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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
At their site of action, drugs interact with molecules termed drug ‘receptors’ or ‘targets’. These are often actual biological receptors, such as hormone receptors, but they may also be any other type of molecule, such as an enzyme or membrane channel. The affinity of a drug-receptor interaction is a measure of how tightly the two molecules bind. An agonist is a substance that has an effect on a specific drug receptor, causing activation of the function of the receptor molecule. A partial agonist has the same type of effect on the function of the receptor molecule, but even at the maximal effect of the drug, the function of the receptor molecule is not activated to its maximal level. An antagonist is a drug that binds, to but opposes, the natural activity of the receptor molecule. Competitive antagonists compete with agonists for the same receptor, but they do not exert an agonist effect themselves and so reduce the effect of any agonist present. In these circumstances, the overall effect will depend on the relative concentrations of agonist and antagonist. A non-competitive antagonist does not compete for the same site but opposes the effect of the agonist by another mechanism. Finally, an irreversible antagonist is an antagonist that inactivates the receptor molecule permanently once it has bound. This effect cannot be reversed, even at high concentration of agonist. Many drug receptors are bound by naturally occurring agonists and antagonists, including hormones and neurotransmitters.
The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Agonists of a given neurotransmitter are substances that bind to the receptor of the neurotransmitter and mimic its action. There are many ACh agonists that bind to ACh receptors and depolarize the endplate. Generally, however, they do not have the same kinetics as ACh, do not desensitize the channel in the same manner, and are not similarly affected by AChE. In low doses, they mimic the action of ACh, but in high doses, or with prolonged application, they initially cause muscular contraction followed by desensitization, accommodation, and eventual neuromuscular block. Because of this, they are termed depolarizing blocking agents. Examples of ACh agonists are nicotine, succinylcholine, and decamethonium. Succinlycholine is applied intravenously during surgery as a short-acting muscle relaxant. It has a rapid onset of about 30 s and a duration of action of 5–10 minutes. It is not hydrolyzed by AChE but by other cholinesterases normally found in the blood.
Other Sleep Modulators
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
Benzodiazepines (BZ) are a group of well-established medicaments having strong anxiolytic, anticonvulsant, muscle-relaxant, sedative, and hypnotic properties with low toxicity. Such characteristics of BZs may imply some similarity to endogenous compounds. Actually, in addition to synthetic agonists and antagonists, such as (β-carboline derivatives and the imidazobenzodiazepine Ro 15-1788, a number of endogenous ligands of BZ receptors have been identified from the central nervous system.87 Currently, the following substances have been documented as endogenous ligands existing in the brain: β-carboline-3-carboxylic acid ethyl ester,88 inosine,89,90 hypoxanthine,89,90N-butyl (β-carboline-3-carboxylate,91 nicotinamide,92 and tribulin (monoamine oxidase inhibitor).93 They are classified into agonists, partial agonists, competitive antagonists, partial inverse agonists, and inverse agonists according to their biological activities.94 Specific protein compounds that bind BZs exist in the brain and in the periphery. At the binding sites, BZs can enhance the ability of the γ-aminobutyric acid (GABA) receptor to open the chloride channel. Today, the BZ receptor is regarded to form a GABA-BZ-barbiturate-picrotoxin-receptor complex.
Commercial valved spacers versus home-made spacers for delivering bronchodilator therapy in pediatric acute asthma: a cost-effectiveness analysis
Published in Journal of Asthma, 2021
Carlos E. Rodríguez-Martínez, Monica P. Sossa-Briceño, Ian P. Sinha
Patient characteristics and details of interventions administered in the randomized controlled trials (RCTs) included in a Cochrane systematic review with a meta-analyses aimed at comparing the response to inhaled beta-2 agonists delivered through MDI using home-made spacers with that using commercially-produced spacers in children with acute exacerbations of wheezing or asthma (17) defined our reference population. Specifically, we analyzed patients aged 2 months to 18 years with mild to moderate asthma exacerbations requiring ED management. Children were excluded if they had a history of cardiac, hepatic, skeletal, neuromuscular, or pulmonary diseases other than asthma; if they had already received beta-2 agonists, xanthines, or oral corticosteroids before going to the hospital, if they were unable to use an MDI and spacer, or if they experienced a severe or life-threatening asthma exacerbation. The beta-2 agonists used were albuterol, terbutaline, and fenoterol hydrobromide. The doses of beta-2 agonists administered ranged from 1000 µg to 2400 µg of albuterol and from 400 µg to 600 µg of fenoterol hydrobromide. The dose of terbutaline was not stated.
A mechanistic evaluation of the potential for octamethylcyclotetrasiloxane to produce effects via endocrine modes of action
Published in Critical Reviews in Toxicology, 2021
In order for a chemical to act as a receptor agonist it must be capable of binding in the agonist binding site of its receptor and stimulating (activating) the receptor once bound. Receptor antagonists must be capable of binding to the receptor and interfering with the ability of the receptor to be stimulated by its agonist. Binding between receptors and their agonists or antagonists and the ability of the agonist to stimulate the receptor require that the two molecules “fit” together with very precise interactions. These include high degrees of specificity for size, shape, charge, and chemical properties. Co-activators, co-repressors, agents that interfere with transport or storage of receptor agonists or antagonists, and substances that act to enhance metabolic breakdown of receptor agonists or antagonists, are indirect secondary effects that do not meet the U.S. EPA criteria for evaluation as potential endocrine disruptors.
Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Xuan Huang, Xiaoyong Zhang, Mengji Lu
TLRs are reportedly related to the pathogenesis of several diseases [27]. Their involvement in diseases is mainly manifested by their overexpression and over-activation or inhibition of specific functions caused by abnormal signaling pathways. TLR signals can be activated by specific ligands to enhance immune responses. Hence, agonists may be effective for the treatment of tumors and infectious diseases. Conversely, blocking TLR signaling may reduce hypersensitivity, so TLRs are favorable therapeutic targets for autoimmune diseases and excessive pathologic reactions caused by bacterial infections (e.g. inflammation and sepsis). In general, the development of bioactive molecules that interact with TLRs has broad prospects in future targeted therapy because of their specificity and availability [57]. TLR7/8 agonists and antagonists in clinical testing for therapeutic treatment are summarized in Tables 1 and 2.