Summary
In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the β-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p=0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the β-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.
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References
Wood AJJ, Feely J (1983) Pharmacokinetic drug interactions with propranolol. Clin Pharmacokinet 8: 253–262
Conrad KA, Byers III JM, Finley PR, Burnham L (1983) Lidocaine elimination: effects of metoprolol and of propranolol. Clin Pharmacol Ther 33: 133–138
Greenblatt DJ, Franke K, Huffman DH (1978) Impairment of antipyrine clearance in humans by propranolol. Circulation 57: 1161–1164
Daneshmend TK, Roberts CJC (1982) The short term effects of propranolol, atenolol and labetolol on antipyrine kinetics in normal subjects. Brit J Clin Pharmacol 13: 817–820
Bax NDS, Lennard MS, Tucker GT (1981) Inhibition of antipyrine metabolism by β-adrenoceptor antagonists. Brit J Clin Pharmacol 12: 779–784
Conrad KA, Nyman DW (1980) Effects of metoprolol and propranolol on theophylline elimination. Clin Pharmacol Ther 28: 463–467
Facino RM, Lanzani R (1979) Interaction of a series of β-adrenergic blocking drugs with rat hepatic microsomal monooxygenase. Pharmacol Res Comm 11: 433–445
Deacon CS, Lennard MS, Max NDS, Woods HF, Tucker GT (1981) Inhibition of oxidative drug metabolism by β-adrenoceptor antagonists is related to their lipid solubility. Brit J Clin Pharmacol 12: 429–431
Klotz U, Avant GR, Hoyumpa A, Schenker S, Wilkinson GR (1975) The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 55: 347–359
Berman M, Weiss MF (1974) SAAM manual; Laboratory of Theoretical Biology, National Institute of Health Bethesda, USA
Betts TA, Crowe A, Knight R, Raffle A, Parsons A, Blake A, Hawksworth G, Petrie JC (1983) Is there a clinically relevant interaction between diazepam and lipophilic β-blocking drugs? Drugs 25 [Suppl 2]: 279–280
Bax NDS, Lennard MS, Al-Asady S, Deacon CS, Tucker GT, Woods HF (1983) Inhibition of drug metabolism by β-adrenoceptor antagonists. Drugs 25 [Suppl 2]: 121–126
Hallstrom C, Treasaden I, Edwards JG, Lader M (1981) Diazepam, propranolol and their combination in the management of chronic anxiety. Brit J Psychiatr 139: 417–421
Tyrer P, Rutherford D, Huggett T (1981) Benzodiazepine withdrawal symptoms and propranolol. Lancet 1: 520–522
Brunk SF, Delle M, Wilson WR (1974) Effect of propranolol on morphine metabolism. Clin Pharmacol Ther 16: 1039–1044
Ochs HR, Carstens G, Roberts G-M, Greenblatt DJ (1983) Metoprolol or propranolol does not alter the kinetics of procainamide. J Cardiovasc Pharmacol 5: 392–395
Klotz U, Reimann I (1983) Einfluß von Histamin H2-Rezeptor-Antagonisten auf die hepatische Elimination von Arzneimitteln. Klin Wochenschr 61: 625–632
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supported by the Robert Bosch Foundation, Suttgart, Federal Republic of Germany
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Klotz, U., Reimann, I.W. Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol. Eur J Clin Pharmacol 26, 223–226 (1984). https://doi.org/10.1007/BF00630289
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DOI: https://doi.org/10.1007/BF00630289