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A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION

A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION. Olavo Fernandes, Pharm.D. Pharmacy Practice Leader, Toronto General Hospital, UHN Assistant Professor, University of Toronto October 2002. SA node primary pacemaker (60-100 bpm)

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A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial Fibrillation RESOURCE SESSION

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  1. A Practical Overview of Antiarrhythmic Drugs Commonly Used in Atrial FibrillationRESOURCE SESSION Olavo Fernandes, Pharm.D. Pharmacy Practice Leader, Toronto General Hospital, UHN Assistant Professor, University of Toronto October 2002

  2. SA node primary pacemaker (60-100 bpm) autonomic nervous system vagus nerve (parasym.) catacholamines (sym) AV node filter (40-60 bpm) controls number of impulses reaching the ventricle from atria Bundle of His conducts impulses to bundle branches Perkinje system < 40 bpm bifarcates into several bundle brunches Cardiac Conduction System

  3. P wave depolarization of atria QRS Complex depolarization of ventricle QRS interval normally < 0.12 secs. widened QRS: prolonged conduction QRS > 0.12 secs: conduction from ventricle or supraventricular T wave repolarization of ventricle U wave uncertain PR interval < 0.2 seconds conduction velocity beginning of P wave to onset of QRS QTc interval < 0.4 seconds refractory period beginning of Q to end of T Electrocardiogram (ECG)

  4. Cardiac Action Potentials Sodium-dependent Fibres/ Fast Fibres • atrial and ventricular tissue • Phase O, 1, 2, 3, 4 Calcium-dependent Fibres • SA and AV nodes • only 3 phases • Ca enters instead of Na in Phase O • higher resting membrane potential • increase in slope of phase 4 Refractory Period Automaticity • intrinsic property of spontaneous impulse generation

  5. Classification(Circulation 2001; 104: 2118-2150)

  6. Atrial Arrhythmias Goals of Therapy • convert to sinus rhythm • control ventricular response rate • relieve associated symptoms (palpitations, fatigue, dyspnea, syncope, angina, heart failure) • prevent recurrence • prevent complications: life threatening arrhythmias, stroke, MI, tachycardia

  7. Atrial Fibrillation- Rate Control • Why use an agent for rate control? • better filling time, better diastolic function • consider risks of conversion, embolic risks, drug side effects OPTIONS • Digoxin • increase vagal tone (decrease AV node conduction), inhibit Na/K Pump • Beta Blockers ( metoprolol, esmolol, atenolol) • slow SA node, slow AV node conduction, effect on refractory period • Calcium Channel Blockers (diltiazem, verapamil) • block slow calcium channels, slow AV node conduction

  8. DIGOXIN vagally mediated slow onset- 4hrs (large VD) poor effectiveness during high sympathetic tone (stress) positive inotrope (benefit with concurrent CHF) proarrhythmic, side effects Rate Control Agent Considerations

  9. BETA BLOCKERS faster onset (minutes) directly effect on AV node (effective during stress) negative inotrope (concern in CHF) may be useful with concurrent CAD/Post MI patients bronchospasm (asthma) effect on blood sugar (DM) main SE: hypotension CALCIUM CHANNEL BLOCKERS faster onset (minutes) directly effect on AV node (effective during stress) negative inotrope (concern in CHF) verapamil > diltiazem may be useful with concurrent CAD/Post MI patients main side effect:hypotension cost diltiazem > verapamil Rate Control Agent Considerations

  10. Conversion of Atrial Fibrillation • Considerations • better cardiac function, more times in A Fib harder to convert to NSR, emboli and anticoagulation, may need rate control during conversion • Direct Current Conversion • 100J, 200J, 300J, 360J • burns, relapse, sedation, worsened arrhythmias • Pharmacological Options • Amiodarone (least proarrhythmic, some AVN block, least negative inotropy, very costly IV) • Procainamide, Sotalol • Quinidine • Ibutilide

  11. Management of newly discovered AF(Circulation 2001; 104: 2118-2150)

  12. Pharmacologic cardioversion of AF<7 days (Circulation 2001; 104: 2118-2150)

  13. Pharmacologic cardioversion of AF>7 days(Circulation 2001; 104: 2118-2150

  14. Pharmacological management of patients with recurrent AF (Circulation 2001;1104: 2118-2150)

  15. Mechanism binds and inhibits Na/K ATPase slows AV node conduction (vagus nerve) Kinetics dist: wide 7-8 L/kg (skeletal muscle, myocardium, kidneys) ptn binding : 20-40% elimination: renal 70-80%; hepatic (up to 30%) time to peak: 1-4 hr (IV); 2-6 hr (po) time to steady state: 5-7 days (2-3 wks in RF) elimination half life: 35-40 hrs (2-5 days in RF) Indications CHF, AF- rate control Dosing load: 0.250mg IV over 15 min repeat in 6hr; 0.250 mg po q6h x 4 (total 1 mg) renal dysfunction load 0.125mg q6h (total 0.5-0.75 mg) initial mx dose: 0.125 - 0.250 mg po Drug Profile: Digoxin

  16. Adverse Effects GI: N, V, A, D CNS: disorientation, confusion Ocular: colour vision disturbances (yellow-green), halos, photophobia CV: bradycardia, heart block, VT more prone to toxicity with hypokalemia (sensitizes myocardium to digoxin effect) toxicity: hyperkalemia, ventricular arrhythmias, visual disturbances DIGIBIND Drug Interactions physically adsorption (antacids, sucralfate, resins) antibiotics (digoxin metabolized by gut bacteria) increased serum level (quinidine, amiodarone, verapamil) assay interference (spironolactone) Monitoring ECG, HR, renal function, potassium, digoxin levels Drug Profile: Digoxin

  17. Therapeutic Range 1.2- 2.5 nmol/L AFib at higher end of target Indications suspected toxicity/ confirmation initiation or change in therapy changes in renal function clinical deterioration addition of interacting medications routine monitoring - yearly subtherapeutic response Sample Collection Time not < 8 hrs and preferably trough level before next dose at least 5 days after starting tx or changing dose Increased levels Increased Levels advanced age, renal disease, hepatic disease, amiodarone, verapamil, CsA, quinidine Decreased levels hyperthyroidism, binding drug interactions Digoxin: serum levels

  18. ADVANTAGES Positive inotrope Maybe useful in patients with concurrent AF / CHF LIMITATIONS Limited to atrial arrhythmias Limited efficacy Pro-arrhythmic Narrow therapeutic range Limited efficacy during high sympathetic tone Caution with adverse effects/ drug interactions Drug Profile: Digoxin

  19. Mechanism: blocks slow calcium channels slows AV node conduction vasodilatation Administration/Dosing bolus and continuous infusion 0.25 mg/kg over 2 minutes, after 15 minutes can give 0.35 mg/kg over 2 minutes continuous infusion 10mg/hr (up to 15mg/hr) x 24 hr D5W, NSS, 2/3-1/3 refrigerated for storage Adverse Effects IV: hypotension, bradycardia worsening CHF symptoms heart block Drug Interactions AV node blocking agents (BB, CCB, digoxin) hypotensive agents negative inotropes Monitor ECG, BP, HR CHF symptoms Drug Profile: Diltiazem

  20. Mechanism: competitive block agonist effect of sympathetic neurotransmitters block adrenergic stimulation of cardiac action potentials Beta-1 selective agent slows AV node conduction Administration/Dosing 12.5 - 100 mg po bid 5mg IV push for acute management ( if necessary 10-15 mg IV q 6h) Adverse Effects IV: hypotension, bradycardia worsening CHF symptoms bronchospasm in asthma heart block Drug Interactions AV node blocking agents ( CCB, digoxin) hypotensive agents negative inotropes Monitor ECG, BP, HR CHF symptoms Drug Profile: Metoprolol

  21. Mechanism: complex pcl profile: actions of all classes conduction slowing (class I) BB activity (class II) prolong APD and refractory period (class III) AVN conduction slowing (IV) blocks cellular K channels Kinetics bioavailability: 35-65% half life: mean 52 days volume of distribution: 5000L elimination: primarily hepatic metabolism / biliary excretion active metabolite: desethyl-amiodarone Kinetic Implications loading doses delayed AA effect delayed elimination if drug stopped compliance role of levels Drug Profile: Amiodarone

  22. Indications IV suppression of recurrent sustained VT, ongoing VT/VF, acute conversion of AF Atrial Fibrillation/Flutter slow VRR (AVN block) convert to NSR maintain NSR after conversion dose lower in atrial arrhythmias Post MI CAMIAT and EMIAT showed amio. - low incidence of proarrhythmia; safe in LV dysfunction Primary prevention of SCD RFs for SCD: LV dysfunction, frequent or complex ectopics GESICSA and CHF STAT MADIT (ICD) Secondary prevention -SCD CASCADE, AVID ICD preferred amio. second line Drug Profile: Amiodarone

  23. Administration/Dosing 150-300 mg IV over 10 minutes followed by 0.5 - 2 mg/kg minute infusion (1000mg / 24 hrs) See handout continue oral load over several weeks Ventricular arrhythmias 1200-1800 mg/d x 1-2 wks; 800mg/d x 2 wks; 600mg/d x 4 wks; then 200-400mg/d Atrial arrhythmias 600-800 mg/d x 4wks; 400 mg/d x 2-4 wks; 200 mg/d thereafter Adverse Effects (IV) hypotension (related to vehicle) peripheral vein phlebitis (run at < 2mg/ml) IV infusions > 2 hrs administer in glass bottles of D5W proarrhythmia : rare 100% liver metabolism Monitor vitals, ECG, BP, HR vein site for phlebitis Drug Profile: Amiodarone

  24. Long term oral therapy 80% report side effects, in trials only 10-20% have side effects necessitating withdrawal SE appear to be dose related minimize doses/ reduce dose is sx occur regular monitoring in preventing and managing SEs CV sinus bradycardia (0-10%), AV conduction disturbances and heart block (2-5%), rare TdP increase plasma cholesterol Pulmonary most feared adverse effect pulmonary fibrosis (2-7%) can be fatal in 10% of cases appears in pts with > 400mg/ day CXR: bilateral and diffuse changes/ interstitial infiltrates Sx: dyspnea, cough, chest pain, pleural rub Amiodarone :Adverse Effects

  25. Pulmonary type 1:hypersensitivity (after first few weeks) with development of fever, SOB, cough; tx : stop amio. type 2: interstitial / alveolar pneumonitis (7 mos - 2 yrs); insidious onset of non-productive cough, fatigue, SOB, pleuritic CP, fever; infiltrates and pulmonary fibrosis on CXR; tx: stop amio GI increase in AST/ALT/ ALP (25%) hepatitis, hepatic failure N, V, A common Thyroid inhibits conversion T4 to T3 hypo (3%) or hyperthyroidism (2%) hypothyroidism: rare after first 18 months responds to thyroid replacement hyperthyroidism occur at any time, difficult to manage (thyroidectomy) Amiodarone : Adverse Effects

  26. Dermatolgicial skin reaction (15%) photosensitivity (10%)- limit sun exposure and sunscreen long term blue-gray discoloration (1-7%) CNS 40% have CNS effects (fatigue, tremor, ataxia, peripheral neuropathy) Optho. corneal deposits rare: visual disturbances sx: photophobia, blurred vision, blue-green halos Monitoring labs (renal function, CBC, LFTs, thyroid function), ECG, CXR baseline, as sx occur and every 4-6 months PFTs, eye exam: baseline and as symptoms occur ECG, HR, BP at regular intervals Drug Interactions warfarin, digoxin, BB, CCB, procainamide, quinidine (see handout) Amiodarone: Adverse Effects

  27. ADVANTAGES effective in a wide range of arrhythmias neutral effects on inotropy (CHF patients) safety in CAD and LV dysfunction low incidence of proarrhythmia some rate control properties in AF LIMITATIONS many chronic side effects drug interactions IV amiodarone - very expensive Drug Profile: Amiodarone

  28. Mechanism: Class 1a AA- blocks Na channels prolongs refractory period and decreases conduction velocity Administration/Dosing IV and PO regimens depends on indication and renal function paradoxical initial increase in HR Kinetic Implications active metabolite- NAPA levels to prevent toxicity (drug and NAPA) Adverse Effects hypotension, bradycardia proarrhythmic (TdP) drug-induced lupus (SLE) GI: nausea, vomiting CNS: disorientation Drug Interactions amiodarone, Septra (TMP/SMX) Monitor ECG, BP, HR Drug Profile: Procainamide

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