Clinical pharmacology: principles of analgesic drug management
Nigel Sykes, Michael I Bennett, Chun-Su Yuan in Clinical Pain Management, 2008
Based on these properties, drugs that bind to receptors can exhibit pure agonist activity, antagonist activity, or act as partial agonists or agonist–antagonists. An agonist acts at a receptor to initiate changes in cell function. Traditionally, an agonist produces the normal biological response of the cell.A partial agonist binds to the receptor, but causes less response than a full agonist; it has a lower efficacy. However, it may have a higher affinity for the receptor, and act as a competitive antagonist in the presence of a full agonist. A typical example would be the partial agonist, buprenorphine, which has a greater affinity for opioid receptors than morphine.An agonist–antagonist acts as an antagonist at certain receptors and an agonist or partial agonist at others. Pentazocine is a typical example, as it acts as μ receptor antagonist, but exerts its opioid effect by agonist activity at the κ receptor.Antagonists occupy the receptor but have no biological activity. A competitive antagonist such as naloxone binds reversibly to the receptor and can displace and is displaced by the agonist. A noncompetitive antagonist binds irreversibly to the receptor.
Graves’ Ophthalmopathy: the Role of Cytokines in Pathogenesis
George H. Gass, Harold M. Kaplan in Handbook of Endocrinology, 2020
Specific blockade of the orbital fibroblast IL-1 receptor in vitro and in vivo is possible using the naturally occurring IL-1 receptor antagonist.40 This antagonist is structurally related to IL-1, is produced by the same cells, and binds to cellular IL-1 receptors without activating them.41 The administration of IL-1 receptor antagonist to animals reduces the severity of inflammatory disorders including streptococcal cell wall-induced arthritis in rats, and immune-complex-induced inflammatory bowel disease in rabbits.26 In a phase I clinical trial in normal individuals, plasma concentrations of IL-1 receptor antagonist as high as 25–30 |ig/ml caused no symptoms or changes in vital signs and did not alter white blood cell counts or routine biochemical parameters.42 Thus, at least in short-term administration, the IL-1 receptor antagonist appears to be safe for human administration.
Hypertension
Anita Sharma, Shauna Dixon, Tanya Claridge in Maximising Quality and Outcomes Framework Quality Points, 2017
NICE recommends that drug treatment should be offered when blood pressure reaches 160/100 mm Hg, with the aim of reducing it to below 140/90 mm Hg, and that the drug treatment should start with an angiotensin converting enzyme for those under 55 years of age with no contraindications. An angiotensin II receptor antagonist should only be used in people who are not able to tolerate ACE inhibitors. For black patients of any age and those over the age of 55 years, a thiazide diuretic or calcium channel blocker should be used.5,13 Contraindications of ACE include pregnancy and reno-vascular disease and caution is advised in renal impairment. Side-effects of ACE include dry cough and, rarely, angioedema, hyper- kalaemia and renal impairment.
Functional mimetic of the G-protein coupled receptor CXCR4 on a soluble antibody scaffold
Published in mAbs, 2019
Adem C. Koksal, Meghan E. Pennini, Marcello Marelli, Xiaodong Xiao, William F. Dall’Acqua
Cell-surface receptor functional inhibition often relies on small molecule inhibitors or, more recently, epitope-specific antibodies. The challenge is, however, that each approach is limited to only one aspect of the receptor, and cannot accommodate alternate binding sites and interactions. In fact, increasing drug tolerance within GPCRs is becoming an area of greater interest. One recent study demonstrated that the use of a small CXCR4-derived peptide from its TM2 and ECL1 was able to act as an antagonist by interacting with SDF-1 without effecting native CXCR4 accumulation or tolerance.38 We posit that ASM can be used as a potent receptor antagonist to block the full complement of receptor–ligand interactions. In this regard, the ASM model’s use as an inhibitor or agonist would have enhanced pharmacokinetics due to its Fc domain and its retention mechanism. Further, mimicking the full GPCR extracellular surface allows ASM to be used as a reliable, soluble antigen for immunization purposes in a vaccine format or in antibody therapeutics generation against the transmembrane extracellular domains.
Current and future pharmacological agents for the treatment of back pain
Published in Expert Opinion on Pharmacotherapy, 2020
Anuj Bhatia, Alyson Engle, Steven P. Cohen
Muscle relaxants are often prescribed for LBP of suspected myofascial origin, with some drugs available in combination with acetaminophen. The class includes medications from different chemical origins that act on a variety of receptors. Examples include tizanidine (alpha-2 agonist), orphenadrine (muscarinic cholinergic antagonist, antihistaminic), carisoprodol (gamma-aminobutyric acid (GABA)-ergic), cyclobenzaprine (5-HT2 receptor antagonist), baclofen (GABA-B agonist), and benzodiazepines. A systematic review on the efficacy of muscle relaxants (not including benzodiazepines) in LBP found only short-term analgesic benefits [21]. The evidence for benzodiazepines for LBP is not robust either, being stronger for acute than chronic pain. For neuropathic pain in general, there is no evidence to support any muscle relaxant with the possible exception of baclofen, which has not been studied for radiculopathy [22]. Muscle relaxants also have the potential for somnolence, dependence, and abuse. In summary, there is no supporting evidence for benefit with long-term use of muscle relaxants for LBP and these medications should be used for short periods of time in patients with severe and frequent muscle spasms accompanying LBP.
Blinding and expectancy confounds in psychedelic randomized controlled trials
Published in Expert Review of Clinical Pharmacology, 2021
Suresh D. Muthukumaraswamy, Anna Forsyth, Thomas Lumley
Similar to the parallel groups design, but here active treatment is preceded by a pharmacological antagonist (Figure 2g). For example, the opioid receptor antagonist naltrexone has been found to block the antidepressant effects of ketamine [137]. Similarly, lamotrogine blocks some of ketamine’s psychedelic properties [138,139]. For classical psychedelics, the 5HT2A receptor antagonist ketanserin has been shown to block the psychological effects of both LSD and psilocybin in a dose dependent manner – with 20 mg ketanserin leading to partial blockade and 40 mg near complete blockade [140,141]. In a recent dose-response crossover design study of LSD, healthy participants were given LSD doses of 25 μg, 50 μg, 100 μg or 200 μg or 200 μg with ketanserin (40 mg) [142]. Participants were asked to retrospectively identify these conditions – after each session and at the end of the study. Accuracy was generally high, indicating de-masking although notably the +ketanserin condition was most commonly mistaken for 50/25 μg of LSD.
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