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Pharmacokinetic determinants of clinical activity
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Given that Nl-dealkylation is a major metabolic pathway for benzodiazepines, and that many clinically important benzodiazepines are N1-substituted, exposure to circulating N-dealkyl metabolites is high. This has important clinical implications, since these metabolites are both biologically active and slowly eliminated from the organism. One such metabolite is desmethyldiazepam. This is produced from many benzodiazepines, most importantly diazepam, but also halazepam, prazepam, oxazolam and others. Indeed, desmethyldiazepam (or nordazepam) is marketed as an anxiolytic in its own right in a number of countries, including Germany. Desmethyldiazepam probably contributes significantly to the biological activity of diazepam and other precursors, particularly after chronic administration, and at later times after single administration. The pharmacokinetic profiles of diazepam and desmethyldiazepam after single administration are illustrated in Figure 7.7. It can be seen that plasma levels of the metabolite actually overtake those of the parent drug during the second day after administration, and remain elevated for over a week, when all traces of diazepam in the organism have essentially disappeared. Desmethyldiazepam is itself slowly metabolised to oxazepam, which is then, as we have seen, rapidly removed from the organism by glucuronoconjugation and renal excretion.
Anxiolytics: Predicting Response/Maximizing Efficacy
Published in Mark S. Gold, R. Bruce Lydiard, John S. Carman, Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
Steady-state plasma levels are reached in about 3 days for short half-life and about 2 weeks for long half-life benzodiazepines.244–246 Short half-life benzodiazepines, e.g., oxazepam, lorazepam, and alprazolam, are conjugated to form glucuronides and eliminated in the urine. Their elimination half-lives are in the 5- to 15-hr range, and they must be administered in divided doses. Long half-life benzodiazepines are metabolized to desmethyldiazepam by microsomal enzymes, e.g., diazepam, clorazepate, prazepam, and halazepam. Desmethyldiazepam is an active benzodiazepine with a 36- to 200-hr half-life (see Figure 9). These are effectively given in once-a-day dosing schedules, and are unlikely to produce rebound anxiety if doses are skipped.246 The role of the liver in catabolism of benzodiazepines is clinically significant in patients with liver failure or in the elderly because half-lives are prolonged and doses must be adjusted downward.247,248 Anti-acids are known to reduce clorazepate absorption from the gut by interfering with hydrolysis to desmethyl-diazepam.249,250 Drugs which compete for microsomal enzymes may similarly increase benzodiazepine half-life, e.g., ETOH, cimetadine, etc.251,252 Care must be taken in the intravenous administration of benzodiazepines that the dose is given slowly (2 mg diazepam per minute) because respiratory arrest does sometimes occur.253
Drug profiles: generic names A-Z
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Clinically important, potentially hazardous interactions with: abiraterone, afatinib, alfentanil, alfuzosin, alprazolam, amiodarone, amitriptyline, amprenavir, aprepitant, astemizole, atazanavir, atorvastatin, atovaquone, atovaquone/proguanil, avanafil, azithromycin, bepridil, boceprevir, bosentan, buprenorphine, bupropion, buspirone, cabazitaxel, cabozantinib, carbamazepine, chlordiazepoxide, ciclesonide, citalopram, clozapine, cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil, colchicine, conivaptan, crizotinib, cyclosporine, cyproterone, darifenacin, dasatinib, deferasirox, delavirdine, diazepam, diclofenac, dihydroergotamine, docetaxel, dronedarone, dutasteride, efavirenz, eletriptan, ergot alkaloids, ergotamine, erlotinib, estazolam, estradiol, eszopiclone, etravirine, everolimus, ezetimibe, fentanyl, fesoterodine, flecainide, flibanserin, flurazepam, fluticasone propionate, halazepam, indacaterol, itraconazole, ivabradine, ixabepilone, ketoconazole, lapatinib, ledipasvir & sofosbuvir, levomepromazine, levothyroxine, lomitapide, macitentan, maraviroc, meloxicam, meperidine, meptazinol, methylergonovine, methysergide, midazolam, mifepristone, nelfinavir, nifedipine, nilotinib, oral contraceptives, osimertinib, paclitaxel, paroxetine hydrochloride, pazopanib, phenytoin, pimozide, piroxicam, pitavastatin, ponatinib, posaconazole, propafenone, propoxyphene, propranolol, quazepam, quinidine, quinine, ranolazine, rifabutin, rifampin, rifapentine, rilpivirine, rimonabant, risperidone, rivaroxaban, romidepsin, rosuvastatin, ruxolitinib, saquinavir, sildenafil, silodosin, simeprevir, simvastatin, sofosbuvir, solifenacin, St John’s wort, sunitinib, tadalafil, telaprevir, telithromycin, temsirolimus, tenofovir disoproxil, ticagrelor, tolvaptan, trabectedin, triazolam, ulipristal, vardenafil, vemurafenib, venetoclax, voriconazole, zolpidem, zuclopenthixol
Trends in concomitant and single opioid and benzodiazepine exposures reported to the California Poison Control System following the Centers for Disease Control and Prevention release of opioid guidelines in 2016
Published in Clinical Toxicology, 2023
Emily Chu, Gina Cocos, Ho Jun Lee, Jane Go, Justin Lewis, Dorie E. Apollonio
Data were obtained from the California Poison Control System, a network of four poison-center sites (San Francisco, Sacramento, San Diego, and Madera/Fresno) that collectively serve a state population of 39 million persons. We used the following inclusion criteria: calls reporting an exposure to both opioid and benzodiazepine (concomitant) or to an opioid or benzodiazepine alone. For single opioid or single benzodiazepine cases, no other types of drugs were reported. Specifically, we defined “single” exposures as calls involving only one substance; exposure calls involving more than one opioid and no other substances were not included as single opioid cases, and exposure calls involving more than one benzodiazepine and no other substances were not included as single benzodiazepine cases. Exposures involved calls in which there was “actual or suspected contact with any substance which has been ingested, inhaled, absorbed, applied to, or injected into the body, regardless of toxicity or clinical manifestation” [11]. The selected drugs in each class included the most commonly prescribed opioids and benzodiazepines in the US [12,13]. For opioids, these included oxycodone, codeine, tramadol, hydrocodone, morphine, hydromorphone, methadone, buprenorphine, pethidine (meperidine), and combination products. For benzodiazepines, these included diazepam, alprazolam, clonazepam, lorazepam, triazolam, chlordiazepoxide, clorazepate, and halazepam. Exposure cases involving illicit opioids, such as heroin or fentanyl, were excluded, as were calls originating from outside of California, involving animal exposures or calling for information but did not report an exposure. We used total human exposures calls as a measure given that the total number of calls made to California Poison Control System for all types of exposures showed no consistent time trend (see Supplement).