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
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of the widening of blood vessels; the process is important in staunching hemorrhage and acute blood loss. When blood vessels constrict, the flow of blood is restricted or decreased, thus retaining body heat or increasing vascular resistance; this makes the skin turn paler because less blood reaches the surface, reducing the radiation of heat. On a larger level, vasoconstriction is one mechanism by which the body regulates and maintains mean arterial pressure. Medications causing vasoconstriction known as vasoconstrictors, are one type of medicine used to raise blood pressure. Generalized vasoconstriction results in an increase in systemic blood pressure, but it may occur in specific tissues, causing a localized reduction in blood flow; the extent of vasoconstriction may be severe depending on the substance or circumstance.
Many vasoconstrictors cause pupil dilation. Medications that cause vasoconstriction include: antihistamines and stimulants. Severe vasoconstriction may result in symptoms of intermittent claudication; the mechanism that leads to vasoconstriction results from the increased concentration of calcium within vascular smooth muscle cells. However, the specific mechanisms for generating an increased intracellular concentration of calcium depends on the vasoconstrictor. Smooth muscle cells are capable of generating action potentials, but this mechanism is utilized for contraction in the vasculature. Hormonal or pharmacokinetic components are more physiologically relevant. Two common stimuli for eliciting smooth muscle contraction are circulating epinephrine and activation of the sympathetic nervous system that directly innervates the muscle; these compounds interact with cell surface adrenergic receptors. Such stimuli result in a signal transduction cascade that leads to increased intracellular calcium from the sarcoplasmic reticulum through IP3-mediated calcium release, as well as enhanced calcium entry across the sarcolemma through calcium channels.
The rise in intracellular calcium complexes with calmodulin, which in turn activates myosin light-chain kinase. This enzyme is responsible for phosphorylating the light chain of myosin to stimulate cross-bridge cycling. Once elevated, the intracellular calcium concentration is returned to its normal concentration through a variety of protein pumps and calcium exchangers located on the plasma membrane and sarcoplasmic reticulum; this reduction in calcium removes the stimulus necessary for contraction, allowing for a return to baseline. Factors that trigger vasoconstriction can be of endogenous origin. Ambient temperature is an example of the former. Cutaneous vasoconstriction will occur because of the body's exposure to the severe cold. Examples of endogenous factors include the autonomic nervous system, circulating hormones, intrinsic mechanisms inherent to the vasculature itself. Examples include stimulants, amphetamines and cocaine. Many are used in medicine to treat hypotension and as topical decongestants.
Vasoconstrictors are used clinically to increase blood pressure or to reduce local blood flow. Vasoconstrictors mixed with local anesthetics are used to increase the duration of local anesthesia by constricting the blood vessels, thereby safely concentrating the anesthetic agent for an extended duration, as well as reducing hemorrhage; the routes of administration vary. They may be both topical. For example, pseudoephedrine is taken orally and phenylephrine is topically applied to the nasal passages or eyes. Examples include: Vasoconstriction is a procedure of the body that averts orthostatic hypotension, it is a part of a body negative feedback loop. For example, vasoconstriction is a hypothermic preventative in which the blood vessels constrict and blood must move at a higher pressure to prevent a hypoxic reaction. ATP is used as a form of energy to increase this pressure to heat the body. Once homeostasis is restored, the blood pressure and ATP production regulates. Vasoconstriction occurs in superficial blood vessels of warm-blooded animals when their ambient environment is cold.
Vasoconstriction can be a contributing factor to erectile dysfunction. An increase in blood flow to the penis causes an erection. Improper vasoconstriction may play a role in secondary hypertension. Addison's disease Inotrope Hypertension Nitric oxide Pheochromocytoma Shock Vasodilation Postural orthostatic tachycardia syndrome Hemostasis Definition of Vasoconstriction on HealthScout Cannabis arteritis revisited--ten new case reports Are coronary heart disease and peripheral arterial disease associated with tobacco or cannabis consumption Vasoconstrictor effects of Cannabis appear to inhibit Migraine attacks
Food and Drug Administration
The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements and over-the-counter pharmaceutical drugs, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, animal foods & feed and veterinary products; as of 2017, 3/4th of the FDA budget is paid by people who consume pharmaceutical products, due to the Prescription Drug User Fee Act. The FDA was empowered by the United States Congress to enforce the Federal Food and Cosmetic Act, which serves as the primary focus for the Agency; these include regulating lasers, cellular phones and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate.
The Commissioner reports to the Secretary of Human Services. Scott Gottlieb, M. D. is the current commissioner, who took over in May 2017. The FDA has its headquarters in Maryland; the agency has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, Costa Rica, Chile and the United Kingdom. In recent years, the agency began undertaking a large-scale effort to consolidate its 25 operations in the Washington metropolitan area, moving from its main headquarters in Rockville and several fragmented office buildings to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring, Maryland; the site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. Only one original building from the naval facility was kept.
All other buildings are new construction. The project is slated to be completed by 2021, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. area as part of the Headquarters divisions, two offices – the Office of Regulatory Affairs and the Office of Criminal Investigations – are field offices with a workforce spread across the country. The Office of Regulatory Affairs is considered the "eyes and ears" of the agency, conducting the vast majority of the FDA's work in the field. Consumer Safety Officers, more called Investigators, are the individuals who inspect production and warehousing facilities, investigate complaints, illnesses, or outbreaks, review documentation in the case of medical devices, biological products, other items where it may be difficult to conduct a physical examination or take a physical sample of the product; the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based on the geographic divisions of the federal court system.
Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are food-related, some laboratories are equipped to analyze drugs and radiation-emitting devices; the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, don't focus on technical aspects of the regulated industries. OCI agents pursue and develop cases where individuals and companies have committed criminal actions, such as fraudulent claims, or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving Title 18 violations, in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents come from other criminal investigations backgrounds, work with the Federal Bureau of Investigation, Assistant Attorney General, Interpol.
OCI receives cases from a variety of sources—including ORA, local agencies, the FBI—and works with ORA Investigators to help develop the technical and science-based aspects of a case. OCI is a smaller branch; the FDA works with other federal agencies, including the Department of Agriculture, Drug Enforcement Administration and Border Protection, Consumer Product Safety Commission. Local and state government agencies work with the FDA to provide regulatory inspections and enforcement action; the FDA regulates more than US$2.4 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of these expenditures are for goods imported into the United States; the FDA's federal budget request for fiscal year 2012 totaled $4.36 billion, while the proposed 2014 budget is $4.7 billion. About $2 billion of this budget is generated by user fees.
Pharmaceutical firms pay th
Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, reduce the likelihood of dementia, heart failure, mortality from cardiovascular disease. There are many classes of antihypertensives. Among the most important and most used drugs are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, beta blockers. Which type of medication to use for hypertension has been the subject of several large studies and resulting national guidelines; the fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack and heart failure. Patient age, associated clinical conditions and end-organ damage play a part in determining dosage and type of medication administered.
The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, cost. The choice of more expensive agents, where cheaper ones would be effective, may have negative impacts on national healthcare budgets; as of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people, an ACE inhibitor is recommended by NICE in the UK for those under 55 years old. Diuretics help the kidneys eliminate excess water from the body's tissues and blood. Loop diuretics: bumetanide ethacrynic acid furosemide torsemide Thiazide diuretics: epitizide hydrochlorothiazide and chlorothiazide bendroflumethiazide methyclothiazide polythiazide Thiazide-like diuretics: indapamide chlorthalidone metalozone Xipamide Clopamide Potassium-sparing diuretics: amiloride triamterene spironolactone eplerenoneIn the United States, the JNC8 recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACE inhibitors, or angiotensin II receptor antagonists.
There are fixed-dose combination drugs, such as ACE thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as as some newer drugs; this is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus promoted by the drug industry. Calcium channel blockers block the entry of calcium into muscle cells in artery walls. Dihydropyridines: amlodipine cilnidipine clevidipine felodipine isradipine lercanidipine levamlodipine nicardipine nifedipine nimodipine nisoldipine nitrendipine non-dihydropyridines: diltiazem verapamilJNC8 recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACE inhibitors, or angiotensin II receptor antagonists for all patients regardless of age or race.
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to -2. ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor. Captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril trandolapril benazeprilA systematic review of 63 trials with over 35,000 participants indicated ACE inhibitors reduced doubling of serum creatinine levels compared to other drugs, the authors suggested this as a first line of defense; the AASK trial showed that ACE inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACE inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status. However, ACE inhibitors should not be a first-line treatment for black hypertensives without chronic kidney disease.
Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE thiazide combinations. Notable side effects of ACE inhibitors include dry cough, fatigue, headaches, loss of taste and a risk for angioedema. Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors. Azilsartan candesartan eprosartan irbesartan losartan olmesartan telmisartan valsartan FimasartanIn 2004, an article in the BMJ examined the evidence for and against the suggestion that angiotensin receptor blockers may increase the risk of myocardial infarction; the matter was debated in 2006 in the medical journal of the American Heart Association.
To date, there is no consensus on whether ARBs have a tendenc
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