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
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
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
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
Chloroform, or trichloromethane, is an organic compound with formula CHCl3. It is a colorless, sweet-smelling, dense liquid, produced on a large scale as a precursor to PTFE, it is a precursor to various refrigerants. It is one of a trihalomethane, it is a powerful anesthetic, euphoriant and sedative when inhaled or ingested. The molecule adopts a tetrahedral molecular geometry with C3v symmetry; the total global flux of chloroform through the environment is 660000 tonnes per year, about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, fungi are believed to produce chloroform in soil. Abiotic process is believed to contribute to natural chloroform productions in soils although the mechanism is still unclear. Chloroform volatilizes from soil and surface water and undergoes degradation in air to produce phosgene, formyl chloride, carbon monoxide, carbon dioxide, hydrogen chloride, its half-life in air ranges from 55 to 620 days. Biodegradation in water and soil is slow.
Chloroform does not bioaccumulate in aquatic organisms. Chloroform was synthesized independently by several investigators circa 1831: Moldenhawer, a German pharmacist from Frankfurt an der Oder, appears to have produced chloroform in 1830 by mixing chlorinated lime with ethanol. Samuel Guthrie, an American physician from Sackets Harbor, New York appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, as well as noting its anaesthetic properties. Justus von Liebig carried out the alkaline cleavage of chloral. Eugène Soubeiran obtained the compound by the action of chlorine bleach on both acetone. In 1834, French chemist Jean-Baptiste Dumas named it. In 1835, Dumas prepared the substance by the alkaline cleavage of trichloroacetic acid. Regnault prepared chloroform by chlorination of chloromethane. In 1842, Robert Mortimer Glover in London discovered the anaesthetic qualities of chloroform on laboratory animals. In 1847, Scottish obstetrician James Y. Simpson was the first to demonstrate the anaesthetic properties of chloroform on humans and helped to popularise the drug for use in medicine.
By the 1850s, chloroform was being produced on a commercial basis by using the Liebig procedure, which retained its importance until the 1960s. Today, chloroform — along with dichloromethane — is prepared and on a massive scale by the chlorination of methane and chloromethane. In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane. At 400–500 °C, a free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds: CH4 + Cl2 → CH3Cl + HCl CH3Cl + Cl2 → CH2Cl2 + HCl CH2Cl2 + Cl2 → CHCl3 + HClChloroform undergoes further chlorination to yield carbon tetrachloride: CHCl3 + Cl2 → CCl4 + HClThe output of this process is a mixture of the four chloromethanes, which can be separated by distillation. Chloroform may be produced on a small scale via the haloform reaction between acetone and sodium hypochlorite: 3 NaClO + 2CO → CHCl3 + 2 NaOH + NaOCOCH3 Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom.
CDCl3 is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the haloform reaction, the reaction of acetone with sodium hypochlorite or calcium hypochlorite; the haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can be prepared by the reaction of sodium deuteroxide with chloral hydrate; the haloform reaction can occur inadvertently in domestic settings. Bleaching with hypochlorite generates halogenated compounds in side reactions. Sodium hypochlorite solution mixed with common household liquids such as acetone, methyl ethyl ketone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone. In terms of scale, the most important reaction of chloroform is with hydrogen fluoride to give monochlorodifluoromethane, a precursor in the production of polytetrafluoroethylene: CHCl3 + 2 HF → CHClF2 + 2 HClThe reaction is conducted in the presence of a catalytic amount of mixed antimony halides.
Chlorodifluoromethane is converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane was a popular refrigerant; the hydrogen attached to carbon in chloroform participates in hydrogen bonding. Worldwide, chloroform is used in pesticide formulations, as a solvent for fats, rubber, waxes, gutta-percha, resins, as a cleansing agent, grain fumigant, in fire extinguishers, in the rubber industry. CDCl3 is a common solvent used in NMR spectroscopy; as a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group. It reacts with aqueous sodium hydroxide in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl2; this reagent effects ortho-formylation of activated aromatic rings such as phenols, producing aryl aldehydes in a reaction known as the Reimer–Tiemann reaction. Alternatively, the carbene can be trapped by an alkene to form a cyclopropane derivative. In the Kharasch addition, chloroform forms the CHCl2 free radical in addition to alkenes.
The anaesthetic qualities of chloroform were first described in 1842 in a thesis by Robert Mortimer Glover, which won t
Pharmacology is the branch of biology concerned with the study of drug action, where a drug can be broadly defined as any man-made, natural, or endogenous molecule which exerts a biochemical or physiological effect on the cell, organ, or organism. More it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals; the field encompasses drug composition and properties and drug design and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, toxicology, chemical biology and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacokinetics. Pharmacodynamics studies the effects of a drug on biological systems, Pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, pharmacokinetics discusses the absorption, distribution and excretion of chemicals from the biological systems.
Pharmacology is not synonymous with pharmacy and the two terms are confused. Pharmacology, a biomedical science, deals with the research and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with application of the principles learned from pharmacology in its clinical settings. In either field, the primary contrast between the two are their distinctions between direct-patient care, for pharmacy practice, the science-oriented research field, driven by pharmacology; the origins of clinical pharmacology date back to the Middle Ages in Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, John of St Amand's Commentary on the Antedotary of Nicholas. Clinical pharmacology owes much of its foundation to the work of William Withering. Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period.
Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. The first pharmacology department was set up by Rudolf Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. Early pharmacologists focused on natural substances plant extracts. Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts. Today pharmacologists use genetics, molecular biology and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, create methods for preventative care and personalized medicine; the word "pharmacology" is derived from Greek φάρμακον, pharmakon, "drug, spell" and -λογία, -logia "study of", "knowledge of".
The discipline of pharmacology can be divided into many sub disciplines each with a specific focus. Clinical pharmacology is the basic science of pharmacology with an added focus on the application of pharmacological principles and methods in the medical clinic and towards patient care and outcomes. Neuropharmacology is the study of the effects of medication on central and peripheral nervous system functioning. Psychopharmacology known as behavioral pharmacology, is the study of the effects of medication on the psyche, observing changed behaviors of the body and mind, how molecular events are manifest in a measurable behavioral form. Psychopharmacology is an interdisciplinary field which studies behavioral effects of psychoactive drugs, it incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs. Another goal of behavioral pharmacology is to develop animal behavioral models to screen chemical compounds with therapeutic potentials.
People in this field use small animals to study psychotherapeutic drugs such as antipsychotics and anxiolytics, drugs of abuse such as nicotine and methamphetamine. Ethopharmacology is a term, in use since the 1960s and derives from the Greek word ἦθος ethos meaning character and "pharmacology" the study of drug actions and mechanism. Cardiovascular pharmacology is the study of the effects of drugs on the entire cardiovascular system, including the heart and blood vessels. Pharmacogenetics is clinical testing of genetic variation that gives rise to differing response to drugs. Pharmacogenomics is the application of genomic technologies to drug discovery and further characterization of older drugs. Pharmacoepidemiology is the study of the effects of drugs in large numbers of people. Safety pharmacology specialises in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities on physiological functions in relation to exposure in the therapeutic range and above.
Systems pharmacology is