Farmacocinetica

SCIENTIFIC REPORT

Pharmacokinetics of Lidocaine With Epinephrine Following Local Anesthesia Reversal With Phentolamine Mesylate
Paul A. Moore, DMD, PhD, MPH, Elliot V. Hersh, DMD, MS, PhD,À Athena S. Papas, DMD, PhD,` J. Max Goodson, DDS, PhD,§ John A. Yagiela, DDS, PhD,I Bruce Rutherford, DDS, PhD," Seigried Rogy, PhD," and Laura Navalta, MS"
*Professor and Chair, Department ofAnesthesiology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, ÀProfessor and Director of Pharmacology Division of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, `Johansen Professor of Dental Research, Head of the Division of Public Health Research and Oral Medicine, Tufts University School ofDental Medicine, Boston, Massachusetts, §Professor, Department of Pharmacology, The Forsyth Institute, Boston, Massachusetts, IProfessor and Chair, Diagnostic and Surgical Sciences, University of California Los Angeles, School of Dentistry, and Professor of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, and "Director, Clinical Operations, Novalar PharmaceuticalsInc, San Diego, California

Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have receive d local anestheti c i njections containi ng a vaso constrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing thesystemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The bloo d levels of phentolamine were determine d following its administration intraorally and intravenously.Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P ), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridgeslidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P ), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L ). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax ), time to peak plasma concentration ( Tmax ), area under the plasma concentration-time curve from 0 to the last timepoint ( AUC last ) or from time 0 to infinity ( AUC inf ), elimination half-life (t1/2 ), clearance ( CL ), and volume of distribution ( Vd). The phentolamine Tmax occurred earlier following the intravenous a dmi ni stration of 1P iv ( 7 min utes than fol lowi ng its sub mucosal administration in treatment 1L1P (15 minutes ) or 4L2P (11 minutes). The phentolamine t1/2, CL, an d Vd values weresimilar for 1L1P, 1Piv, an d 4L2P. The Tmax for lidocaine occurred later and the C max for lidocaine was slightly higher when comparing the 4L2P treatment and the 4L treatment. The phentolamine-in duced delay of the li docaine Tmax likely represents phentolamine’s

Received November 6, 2007; accepted for publication March 5, 2008. Address correspondence to Dr Paul A. Moore, University of Pittsburgh,552 Salk Hall, Pittsburgh, PA 15261; pam7@pitt.edu. Anesth Prog 55:40^48 2008 E 2008 by the American Dental Society of Anesthesiology

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Anesth Prog 55:40^48 2008

Moore et al

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ability to accelerate the systemic absorption of lidocaine from oral tissues into the systemic circulation. Key Words: Pharmacokinetics; Dental local anesthesia; Lidocaine; Phentolamine; Epinephrine. oft...