G proteins known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate to guanosine diphosphate; when they are bound to GTP, they are'on', when they are bound to GDP, they are'off'. G proteins belong to the larger group of enzymes called GTPases. There are two classes of G proteins; the first function as monomeric small GTPases, while the second function as heterotrimeric G protein complexes. The latter class of complexes is made up of alpha and gamma subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex. Heterotrimeric G proteins located within the cell are activated by G protein-coupled receptors that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell, an intracellular GPCR domain in turn activates a particular G protein.
Some inactive-state GPCRs have been shown to be "pre-coupled" with G proteins. The G protein activates a cascade of further signaling events that results in a change in cell function. G protein-coupled receptor and G proteins working together transmit signals from many hormones, neurotransmitters, other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter proteins, other parts of the cell machinery, controlling transcription, motility and secretion, which in turn regulate diverse systemic functions such as embryonic development and memory, homeostasis. G proteins were discovered when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline, they found that when adrenaline binds to a receptor, the receptor does not stimulate enzymes directly. Instead, the receptor stimulates a G protein, which stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP. For this discovery, they won the 1994 Nobel Prize in Medicine.
Nobel prizes have been awarded for many aspects of signaling by G GPCRs. These include receptor antagonists, neurotransmitters, neurotransmitter reuptake, G protein-coupled receptors, G proteins, second messengers, the enzymes that trigger protein phosphorylation in response to cAMP, consequent metabolic processes such as glycogenolysis. Prominent examples include: The 1947 Nobel Prize in Physiology or Medicine to Carl Cori, Gerty Cori and Bernardo Houssay, for their discovery of how glycogen is broken down to glucose and resynthesized in the body, for use as a store and source of energy. Glycogenolysis is stimulated by numerous neurotransmitters including adrenaline; the 1970 Nobel Prize in Physiology or Medicine to Julius Axelrod, Bernard Katz and Ulf von Euler for their work on the release and reuptake of neurotransmitters. The 1971 Nobel Prize in Physiology or Medicine to Earl Sutherland for discovering the key role of adenylate cyclase, which produces the second messenger cyclic AMP; the 1988 Nobel Prize in Physiology or Medicine to George H. Hitchings, Sir James Black and Gertrude Elion "for their discoveries of important principles for drug treatment" targeting GPCRs.
The 1992 Nobel Prize in Physiology or Medicine to Edwin G. Krebs and Edmond H. Fischer for describing how reversible phosphorylation works as a switch to activate proteins, to regulate various cellular processes including glycogenolysis; the 1994 Nobel Prize in Physiology or Medicine to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells"; the 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson and Paul Greengard, for research on neurotransmitters such as dopamine, which act via GPCRs. The 2004 Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled olfactory receptors; the 2012 Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz for their work on GPCR function. G proteins are important signal transducing molecules in cells. "Malfunction of GPCR signaling pathways are involved in many diseases, such as diabetes, allergies, cardiovascular defects, certain forms of cancer.
It is estimated that about 30% of the modern drugs' cellular targets are GPCRs." The human genome encodes 800 G protein-coupled receptors, which detect photons of light, growth factors and other endogenous ligands. 150 of the GPCRs found in the human genome have still-unknown functions. Whereas G proteins are activated by G protein-coupled receptors, they are inactivated by RGS proteins. Receptors stimulate GTP binding. RGS proteins stimulate GTP hydrolysis. All eukaryotes has evolved a large diversity of G proteins. For instance, humans encode 18 different Gα proteins, 5 Gβ proteins, 12 Gγ proteins. G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins, are activated by G protein-coupled receptors and are made up of alpha and gamma subunits. "Small" G proteins belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha subunit found in heterotrimers, but are in fact monomeric, consisting of only a single unit.
However, like their larger relatives, they al
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Drug metabolism is the metabolic breakdown of drugs by living organisms through specialized enzymatic systems. More xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison; these pathways are a form of biotransformation present in all major groups of organisms, are considered to be of ancient origin. These reactions act to detoxify poisonous compounds; the study of drug metabolism is called pharmacokinetics. The metabolism of pharmaceutical drugs is an important aspect of medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism affects multidrug resistance in infectious diseases and in chemotherapy for cancer, the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions; these pathways are important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment.
The enzymes of xenobiotic metabolism the glutathione S-transferases are important in agriculture, since they may produce resistance to pesticides and herbicides. Drug metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics; these modified compounds are conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. In phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. Drug metabolism converts lipophilic compounds into hydrophilic products that are more excreted; the exact compounds an organism is exposed to will be unpredictable, may differ over time. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal metabolism.
The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems. All organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, the uptake of useful molecules is mediated through transport proteins that select substrates from the extracellular mixture; this selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, organisms, cannot exclude lipid-soluble xenobiotics using membrane barriers. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics; these systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise any non-polar compound.
Useful metabolites are excluded since they are polar, in general contain one or more charged groups. The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and share their polar characteristics. However, since these compounds are few in number, specific enzymes can remove them. Examples of these specific detoxification systems are the glyoxalase system, which removes the reactive aldehyde methylglyoxal, the various antioxidant systems that eliminate reactive oxygen species; the metabolism of xenobiotics is divided into three phases:- modification and excretion. These reactions act in concert to remove them from cells. In phase I, a variety of enzymes act to introduce polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system; these enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates.
The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme: O2 + NADPH + H+ + RH → NADP+ + H2O + ROHPhase I reactions may occur by oxidation, hydrolysis, cyclization and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases in the liver. These oxidative reactions involve a cytochrome P450 monooxygenase, NADPH and oxygen; the classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be excreted at this point. However, many phase I products are not eliminated and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to
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
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
Glutamate receptors are synaptic and non synaptic receptors located on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but in the nervous system and prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, are important for neural communication, memory formation and regulation. Glutamate receptors are implicated in a number of neurological conditions, their central role in excitotoxicity and prevalence in the central nervous system has been linked or speculated to be linked to many neurodegenerative diseases, several other conditions have been further linked to glutamate receptor gene mutations or receptor autoantigen/antibody activity. Glutamate is the most prominent neurotransmitter in the body, is the main excitatory neurotransmitter, being present in over 50% of nervous tissue.
Glutamate was discovered to be a neurotransmitter in insect studies in the early 1960s. Glutamate is used by the brain to synthesize GABA, the main inhibitory neurotransmitter of the mammalian central nervous system. GABA plays a role in regulating neuronal excitability throughout the nervous system and is directly responsible for the regulation of muscle tone in humans. Mammalian glutamate receptors are classified based on their pharmacology. However, glutamate receptors in other organisms have different pharmacology, therefore these classifications do not hold. One of the major functions of glutamate receptors appears to be the modulation of synaptic plasticity, a property of the brain thought to be vital for memory and learning. Both metabotropic and ionotropic glutamate receptors have been shown to have an effect on synaptic plasticity. An increase or decrease in the number of ionotropic glutamate receptors on a postsynaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively.
Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating postsynaptic protein synthesis through second messenger systems. Research shows; these glutamate receptors are suggested to play a role in modulating gene expression in glial cells, both during the proliferation and differentiation of glial precursor cells in brain development and in mature glial cells. Ionotropic glutamate receptors form the ion channel pore that activates when glutamate binds to the receptor. Metabotropic glutamate receptors affect the cell through a signal transduction cascade, they may be activating or inhibitory. Ionotropic receptors tend to be quicker in relaying information, but metabotropic ones are associated with a more prolonged stimulus; the signalling cascade induced by metabotropic receptor activation means that a brief or small synaptic signal can have large and long-lasting effects, i.e. the system can have high "gain." NMDA receptor activation is complex, as channel opening requires not only glutamate binding but glycine or serine binding at a separate site, it displays a degree of voltage dependence due to Zn2+ or Mg2+ binding in the pore.
Furthermore, Ca2+ currents through the NMDA receptor modulate not just the membrane potential but act as an important second messenger system. The particular dynamics of the NMDAR allow it to function as a neural coincidence detector, the NMDAR Ca2+ currents are critical in synaptic plasticity and learning and memory in general. Of the many specific subtypes of glutamate receptors, it is customary to refer to primary subtypes by a chemical that binds to it more selectively than glutamate; the research, however, is chemical affinities measured. Several compounds are used in glutamate receptor research and associated with receptor subtypes: Due to the diversity of glutamate receptors, their subunits are encoded by numerous gene families. Sequence similarities between mammals show a common evolutionary origin for many mGluR and all iGluR genes. Conservation of reading frames and splice sites of GluR genes between chimpanzees and humans is complete, suggesting no gross structural changes after humans diverged from the human-chimpanzee common ancestor.
However, there is a possibility that two human-specific "fixed" amino acid substitutions, D71G in GRIN3A and R727H in GRIN3B, are associated with human brain function. Mammalian ionotropic glutamate receptor subunits and their genes: Mammalian metabotropic glutamate receptors are all named mGluR# and are further broken down into three groups: In other organisms, the classification and subunit composition of glutamate receptors is different. Glutamate receptors exist in the central nervous system; these receptors can be found on the dendrites of postsynaptic cells and bind to glutamate released into the synaptic cleft by presynaptic cells. They are present on both astrocytes and oligodendrocytes. Ionotropic and metabotropic glutamate receptors, with the exception of NMDA, are found on cultured glial cells, which can open in response to glutamate and cause cells to activate second messengers to regulate gene expression and release neuroactive compounds. Furthermore, brain slices show glutamate receptors are ubiquitously expressed in both developing and mature astrocytes and oligodendrocytes in vivo.
Because of this, glial glutamate receptors are t
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may be considered ligands which display both agonistic and antagonistic effects—when both a full agonist and partial agonist are present, the partial agonist acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present; some common drugs that have been classed as partial agonists at particular receptors include buspirone, buprenorphine and norclozapine. Examples of ligands activating peroxisome proliferator-activated receptor gamma as partial agonists are honokiol and falcarindiol.
Delta 9-tetrahydrocannabivarin is a partial agonist at CB2 receptors and this activity might be implicated in ∆9-THCV-mediated anti-inflammatory effects. Competitive antagonist Intrinsic sympathomimetic activity of beta blockers Inverse agonist Mixed agonist/antagonist