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Brevibloc (Esmolol HCl) ß-Adrenergic Receptor Activity Site ß1 ß2 Clinical Effect Heart Rate Heart: Inotropy Conduction Velocity Excitability Renin Release Kidney: Release of free fatty acids Adipose tissue: Peripheral Vessel: Arteriolar Dilation Brochodilatatiion Lungs: Insulin Release Pancreas: ß-Blockers • ß-adrenergic blocking agents --- competitive antagonism • Selectivity: ß1 cardio, ß2 broncho • Indication --- hypertension --- arrhythmia --- angina pectoris --- myocardial infarction --- glaucoma Properties of Drugs - Used Parentally to Control HR and/or BP Indication HR BP Peak Effect (min) Esmolol Yes Yes 2 9 min 10-20 min 1 Atenolol No Yes 2 6-7 h 12 h 1 Labetalol No Yes 5 5.5 h 3-5 h 1,1&2 Metoprolol No Yes 20 3-7 h 5-8 h 1 Propranolol Yes No <10 4h Variable 1&2 Diltiazem Yes No 2-5 3.4 h 1-3 h Ca2+ Verapamil Yes No 3-5 2-5 h 1-2 h Ca2+ T1/2 Duration Receptor Formulary Data • Brevibloc (Esmolol Hcl) • Bristol-Myers Squibb Company • Ultrashort-acting, Cardioselective (ß1) Beta blocker(IV) • Indication: --- Supraventricular Tachycardia --- Atrial Fibrillation --- Atrial Flutter --- Peri-OP, Post-OP Tachycardia / Hypertension --- Acute Myocardial Ischemia Chemical Structure Features • ß1-selective Adrenergic Receptor Blocker, ß1:ß2 = 40:1 (highly cardioselective) • • • • • • Very Soluble in Water No Intrinsic Sympathomimetic Activity No Membrane Stabilizing Activity No Significant Drug Interaction Rapid Onset: 2 mins Ultra-short Action: 10-20 mins Pharmacokinetics • Distribution Half-Life: 2 mins --- volume of distribution: 3.43 L/kg (4 times the volume of central compartment ) --- Recovery within 10-20 mins (duration of action) when infusion terminated • Metabolism --- Hydrolysis of the ester linkage --- By esterase in the cytosol of RBC • Elimination Half-Life: 9 mins --- Not detected in serum in 30 mins when infusion terminated • Total Body Clearance: 20 L/kg/Hr --- greater than cardiac output --- not limited or affected metabolism by hepatic or renal flow Pharmacodynamics • Decrease in --- heart rate (peak effect in 60 sec) --- blood pressure (peak effect in 2 min) --- cardiac index --- rate pressure product (RPP) --- left and right ventricular ejection fraction • Prolongation of --- sinus cycle length --- decrease AV node conduction velocity --- decrease the rate of SA node activity --- antegrade Wenckebach cycle length --- the sinus node recovery time --- increase AV nodal refractoriness interval The Advantage of Brevibloc I • A Selective Approach: – Targeted to the Heart – Little effect on Bronchial Smooth Muscle – Maybe used with caution in p'ts with asthma, COPD • A Flexible Approach: – Administer as long as indicated….. – Maintenance infusions up to 48 hrs or short as you want; rapid reversal of effect within minutes The Advantage of Brevibloc II • A Confident Approach: – Easy to titrate upward or downward to desired heart rate – Allows maximum beta blockade while still maintaining ventricular function • An Effective Approach: – Rapid control of atrial fibrillation,atrial flutter and sinus tachycardia The Advantage of Brevibloc III Indication and Dosage • Indication - Supraventricular tachycardia (SVT) - Peri-OP, post-OP Tachycardia / Hypertension - Acute Myocardial Ischemia • Dosage Loading: 0.5 mg/kg, over 1 min Maintenance: 0.05-0.2 mg/kg/min; *0.2 mg/kg/min --- average effective dosage: 0.1 mg/kg/min Dosage Guideline Warnings? • PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. --- YES for Brevibloc (ß1-selective; 40:1) --- well-suited to many patients types, including COPD, LVD --- titratable --- predictable --- reversible Reference (I) - Asthma • • • • J Clin Pharmacol 1986; 26: 169-174 Effects of Esmolol on Airway Function in P'ts with Asthma Double-blind, randomized, cross-over study Specific Airway Resistance (SRaw) --- measured during (1) increasing dose of esmolol infusion, (2) dry air provocation test, and (3) following IV isoproteronol infusion • All p'ts were able to tolerate the maximum dose of esmolol (0.3 mg/kg/min). • Esmolol may be preferred over propranolol in p'ts with asthma who require Tx with an IV beta-blocking agent. Reference (II) - COPD • Chest 1991; 100: 1215-1218 • Esmolol and ventilatory function in cardiac patients with COPD • To assess the effects of acute cardioselective -blockade on ventilatory function in p'ts with COPD and cardiac disorders • 50 p'ts, Esmolol infusion: 8-24 mg/min • Significant reduction in HR, SBP, and DBP (p<0.01) • No significant effect on FEV1, peak flow, or forced vital capacity Respiratory function was well preserved while esmolol producing marked hemodynamic effects. • No p'ts experienced dyspnea or wheezing with esmolol • Acute -blockade with esmolol can be achieved in patients with COPD and cardiac disorders with little risk of bronchospasm. Reference (III) - AF • Am J Cardiol 1989; 63: 925-929 • Esmolol vs. Verapamil in the Acute Tx of AFs • Efficacy: Ventricular rate reduction, Conversion to sinus rhythm --- both drugs produced a decrease in HR within 2 min --- both drugs decreased HR in 30%; BP in 10% --- 50% p'ts with new onset of AF who received ESMOLOL converted to sinus rhythm. • Safety: (Adverse Experiences) Hypotension --- Esmolol: resolved within 5-20 min after dosage was discontinued or reduced --- Verapamil: required intervention (leg elevation, IV fluids) to resolve • Esmolol compares favorably with verapamil with respect to both efficacy and safety in acutely decreasing ventricular response during atrial fibrillation or flutter. • Conversion to sinus rhythm is significantly more likely with esmolol. Reference (IV) - Modified Dosage • J Am Coll cardiol 1994; 23: 302-306 • A New Dosing Regimen for Esmolol to Treat Supraventricular Tachyarrhythmia in Chinese Patients ( Dr. Wen-Je Ko, NTUH) • To find a safe dosing regimen for esmolol infusion to rapidly control supraventricular tachyarrhythmia after cardiac surgery in Chinese p'ts • Esmolol's Advantages: rapid onset of action; ultrashort duration; metabolized by esterase in RBC; metabolism not affected by renal or hepatic diseases; complete dissipation of side effects occurred within 20-30 mins after infusion terminated • Initial infusion rate: 150 or 100 g/kg/min, depending on p'ts age and BP • Maintenance rate = Initial rate x (1- e-0.077t), t is the time period in minutes required by the initial infusion to achieve the therapeutic effect without experience of side effect of hypotension • 5 min to therapeutic response, Maintenance = 1/3 Initial Dose 10 min, Maintenance = 1/2 Initial Dose 15 min, Maintenance = 2/3 Initial Dose THANKS