Le Journal canadien de la pharmacie hospitaliere Volume 48, N° 6, decembre 1995 360
PHARMACY PRACTICE
Therapeutic Alternatives in Atrial Fibrillation
William John Perks, Carmine Stumpo, Brian Jurewitsch and Christian Klem
INTRODUCTION verting to normal sinus rhythm in equipotent doses to control the Atrial Fibrillation (AF) is the most (NSR); and, VRR. Esmolol was considered the common sustained dysrhythmia. It is maintaining NSR after initial prototype because of its short half more prevalent in the elderly and is a conversion; life, and ease of titration. Use of common complication of cardiac sur b) onset of effect; esmolol can demonstrate how a patient gery. Treatment of AF is often based c) usual dosing regimens; will respond to a beta-blocker in terms on previous experience and the most d) pharmacoki netics; of causing hypotension or brady appropriate therapeutic regimen for e) toxicity; cardia. The short half-life of esmolol each patient may not be selected. f) drug interactions; and should ensure a short duration of the Therefore, this Therapeutic Alterna g) availability/cost. adverse effect. Other less expensive tive Chart for AF was developed to These agents were also classified beta-blockers such as metoprolol, help both medical and pharmacy clin into groups by their pharmacologic propranolol, atenolol, and others may icians choose and utilize the most effects which: be substituted for longer-term control appropriate therapy for the treatment i) only control VRR (i.e., beta of VRR once response to a beta of AF in a specific patient. Currently blockers, calcium channel blocker has been demonstrated. For the chart is used by practicing phar blockers, digoxin); the post-operative patient, the macists at St. Michael's Hospital as a ii) only convert to NSR (i.e., pro intravenous forms of these drugs arc tool in providing pharmaceutical care. cainamide, quinidine, disopyra used initially because of their more Additionally, it is used as an educa mide); rapid onset; the parenteral forms can tional tool for pharmacists, residents, iii) control both VRR and convert be substituted with oral agents once students, and other health profes to NSR (i.e., sotalol, amio the patient is stabilized and is sionals. darone, flecainide, propa absorbing enterally. Similar oral fenone). conversions for other anti-arrhyth METHODS Disopyramide was not included in mic drugs can also be made. A thorough review of the current the chart as the authors felt that its use Although no column in the chart biomedical literature was undertaken is quite infrequent secondary to its was set aside specifically for the using a Medline search of the primary negative inotropic and anticholinergic duration of action, the overall duration literature back to 1984. All effective effects. of action of a drug is a function of the agents captured in this literature pharmacokinetic half-life (listed on search were then reviewed specif DISCUSSION the chart under kinetics), pharma ically for: While the therapeutic chart only codynamic half-life, and receptor includes esmolol under the beta response (i.e., up or down regulated). a) efficacy in: controlling ventri blocker row, other beta-blockers The duration of effect may, therefore, cular response rate (VRR); con- would be equally effective when used differ depending on the patient, the
William John Perks, B.Sc.Phm. is a Staff Pharmacist, Department of Pharmacy, St. Michael's Hospital, Toronto, Ontario. Carmine Stumpo, B.Sc.Phm, at time of writing, Mr. Stumpo was a Pharmacy Resident, St. Michael's Hospital, Toronto, Ontario. Currently Mr. Stumpo is a Pharm.D. candidate at the College of Pharmacy, Wayne State University, Detroit, Michigan. Brian Jurewitsch, B.Sc.Phm., is a Staff Pharmacist, Department of Pharmacy, St. Michael's Hospital. Christian Klem, Pharm.D. at time of writing, Dr. Klem was Clinical Coordinator, Critical Care at St. Michael's Hospital. Currently Dr. Klem is a Pharmacotherapy Specialist, Tampa General HealthCare and Assistant Professor, University of South Florida, Tampa, Florida. Address Correspondence to: Mr. Wm. Perks, B.Sc.Phm., Department of Pharmacy, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B IWS. Acknowledgements: The authors would like to thank Dr. Al Rasymas, Pharm.D., Clinical Coordinator, St. Michael's Hospital for his guidance and coordination in the preparation of this paper. U.,) Table I: Therapeutic Alternatives in Atrial Fibrillation °'._ Drug Efficacy Onset Dose Kinetics Toxicity Drug Interactions Comments Availability/Cost
8-Blockers VRR = excellent (similar to PO= l-2hrs Complex (multiple bolus infusions) Ester hydrolysis by RBC bradycardia, symptomatic calcium channel blockers, -little risk of proarrhythmic effects / IV: IOOmg/JOml= $9.48 verapamil)1 500 mcg/kg over I min then 300 esterases. hypotension (10%)1 · 4· 34 digoxin, disopyramide torsades des pointes 2.5G/10ml = $134.10 2 E~molol CONY = similar to placebo IV= 2-5 min (may mcg/kg/min x 3 min then 50-300 tl/2=9min .J.contractility, .J.conduction, -may aggravate asthma, AV block, 11 (Brevibloc®l -may be higher than placebo take longer to mcg/kg/min bronchospasm, .J.glycogenesis diabetes, CHF Metoprolol if hyperadrenergic state 1 titrate)30 (quick offset with esmolol) -benefit in hyperadrenergic post-op Others patients
4 30 Diltiazem VRR = 94% bolus3• IV= 2-5 min3 0.25 mg/kg over 2 min. Hepatic elimination symt hypotension 3%3. B-blockers,digoxin - .J.HR is dose-related IV: 25mg/5ml = $13.00 (Cardizem®l = 76% infusion3· 4 (duration 3 hours)30 If no response in 15 min tl/2=3-5h bradycardia, less -ve inotropic - Calcium infusion may decrease 50mg/10ml = $24.00 CONY= similar to placebo5 PO= 1-2 hrs then O.35 mg/kg over 2 Active metabolites:4 effects vs. verapamiJ35·38 hypotension PO: 60mg = $0.33 min then 5-15mg/hr11 desacetyl/N-desmethyldiltiazem -Use dependent effects46 120mg SR= $0.58
Verdpamil* VRR = excellent IV= 2-5 min 2.5-10 mg IV (0.0375-0.15mglkg) Hepatic elimination symt hypotension (10%)1.30.39, 8-blockers - Calcium infusion may decrease IV: 5mg/2ml = $17.80 (lsoptin®) (similar to diltiazem)4 (30-90 min duration over 2 min then 2.5-10 mg/hr bradycardia. diltiazem hypotension39.47 PO: 80mg = $0.20 2 11 CONY = similar to placebo post bolus) .J.contractility, .J.conduction warfarin 120mg=$0.33 PO= l-2hrs 80-120 mg PO Q6-8h 11 constipation. digoxin 240mg SR= $1.33
Digoxin* VRR = moderate (loss of effect IV= 3-4 hrs IV loading = I 0-15 mcg/kg (7-11 Renal elimination bradycardia, nausea, GI effects, quinidine, verapamil, -beneficial effect~ in LV dysfunction IV: 0.5mg/2ml = $3.27 (Lanoxin®J with i adrenergic states)6-7 PO =4-6 hrs mcg/kg if renal dysfunction) in (May require dose adjustment arrhythmias, i PR interval, diltiazem, amiodarone, -may require higher plasma level PO: 0.125mg = $0.09 CONY = similar to placebo2-6,8 divided doses over 24 hours and/or closer monitoring with .J. AV block, CNS effects cholestyramine, antacids, for effect 1-2.6 nmol/L 0.25mg = $0.09 then 0.0625-0.25 mg/day11 renal function interactions)32 propafenone32 (0.8-2 ng/ml)32,48
40 Procainamidet VRR=poor IV= 10-30 min 10-15 mg/kg IV (max 50 mg/min) Hepatic & renal (50%) proarrhythmia (9%) digoxin, amiodamne, -requires prior VRR control IV: lg/lOml = $10.15 ~ (Pronestyl®J CONY= 38-80%2·9·13 PO= 2-4 hrs then 2-4 mg/min elimination. cimetidine, lrimethoprim -levels:4-8 mcg/ml (17-34 µmol/L) PO: 250mg = $0. I 8 (1:, MAINT=? tl/2 = 2.5-5 hrs nausea/vomiting, tremors, -NAPA-toxic/activemet(l4-29µmol/L) 375mg = $0.23 ~ 250-750 mg PO Q3-4h hypotension (IV), ANA (SLE- (may require dose adjustment/ 500mg SR= $0.48 ;:::: 1 500-1000 mg SR PO Q6h I NAPA is primarily renally like symptoms) (20-30%), monitoring of levels with .J.renal ~ eliminated. blood dyscrasia.~(0.5% ) 11 function) ~ ;:::: Quinidinet VRR=poor IV= 1-2 hrs 5-10 mg/kg IV over 30 min Hepatic elimination proarrhythmia (15%) 40 digoxin, amiodarone, -requires prior VRR control IV: 190mg/lml=$4.98(sulfate) (Quinate®, 21214 (infuse 0.9% NaCl to 5-9 hrs Torsades des JX>intes 41 warfarin, verapamil -3% mortality with use15 800mg/10ml (gluconate) ~ CONY= 60-80% · · PO= 4-24 hrs concomitantly tl/2 = ()-8%) :::: Cardioquin®) MAINT = 50%15 maintain preload).May repeat 400mg F=0.7 pain with IV admin./phlebitis -levels: 2-6 mcg/ml (6-18 µmo1!L)48 ~ iv q2h to max 3g daily. Vo=3L/kg nausea/vomiting, diarrhea, cinchonism PO: sulfate 200mg = $0.05 :2.. dizziness, tinnitus, nystagmus (22%) gluconate 375mg = $0.26 200-300 mg PO Q6-8h 11 blood dyscrasia,19 ~ ~ Propafenone1 VRR = moderate to good16-17 IV = 10-30 min18 2 mg/kg JV then 2mg/min Hepatic elimination (saturnble) proarrhythmia (4-8%)16-40 8-blockers, calcium -
~ 4043 Aecainide'JI VRR = modc·rate20 IV = 10-60 min 2 mg/kg JV over IO min. Renal (25%) & hepatic proarrhythmia (4-12% ) - procainamide. sotalol, -use- * Useful for controlling Ventricular Response Rate (VRR) only t Useful for converting to Normal Sinus Rhythm (NSR)/maintaining NSR only ~Useful for controlling VRR. converting to NSR and maintaining NSR \0 VRR: Ventricular Re,-ponse Rate Control CONY: Conversion to Normal Sinus Rhythm (variable period) MAINT: Maintenance of Normal Sinus Rhythm once converted (variable period) ~ Le Journal canadien de la pha,macie hospitaliere - Volume 48, N° 6, decembre 1995 362 dose used, the route of administration, • cardiac conditions including: ation for electrical conversion, and many other factors. Generally, - left ventricular function; pharmacologic conversion with the stated half-life will give an estimate - left atrial size; procainamide or quinidine, or chronic of how long the drug will provide its - hemodynamic effect of the rate control along with adequate given response. arrhythmia; anticoagulation. 34 Alternately, Similarly, the onset of action of - duration of dysrhythmia; combined rate control and conversion these drugs depends on a number of - heart rate; and to NSR may be achieved with patient and drug specific factors. The - cardiac conduction amiodarone, flecainide, propafenone, listings for onset refer to the onset of abnormalities. or sotalol. activity, not necessarily the time to • renal/hepatic function; When using the chart, consider peak effect. In some cases, the peak • pulmonary function (reversible various factors about the patient and effect may take days to occur as with airway disease); disease state of AF. Up to 40% or amiodarone. Because of amiodarone' s • serum electrolytes and fluid status; more of patients with recent onset AF long half-life, and large volume of • thyroid function; (<48 hours) convert spontaneously to distribution due to a high degree of • past or present antiarrhythmic usage NSR. 13 Unfortunately, approximately tissue binding, large loading doses of and present drug therapy; 7 5% of patients experience recurrence amiodarone are required for initiation • sympathetic state of patient (e.g., of the AF15,27·28 thus, some patients of treatment. The intravenous route pain control, recent stress, etc.); may require maintenance antiar of administration of the drug will • other disease states (e.g., diabetes, rhythmic therapy to improve the usually provide a faster onset of action etc.); chance of maintaining NSR. Patients compared to the oral route. • patient preferences (i.e., adverse with heart failure, enlarged left atrial The drug interactions listed in the effects, drug plan coverage, etc.). size(> 45 mm), and longer duration chart are not meant to be all inclusive. of AF (> 2 months) have a smaller Those included were felt to be more The approach to the patient with chance of remaining in NSR once commonly encountered and/or AF would first be to treat any under converted. 14 Patients whose AF was clinically significant. Interactions may lying risk factors such as hypomag related to a definite risk factor which result in either an increase in effect, nesemia, hypokalemia, or hyperthy has been corrected e.g., electrolyte with resultant toxicity, or a decrease roidism. Consideration should be disorder, drugs, or hyperadrenergic in effect requiring additional moni given towards withdrawal or dosage state have a better chance of staying toring or intervention. These may reduction of any arrhythmogenic in NSR. In determining whether to include adjustment of doses, medications the patient is receiving. employ maintenance antiarrhythmic withdrawal of a drug or more intense These could include theophylline, therapy, the risks of drug treatment monitoring of clinical effects or catecholamines, thyroxine, etc. The including the possibility for side toxicities, and serum concentration patient should then be assessed to effects, proarrhythmia and even monitoring. More detail on any of determine the hemodynamic effects increased mortality should be weighed the listed interactions may be found of the arrhythmia. Ifthe AF is causing against the risk of reverting back into in standard drug interaction refer hemodynamic compromise, electrical AF, which although bothersome is ences. 45,51-53 cardioversion may precede pharma not usually fatal. The chart, when used in cologic conversion. If the AF is new In the acute setting of AF, a number combination with patient-specific in onset, the goal of therapy would be of treatment choices are available information and clinical judgement, to return the patient to normal sinus including: controlling the VRR, will assist in the rational treatment of rhythm without any adverse drug controlling the VRR and converting patients with AF. No one drug or drug effects. Initial control of AF may be pharmacologically or electrically or combination listed in the chart is the achieved by controlling the rate with converting electrically. If the AF drug of choice for every patient. The either beta-blockers, calcium channel converts to NSR, the treatment options chart is useful because all the potential blockers, or digoxin. Beta-blockers, include: the use of VRR controlling options are listed, and best regimen which are normally useful only for agents to prevent rapid ventricular for a specific patient may be selected. rate control may be helpful in response if the patient reverts back to Some of the specific patient conversion of a patient with a AF; using antiarrhythmic agents to information required before a rational hyperadrenergic state (e.g., post increase the chance of remaining in choice for treatment of AF can be operative patients). These and other NSR; or no therapy at all. made includes assessment of: rate controlling drugs can decrease If the AF is felt to be resistant to • patient demographics (i.e., age, the hemodynamic and symptomatic conversion, chronic control of VRR level of physical activity, etc.); effects of the arrhythmia in prepar- may be employed with anticoagu- 363 The Canadian Journal of Hospital Pharmacy - Volume 48, No. 6 , December 1995 lation to help prevent thrombotic information, the chart is helpful in PACE 1994; 17:1016-8. 13. Sullivan M, Atwood JE. Pharmacologic complications. assessing the many pharmacologic therapy for atrial fibrillation: current Our experience at St. Michael's alternatives for the treatment of atrial approaches. Hosp Formul 1992; 27 Hospital documents efficacy in AF fibrillation. We believe that the (suppl 3):S33-5. control with many of the drugs listed development of Therapeutic Alter 14. Nattel S, Hadjis T, Talajic M. The on the chart. A commonly used drug native Charts for other disease states treatment of atrial fibrillation. Drugs 1994; 48:345-71. for converting AF to NSR is would be useful to help improve 15. Coplen SE, Antman EM, Berlin JA, et procainamide, although a drug patient specific therapeutic decision al. Efficacy and safety of quinidine regimen of choice should be chosen making and to increase the visibility therapy for maintenance of sinus rhythm with a specific patient in mind. and responsibility of pharmacists in after cardioversion of atrial fibrillation: a Amiodarone, and more recently contributing to patient care. ~ meta-analysis of randomized controlled trials. Circulation 1990; 82: 1106-16. sotalol are becoming more frequently [Published erratum appears in Circula utilized. The enthusiasm for the long REFERENCES tion 1991; 83:714] term use of amiodarone is curtailed I. Platia EV, Michelson EL, Porterfield JK, 16. Kishore AG, Camm AJ. Guidelines for et al. 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