharmacol. 1999;13:72. Sun W, et al. J Cardiovasc Pharmacol. May 2002;39(5): Varro A, et al. Brit J Pharmacol. 2001;133:
28 Dronedarone Clinical Trial Atrial Fibrillation LV Dysfunction 2a DAFNE ACT2401 2b EURIDIS/ADONIS 2c ERATO 2d ANDROMEDA 3a ATHENA 3b ATHENA Post-hoc Analysis
29 ANtiarrhythmic trial with DROnaderone in Moderate to severe CHF Evaluating morbidity DecreAse
30 Efficacy Vs. Amiodarone?
31 DIONYSOS Cardiovasc Electrophysiol, Mean duration 7 months. AF recurrence with dronedarone-63.5% compared with amiodarone 42.0% Premature drug discontinuation dronedarone 10.4% vs Amiodarone 13.3% Dronedarone had a better safety profile thyroid neurologic events lack of interaction with oral anticoagulants.
32 Meta-analysis randomized studies Amiodarone (A) vs. placebo (4) Dronedarone (D) vs placbo (4). Amiodarone vs. Dronedarone (1) Conclusions: Dronedarone is less effective than amiodarone for the maintenance of sinus rhythm Dronedarone has fewer adverse effects For every 1,000 patients treated with dronedarone instead of amiodarone ~ 228 more recurrences of AF 9.6 fewer deaths 62 fewer adverse events requiring discontinuation of drug.
33 Dronedarone - MULTAQ
34 Black Box Warning מולטאק אינה מתאימ ה ל חולי אי-ספיקתלב לב ח מורהאו או (NYHA FC III IV) בל בל תי-יציבה קראטינין-צפויה צפויהעליה עליהשל שלעד עד כ % ברמותהקר הקר אטינין טיניןבכ- בכ- 5% 5% מהחולים,המבט המבטאת אתהפ הפרעה רעה בהפרשה ט ובולריתולא ולא הפרעה גלומרולרית,שיעורהסינון הסינון הכלייתי (( (GFR; אינונפ נפגע. גע. עלייהזו זו מתייצבתתוך תוךמספר מספרימים ימיםולכן ולכןמומלץ מומלץלמדוד למדודאת אתרמות רמותהקר הקראטינין אטינין כשבועלאחר לאחר תחילת הטיפול ולהתייחסלרמת לרמת הקראטיניןכרמת כרמתהבסיס הבסיס החדשה. :CYP3A4 :CYP3A4 מולטא מולטא קעוברת עוברת מטבוליזםכבדי כבדיב- ב- 3A4 CYP.יש 3A4 ישלנקוט לנקוט זהירות ציטוכרום. בטיפולעם עם תרופות נוספותאחרות אחרות העוברות מטבוליזםבאותו באותו
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36 Choice of AAD - Underlying Pathology
37 Vernakalant Blocks K+ Channels Important in Atrial Repolarization 0 mv I to I Kur Current IC 50 (µm) I to 5-30 I Kr I Kur 3-13 I KACh 10 I KACh I Kr 7-21 I Ks > ms I K1 > 100 Fedida et al. J Cardiovasc Electrophysiol 2005
38 Vernakalant Mechanism of Action Summary Multiple ion channel blocker I K, I Na Activity potentiated in atria during AF Converts AF rapidly and suppresses torsade de pointes in animal models Pharmacologic effects consistent with ion channel blocking profile 11/9/ :43 AM
39 Vernakalant Consistent Conversion Rates All Patients 52.9% * ** ** ** 51.0% 51.2% 47.0% 50.9% 14.0% 5.3% 4.0% 3.6% CRAFT ACT I ACT III ACT II ACT IV Vernakalant Placebo CRAFT: Dosing was 2+3 mg/kg; data represents % converted at 60 min post t last dose; AF duration hours ACT I, III & IV: AF <7 days ACT II: Post CABG and valvular AF study; AF duration hours * P= ACT IV: : A placebo group was not included in the ACT IV study ** P P
40 Class IV Verapamil Diltiazem
41 Mechanisms of Action of Antiarrhythmic Drugs Class IV 0 2 mvs time (msec) RECALL: INWARD Ca++ CURRENT CAUSES DEPOLARIZATION
42 Therapeutic Uses Treatment and prophylaxis of SVT Slows ventricular rate in AFib and flutter Electropharmacological Actions - Atrial Fibrillation Idiopathic Ventricular Tachycardia (verapamil)
43 Adenosine Interacts with A1 receptors present on the extracellular surface of cardiac cells Direct effects mediated through the guanine nucleotide Activating K+ channels (IK Ach, IK Ado) acetylcholine like Increase in K+ conductance shortens atrial APD Decreases atrial contractility In the sinus and AV nodes Indirect Antagonizes catecholamine-stimulated adenylate cyclase to decrease c amp decrease ICa-L and the pacemaker current If in sinus node cells slows the sinus rate -> reflex increase in sinus rate N region of the AV node, conduction is depressed Prolongation of the AH interval results, often with transient first-, second-, or third-degree AV node block Delay in AV nodal conduction is rate dependent
44 Adenosine SVT: -AVNRT -AVRT VT: - AT: -
45 DIGOXIN Na-K ATPase Na + K + M2 agonist Na-Ca Exchange Na + Ca ++ K + Na + Myofilaments Ca ++ CONTRACTILITY
46 Digoxin Autonomic nervous system Enhancing both central and peripheral vagal tone Slowing the sinus node discharge rate Shortening atrial refractoriness Prolonging AV nodal refractoriness Denervated hearts little effect
47 Ranolazine Noval anti anginal agent with Antiarrhythmic properties: Ion channel effect similar to chronic amiodarone Rx Reduced Ikr Iks Late INa ICa Suppress EAD & TdP MERILIN TIMI 36
48 לכל יצור הומאוטרמי מספר נתון של פעימות לב Sinoatrial I f current blocker a new target for heart rate reduction הממהר מקצר ימיו המאיט מאריך ימיו Ivabradine = Corlan BEAUTIFUL, SHIFT ההתוויה המ אוש ר ת ע"י מ שרד הבר יאות היש רא לי כ מו גם במדינות אח רו ת היא: Symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contra-indication or intolerance for betablockers
49 Pharmacokinetics of Antiarrhythmic Drugs Drug Bioavila bility. % Protein Binding % Time to peak hr Elimination ½T hr Elimination route Quinidine Liver Procainamide Liver & Kidney Disopyramide 85 variable Liver & Kidney Lidocaine Liver Mexiletine Liver Flecainide Liver & Kidney Propafenone Liver Amiodarone d Liver Sotalol Kidney
50 Proarrhythmia
51 Types of Proarrhythmia During Treatment With Various Antiarrhythmic Drugs for AF or Atrial Flutter According to the Vaughan Williams Classification
52
53
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57 התחלת טי פ ו ל: א מבול טור י א ו בא י ש פ וז? אין קונצנזוס - :AHA חולים עם EF נמוך - באישפוז - לב תקין, QT תקין אמבולטורי התחלה אמבולטורית - מינון נמוך - מ עקב QT - מע קב א.ק.ג מודאג? באשפוז סיכון גבוה: EF ירוד,,CHF סיכון ל TdP נשי ם,,K Mg אנטי ב י וטי קה, א נטיה י סטמי ניקה
58 אפקט על ספ י קיצוב ודפי ב רי לציה
59 אפקט על ספ י קיצוב ודפי ב רי לציה
60 Drug Pacing Defibrillation עשוי לעלות בריכוז גבוה מעלה בריכוז גבוה Quinidine ללא אפקט מעלה בריכוז גבוה Procainamide? מעלה בריכוז טוקסי Disopyramide ) 0 או + ( Lidocaine מעלה ) 0 או + ( Mexiletine ) 0 או + ( * ) 0 או + ( מעלה Flecainide ) 0 או + ( מעלה Propafenone מעלה Amiodarone 0 מוריד Sotalol 0
61 אינטראק ציה הת אמה למחלו ת ר קע לא CV
62 שינוי מינון במח לות שונו ת או עם ת רופות אח רות
63 שינוי מינון במ ח לות שונות או עם ת רופות אחרות
64 שינוי מינון במ ח לות שונות או עם ת רופות אחרות
65 שינוי מינון במ ח לות שונות או עם ת רופות אחרות
66 New Approach to Antiarrhythmic Therapy Members of the Sicilian Gambit Circulation 2001;104:2865
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68 Upstream Therapy
69 2010 European Heart Journal
70
71 השפעת ת רופות אנטיאריתמיות ע ל ת מותה JAMA 1993
72 AA drugs have not been shown to be effective for primary prevention (exception of BB) AA may be effective as adjunctive therapy under special circumstances Potential adverse side effects Both sotalol and amiodarone have also been shown to reduce the frequency of ICD shock therapy
73 Brugada Syndrome
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75 ACLS 2005
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77 WPW תרופ ו ת ה משפ יע ו ת על AP תרופ ו ת ה משפ יע ו ת על AVN תרופ ו ת ה משפ יע ו ת על AVN ועל AP
78 Amiodarone
79 תרו פות אנטיאריתמיות בהריון חלק מ ן התרו פ ו ת נכנ ס ו לש י מ ו ש בשל העדר דיו וחים על ת ו פעו ת ל ו וא י D - Amiodarone D - Atenolol B - Sotalol אחרים - C
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81 Antiarrhythmic Drugs: Agents with occasionally beneficial side-effects effects תרופות אנטיאריתמיות הינן תרופות ב על ות תופ ע ות לוו אי אלקטרופיזי ולוגיים אשר ל עיתים גם מוע ילים
Antiarrhythmic Drugs
Antiarrhythmic Drugs DR ATIF ALQUBBANY A S S I S T A N T P R O F E S S O R O F M E D I C I N E / C A R D I O L O G Y C O N S U L T A N T C A R D I O L O G Y & I N T E R V E N T I O N A L E P A C H D /
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