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
Imidazole is an organic compound with the formula C3N2H4. It is a white or colourless solid, soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, has non-adjacent nitrogen atoms. Many natural products alkaloids, contain the imidazole ring; these imidazoles feature varied substituents. This ring system is present in important biological building blocks, such as histidine and the related hormone histamine. Many drugs contain an imidazole ring, such as certain antifungal drugs, the nitroimidazole series of antibiotics, the sedative midazolam; when fused to a pyrimidine ring, it forms a purine, the most occurring nitrogen-containing heterocycle in nature. The name "imidazole" was coined in 1887 by the German chemist Arthur Rudolf Hantzsch. Imidazole is a planar 5-membered ring, it exists in two equivalent tautomeric forms, because hydrogen can be bound to one or the other nitrogen atom. Imidazole is a polar compound, as evidenced by its electric dipole moment of 3.67 D.
It is soluble in water. The compound is classified as aromatic due to the presence of a planar ring containing 6 π-electrons; some resonance structures of imidazole are shown below: Imidazole is amphoteric. That is, it can function as both an acid and as a base; as an acid, the pKa of imidazole is 14.5, making it less acidic than carboxylic acids and imides, but more acidic than alcohols. The acidic proton is the one bound to nitrogen. Deprotonation gives the imidazole anion, symmetrical; as a base, the pKa of the conjugate acid is 7, making imidazole sixty times more basic than pyridine. The basic site is the nitrogen with the lone pair. Protonation gives the imidazolium cation, symmetrical. Imidazole was first reported in 1858 by the German-British chemist Heinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s, it was shown that glyoxal and ammonia condense to form imidazole. This synthesis, while producing low yields, is still used for generating C-substituted imidazoles.
In one microwave modification, the reactants are benzil and ammonia in glacial acetic acid, forming 2,4,5-triphenylimidazole. Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can be applied to substituted imidazoles by varying the functional groups on the reactants; these methods are categorized by the number of reacting components. One componentThe or bond can be formed by the reaction of an imidate and an α-aminoaldehyde or α-aminoacetal; the example below applies to imidazole. Two componentThe and bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating catalyst, such as platinum on alumina, is required; the and bonds can be formed from N-substituted α-aminoketones and formamide with heat. The product will be a 1,4-disubstituted imidazole, but here since R1 = R2 = hydrogen, imidazole itself is the product; the yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution.
Three componentThis method proceeds in good yields for substituted imidazoles. An adaptation of the Debus method, it is called the Debus-Radziszewski imidazole synthesis; the starting materials are substituted glyoxal, aldehyde and ammonia or an ammonium salt. Formation from other heterocyclesImidazole can be synthesized by the photolysis of 1-vinyltetrazole; this reaction will give substantial yields only if the 1-vinyltetrazole is made efficiently from an organotin compound, such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole. Imidazole can be formed in a vapor-phase reaction; the reaction occurs with formamide and hydrogen over platinum on alumina, it must take place between 340 and 480 °C. This forms a pure imidazole product. Van Leusen reactionThe Van Leusen reaction can be employed to form imidazoles starting from TosMIC and an aldimine; the Van Leusen Imidazole Synthesis allows the preparation of imidazoles from aldimines by reaction with tosylmethyl isocyanide.
The reaction has been expanded to a two-step synthesis in which the aldimine is generated in situ: the Van Leusen Three-Component Reaction. Imidazole is incorporated into many important biological molecules; the most pervasive is the amino acid histidine. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Imidazole-based histidine compounds play a important role in intracellular buffering. Histidine can be decarboxylated to histamine, a common biological compound. Histamine can cause urticaria; the relationship between histidine and histamine is shown below: One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography. Imidazole is used to elute tagged proteins bound to nickel ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel coordination, freeing the His-tagged proteins.
Imidazole has become an important part of many pharmace
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
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
Pfizer Inc. is an American multinational pharmaceutical corporation headquartered in New York City, with its research headquarters in Groton, Connecticut. It is one of the world's largest pharmaceutical companies, it is listed on the New York Stock Exchange, its shares have been a component of the Dow Jones Industrial Average since 2004. Pfizer ranked No. 57 on the 2018 Fortune 500 list of the largest United States corporations by total revenue. On December 19, 2018, Pfizer announced a joint merger of their consumer healthcare division with UK pharma giant GlaxoSmithKline; the company develops and produces medicines and vaccines for a wide range of medical disciplines, including immunology, cardiology and neurology. Its products include the blockbuster drug Lipitor, used to lower LDL blood cholesterol. In 2016, Pfizer Inc. was expected to merge with Allergan, Plc to create the Ireland-based "Pfizer plc" in a deal that would have been worth $160 billion. The merger was called off in April 2016, because of new rules from the United States Treasury against tax inversions, a method of avoiding taxes by merging with a foreign company.
The company has made the second-largest pharmaceutical settlement with the United States Department of Justice. Pfizer was founded in 1849 by German-American Charles Pfizer and his cousin Charles F. Erhart from Ludwigsburg, Germany, they launched the chemicals business Charles Pfizer and Company from a building at the intersection of Harrison Avenue and Bartlett Street in Williamsburg, where they produced an antiparasitic called santonin. This was an immediate success, although it was the production of citric acid that kick-started Pfizer's growth in the 1880s. Pfizer continued to buy property to expand its lab and factory on the block bounded by Bartlett Street, Harrison Avenue, Gerry Street, Flushing Avenue. Pfizer's original administrative headquarters was at 81 Maiden Lane in Manhattan. By 1906, sales totaled $3.4 million. World War I caused a shortage of calcium citrate which Pfizer imported from Italy for the manufacture of citric acid, the company began a search for an alternative supply.
Pfizer chemists learned of a fungus that ferments sugar to citric acid, they were able to commercialize production of citric acid from this source in 1919, the company developed expertise in fermentation technology as a result. These skills were applied to the mass production of the antibiotic penicillin during World War II in response to the need to treat injured Allied soldiers. Penicillin became inexpensive in the 1940s, Pfizer searched for new antibiotics with greater profit potential, they discovered Terramycin in 1950, this changed the company from a manufacturer of fine chemicals to a research-based pharmaceutical company. Pfizer developed a drug discovery program focusing on in vitro synthesis in order to augment its research in fermentation technology; the company established an animal health division in 1959 with an 700-acre farm and research facility in Terre Haute, Indiana. By the 1950s, Pfizer had established offices in Belgium, Canada, Mexico, Puerto Rico, the United Kingdom. In 1960, the company moved its medical research laboratory operations out of New York City to a new facility in Groton, Connecticut.
In 1980, they launched Feldene, a prescription anti-inflammatory medication that became Pfizer's first product to reach one billion dollars in total sales. During the 1980s and 1990s, Pfizer Corporation growth was sustained by the discovery and marketing of Zoloft, Norvasc, Aricept and Viagra. In this decade, Pfizer grew by mergers, including those with Warner–Lambert and Wyeth. In 2003, the company acquired Esperion Therapeutics for $1.3 billion, protecting Lipitor from ETC-216. In 2004, Pfizer announced. In 2005, the company made a number of acquisitions: Vicuron Pharmaceuticals for $1.9 billion, Idun for just less than $300 million and Angiosyn for $527 million. On June 26, 2006, Pfizer announced it would sell its Consumer Healthcare unit to Johnson & Johnson for $16.6 billion. Development of torcetrapib, a drug that increases production of HDL, or "good cholesterol", which reduces LDL thought to be correlated to heart disease, was cancelled in December 2006. During a Phase III clinical trial involving 15,000 patients, more deaths occurred in the group that took the medicine than expected, a sixty percent increase in mortality was seen among patients taking the combination of torcetrapib and Lipitor versus Lipitor alone.
Lipitor alone was not implicated in the results, but Pfizer lost nearly $1 billion developing the failed drug and the market value of the company plummeted afterwards. The company announced it would acquire Powermed and Rivax. In September 2009, Pfizer pleaded guilty to the illegal marketing of the arthritis drug Bextra for uses unapproved by the U. S. Food and Drug Administration, agreed to a $2.3 billion settlement, the largest health care fraud settlement at that time. A July 2010 article in BusinessWeek reported that Pfizer was seeing more success in its battle against makers of counterfeit prescription drugs by pursuing c
An antifungal medication known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, candidiasis, serious systemic infections such as cryptococcal meningitis, others. Such drugs are obtained by a doctor's prescription, but a few are available OTC. A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a hydroxylated region on the ring opposite the conjugated system; this makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol; this changes the transition temperature of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. As a result, the cell's contents including monovalent ions, small organic molecules leak and this is regarded one of the primary ways cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible.
However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic; as a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals. Amphotericin B Candicidin Filipin – 35 carbons, binds to cholesterol Hamycin Natamycin – 33 carbons, binds well to ergosterol Nystatin Rimocidin Azoles inhibit conversion of lanosterol to ergosterol by inhibition of lanosterol 14-alpha demethylase. Bifonazole Butoconazole Clotrimazole Econazole Fenticonazole Isoconazole Ketoconazole Luliconazole Miconazole Omoconazole Oxiconazole Sertaconazole Sulconazole Tioconazole Albaconazole Efinaconazole Epoxiconazole Fluconazole Isavuconazole Itraconazole Posaconazole Propiconazole Ravuconazole Terconazole Voriconazole Abafungin Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis.
Examples include amorolfin, butenafine and terbinafine. Echinocandins inhibit the creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase: Anidulafungin Caspofungin MicafunginEchinocandins are administered intravenously for the treatment of resistant Candida species. Aurones - have been shown to possess antifungal properties Benzoic acid – has antifungal properties, such as in Whitfield's ointment, Friar's Balsam, Balsam of Peru. Ciclopirox – – is a hydroxypyridone antifungal that interferes with active membrane transport, cell membrane integrity, fungal respiratory processes, it is most useful against tinea versicolour. Flucytosine or 5-fluorocytosine – an antimetabolite pyrimidine analog Griseofulvin – binds to polymerized microtubules and inhibits fungal mitosis Haloprogin – discontinued due to the emergence of more modern antifungals with fewer side effects Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase Undecylenic acid – an unsaturated fatty acid derived from natural castor oil.
Crystal violet – a triarylmethane dye, it has antibacterial and anthelmintic properties and was important as a topical antiseptic. Castellani's paint Orotomide - pyrimidine synthesis inhibitor. Miltefosine disrupts fungal cell membrane dynamics by interacting with ergosterol Potassium iodide is the preferred treatment for lymphocutaneous sporotrichosis and subcutaneous zygomycosis; the mode of action is obscure. Coal tar Copper sulfate Selenium disulfide Sodium thiosulfate Piroctone olamine Iodoquinol, clioquinol Acrisorcin Zinc pyrithione Sulfur Apart from side effects like altered estrogen levels and liver damage, many antifungal medicines can cause allergic reactions in people. For example, the azole group of drugs is known to have caused anaphylaxis. There are many drug interactions. Patients must read in detail the enclosed data sheet of any medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-glycoprotein, which excretes toxins and drugs into the intestines.
Azole antifungals are both substrates and inhibitors of the cytochrome P450 family CYP3A4, causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, tricyclic antidepressants, macrolides and SSRIs. Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be made. Half of suspected cases of fungal infection in nails have a non-fungal cause; the side effects of oral treatment are significant and people without an infection should not take these drugs. Azoles are the group of anti fungals, they inhibit the enzyme 14 - alpha-sterol demethylase, a microsomal CYP, required for biosynthesis of Ergosterol for cytoplasmic membrane. This leads to accumulation of 14-alpha-methylsterols resulting in impairment of function of certain membrane bound enzymes and disruption close packing of acyl chains of phospholipids, thus inhibiting growth of the fungi; some azoles directly increase permeability of fungal cell membrane.
Antifungals portal Antimicrobial Fungicide Antifungal Drugs – Detailed information on antifungals