A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A potent drug evokes a given response at low concentrations, while a drug of lower potency evokes the same response only at higher concentrations. Higher potency does not mean more side effects; the IUPHAR has stated that'potency' is "an imprecise term that should always be further defined", for instance as EC 50, IC 50, ED50, LD50 and so on. Harris, Robert. "Formulating High Potency Drugs". Contract Pharma. Retrieved 2013-11-13. Walker MG, Page CP, Hoffman BF, Curtis M. Integrated Pharmacology. St. Louis: Mosby. ISBN 978-0-323-04080-8
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, co-sponsored by the American Medical Association, the United States Pharmacopeial Convention, the American Pharmacists Association; the USAN Program states that its goal is to select simple and unique nonproprietary names for drugs by establishing logical nomenclature classifications based on pharmacological or chemical relationships. In addition to drugs, the USAN Council names agents for gene therapy and cell therapy, contact lens polymers, surgical materials, diagnostics and substances used as an excipient; the USAN Council works in conjunction with the World Health Organization International Nonproprietary Name Expert Committee and national nomenclature groups to standardize drug nomenclature and establish rules governing the classification of new substances. The USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee.
The American Pharmacists Association became the third sponsoring organization in 1964, at which point the name of the committee was changed to the USAN Council, United States Adopted Name became the official term to describe any nonproprietary name negotiated and formally adopted by the Council. In 1967, a liaison representative from the Food and Drug Administration was appointed to serve on the USAN Council; the FDA announced in 1984 that it would discontinue adding drug names to its official list and use the USAN as the established name for labeling and advertising new single-entity drugs marketed in the United States. The AMA Council on Drugs no longer exists as a separate entity. FDA now has a representative on the USAN Council, which has moved away from chemically derived names; the USAN Council has five members, one from each sponsoring organization, one from the FDA, a member-at-large. One member is nominated to the USAN Council annually by each sponsoring organization; the member-at-large is selected by the sponsoring organizations from a list of candidates proposed by the AMA, APhA, the USP.
The five nominees to the Council must be approved annually by the board of trustees of the three sponsoring organizations. Judith Jones Thomas P. Reinders David Lewis Peter Rheinstein, Chair Armen Melikian By definition, nonproprietary names are not subject to proprietary trademark rights but are in the public domain; this distinguishes them from the trademarked names. Assignment of a USAN takes into account practical considerations, such as the existence of trademarks, international harmonization of drug nomenclature, the development of new classes of drugs, the fact that the intended uses of substances for which names are being selected may change. USANs assigned today reflect both present nomenclature practices and older methods used to name drug entities. Early drug nomenclature was based on the chemical structure; as newer drugs became chemically more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce, or remember. Additionally, chemically derived names provided little useful information to non-chemist health practitioners.
Considering the needs of health professionals led to a system in which USANs reflect relationships between new entities and older drugs, avoid names that might suggest non-existent relationships. Current nomenclature practices involve the adoption of standardized syllables called "stems" that relate new chemical entities to existing drug families. Stems may be suffixes, or infixes in the nonproprietary name; each stem can emphasize a specific chemical structure type, a pharmacologic property, or a combination of these attributes. The recommended list of USAN stems is updated to keep pace to accommodate drugs with new chemical and pharmacologic properties; as a general rule, the application for a USAN should be forwarded to the USAN Council after the Investigational New Drug is active and clinical trials have begun. Many drug manufacturers seeking a USAN are multinational companies with subsidiaries in various parts of the world or contractual agreements with drug firms outside the United States.
Therefore, it is desirable to the pharmaceutical company, the various nomenclature committees, the medical community in general that a global name be established for each new single-entity compound introduced. Assigning a USAN and standardizing names internationally can take anywhere from several months to a few years. Examples of drugs for which the USAN differs from the INN include: British Approved Name International Nonproprietary Name Nomenclature of monoclonal antibodies United States Pharmacopeia US Adopted Names Program
The serotonin transporter known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron; this transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is the target of many antidepressant medications of the SSRI and tricyclic antidepressant classes, it is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake and may play a role in sudden infant death syndrome, aggressive behavior in Alzheimer disease patients, post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma. Serotonin-reuptake transporters are dependent on both the concentration of potassium ion in the cytoplasm and the concentrations of sodium and chloride ions in the extracellular fluid.
In order to function properly the serotonin transporter requires the membrane potential created by the sodium-potassium adenosine triphosphatase. The serotonin transporter first binds a sodium ion, followed by the serotonin, a chloride ion, thus it is allowed, thanks to the membrane potential, to flip inside the cell freeing all the elements bound. Right after the release of the serotonin in the cytoplasm a potassium ion binds to the transporter, now able to flip back out returning to its active state; the serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons. Thus, it terminates the effects of serotonin and enables its reuse by the presynaptic neuron. Neurons communicate by using chemical messengers like serotonin between cells; the transporter protein, by recycling serotonin, regulates its concentration in a gap, or synapse, thus its effects on a receiving neuron's receptors. Medical studies have shown that changes in serotonin transporter metabolism appear to be associated with many different phenomena, including alcoholism, clinical depression, obsessive-compulsive disorder, romantic love and generalized social phobia.
The serotonin transporter is present in platelets. It serves as a signalling molecule to induce platelet aggregation. SERT spans the plasma membrane 12 times, it belongs to SERT monoamine transporter family. Transporters are important sites for agents. Drugs that reduce the binding of serotonin to transporters are used to treat mental disorders; the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant clomipramine are examples of serotonin reuptake inhibitors. Following the elucidation of structures of the homologous bacterial transporter, LeuT, co-crystallized with tricyclic antidepressants in the vestibule leading from the extracellular space to the central substrate site it was inferred that this binding site did represent the binding site relevant for antidepressant binding in SERT. However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhbitors bind to the central binding site overlapping the substrate binding site; the Drosophila dopamine transporter, which displays a pharmacology similar to SERT, was crystallized with tricyclic antidepressants and confirmed the earlier finding that the substrate binding site is the antidepressant binding site.
The crystal structure of human SERT was resolved DASB compound 4b: Ki = 17 pM. Isosteres 3-cis-indole 8a: Ki = 220 pM allosteric modulator: 3′-Methoxy-8-methyl-spiro The gene that encodes the serotonin transporter is called solute carrier family 6, member 4. In humans the gene is found on chromosome 17 on location 17q11.1–q12. Mutations associated with the gene may result in changes in serotonin transporter function, experiments with mice have identified more than 50 different phenotypic changes as a result of genetic variation; these phenotypic changes may, e.g. be increased gut dysfunction. Some of the human genetic variations associated with the gene are: Length variation in the serotonin-transporter-gene-linked polymorphic region rs25531 — a single nucleotide polymorphism in the 5-HTTLPR rs25532 — another SNP in the 5-HTTLPR STin2 — a variable number of tandem repeats in the functional intron 2 G56A on the second exon I425V on the ninth exon The promotor region of the SLC6A4 gene contains a polymorphism with "short" and "long" repeats in a region: 5-HTT-linked polymorphic region.
The short variation has 14 repeats of a sequence. The short variation leads to less transcription for SLC6A4, it has been found that it can account for anxiety-related personality traits; this polymorphism has been extensively investigated in over 300 scientific studies. The 5-HTTLPR polymorphism may be subdivided further: One study published in 2000 found 14 allelic variants in a group of around 200 Japanese and Caucasian people. In addition to altering the expression of SERT protein and concentrations of extracellular serotonin in the brain, the 5-HTTLPR variation
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th
Metabolism is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; these enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, respond to their environments.. Metabolic reactions may be categorized as catabolic - the breaking down of compounds. Catabolism releases energy, anabolism consumes energy; the chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts - they allow a reaction to proceed more - and they allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.
The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals; the basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions. A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants; these similarities in metabolic pathways are due to their early appearance in evolutionary history, their retention because of their efficacy. Most of the structures that make up animals and microbes are made from three basic classes of molecule: amino acids and lipids; as these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion.
These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life. Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds. Many proteins are enzymes. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape. Proteins are important in cell signaling, immune responses, cell adhesion, active transport across membranes, the cell cycle. Amino acids contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress. Lipids are the most diverse group of biochemicals, their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. Lipids are defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform.
The fats are a large group of compounds that contain fatty glycerol. Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, hydrophilic groups such as phosphate as in phospholipids. Steroids such as cholesterol are another major class of lipids. Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, fill numerous roles, such as the storage and transport of energy and structural components; the basic carbohydrate units are called monosaccharides and include galactose and most glucose. Monosaccharides can be linked together to form polysaccharides in limitless ways; the two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group, attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, its interpretation through the processes of transcription and protein biosynthesis.
This information is propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome. RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made
Angelini is a medium-sized private international group. Founded in Italy in the early twentieth century, the Angelini group has offices in 20 countries. Led by President Francesco Angelini, the industrial group employs 4000 people; the antidepressant medication Trazodone was developed in the 1960s by scientists at Angelini. In a 2018 evaluation of life sciences companies issued by Reputation Institute, Angelini ranked 66th worldwide and second in Italy. Official Website