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Pharmacology of Opioids
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
According to their intrinsic activity at the opioid receptors, opioid drugs are classified as follows (Schumacher & Fukuda, 2020):Agonists: Drugs that bind to and stimulate opioid receptors and are capable of producing a maximal response from the receptor (that is, have no ceiling effect). Opioid agonists in general use fall into two main groups—conventional (including morphine, oxycodone, fentanyl, hydrocodone, hydromorphone, and methadone) and atypical (tramadol, tapentadol, and buprenorphine). The effects of conventional opioids are mediated almost exclusively via their activity at the μ-opioid receptor, whereas the effects of atypical opioids result from μ-opioid receptor activation in synergy with other mechanisms, which may also contribute to their side effect profile.Antagonists: Drugs that bind to but do not stimulate opioid receptors and may reverse the effect of opioid agonists.Partial agonists: Drugs that stimulate opioid receptors but have a ceiling effect (that is, produce a submaximal response compared with an agonist).Agonist-antagonists: Drugs that are agonists at one opioid receptor type and antagonists at another.
Pharmacokinetic-Pharmacodynamic Correlations of Benzodiazepines
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Samir K. Gupta, Everett H. Ellinwood
In pharmacodynamic models, complications arise when the parameters change with time, due to an altered receptor responsiveness.51 Prolonged, as well as in some cases acute, exposure to a CNS drug can lead to tolerance or sensitization by a change in drug receptor number and affinity and may be drug concentration-dependent. It is likely that the downregulation of the receptor density primarily affects the intrinsic activity of a drug and not its binding properties. However, it is important to understand that there can be some adaptive changes in the stimulus leading to the effect, e.g., the availability of second messenger.52
Adrenoceptors: Classification and Distribution
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
According to this relationship, full agonists have an intrinsic activity = 1 and are able to produce the maximum possible response of the tissue via the receptor under study. Furthermore, antagonists would have zero intrinsic activity while partial agonists have values ranging between zero and unity; and the KA is given by the EC50.
The North American opioid epidemic: opportunities and challenges for clinical laboratories
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Sarah R. Delaney, Danyel H. Tacker, Christine L. H. Snozek
Adulteration or specimen validity testing is a component of urine drug testing that is intended to detect dilution, substitution, or alteration of specimens to falsify test results [22,23,25,53,54]. Adulteration can invalidate both IA- and MS-based testing methods, depending on the nature of the adulteration. For example, substituting drug-free urine will provide negative results by both IA and MS, whereas various chemical additives may alter antibody-drug binding (thereby disrupting IAs) or convert drugs to derivatives that escape MS-based testing [25,53,54]. The effects of specific adulterants are well reviewed elsewhere [53]. Specimen validity testing typically includes specific gravity and creatinine to indicate sample dilution, either from consuming excessive amounts of liquid or from adding fluid to the sample following collection. Oxidant, nitrite, and pH testing are used to detect a broad array of adulterants, including household products such as detergent, vinegar, salt, hydrogen peroxide, eye drops, and ammonia, and chemicals marketed as urine adulterants, e.g. UrinAid (glutaraldehyde), Stealth® (peroxide), UrineLuck (pyridinium chlorochromate), and Klear® (potassium nitrite). Guidelines for testing in pain management, employment screening, and other settings recommend specimen validity testing to ensure the correct interpretation of urine drug screens [22,23,25]. Many POC tests for DOA are outfitted with temperature and adulteration testing within the device, while central laboratories may perform specimen validity testing on an automated platform using dedicated reagents.
Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain
Published in Expert Opinion on Drug Discovery, 2022
Ammar A.H. Azzam, David G. Lambert
The issue of intrinsic activity has been addressed in a systematic analysis of a wide range of opioids (encompassing the main putative biased MOP ligands; oliceridine, PZM-21, and SR-17018) by Gillis and colleagues in 2020 [29]. In this pivotal piece of work, they utilized a comprehensive range of in vitro signaling assays through to in vivo behavioral testing. In assays of G-protein signaling (Nb33 nanobody and mini Gi recruitment, activation of Gαi2, inhibition of cAMP and GIRK activation) against DAMGO; oliceridine, PZM21, and SR-17018 all displayed low intrinsic activity. Moreover, low intrinsic activity for these ‘putative biased’ agonists against DAMGO was also reported in assays for receptor regulation (GRK2 and β-Arrestin-2 recruitment and MOP trafficking in Rab5 positive endosomes). Receptor phosphorylation barcode also correlated with intrinsic efficacy [29].
Rapid buprenorphine microdosing for opioid use disorder in a hospitalized patient receiving very high doses of full agonist opioids for acute pain management: Titration, implementation barriers, and strategies to overcomes
Published in Substance Abuse, 2021
Jonathan P. DeWeese, James R. Krenz, Sarah E. Wakeman, Alyssa M. Peckham
Buprenorphine is a partial agonist at the mu-opioid receptor (MOR) with lower intrinsic activity than other opioid agonists, high affinity for MORs, and longer receptor occupancy time than most full opioid agonists.4 This allows for effective treatment of opioid cravings, reduced risk of euphoria and respiratory depression, and overdose risk reduction in the case of concurrent full opioid agonist use.4 Despite this, buprenorphine’s higher receptor affinity may also pose treatment challenges when initiating therapy in patients continuing to use full agonist opioids as there is a risk for precipitated withdrawal. Patients who experience precipitated withdrawal are more likely to discontinue treatment and may resume non-prescribed opioid use.5 Due to this risk, it is usually recommended for patients to be experiencing mild to moderate opioid withdrawal prior to the first dose of buprenorphine.1 However, requiring withdrawal prior to buprenorphine initiation may be intolerable for some patients and may result in a return to non-prescribed opioid use. Similarly, it may also be unreasonable for some patients, such as those with pain management needs.