CONTENTS Drug metabolism Xenobiotic metabolism Enzyme inhibitor Pharmacognosy Pharmacophore

Galenic formulation Pharmacopoeia Pharmaceutical formulation Dosage form Route of administration Injection ( medicine ) Drug injection Catheter Medical inhalants

Drug metabolism
Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs. Drug metabolism can result in toxication or detoxication - the activation or

deactivation of the chemical. While both occur, the major metabolites of most drugs are detoxication products. Drugs are almost all xenobiotics. Other commonly used organic chemicals are also xenobiotics, and are metabolized by the same enzymes as drugs. This provides the opportunity for drug-drug and drug-chemical interactions or reactions. Contents * 1 Phase I vs. Phase II * 2 Sites * 3 Major enzymes and pathways o 3.1 Phase I + 3.1.1 Oxidation + 3.1.2 Reduction + 3.1.3 Hydrolysis o 3.2 Phase II + 3.2.1 Methylation + 3.2.2 Sulphation + 3.2.3 Acetylation + 3.2.4 Glucuronidation * 4 Factors that affect Drug Metabolism * 5 See also * 6 References * 7 External links Phase I vs. Phase II Phase I and Phase II reactions are biotransformations of chemicals that occur during drug metabolism. Phase I reactions usually precede Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. In the case of pharmaceutical drugs, Phase I reactions can lead either to activation or inactivation of the drug. Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization reactions. Oxidation involves the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a

subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate. A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification). A famous example is acetonitrile, CH3CN. Simple hydrolysis in the stomach transforms acetonitrile into acetate and ammonia, which are comparatively innocuous. But Phase I metabolism converts acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic. Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.[1] This example of a biomimetic reaction tends to give a mixture of products that often contains the Phase I metabolites, and Alpha Chimica's approach to preparing prospective drug candidates makes use of this in vitro chemistry. Phase II reactions — usually known as conjugation reactions (e.g., with glucuronic acid, sulfonates (commonly known as sulfation) , glutathione or amino acids) — are usually detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites. Sites on drugs where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH2), and sulfhydryl (-SH) groups. Products of conjugation reactions have increased molecular weight and are usually inactive unlike Phase I reactions which often produce active metabolites. Sites Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized and is said to show the first pass effect. Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions. Major enzymes and pathways Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions:

Phase I Oxidation * Cytochrome P450 monooxygenase system * Flavin-containing monooxygenase system * Alcohol dehydrogenase and aldehyde dehydrogenase * Monoamine oxidase * Co-oxidation by peroxidases Reduction * NADPH-cytochrome P450 reductase * Reduced (ferrous) cytochrome P450 It should be noted that during reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion). Hydrolysis * Esterases and amidases * Epoxide hydrolase Phase II Methylation * methyltransferase Sulphation * Glutathione S-transferases * Sulfotransferases Acetylation * N-acetyltransferases * Amino acid N-acyl transferases Glucuronidation * UDP-glucuronosyltransferases o Mercapturic acid biosynthesis Factors that affect Drug Metabolism

The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system is the most important pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition). Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences. In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background. Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases. In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.This can be used to identify individuals most at risk from adverse reaction. See also

Xenobiotic metabolism
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 drugs and poisons. These pathways are a form of

biotransformation present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds; however, in some cases, the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects. Xenobiotic 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 then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. The reactions in these pathways are of particular interest in medicine as part of drug metabolism and as a factor contributing to multidrug resistance in infectious diseases and cancer chemotherapy. 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 also 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, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides. Contents * 1 Permeability barriers and detoxification * 2 Phases of detoxification o 2.1 Phase I - modification o 2.2 Phase II - conjugation o 2.3 Phase III - further modification and excretion * 3 Endogenous toxins * 4 History * 5 See also * 6 References * 7 Further reading * 8 External links Permeability barriers and detoxification That the exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time, is a major characteristic of xenobiotic toxic stress. 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, and the uptake of useful molecules is mediated through transport proteins that specifically 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, and organisms, therefore, cannot exclude lipidsoluble 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 almost any non-polar compound. Useful metabolites are excluded since they are polar, and 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 usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system, which removes the reactive aldehyde methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species. Phases of detoxification Phases I and II of the metabolism of a lipophilic xenobiotic. The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells. Phase I - modification In phase I, a variety of enzymes acts to introduce reactive and 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:

\mbox{NADPH} + \mbox{H}^+ + \mbox{RH} \rightarrow \mbox{NADP}^+ + \mbox{H}_2\mbox{O} +\mbox{ROH} \, Phase II - conjugation In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. These reactions are catalysed by a large group of broadspecificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important of these groups are the glutathione S-transferases (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported. Phase III - further modification and excretion After phase II reactions, the xenobiotic conjugates may be further metabolised. A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates.[7] Here, the γ-glutamate and glycine residues in the glutathione molecule are removed by Gamma-glutamyl transpeptidase and dipeptidases. In the final step, the cystine residue in the conjugate is acetylated. Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein (MRP) family. These proteins are members of the family of ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted. Endogenous toxins The detoxification of endogenous reactive metabolites such as peroxides and reactive aldehydes often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system, which acts to dispose of the reactive aldehyde methylglyoxal, and the various antioxidant systems that remove reactive oxygen species.

History Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehyde could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation, acetylation, and sulfonation. In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams of the book Detoxication mechanisms in 1947. This modern biochemical research resulted in the identification of glutathione S-transferases in 1961,followed by the discovery of cytochrome P450s in 1962, and the realization of their central role in xenobiotic metabolism in 1963.

Enzyme inhibitor
Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme activators bind to enzymes and increase their enzymatic activity. The binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalysing its reaction. Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind noncovalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both. Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme). A high specificity and potency ensure that a drug will have few side effects and thus low toxicity. Enzyme inhibitors also occur naturally and are involved in the regulation of

metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows flux through a pathway when the products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular enzyme inhibitors are proteins that specifically bind to and inhibit an enzyme target. This can help control enzymes that may be damaging to a cell, such as proteases or nucleases; a wellcharacterised example is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions. Natural enzyme inhibitors can also be poisons and are used as defenses against predators or as ways of killing prey. Contents * 1 Reversible inhibitors o 1.1 Types of reversible inhibitor o 1.2 Quantitative description of reversible inhibition o 1.3 Measuring the dissociation constants of a reversible inhibitor o 1.4 Special cases o 1.5 Examples of reversible inhibitors * 2 Irreversible inhibitors o 2.1 Types of irreversible inhibition o 2.2 Analysis of irreversible inhibition o 2.3 Special cases o 2.4 Examples of irreversible inhibitors * 3 Discovery and design of inhibitors * 4 Uses of inhibitors o 4.1 Chemotherapy o 4.2 Metabolic control o 4.3 Acetylcholinesterase inhibitors o 4.4 Natural poisons * 5 See also * 6 References * 7 External links Reversible inhibitors Types of reversible inhibitor Reversible inhibitors bind to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis. Competitive inhibition: substrate (S) and inhibitor (I) compete for the active site.

There are four kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor. * In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the left. This usually results from the inhibitor having an affinity for the active site of an enzyme where the substrate also binds; the substrate and inhibitor compete for access to the enzyme's active site. This type of inhibition can be overcome by sufficiently high concentrations of substrate, i.e., by out-competing the inhibitor. Competitive inhibitors are often similar in structure to the real substrate (see examples below). * In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme complex, it should not be confused with non-competitive inhibitors. Both maximum velocity (Vmax) and binding efficiency (Km) decrease. * In mixed inhibition, the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, the binding of the inhibitor affects the binding of the substrate, and vice versa. This type of inhibition can be reduced, but not overcome by increasing concentrations of substrate. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation (i.e., tertiary structure or three-dimensional shape) of the enzyme so that the affinity of the substrate for the active site is reduced. * Non-competitive inhibition is a form of mixed inhibition where the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate. As a result, the extent of inhibition depends only on the concentration of the inhibitor. Quantitative description of reversible inhibition Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme–substrate complex, and its effects on the kinetic constants of the enzyme. In the classic Michaelis–Menten scheme below, an enzyme (E) binds to its substrate (S) to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release product P and free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation constants Ki or Ki', respectively. * Competitive inhibitors can bind to E, but not to ES. Competitive inhibition increases Km (i.e., the inhibitor interferes with substrate binding), but does not affect Vmax (the inhibitor does not hamper catalysis in ES because it cannot bind to ES).

* Non-competitive inhibitors have identical affinities for E and ES (Ki = Ki'). Non-competitive inhibition does not change Km (i.e., it does not affect substrate binding) but decreases Vmax (i.e., inhibitor binding hampers catalysis). * Mixed-type inhibitors bind to both E and ES, but their affinities for these two forms of the enzyme are different (Ki ≠ Ki'). Thus, mixed-type inhibitors interfere with substrate binding (increase Km) and hamper catalysis in the ES complex (decrease Vmax). Kinetic scheme for reversible enzyme inhibitors When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered. This results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with substrate A for the first binding site, but be a non-competitive inhibitor with respect to substrate B in the second binding site. Measuring the dissociation constants of a reversible inhibitor Lineweaver–Burk plots of different types of reversible enzyme inhibitors. The arrow shows the effect of increasing concentrations of inhibitor. As noted above, an enzyme inhibitor is characterized by its two dissociation constants, Ki and Ki', to the enzyme and to the enzyme-substrate complex, respectively. The enzyme-inhibitor constant Ki can be measured directly by various methods; one extremely accurate method is isothermal titration calorimetry, in which the inhibitor is titrated into a solution of enzyme and the heat released or absorbed is measured.However, the other dissociation constant Ki' is difficult to measure directly, since the enzyme-substrate complex is shortlived and undergoing a chemical reaction to form the product. Hence, Ki' is usually measured indirectly, by observing the enzyme activity under various substrate and inhibitor concentrations, and fitting the data[5] to a modified Michaelis–Menten equation V = \frac{V_{max}[S]}{\alpha K_{m} + \alpha^{\prime}[S]} = \frac{(1/\alpha^{\prime})V_{max}[S]}{(\alpha/\alpha^{\prime}) K_{m} + [S]} where the modifying factors α and α' are defined by the inhibitor concentration and its two dissociation constants \alpha = 1 + \frac{[I]}{K_{i}} \alpha^{\prime} = 1 + \frac{[I]}{K_{i}^{\prime}}. Thus, in the presence of the inhibitor, the enzyme's effective Km

and Vmax become (α/α')Km and (1/α')Vmax, respectively. However, the modified Michaelis-Menten equation assumes that binding of the inhibitor to the enzyme has reached equilibrium, which may be a very slow process for inhibitors with sub-nanomolar dissociation constants. In these cases, it is usually more practical to treat the tight-binding inhibitor as an irreversible inhibitor (see below); however, it can still be possible to estimate Ki' kinetically if Ki is measured independently. The effects of different types of reversible enzyme inhibitors on enzymatic activity can be visualized using graphical representations of the Michaelis– Menten equation, such as Lineweaver–Burk and Eadie-Hofstee plots. For example, in the Lineweaver–Burk plots at the right, the competitive inhibition lines intersect on the y-axis, illustrating that such inhibitors do not affect Vmax. Similarly, the non-competitive inhibition lines intersect on the x-axis, showing these inhibitors do not affect Km. However, it can be difficult to estimate Ki and Ki' accurately from such plots,[6] so it is advisable to estimate these constants using more reliable nonlinear regression methods, as described above. Special cases The mechanism of partially competitive inhibition is similar to that of noncompetitive, except that the EIS complex has catalytic activity, which may be lower or even higher (partially competitive activation) than that of the enzyme– substrate (ES) complex. This inhibition typically displays a lower Vmax, but an unaffected Km value. * Uncompetitive inhibition occurs when the inhibitor binds only to the enzyme– substrate complex, not to the free enzyme; the EIS complex is catalytically inactive. This mode of inhibition is rare and causes a decrease in both Vmax and the Km value. * Substrate and product inhibition is where either the substrate or product of an enzyme reaction inhibit the enzyme's activity. This inhibition may follow the competitive, uncompetitive or mixed patterns. In substrate inhibition there is a progressive decrease in activity at high substrate concentrations. This may indicate the existence of two substrate-binding sites in the enzyme. At low substrate, the high-affinity site is occupied and normal kinetics are followed. However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the enzyme. Product inhibition is often a regulatory feature in metabolism and can be a form of negative feedback. * Slow-tight inhibition occurs when the initial enzyme–inhibitor complex EI undergoes isomerisation to a second more tightly held complex, EI*, but the overall inhibition process is reversible. This manifests itself as slowly increasing enzyme inhibition. Under these conditions, traditional Michaelis–Menten kinetics give a false value for Ki, which is time–dependent. The true value of Ki can be

obtained through more complex analysis of the on (kon) and off (koff) rate constants for inhibitor association. See irreversible inhibition below for more information. Examples of reversible inhibitors Peptide-based protease inhibitor ritonavir As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in structure to the substrates of their targets. An example of these substrate mimics are the protease inhibitors, a very successful class of antiretroviral drugs used to treat HIV. The structure of ritonavir, a protease inhibitor based on a peptide and containing three peptide bonds, is shown on the right. As this drug resembles the protein that is the substrate of the HIV protease, it competes with this substrate in the enzyme's active site. Enzyme inhibitors are often designed to mimic the transition state or intermediate of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding affinity (lower Ki) than substrate-based designs. An example of such a transition state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the reaction of the viral enzyme neuraminidase. Nonpeptidic protease inhibitor tipranavir However, not all inhibitors are based on the structures of substrates. For example, the structure of another HIV protease inhibitor tipranavir is shown on the left. This molecule is not based on a peptide and has no obvious structural similarity to a protein substrate. These non-peptide inhibitors can be more stable than inhibitors containing peptide bonds, because they will not be substrates for peptidases and are less likely to be degraded. In drug design it is important to consider the concentrations of substrates to which the target enzymes are exposed. For example, some protein kinase inhibitors have chemical structures that are similar to adenosine triphosphate, one of the substrates of these enzymes. However, drugs that are simple competitive inhibitors will have to compete with the high concentrations of ATP in the cell. Protein kinases can also be inhibited by competition at the binding sites where the kinases interact with their substrate proteins, and most proteins are present inside cells at concentrations much lower than the concentration of ATP. As a consequence, if two protein kinase inhibitors both bind in the active site with similar affinity, but only one has to compete with ATP, then the competitive inhibitor at the protein-binding site will inhibit the enzyme more effectively. Irreversible inhibitors

Types of irreversible inhibition Reaction of the irreversible inhibitor diisopropylfluorophosphate (DFP) with a serine protease Irreversible inhibitors usually covalently modify an enzyme, and inhibition cannot therefore be reversed. Irreversible inhibitors often contain reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulphonates, or fluorophosphonates. These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine (as in DFP, right), cysteine, threonine or tyrosine. Irreversible inhibition is different from irreversible enzyme inactivation. Irreversible inhibitors are generally specific for one class of enzyme and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target. For example, extremes of pH or temperature usually cause denaturation of all protein structure, but this is a nonspecific effect. Similarly, some non-specific chemical treatments destroy protein structure: for example, heating in concentrated hydrochloric acid will hydrolyse the peptide bonds holding proteins together, releasing free amino acids Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterized by an IC50 value. This is because the amount of active enzyme at a given concentration of irreversible inhibitor will be different depending on how long the inhibitor is pre-incubated with the enzyme. Instead, kobs/[I] values are used,[15] wherekobs is the observed pseudo-first order rate of inactivation (obtained by plotting the log of % activity vs. time) and [I] is the concentration of inhibitor. The kobs/[I] parameter is valid as long as the inhibitor does not saturate binding with the enzyme (in which case kobs = kinact). [edit] Analysis of irreversible inhibition Kinetic scheme for irreversible inhibitors As shown in the figure to the left, irreversible inhibitors form a reversible noncovalent complex with the enzyme (EI or ESI) and this then reacts to produce the covalently modified "dead-end complex" EI*. The rate at which EI* is formed is called the inactivation rate or kinact. Since formation of EI may compete with ES, binding of irreversible inhibitors can be prevented by competition either with substrate or with a second, reversible inhibitor. This protection effect is good evidence of a specific reaction of the irreversible inhibitor with the active site. The binding and inactivation steps of this reaction are investigated by incubating the enzyme with inhibitor and assaying the amount of activity remaining over time. The activity will be decrease in a time-dependent manner, usually following exponential decay. Fitting these data to a rate equation gives the rate of

inactivation at this concentration of inhibitor. This is done at several different concentrations of inhibitor. If a reversible EI complex is involved the inactivation rate will be saturable and fitting this curve will give kinact and Ki. Another method that is widely used in these analyses is mass spectrometry. Here, accurate measurement of the mass of the unmodified native enzyme and the inactivated enzyme gives the increase in mass caused by reaction with the inhibitor and shows the stoichiometry of the reaction. This is usually done using a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass fingerprinting involves digestion of the native and modified protein with a protease such as trypsin. This will produce a set of peptides that can be analysed using a mass spectrometer. The peptide that changes in mass after reaction with the inhibitor will be the one that contains the site of modification. Special cases Chemical mechanism for irreversible inhibition of ornithine decarboxylase by DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from Not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so tightly to their target enzyme that they are essentially irreversible. These tight-binding inhibitors may show kinetics similar to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly bind to the enzyme in a low-affinity EI complex and this then undergoes a slower rearrangement to a very tightly bound EI* complex (see figure above). This kinetic behaviour is called slow-binding This slow rearrangement after binding often involves a conformational change as the enzyme "clamps down" around the inhibitor molecule. Examples of slow-binding inhibitors include some important drugs, such methotrexate, allopurinol,and the activated form of acyclovir. Examples of irreversible inhibitors Trypanothione reductase with the lower molecule of an inhibitor bound irreversibly and the upper one reversibly. Created from PDB 1GXF. Diisopropylfluorophosphate (DFP) is shown as an example of an irreversible protease inhibitor in the figure above right. The enzyme hydrolyses the phosphorus–fluorine bond, but the phosphate residue remains bound to the serine in the active site, deactivating it. Similarly, DFP also reacts with the active site of acetylcholine esterase in the synapses of neurons, and consequently is a potent neurotoxin, with a lethal dose of less than 100 mg. Suicide inhibition is an unusual type of irreversible inhibition where the enzyme converts the inhibitor into a reactive form in its active site. An example is the inhibitor of polyamine biosynthesis, αdifluoromethylornithine or DFMO, which is an analogue of the amino acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness). Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of

ornithine, as shown above. However, this decarboxylation reaction is followed by the elimination of a fluorine atom, which converts this catalytic intermediate into a conjugated imine, a highly electrophilic species. This reactive form of DFMO then reacts with either a cysteine or lysine residue in the active site to irreversibly inactivate the enzyme. Since irreversible inhibition often involves the initial formation of a non-covalent EI complex, it is sometimes possible for an inhibitor to bind to an enzyme in more than one way. For example, in the figure showing trypanothione reductase from the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor called quinacrine mustard are bound in its active site. The top molecule is bound reversibly, but the lower one is bound covalently as it has reacted with an amino acid residue through its nitrogen mustard group. Discovery and design of inhibitors Robots used for the high-throughput screening of chemical libraries to discover new enzyme inhibitors New drugs are the products of a long drug development process, the first step of which is often the discovery of a new enzyme inhibitor. In the past the only way to discover these new inhibitors was by trial and error: screening huge libraries of compounds against a target enzyme and hoping that some useful leads would emerge. This brute force approach is still successful and has even been extended by combinatorial chemistry approaches that quickly produce large numbers of novel compounds and high-throughput screening technology to rapidly screen these huge chemical libraries for useful inhibitors. More recently, an alternative approach has been applied: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors. These predictions are then tested and one of these tested compounds may be a novel inhibitor. This new inhibitor is then used to try to obtain a structure of the enzyme in an inhibitor/enzyme complex to show how the molecule is binding to the active site, allowing changes to be made to the inhibitor to try to optimise binding. This test and improve cycle is then repeated until a sufficiently potent inhibitor is produced. Computer-based methods of predicting the affinity of an inhibitor for an enzyme are also being developed, such as molecular docking and molecular mechanics. Uses of inhibitors Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry. Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate, or disinfectants such as triclosan.

Chemotherapy The structure of sildenafil (Viagra) The coenzyme folic acid (left) compared to the anti-cancer drug methotrexate (right) The structure of a complex between penicillin G and the Streptomyces transpeptidase. Generated from PDB 1PWC. The most common uses for enzyme inhibitors are as drugs to treat disease. Many of these inhibitors target a human enzyme and aim to correct a pathological condition. However, not all drugs are enzyme inhibitors. Some, such as antiepileptic drugs, alter enzyme activity by causing more or less of the enzyme to be produced. These effects are called enzyme induction and inhibition and are alterations in gene expression, which is unrelated to the type of enzyme inhibition discussed here. Other drugs interact with cellular targets that are not enzymes, such as ion channels or membrane receptors. An example of a medicinal enzyme inhibitor is sildenafil (Viagra), a common treatment for male erectile dysfunction. This compound is a potent inhibitor of cGMP specific phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate.[30] This signalling molecule triggers smooth muscle relaxation and allows blood flow into the corpus cavernosum, which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time. Another example of the structural similarity of some inhibitors to the substrates of the enzymes they target is seen in the figure comparing the drug methotrexate to folic acid. Folic acid is a substrate of dihydrofolate reductase, an enzyme involved in making nucleotides that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts the production of nucleotides. This block of nucleotide biosynthesis is more toxic to rapidly growing cells than non-dividing cells, since a rapidly-growing cell has to carry out DNA replication, therefore methotrexate is often used in cancer chemotherapy. Drugs also are used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and then cross-link the strands of this polymer together. This causes the cell wall to lose strength and the bacteria to burst. In the figure, a molecule of penicillin (shown in a ball-and stick form) is shown bound to its target, the transpeptidase from the bacteria Streptomyces R61 (the protein is shown as a ribbon-diagram). Drug design is facilitated when an enzyme that is essential to the pathogen's

survival is absent or very different in humans. In the example above, humans do not make peptidoglycan, therefore inhibitors of this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids. [edit] Metabolic control Enzyme inhibitors are also important in metabolic control. Many metabolic pathways in the cell are inhibited by metabolites that control enzyme activity through allosteric regulation or substrate inhibition. A good example is the allosteric regulation of the glycolytic pathway. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6bisphosphate and ADP are examples of metabolites that are allosteric activators. Physiological enzyme inhibition can also be produced by specific protein inhibitors. This mechanism occurs in the pancreas, which synthesises many digestive precursor enzymes known as zymogens. Many of these are activated by the trypsin protease, so it is important to inhibit the activity of trypsin in the pancreas to prevent the organ from digesting itself. One way in which the activity of trypsin is controlled is the production of a specific and potent trypsin inhibitor protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the trypsin activity that would otherwise be detrimental to the organ. Although the trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the protease by excluding water from trypsin's active site and destabilising the transition state. Other examples of physiological enzyme inhibitor proteins include the barstar inhibitor of the bacterial ribonuclease barnase and the inhibitors of protein phosphatases. Acetylcholinesterase inhibitors Acetylcholinesterase (AChE) is an enzyme found in animals from insects to humans. It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline. This is somewhat unique among neurotransmitters as most, including serotonin, dopamine, and norepinephrine, are absorbed from the synaptic cleft rather than cleaved. A large number of AChE inhibitors are used in both medicine and agriculture. Reversible competitive inhibitors, such as edrophonium, physostigmine, and neostigmine, are used in the treatment of myasthenia gravis and in anaesthesia. The carbamate pesticides are also examples of reversible

AChE inhibitors. The organophosphate insecticides such as malathion, parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase. To discourage seed predators, pulses contain trypsin inhibitors that interfere with digestion. Natural poisons Animals and plants have evolved to synthesize a vast array of poisonous products including secondary metabolites, peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton. Many natural poisons act as neurotoxins that can cause paralysis leading to death and have functions for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses.[ An example of a neurotoxin are the glycoalkaloids, from the plant species in the Solanaceae family (includes potato, tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death. Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade (Atropa belladonna) that functions as a competitive antagonist of the muscarinic acetylcholine receptors Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin, which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA. The algal toxin microcystin is also a peptide and is an inhibitor of protein phosphatases. This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver hemorrhage and death at higher doses. Proteins can also be natural poisons or antinutrients, such as the trypsin inhibitors (discussed above) that are found in some legumes, as shown in the figure above. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin, an extremely potent protein toxin found in castor oil beans. This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell

Pharmacognosy is the study of medicines derived from natural sources. The American Society of Pharmacognosy[1] defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources." Contents * 1 Introduction o 1.1 Origin * 2 Ethnopharmacology * 3 Issues in phytotherapy o 3.1 Constituents and drug synergyism o 3.2 Herb and drug interactions * 4 Natural products chemistry * 5 Loss of biodiversity * 6 Sustainable sources of plant and animal drugs * 7 External links * 8 References Introduction The word "pharmacognosy" is derived from the Greek words pharmakon (drug), and gnosis or "knowledge". The term pharmacognosy was used for the first time by the Austrian physician Schmidt in 1811. Originally - during the 19th century and the beginning of the 20th century - "pharmacognosy" was used to define the branch of medicine or commodity sciences ("Warenkunde" in German) which dealt with drugs in their crude, or unprepared, form. Crude drugs are the dried, unprepared material of plant, animal or mineral origin, used for medicine. The study of these materials under the name pharmakognosie was first developed in German-speaking areas of Europe, while other language areas often used the older term materia medica taken from the works of Galen and Dioscorides. In German the term drogenkunde ("science of crude drugs") is also used synonymously. Although most pharmacognostic studies focus on plants and medicines derived from plants, other types of organisms are also regarded as pharmacognostically

interesting, in particular, various types of microbes (bacteria, fungi, etc.), and, recently, various marine organisms. Pharmacognosy is interdisciplinary, drawing on a broad spectrum of biological and socio-scientific subjects, including botany, ethnobotany, medical anthropology, marine biology, microbiology, herbal medicine, chemistry,biotechnology, (phytochemistry), pharmacology, pharmaceutics, clinical pharmacy and pharmacy practice. The contemporary study of pharmacognosy can be divided into the fields of * medical ethnobotany: the study of the traditional use of plants for medicinal purposes; * ethnopharmacology: the study of the pharmacological qualities of traditional medicinal substances; * the study of phytotherapy (the medicinal use of plant extracts); and * phytochemistry, the study of chemicals derived from plants (including the identification of new drug candidates derived from plant sources). * Zoopharmacognosy, the process by which animals self-medicate, by selecting and using plants, soils, and insects to treat and prevent disease. * Pharmcognosy-Biotechnology, the synthesis of natural bioactive molecules using biotechnology. * Herbal interactions, the interactions of herbs with other drugs and body. * Marine Pharmacognosy, the study of chemicals derived from marine organisms. Origin The word Pharmacognosy had its debut in the early 19th century to designate the discipline related to medicinal plants, it is derived from the Greek word pharmakon meaning “a drug” and gnosco meaning “ to acquire a knowledge” and as recorded by Dr. K Ganzinger. Pharmacognosy appears again in 1815 in a small work by Crr. Anotheus ssedler entitled Analecta Pharmacognostica. Pharmacognosy is closely related to botany and plant chemistry and indeed, both originated from the earlier scientific studies of medicinal plants. As the late as the beginning of the 20th century, the subject had developed mainly in the botanical side, being concerned with the description and identification of drugs. Both in the whole state and in porodler, and with their history. Commerce, collection, preparation, and storage. Such branches of pharmacognosy are still of fundamental importance, particularly for pharmacopoeial identification and quality control purposes, but rapid development in other areas has enormously expanded the subject.

At the 9th congress of Italian society of pharmacognosy it was stated that current return of phyto-therapy was clearly reflected by the increased market of such products. In 1998 the later for Europe, reached a figure of $6 billion, with consumption for Germany of $2.5 billion, France $1.6 billion and Italy $600 billion. In the US, where the use of herbal products has never been as prevalent as in continental Europe, the market for all herb sales reached a peak in 1998 of $700 billion. This welcomed the scientific investigation of a rigorous nature. The plant kingdom still holds many species of plants containing substances of medicinal value which have yet to be discovered. Large numbers of plants are constantly being screened for their possible pharmacological value. Ethnopharmacology When studying the effectiveness of herbal medicines and other nature-derived remedies, information on the traditional uses of certain extracts or even extract combinations plays a key role. The lack of studies proving the use of herbs in traditional care is especially an issue in the United States, where treatment with herbal medicine has fallen out of use since the Second World War. Herbal medicine has also been considered suspect since the Flexner Report of 1910 led to the closing of the eclectic medical schools where botanical medicine was exclusively practiced. This situation is further complicated by most herbal studies in the latter part of the 20th Century having been published in languages other than English such as German, Dutch, Chinese, Japanese, Korean and Persian. As it may be more difficult to review foreign language publications, much of the relevant information may be unavailable to English speaking scholars. Some of the important botanicals have been incorporated into the U.S. Food and Drug Administration (FDA) determinations of drug safety. In 1994, US Congress passed the Dietary Supplement Health and Education Act (DSHEA), regulating labeling and sales of herbs and other supplements. Most of the 2000 US companies making herbal or natural products[2] choose to market their products as food supplements that do not require substantial testing. [edit] Issues in phytotherapy The part of pharmacognosy focusing on use of crude extracts or semi-pure mixtures originating from nature, namely phytotherapy, is probably the best known and also the most debated area in pharmacognosy. Although phytotherapy is sometimes connected to alternative medicine, when critically conducted, it may be considered the scientific study on the effects and clinical use of herbal medicines. Constituents and drug synergyism One characteristic of crude drug material is that constituents may have an opposite, moderating or enhancing effect. Hence, the final effect of any crude

drug material will be a product of the interactions between the constituents and the effect of each constituent on its own. To effectively study the existence and affect of such interactions, scientific studies must examine the affect that multiple constituents, given concurrently, have on the system. Herbalists assert that as phytopharmaceuticals rely upon synergy for their activities, plants with high levels of active constituents like ginsenosides or hypericin may not correlate with the strength of the herbs. In phytopharmaceutical or herbal medicine, the therapeutic effects of herbs cannot be determined unless its active ingredient or cofactors are identified or the herb is adminsistered as a whole. One way manufacturers have attempted to indicate strength is to engage in standardization to a marker compound. Companies use different markers, or different levels of the same markers, or different methods of testing for marker compounds. Many herbalists believe that the active ingredient in a plant is the plant itself. Herb and drug interactions The Sloan Kettering Memorial Cancer Center stated, in a review of a juice product, which had been marketed as preventing cancer, that antioxidants could theoretically interfere with chemotherapy.[4] A recent review of the effect of antioxidants on chemotherapy, however, found no evidence for any deleterious effects of antioxidants on chemotherapy.[5] A study of herb drug interactions indicated that the vast majority of drug interactions occurred in four classes of drugs, the chief class being blood thinners, but also including protease inhibitors, cardiac glycosides and the immuno-suppressant cyclosporin. The major herbs that have caused interactions include St. Johns Wort, which will counteract immunosuppressive drugs and interfere with digoxin and protease inhibitors. A complete list can be found at: The constituents of garlic, peppermint and milk thistle have been shown to have effects on the CYP3A4 enzymes in vitro, but it is not clear whether these constituents will have the same effect in vivo (humans). Natural products chemistry Most bioactive compounds of natural origin are secondary metabolites, i.e., species-specific chemical agents that can be grouped into various categories[citation needed]. A typical protocol to isolate a pure chemical agent from natural origin is bioassay-guided fractionation, meaning step-by-step separation of extracted components based on differences in their physicochemical properties, and assessing the biological activity, followed by next round of separation and assaying. Typically, such work is initiated after a given crude drug formulation (typically prepared by solvent extraction of the natural material) is deemed "active" in a particular in vitro assay. If the end-goal of the work at hand is to identify which one(s) of the scores or hundreds of

compounds are responsible for the observed in vitro activity, the path to that end is fairly straightforward: 1. fractionate the crude extract, e.g. by solvent partitioning or chromatography. 2. test the fractions thereby generated with in vitro assay. 3. repeat steps 1) and 2) until pure, active compounds are obtained. 4. determine structure(s) of active compound(s), typically by using spectroscopic methods. In vitro activity does not necessarily translate to activity in humans or other living systems. The most common means for fractionation are solventsolvent partitioning and chromatographic techniques such as high-performance liquid chromatography (HPLC), medium-pressure liquid chromatography, "flash" chromatography, open-column chromatography, vacuum-liquid chromatography (VLC), thin-layer chromatography (TLC), with each technique being most appropriate for a given amount of starting material. Countercurrent chromatography (CCC) is particularly well-suited for bioassay-guided fractionation because, as an all-liquid separation technique, concern about irreversible loss or denaturation of active sample components is minimized. After isolation of a pure substance, the task of elucidating its chemical structure can be addressed. For this purpose, the most powerful methodologies available are nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS) [citation needed]. In the case of drug discovery efforts, structure elucidation of all components that are active in vitro is typically the end goal. In the case of phytotherapy research, the investigator may use in vitro BAGF as a tool to identify pharmacologically interesting or important components of the crude drug. The work does not stop after structural identification of in vitro actives, however. The task of "dissecting and reassembling" the crude drug one active component at a time, in order to achieve a mechanistic understanding of how it works in phytotherapy, is quite daunting. This is because it is simply too difficult, from cost, time, regulatory, and even scientific perspectives, to study experimental fractions of the crude drug in humans. In vitro assays are therefore used to identify chemical components of the crude drug that may rationally be expected to have a given pharmacological effect in humans, and to provide a rational basis for standardization of a crude drug formulation to be tested in [and sold/marketed to] humans. Loss of biodiversity Farnsworth for example, has found that 25% of all prescriptions dispensed from community pharmacies in the United States from 1959 to 1980 contained active ingredients extracted from higher plants. In some countries in Asia and Africa 80% of the population relies on traditional medicine (including herbal medicine) for primary health care.Constituents of substances used by traditional healers, have rarely been incorporated into modern medicine. Quinine, physostigmine, dtubocurarine, pilocarpine and ephedrine, have been demonstrated to have active effects Knowledge of traditional medicinal practices is fast disappearing(?), particularly in the Amazon, as native healers die out and are replaced by more modern medical practitioners. Botanists and pharmacologists are racing to learn these ancient practices[citation needed], which, like the forest plants they

employ, are also endangered An explanation for some species loss is habitat lost due to invasive species introduction. Herbalist David Winston has suggested that a high proportion of nonnative species seen as invasive (kudzu, Japanese knotweed, mimosa, lonicera, St. Johnswort and purple loosestrife) may be harvested for the domestic herbal medicine market Species extinction is not only due to habitat loss. Overharvesting of medicinal species of plants and animals also contributes to species loss. This is particularly notable in the matter of Traditional Chinese Medicine where crude drugs of plant and animal origin are used with increasing demand. People with a stake in TCM often seek chemical and biological alternatives to endangered species because they realize that plants and animals lost from the wild are also lost to medicine forever but different cultural attitudes bedevil conservation efforts[citation needed]. Still conservation is not a new idea: Chinese advice against overexploitation of natural medicinal species dates from at least Mencius, a philosopher living in the 4th century BC[citation needed]. Cooperation between western conservationists and practitioners have been beset by cultural difficulties. Westerners may emphasise urgency in matters of conservation, while Chinese may wish for the products used in TCM to remain publicly available. One repeated fallacy[citation needed] is that rhinoceros horn is used as an aphrodisiac in TCM. It is, in fact, prescribed for fevers and convulsions by TCM practitioners. There are no peer-reviewed studies showing that this treatment is effective. In 1995 representatives of the oriental medicine communities in Asia met with conservationists at a symposium in Hong Kong, organized by TRAFFIC. The two groups established a clear willingness to cooperate through dialogue and mutual understanding. This has led to several meetings, including the 1997 First International Symposium on Endangered Species Used in Traditional East Asian Medicine where China was among 136 nations to sign a formal resolution recognizing that the uncontrolled use of wild species in traditional medicine threatens their survival and the continuation of these medical practices. The resolution, drawn up by the UN Convention on International Trade in Endangered Species (CITES), aims to initiate new partnerships in conservation Sustainable sources of plant and animal drugs As species face loss of habitat or overharvesting, there have been new issues to deal with in sourcing crude drugs. These include changes to the herb from farming practices, substitution of species or other plants altogether, adulteration and cross-pollination issues. For instance, ginseng which is field farmed may have significant problems with fungus, making contamination with fungicides an issue. This may be remedied with woods grown programs, but they are insufficient to produce enough ginseng to meet demand. The wildcrafted

echinacea, black cohosh and American ginseng often rely upon old growth root, often in excess of 50 years of age and it is not clear that younger stock will have the same pharmaceutical effect. Black cohosh may be adulterated with the related Chinese actea species, which is not the same. Ginseng may be replaced by ginseniodes from Jiaogulan which has been stated to have a different effect than the full panax root The problem may be exacerbated by the growth of pills and capsules as the preferred method of ingesting medication as they are cheaper and more available than traditional, individually tailored prescriptions of raw medicinals but the contents are harder to track. Seahorses are a case in point: Seahorses once had to be of a certain size and quality before they were accepted by practitioners and consumers. But declining availability of the preferred large, pale and smooth seahorses has been offset by the shift towards prepackaged medicines, which make it possible for TCM merchants to sell previously unused juvenile, spiny and dark-coloured animals. Today almost a third of the seahorses sold in China are prepackaged. The farming of plant or animal species, used for medicinal purposes has caused difficulties. Rob Parry Jones and Amanda Vincent write: * One solution is to farm medicinal animals and plants. Chinese officials have promoted this as a way of guaranteeing supplies as well as protecting endangered species. And there have been some successes—notably with plant species, such as American ginseng—which is used as a general tonic and for chronic coughs. Red deer, too, have for centuries been farmed for their antlers, which are used to treat impotence and general fatigue. But growing your own is not a universal panacea. Some plants grow so slowly that cultivation in not economically viable. Animals such as musk deer may be difficult to farm, and so generate little profit. Seahorses are difficult to feed and plagued by disease in captivity. Other species cannot be cultivated at all. Even when it works, farming usually fails to match the scale of demand. Overall, cultivated TCM plants in China supply less than 20 per cent of the required 1.6 million tonnes per annum. Similarly, China's demand for animal products such as musk and pangolin scales far exceeds supply from captive-bred sources. * Farming alone can never resolve conservation concerns, as government authorities and those who use Chinese medicine realise. For a start, consumers often prefer ingredients taken from the wild, believing them to be more potent. This is reflected in the price, with wild oriental ginseng fetching up to 32 times as much as cultivated plants. Then there are welfare concerns. Bear farming in China is particularly controversial. Around 7600 captive bears have their bile "milked" through tubes inserted into their gall bladders. The World Society for the Protection of Animals states that bear farming is surrounded by "appalling levels of cruelty and neglect" . Chinese officials state that 10 000 wild bears would need to be killed each year to produce as much bile, making bear farming the more

desirable option. The World society for the Protection of Animals, however, states that "it is commonly believed in China that the bile from a wild bear is the most potent, and so farming bears for their bile cannot replace the demand for the product extracted from wild animals". * One alternative to farming involves replacing medical ingredients from threatened species with manufactured chemical compounds. In general, this sort of substitution is difficult to achieve because the active ingredient is often not known. In addition, most TCM users believe that TCM compounds may act synergistically so several ingredients may interact to give the required effect. Thus TCM users often people prefer the wild source. Tauro ursodeoxycholic acid, the active ingredient of bear bile, can be synthesised and is used by some Western doctors to treat gallstones, but many TCM consumers reject it as being inferior to the natural substance from wild animals.

A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries (phoros) the essential features responsible for a drug’s (=pharmacon's) biological activity" (Ehrlich. Dtsch. Chem. Ges. 1909, 42: p.17). In 1977, this definition was updated by Peter Gund to "a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity" (Gund. Prog. Mol. Subcell. Biol. 1977, 5: pp 117– 143). The IUPAC definition of a pharmacophore is "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response". In modern computational chemistry, pharmacophores are used to define the essential features of one or more molecules with the same biological activity. A database of diverse chemical compounds can then be searched for more molecules which share the same features located a similar distance apart from each other. Typical pharmacophore features are for where a molecule is hydrophobic, aromatic, a hydrogen bond acceptor, a hydrogen bond donor, a cation, or an anion. The features need to match different chemical groups with similar properties, in order to identify novel ligands. Ligands receptor interactions are typically “polar positive”, “polar negative” or “hydrophobic”. A well-defined pharmacophore model includes both hydrophobic volumes and hydrogen bond vectors.

Galenic formulation
Galenic formulation deals with the principles of preparing and compounding medicines in order to optimize their absorption. Galenic formulation is named after Claudius Galen, a 3rd Century AD Greek physician, who codified the preparation of drugs using multiple ingredients. Today, galenic formulation is part of pharmaceutical formulation. The pharmaceutical formulation of a medicine has an impact on the pharmacokinetics, pharmacodynamics and safety profile of a drug.

Pharmacopoeia (literally, the art of the drug compounder), in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society In a broader sense is a reference work for pharmaceutical drug specifications. The name has also been applied to similar compendia issued by private individuals. Contents * 1 History o 1.1 National Pharmacopoeia o 1.2 International Pharmacopoeia * 2 Preparations * 3 See also * 4 References * 5 External links History Pliny’s pharmacopoeia is considered to be the cradle of pharmacotherapy.[1] Pedanius Dioscorides is famous for writing a five volume book in his native Greek Περί ύλης ιατρικής (De Materia Medica - in the Latin translation) that is a precursor to all modern pharmacopoeias, and is one of the most influential herbal books in history. In fact it remained in use until about CE 1600.

Some of the earliest pharmacopoeia books were written by Persian physicians.[3] These included The Canon of Medicine of Avicenna in 1025, and other pharmacopoeia books by Abu-Rayhan Biruni in the 11th century,[4] Ibn Zuhr (Avenzoar) in the 12th century (and printed in 1491),[5] and Ibn Baytar in the 14th century The first work of the kind published under government authority appears to have been that of Nuremberg in 1542; a passing student named Valerius Cordus showed a collection of medical receipts, which he had selected from the writings of the most eminent medical authorities, to the physicians of the town, who urged him to print it for the benefit of the apothecaries, and obtained for his work the sanction of the senatus. An earlier work, known as the Antidotarium Florentinum, had been published under the authority of the college of medicine of Florence. The term pharmacopoeia first appears as a distinct title in a work published at Basel in 1561 by Dr A. Foes, but does not appear to have come into general use until the beginning of the 17th century. Before 1542 the works principally used by apothecaries were the treatises on simples by Avicenna and Serapion; the De synonymis and Quid pro quo of Simon Januensis; the Liber servitoris of Bulchasim Ben Aberazerim, which described the preparations made from plants, animals and minerals, and was the type of the chemical portion of modern pharmacopoeias; and the Antidotarium of Nicolaus de Salerno, containing Galenical compounds arranged alphabetically. Of this, last work there were two editions in use — Nicolaus magnus and Nicolaus parvus: in the later several of the compounds described in the large edition were omitted and the formulae given on a smaller scale. Until 1617 such drugs and medicines as were in common use were sold in England by the apothecaries and grocers. In that year the apothecaries obtained a separate charter, and it was enacted that no grocer should keep an apothecary’s shop. The preparation of physicians’ prescriptions was thus confined to the apothecaries, upon whom pressure was brought to bear to make them dispense accurately, by the issue of a pharmacopoeia in May 1618 by the College of Physicians, and by the power which the wardens of the apothecaries received in common with the censors of the College of Physicians of examining the shops of apothecaries within 7 m. of London and destroying all the compounds which they found unfaithfully prepared. This, the first authorized London Pharmacopoeia, was selected chiefly from the works of Mezue and Nicolaus de Salerno, but it was found to be so full of errors that the whole edition was cancelled, and a fresh edition was published in the following December. At this period the compounds employed in medicine were often heterogeneous mixtures, some of which contained from 20 to 70, or more, ingredients, while a large number of simples were used in consequence of the same substance being

supposed to possess different qualities according to the source from which it was derived. Thus crabs’ eyes (i.e., gastroliths), pearls, oyster-shells and coral were supposed to have different properties. Among other ingredients entering into some of these formulae were the excrements of human beings, dogs, mice, geese and other animals, calculi, human skull and moss growing on it, blind puppies, earthworms, etc. Although other editions of the London Pharmacopoeia were issued in 1621, 1632, 1639 and 1677, it was not until the edition of 1721, published under the auspices of Sir Hans Sloane, that any important alterations were made. In this issue many of the ridiculous remedies previously in use were omitted, although a good number were still retained, such as dogs’ excrement, earthworms, and moss from the human skull; the botanical names of herbal remedies were for the first time added to the official ones; the simple distilled waters were ordered of a uniform strength; sweetened spirits, cordials and ratifias were omitted as well as several compounds no longer used in London, although still in vogue elsewhere. A great improvement was effected in the edition published in 1746, in which only those preparations were retained which had received the approval of the majority of the pharmacopoeia committee; to these was added a list of those drugs only which were supposed to be the most efficacious. An attempt was made to simplify further the older formulae by the rejection of superfluous ingredients. In the edition published in 1788 the tendency to simplify was carried out to a much greater extent, and the extremely compound medicines which had formed the principal remedies of physicians for 2000 years were discarded, while a few powerful drugs which had been considered too dangerous to be included in the Pharmacopoeia of 1765 were restored to their previous position. In 1809 the French chemical nomenclature was adopted, and in 1815 a corrected impression of the same was issued. Subsequent editions were published in 1824, 1836 and 1851. The first Edinburgh Pharmacopoeia was published in 1699 and the last in 1841; the first Dublin Pharmacopoeia in 1807 and the last in 1850. National Pharmacopoeia The preparations contained in these three pharmacopoeias were not all uniform in strength, a source of much inconvenience and danger to the public, when powerful preparations such as dilute hydrocyanic acid were ordered in the one country and dispensed according to the national pharmacopoeia in another. As a result, the Medical Act of 1858 ordained that the General Medical Council should publish a book containing a list of medicines and compounds, to be called the British Pharmacopoeia, which would be a substitute throughout Great Britain and Ireland for the separate pharmacopoeias. Hitherto these had been published in Latin. The first British Pharmacopoeia was published in the English language in 1864, but gave such general dissatisfaction both to the medical profession and to chemists and druggists that the General Medical Council brought out a new and amended edition in 1867. This dissatisfaction was probably owing partly to the fact that the majority of the compilers of the work were not engaged in the

practice of pharmacy, and therefore competent rather to decide upon the kind of preparations required than upon the method of their manufacture. The necessity for this element in the construction of a pharmacopoeia is now fully recognized in other countries, in most of which pharmaceutical chemists are represented on the committee for the preparation of the legally recognized manuals. There are national and international pharmacopoeias, like the EU and the US pharmacopoeias. All the pharmacopoeias were issued under the authority of government, and their instructions have the force of law in their respective territories, except that of the United States, which was prepared by commissioners appointed by medical and pharmaceutical societies, and has no other authority, although generally accepted as the national textbook. International Pharmacopoeia Increased facilities for travel have brought into greater prominence the importance of an approach to uniformity in the formulae of the more powerful remedies, in order to avoid danger to patients when a prescription is dispensed in a different country from that in which it was written. Attempts have been made by international pharmaceutical and medical conferences to settle a basis on which an international pharmacopoeia could be prepared, but due to national jealousies and the attempt to include too many preparations nothing has yet been achieved. Nonetheless, some progress has been made under the banner of the ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human, a tri-regional organisation that represents the drug regulatory authorities of the European Union, Japan and the United States. Representatives from the Pharmacopoeias of these three regions have met twice yearly since 1990 in the Pharmacopoeial Discussion Group to try to work towards "compendial harmonisation"’. Specific monographs are proposed, and if accepted, proceed through stages of review and consultation leading to adoption of a common monograph that provides a common set of tests and specifications for a specific material. Not surprisingly, this is a slow process. Preparations The rapid increase in medical and pharmaceutical knowledge renders necessary frequent new editions of the national pharmacopoeias, the office of which is to furnish definite formulae for preparations that have already come into extensive use in medical practice, so as to ensure uniformity of strength, and to give the characters and tests by which their purity and potency may be determined. But each new edition requires several years to carry out numerous experiments for devising suitable formulae, so that the current Pharmacopoeia can never be quite up to date. This difficulty has hitherto been met by the publication of such nonofficial formularies as Squire's Companion to the Pharmacopoeia and

Martindale: The complete drug reference (formerly Martindale's : The Extra Pharmacopoeia), in which all new remedies and their preparations, uses and doses are recorded, and in the former the varying strengths of the same preparations in the different pharmacopoeias are also compared (Squire's was incorporated into Martindal in 1952). The need of such works to supplement the Pharmacopoeia is shown by the fact that they are even more largely used than the Pharmacopoeia itself, the first issued in 18 editions and the second in 13 editions at comparatively short intervals. In the UK, the task of elaborating a new Pharmacopoeia is entrusted to a body of a purely medical character, and legally the pharmacist has not, contrary to the practice in other countries, a voice in the matter, notwithstanding the fact that, although the medical practitioner is naturally the best judge of the drug or preparations that will afford the best therapeutic result, he is not so competent as the pharmacist to say how that preparation can be produced in the most effective and satisfactory manner, nor how the purity of drugs can be tested. The change occurred with the fourth edition of the British Pharmacopoeia in 1898. A committee of the Royal Pharmaceutical Society of Great Britain was appointed at the request of the General Medical Council to advise on pharmaceutical matters. A census of prescriptions was taken to ascertain the relative frequency with which different preparations and drugs were used in prescriptions, and suggestions and criticisms were sought from various medical and pharmaceutical bodies across the British Empire. As regards the purely pharmaceutical part of the work a committee of reference in pharmacy, nominated by the pharmaceutical societies of Great Britain and Ireland (as they were then), was appointed to report to the Pharmacopoeia Committee of the Medical Council. Some difficulty has arisen since the passing of the Adulteration of Food and Drugs Act[citation needed] concerning the use of the Pharmacopoeia as a legal standard for the drugs and preparations contained in it. The Pharmacopoeia is defined in the preface as only "intended to afford to the members of the medical profession and those engaged in the preparation of medicines throughout the British Empire one uniform standard and guide whereby the nature and composition of, substances to be used in medicine may be ascertained and determined." It is obvious that it cannot be an encyclopaedia of substances used in medicine, and can only be used as a standard for the substances and preparations contained in it, and for no others. It has been held in the Divisional Courts (Dickins v. Randerson) that the Pharmacopoeia is a standard for official preparations asked for under their pharmacopoeial name. But there are many substances in the Pharmacopoeia which are not only employed in medicine, but have other uses, such as sulphur, gum benzoin, tragacanth, gum arabic, ammonium carbonate, beeswax, oil of turpentine, linseed oil, and for these a commercial standard of purity as distinct from a medicinal one is needed, since the preparations used in medicine should be of the highest possible degree of purity obtainable, and this standard would be too high and too expensive for

ordinary purposes. The use of trade synonyms in the Pharmacopoeia, such as saltpetre for purified potassium nitrate, and milk of sulphur for precipitated sulphur, is partly answerable for this difficulty, and has proved to be a mistake, since it affords ground for legal prosecution if a chemist sells a drug of ordinary commercial purity for trade purposes, instead of the purified preparation which is official in the Pharmacopoeia for medicinal use. This would not be the case if the trade synonym were omitted. For many drugs and chemicals not in the Pharmacopoeia there is no standard of purity that can be used under the Adulteration of Food and Drugs Act, and for these, as well as for the commercial quality of those drugs and essential oils which are also in the Pharmacopoeia, a legal standard of commercial purity is much needed. This subject formed the basis of discussion at several meetings of the Pharmaceutical Society, and the results have been embodied in a work entitled Suggested Standards for Foods and Drugs, by C. G. Moor, which indicates the average degree of purity of many drugs and chemicals used in the arts, as well as the highest degree of purity obtainable in commerce of those used in medicine. An important step has also been taken in this direction by the publication under the authority of the Council of the Pharmaceutical Society of Great Britain of the British Pharmaceutical Codex, in which the characters of and tests for the purity of many nonofficial drugs and preparations are given as well as the character of many glandular preparations and antitoxins that have come into use in medicine, but have not yet been introduced into the Pharmacopoeia. This work may also possibly serve as a standard under the Adulteration of Food and Drugs Act for the purity and strength of drugs not included in the Pharmacopoeia and as a standard for the commercial grade of purity of those in the Pharmacopoeia which are used for non-medical purposes. Another legal difficulty connected with modern pharmacopoeias is the inclusion in some of them of synthetic chemical remedies, the processes for preparing which have been patented, whilst the substances are sold under trade-mark names such as verona. The scientific chemical name is often long and unwieldy, and the physician prefers when writing a prescription to use the shorter name under which it is sold by the patentees. In this case the pharmacist is compelled to use the more expensive patented article and the patient complains of the price. If he uses the same article under its pharmacopoeial name when the patented article is prescribed s/he lays oneself open to prosecution by the patentee for infringement of patent rights. The only plan, therefore, is for the physician to use the chemical name (which cannot be patented) as given in the Pharmacopoeia, or for those synthetic remedies not included in the Pharmacopoeia, to use the scientific and chemical name given in the British Pharmaceutical Codex.

Pharmaceutical formulation
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. Contents * 1 Stages and timeline * 2 Oral formulations o 2.1 Tablet form o 2.2 Capsule form * 3 Topical medication forms * 4 See also * 5 References * 6 External links Stages and timeline Formulation studies involve developing a preparation of the drug which is both stable and acceptable to the patient. For orally taken drugs, this usually involves incorporating the drug into a tablet or a capsule. It is important to appreciate that a tablet contains a variety of other substances apart from the drug itself, and studies have to be carried out to ensure that the drug is compatible with these other substances. Preformulation involves the characterization of a drug's physical, chemical, and mechanical properties in order to choose what other ingredients should be used in the preparation. In dealing with protein pre-formulation, the important aspect is to understand the solution behavior of a given protein under a variety of stress conditions such as freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation and therefore its mitigation. Formulation studies then consider such factors as particle size, polymorphism, pH, and solubility, as all of these can influence bioavailability and hence the activity of a drug. The drug must be combined with inactive additives by a method which ensures that the quantity of drug present is consistent in each dosage unit e.g. each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, or capsule disintegration.

It is unlikely that formulation studies will be complete by the time clinical trials commence. This means that simple preparations are developed initially for use in phase I clinical trials. These typically consist of hand-filled capsules containing a small amount of the drug and a diluent. Proof the long-term stability of these formulations is not required, as they will be used (tested) in a matter of days. Consideration has to be given to what is called the drug load - the ratio of the active drug to the total contents of the dose. A low drug load may cause homogeneity problems. A high drug load may pose flow problems or require large capsules if the compound has a low bulk density. By the time phase III clinical trials are reached, the formulation of the drug should have been developed to be close to the preparation that will ultimately be used in the market. A knowledge of stability is essential by this stage, and conditions must have been developed to ensure that the drug is stable in the preparation. If the drug proves unstable, it will invalidate the results from clinical trials since it would be impossible to know what the administered dose actually was. Stability studies are carried out to test whether temperature, humidity, oxidation, or photolysis (ultraviolet light or visible light) have any effect, and the preparation is analysed to see if any degradation products have been formed. It is also important to check whether there are any unwanted interactions between the preparation and the container. If a plastic container is used, tests are carried out to see whether any of the ingredients become adsorbed on to the plastic, and whether any plasticizers, lubricants, pigments, or stabilizers leach out of the plastic into the preparation. Even the adhesives for the container label need to be tested, to ensure they do not leach through the plastic container into the preparation. Oral formulations The way a drug is formulated can avoid some of the problems associated with oral administration. Drugs are normally taken orally as tablets or capsules. The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size and crystal form can significantly affect dissolution. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma levels. Treatment of active ingredient by special way as spherical crystallization can have some advantages for drug formulation. Tablet form A tablet is usually a compressed preparation that contains:

* 5-10% of the drug (active substance); * 80% of fillers, disintegrants, lubricants, glidants, and binders; and * 10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine. The disintegration time can be modified for a rapid effect or for sustained release. Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum as a result of enzyme action or alkaline pH. Pills can be coated with sugar, varnish, or wax to diguise the taste. Some tablets are designed with an osmotically active core, surrounded by an impermeable membrane with a pore in it. This allows the drug to percolate out from the tablet at a constant rate as the tablet moves through the digestive tract. Capsule form A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestion in order to delay absorption. They may also contain a mixture of slow- and fast-release particles to produce rapid and sustained absorption in the same dose. Topical medication forms

* Cream - Emulsion of oil and water in approximately equal proportions. Penetrates stratum corneum outer layer of skin well. * Ointment - Combines oil (80%) and water (20%). Effective barrier against moisture loss. * Gel - Liquefies upon contact with the skin. * Paste - Combines three agents - oil, water, and powder; an ointment in which a powder is suspended. * Powder

Dosage form
A dosage form (DF) is the physical form of a dose of a chemical compound used

as a drug or medication intended for administration or consumption. Common dosage forms include pill, tablet, or capsule, drink or syrup, aerosol or inhaler, liquid injection, pure powder or solid crystal (e.g., via oral ingestion or freebase smoking), and natural or herbal form such as plant or or food of sorts, among many others. Notably, the route of administration (ROA) for drug delivery is dependent on the dosage form of the substance in question. Various dosage forms may exist for a single particular drug, since different medical conditions can warrant different routes of administration. For example, persistent nausea and emesis or vomiting may make it difficult to use an oral dosage form, and in such a case, it may be necessary to utilize an alternate route such as inhalational, buccal, sublingual, nasal, suppository, or parenteral instead. Additionally, a specific dosage form may be a requirement for certain kinds of drugs, as there may be issues with various factors like chemical stability or pharmacokinetics. As an example, insulin cannot be given orally because upon being administered in this manner, it is extensively metabolized in the gastrointestinal tract (GIT) before reaching the blood stream, and is thereby incapable of sufficiently reaching its therapeutic target destinations. Contents * 1 Types o 1.1 Oral o 1.2 Inhalational o 1.3 Parenteral Injection o 1.4 Topical o 1.5 Suppository * 2 See Also * 3 References * 4 External Links Types Oral * Pill, tablet, or capsule * Specialty tablet like buccal, sublingual, or orally-disintegrating * Thin film (e.g., Listerine PocketPaks) * Liquid solution or suspension (e.g., drink or syrup) * Powder or liquid or solid crystals * Natural or herbal plant, seed, or food of sorts (e.g., marijuana such as that found in "special brownies") Inhalational * Aerosol

* Inhaler * Nebulizer * Smoking (often in natural herb or freebase powder form (e.g., tobacco or marijuana and cocaine or methamphetamine, respectively)) * Vaporizer (usually to vaporize natural herbs like marijuana) Parenteral Injection * Intradermal (ID) * Intramuscular (IM) * Intraosseous (IR) * Intraperitoneal (IP) * Intravenous (IV) * Subcutaneous (SC) Topical * Cream, gel, liniment or balm, lotion, or ointment, etc * Ear drops (optic) * Eye drops (ophthalmic) * Skin patch (transdermal) Suppository * Rectal (e.g., enema) * Vaginal (e.g., douche, pessary, etc)

Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is brought into contact with the body. A substance must be transported from the site of entry to the part of the body where its action is desired to take place (even if this only means penetration through the stratum corneum into the skin). Using the body's transport mechanisms for this purpose, however, is not trivial. The pharmacokinetic properties of a drug (that is, those related to processes of uptake, distribution, and elimination) are critically influenced by the route of administration. Contents

* 1 Classification o 1.1 Topical o 1.2 Enteral o 1.3 Parenteral by injection or infusion o 1.4 Other parenteral o 1.5 Other * 2 Advantages and disadvantages o 2.1 Inhalation o 2.2 Injection * 3 Uses * 4 Notes * 5 See also * 6 References * 7 External links Classification Routes of administration can broadly be divided into: * topical: local effect, substance is applied directly where its action is desired. * enteral: desired effect is systemic (non-local), substance is given via the digestive tract. * parenteral: desired effect is systemic, substance is given by routes other than the digestive tract. The U.S. Food and Drug Administration recognizes 111 distinct routes of administration. The following is a brief list of some routes of administration. Topical * epicutaneous (application onto the skin), e.g. allergy testing, typical local anesthesia * inhalational, e.g. asthma medications * enema, e.g. contrast media for imaging of the bowel * eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis * ear drops - such as antibiotics and corticosteroids for otitis externa * intranasal route (into the nose), e.g. decongestant nasal sprays. Nasal administration can also be used for systemic effect. This is related to the transmucosal route through a mucous membrane via insufflation. * vaginal, e.g. topical estrogens, antibacterials Enteral Enteral is any form of administration that involves any part of the gastrointestinal tract:

* by mouth (orally), many drugs as tablets, capsules, or drops * by gastric feeding tube, duodenal feeding tube, or gastrostomy, many drugs and enteral nutrition * rectally, various drugs in suppository or enema form Parenteral by injection or infusion * intravenous (into a vein), e.g. many drugs, total parenteral nutrition * intraarterial (into an artery), e.g. vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism * intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term psychoactive agents. Recreationally the colloquial term 'muscling' is used. * intracerebral (into the cerebrum) direct injection into the brain. Used in experimental research of chemicals[3] and as a treatment for malignancies of the brain.[4] The intracerebral route can also interrupt the blood brain barrier from holding up against subsequent routes. * intracerebroventricular (into the cerebral ventricles) 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.[6] * intracardiac (into the heart), e.g. adrenaline during cardiopulmonary resuscitation (no longer commonly performed) * subcutaneous (under the skin), e.g. insulin, a slang term for this method of administration is skin popping (usually done with recreational drugs) * intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system. This route is occasionally used for drugs and fluids in emergency medicine and paediatrics when intravenous access is difficult. * intradermal, (into the skin itself) is used for skin testing some allergens, and also for mantoux test for Tuberculosis * intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and chemotherapy * intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis * Intravesical infusion is into the urinary bladder. * Intracavernosal injection is into the base of the penis. Other parenteral * transdermal (diffusion through the intact skin), e.g. transdermal patches such as fentanyl in pain therapy, nicotine patches for treatment of addiction * transmucosal (diffusion through a mucous membrane), e.g. insufflation (snorting) of cocaine, sublingual, i.e. under the tongue, nitroglycerine, buccal (absorbed through cheek near gumline), vaginal suppositories * inhalational, e.g. inhalational anesthetics * intracisternal: given between the first and second cervical vertebrae – used to

withdraw cerebrospinal fluid for dignostic purposes. Other * epidural (synonym: peridural) (injection or infusion into the epidural space), e.g. epidural anesthesia * intravitreal, through the eye Advantages and disadvantages There are advantages and disadvantages to each route of administration [edit] Inhalation Advantages * Fastest method, 7–10 seconds for the drug to reach the brain * User can titrate (regulate the amount of drug they are receiving) Disadvantages * Typically a more addictive route of administration because it is the fastest, leading to instant gratification. In addition, drugs taken by inhalation do not stay in the bloodstream for as long, causing the user to redose more quickly and intensifying the association between consuming the drug and it's effects. * Difficulties in regulating the exact amount of dosage * Patient having difficulties in giving themselves a drug by inhaler Injection Injection incompasses intravenous (IV), intramuscular (IM), and subcutaneous (subcut) (sub-Q no longer a safe abbreviation[why?]) Advantages * Fast: 15–30 seconds for IV, 3–5 minutes for IM and subcutaneous * 100% bioavailability * suitable for drugs not absorbed by the gut or those that are too irritant (anticancer) * One injection can be formulated to last days or even months, e.g., DepoProvera, a birth control shot that works for three months * IV can deliver continuous medication, e.g., morphine for patients in continuous pain, or saline drip for people needing fluids Disadvantages

* Onset of action is quick, hence more risk of addiction when it comes to injecting drugs of abuse * Patients are not typically able to self-administer * Belonephobia, the fear of needles and injection. * If needles are shared, there is risk of HIV and other infectious diseases * It is the most dangerous route of administration because it bypasses most of the body's natural defenses, exposing the user to health problems such as hepatitis, abscesses, infections, and undissolved particles or additives/contaminants * If not done properly, potentially fatal air boluses (bubbles) can occur. * Need for strict asepsis Uses Some routes can be used for topical as well as systemic purposes, depending on the circumstances. For example, inhalation of asthma drugs is targeted at the airways (topical effect), whereas inhalation of volatile anesthetics is targeted at the brain (systemic effect). On the other hand, identical drugs can produce different results depending on the route of administration. For example, some drugs are not significantly absorbed into the bloodstream from the gastrointestinal tract and their action after enteral administration is therefore different from that after parenteral administration. This can be illustrated by the action of naloxone (Narcan), an antagonist of opiates such as morphine. Naloxone counteracts opiate action in the central nervous system when given intravenously and is therefore used in the treatment of opiate overdose. The same drug, when swallowed, acts exclusively on the bowels; it is here used to treat constipation under opiate pain therapy and does not affect the pain-reducing effect of the opiate. Enteral routes are generally the most convenient for the patient, as no punctures or sterile procedures are necessary. Enteral medications are therefore often preferred in the treatment of chronic disease. However, some drugs can not be used enterally because their absorption in the digestive tract is low or unpredictable. Transdermal administration is a comfortable alternative; there are, however, only a few drug preparations are suitable for transdermal administration. In acute situations, in emergency medicine and intensive care medicine, drugs are most often given intravenously. This is the most reliable route, as in acutely ill patients the absorption of substances from the tissues and from the digestive tract can often be unpredictable due to altered blood flow or bowel motility. Notes 1. ^ "Exposition" may be a more appropriate term in toxicology.

"Administration", however, can be used for deliberate substance use. 2. ^ Fenway Community Health 3. ^ MDMA (ecstasy) metabolites and neurotoxicity: No occurrence of MDMA neurotoxicity from metabolites when injected directly into brain, study shows. 4. ^ A potential application for the intracerebral injection of drugs entrapped within liposomes in the treatment of human cerebral gliomas. 5. ^ Blood-brain barrier changes following intracerebral injection of human recombinant tumor necrosis factor-α in the rat 6. ^ Acute Decreases in Cerebrospinal Fluid Glutathione Levels after Intracerebroventricular Morphine for Cancer Pain

Injection (medicine)
An injection (often referred to as a "shot") is an infusion method of putting liquid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body. An injection follows a parenteral route of administration, that is, administered other than through the digestive tract. Hypodermic syringe injection There are several methods of injection or infusion, including intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal. Long-acting forms of subcutaneous/intramuscular injections are available for various drugs, and are called depot injections. Contents * 1 Intramuscular injection * 2 Depot injection * 3 Hypodermic injections in nature * 4 Injection pain * 5 References * 6 See also * 7 External links Intramuscular injection Main article: Intramuscular injection In an intramuscular injection, the medication is delivered directly into a muscle. Many vaccines are administered intramuscularly, as well as codeine, metoclopramide, and many other medications. Many drugs injected

intramuscularly are absorbed into the muscle fairly quickly, while others are more gradual. Generally, intramuscular injections are not self-administered, but rather by a trained medical professional. However, prescribed self-administered intramuscular injections are becoming more common for patients who require these injections routinely. Depot injection A depot injection is an injection, usually subcutaneous or intramuscular, of a pharmacological agent which releases its active compound in a consistent way over a long period of time. Depot injections are usually either solid or oil-based. Depot injections may be available as certain forms of a drug, such as decanoate salts or esters. Examples of depot injections include Depo Provera and haloperidol decanoate. The advantages of using a long-acting depot injection include increased medication compliance due to reduction in the frequency of dosing, as well as more consistent serum concentrations. A significant disadvantage is that the drug is not immediately reversible, since it is slowly released. Hypodermic injections in nature Various animals, and some plants, have been injecting for various reasons long before humans began doing so. This process is often called stinging. Some examples include: * Snakes, wasps, scorpions: poison, to kill prey and self-defense. * Some bees: poison, for self-defense and to defend their nests. * Cnidaria (jellyfish, etc.): poison, to kill prey. * Stinging nettles: poison, to try to avoid being eaten. Injection pain The pain of an injection may be lessened by prior application of ice or topical anesthetic or simultaneous pinching of the skin. Recent studies suggest that forced coughing during an injection stimulates a transient rise in blood pressure which inhibits the perception of pain. Sometimes, as with an amniocentesis, a local anesthetic is given.[1] The most common technique to reduce the pain of an injection is simply to distract the patient.

Drug injection
Drug injection of recreational drugs is a method of introducing the drug into the body with a hollow needle and a syringe which is pierced through the skin into the body (usually intravenous, but also intramuscular or subcutaneous). This act is often colloquially referred to as shooting or banging. Although there are various methods of taking drugs, injection is favoured by some users as the full effects of the drug are experienced very quickly, typically in five to ten seconds. It also bypasses first-pass metabolism in the liver, resulting in a higher bioavailability for many drugs than oral ingestion would (so users get a stronger effect from the same amount of the drug). This shorter, more intense high can lead to a dependency, both physical and psychological, developing more quickly than with other methods of taking drugs. A wide variety of drugs are injected, among the most popular in many countries are morphine, heroin, cocaine, amphetamine and methamphetamine. Prescription drugs, including tablets, capsules, or even liquids or suppositories, are also sometimes injected, especially prescription opioids, since many opioid addicts already inject heroin. Injecting preparations not intended for this purpose is particularly dangerous because of the presence of excipients (fillers), which can cause blood clots. Injecting codeine into the bloodstream directly is dangerous because it causes a rapid histamine release, which can lead to potentially fatal anaphylaxis and pulmonary edema. Dihydrocodeine, hydrocodone, nicocodeine, thebaine and other codeine-based products also carry a moderate risk in this case.[citation needed] Some manufacturers add the narcotic antagonist naloxone or the anticholinergics atropine and homatropine (in lower than therapeutic doses) to their pills to prevent injection. Unlike naloxone, atropine does indeed help morphine and other narcotics combat neuralgia. The atropine may very well not present a problem, and there is the possibility of atropine content reduction of soluble tablets by placing them on an ink blotter with a drop of water on top, then preparing a shot from the remainder of the pill. Canada and many other countries prohibit manufacturers from including secondary active ingredients for the above reason; their Talwin PX does not contain naloxone. However, as a narcotic agonistantagonist, pentazocine and its relatives can cause withdrawal in those physically dependent upon narcotics. Of all the ways to ingest drugs, injection, by far, carries the most risks as it bypasses the body's natural filtering mechanisms against viruses, bacteria and foreign objects. There will always be much less risk of overdose, disease, infections and health problems with alternatives to injecting, such as smoking, insufflation (snorting or nasal ingestion), or swallowing.

Viruses such as HIV and hepatitis C are prevalent among IV drug users in many countries, mostly due to small groups sharing injection equipment combined with a lack of proper sterilization. Other health problems arise from poor hygiene and injection technique (be it IV, IM, or SC), such as cotton fever, phlebitis, abscesses, vein collapse, ulcers, malaria, gas gangrene, tetanus, septicaemia, thrombosis, embolism and all results thereof. Drug injection is also commonly a component in HIV-related syndemics. Fragments from injection of pills are known to clog the small blood vessels of the lungs, brain and elsewhere. Hitting arteries and nerves is dangerous, painful, and presents its own similar spectrum of problems. Contents * 1 History * 2 Advantages * 3 Disadvantages * 4 Preparation of intravenous injection * 5 Harm reduction * 6 Safer injection of illicit drugs * 7 Epidemiology * 8 Alternatives to injection * 9 See also * 10 References * 11 External links History IV drug use is a relatively recent phenomenon arising from the invention of reusable syringes and the synthesis of chemically pure morphine and cocaine. It was noted that administering drugs intravenously strengthened their effect and since such drugs as heroin and cocaine were already being used to treat a wide variety of ailments, many patients were given injections of 'hard drugs' for such ailments as alcoholism and depression. By the time of Aleister Crowley[citation needed] intravenous drug culture already had a small, but loyal following. Sir Arthur Conan Doyle writes that Sherlock Holmes used to inject cocaine to occupy his mind between cases. Advantages There are a variety of reasons why drugs would be injected rather than taken through other methods. * Increased effect — Injecting a drug intravenously means that more of the drug will reach the brain more quickly. This also means that the drug will have a very

strong and rapid onset (or rush). * More efficient usage — Injection ensures that all of the drug will be absorbed. * Bypasses the digestive system — Some people with sensitive stomachs find it very unpleasant to swallow drugs because of persistent cramps or nausea. * Does not harm the lungs or mucous membranes — The mucous membranes can be permanently damaged by habitual insufflation (snorting), and the lungs can be damaged by smoking. Disadvantages In addition to general problems associated with any IV drug administration (see risks of IV therapy) there are some specific problems associated with the informal injection of drugs by non-professionals. * Increased chance of infection — This is generally a twofold problem. o Needle sharing transmits blood-borne diseases between users. o Abscessed infections of injection sites are caused by lack of hygiene and a lack of aseptic technique. In addition, the use of cotton to filter some drugs can lead to cotton fever. * Increased chance of overdose — Because IV injection delivers a dose of drug straight into the bloodstream it is harder to gauge how much to use (as opposed to smoking or snorting where the dose can be increased incrementally until the desired effect is achieved). In addition, because of the rapid onset, overdose can occur very quickly, requiring immediate action. * Scarring of the peripheral veins — This arises from the use of blunt injecting equipment. This is particularly common with users who have been injecting while in jail and re-use disposable syringes sometimes hundreds of times. IV drug use for an extended period may result in collapsed veins. Though rotating sites and allowing time to heal before reuse may decrease the likelihood of this occurring, collapse of peripheral veins may still occur with prolonged IV drug use. IV drug users are among the most difficult patient populations to obtain blood-specimens from because of peripheral venous scarring. The darkening of the veins due to scarring and toxin buildup produce tracks along the length of the veins and are known as track marks. * Increased chance of addiction — The heightened effect of administering drugs intravenously can make the chances of addiction more likely. * Needle phobia — Quite a number of people have an intense aversion to needles which, in extreme cases, is called trypanophobia and can make them feel nauseous or faint. * Social stigma — In many societies there is a social stigma attached to IV drug use, in addition to the more general stigma around illegal drug use and addiction. Many people feel that it is somehow "unclean" to take drugs in such a manner, even though they may be perfectly comfortable taking them by another route. This may be because of its common use in inner cities and with lower-income

people. Preparation of intravenous injection A clandestine kit containing materials to inject illicit drugs. The drug, usually in a powder or crystal form (though not always), is dissolved in water, normally in a spoon. Users draw the required amount of water into a syringe and squirt this over the drugs. The solution is then mixed and heated from below if necessary. Heating is used mainly with heroin, (though not always, depending on the type of heroin)[1] but is also used when pharmaceutical drugs such morphine, OxyContin or Dilaudid are injected to better separate the drug from the waxy filler; amphetamines lose potency when heated and cocaine HCl (powdered cocaine) dissolves quite easily. Heroin prepared for the European market is insoluble in water and usually requires the addition of an acidifier such as citric acid or ascorbic acid (Vitamin C) powder to dissolve the drug. Due to the dangers from using lemon juice or vinegar to acidify the solution, packets of citric acid and Vitamin C powder are available at needle exchanges in Europe. In the U.S., vinegar and lemon juice are used to shoot crack cocaine. The acids break down the rock-like substance and form a liquid mixture. Once the drugs are dissolved a small syringe, usually 0.5 or 1 cc, is used to draw the solution through a filter, usually cotton from a cigarette filter or cotton swab (cotton bud). The preferred injection site is the crook of the elbow (i.e., the Median Cephalic vein), on the user's non-writing hand. Other users opt to use the Basilic vein; While it may be easier to "hit", caution must be exercised as two nerves run parallel to the vein increasing the chance of nerve damage, as well as the chance of an arterial "nick". Harm reduction Note that it is quite common for an IV user to use a single needle repeatedly or share with other users. It's also quite uncommon for a sterilizing agent to be used. Compare this legitimate injection kit obtained from a needle-exchange program to the user-compiled one above. Harm reduction is an approach to public health intended to be a progressive alternative to an approach requiring complete abstinence from drug use. While it does not condone the taking of illicit drugs, it does seek to reduce the harms arising from their use, both for the person taking illicit drugs and the wider community. A prominent method for addressing the issue of disease transmission among intravenous drug users are needle exchange programs, in which facilities are available to exchange used injection equipment for safe sterile equipment, often without a prescription or fee. Such establishments also tend to offer free condoms to promote safe sex and reduce disease transmission. The idea is to slow disease transmission and promote public health by reducing the practice of

sharing used needles. Safer injection of illicit drugs A philosophy of harm reduction promotes information and resources for IV drug users. General guidelines on safer injecting of various substances intravenously are typically based on the following steps: The area for drug preparation should be cleaned with warm soapy water or an alcohol swab to minimize the risk of bacterial infection. The equipment required involves new syringes and needles, swabs, sterile water, filter, tourniquet and a clean spoon or stericup. In order to minimize the chance of bacteria or viruses entering the bloodstream, people are advised to wash their hands with soap and warm water. However, as people do not always have access to hot water and soap when they are injecting, the philosophy of harm reduction seeks to find the most realistic option that people can take. Alcohol swabs are commonly distributed with injecting equipment, and while they are less effective than hand washing, their use is more effective than nothing. Any sharing of injecting equipment, even tourniquets, is highly discouraged, due to the high danger of transmitting bacteria and viruses via the equipment. Sterile water is also recommended to prevent infection. Many needle and syringe programs distribute vials or ampoules of USP sterile water for this reason. Where sterile water is not obtainable, the harm reduction approach recommends tap water boiled for five minutes, and then allowed to cool. Once the water and substance are combined in the mixing vessel, heat is sometimes applied to assist the mixing. Filtering is recommended by health services, as the mix can consist of wax or other non-soluble materials which are damaging to veins. Wheel filters are the most effective filters, however cotton wool or tampons can be used, although to be more effective, several filtrations should be undertaken. Once the mix is drawn into the syringe, air bubbles should be removed by flicking the barrel with the needle pointed upwards and pressing the plunger to expel the bubbles that pool at the top. This is done to prevent injection of air into the bloodstream. A tourniquet can be used to assist vein access. The tourniquet should not be on too tight, or left on for too long, as this causes the veins to swell and stretch. When injecting, the needle's 'hole' should face upward and be eased into the vein at a 45 degree angle. In order to prevent stress on the vein, the needle should be pointing towards the heart. The plunger should be pulled back slightly (colloquially known as ‘jacking back’)

to ensure the needle is in the vein. Blood should appear in the barrel of the syringe if this is the case. This process is termed aspirating the needle or registering. When accessing a vein with unobstructed blood flow a "flashback," or sudden flash of red blood inside the needle tip, may occur spontaneously when the needle enters the vein. Because sudden appearance of blood in the needle/syringe alone does not guarantee proper needle placement (flashbacks can also occur when a needle passes through a vein completely, enters an artery inadvertantly, or otherwise is extravasated), aspirating the plunger on the syringe is still considered a requisite step. The tourniquet should then be taken off and the plunger gently pushed. After injection, a clean tissue or cotton wool should be pressed against the injection site to prevent bleeding. Although many people use an alcohol swab for this purpose it is discouraged by health services as the alcohol interferes with blood clotting. Dispose of injecting gear using a 'sharps bin' if supplied. Other rigid-walled containers such as a bottle are recommended as a second best option. Epidemiology An estimated 16 million people world wide use intravenous drugs, 3 million of these are believed to be HIV positive. Alternatives to injection The safest alternative is, of course, not to take illicit drugs. The majority of legal systems around the world encourage this option. Harm reduction acknowledges that some people in a society will not choose this option and should at least be provided information on safer means of taking illicit drugs to minimize the individual health risks and the spread of viruses such as HIV and hepatitis C to the wider community. Snorting or sniffing (insufflation or nasal ingestion) is usually safer than injection in terms of the relative danger of transmission of blood-borne viruses. However, the membranes in the nose are very delicate and can rupture when snorting so users should have their own snorting equipment not shared with anyone else, to prevent viral transmission. As with injection, a clean preparation surface is required to prepare a drug for snorting. Nasal membranes can be seriously damaged from regular snorting. Drugs can also be smoked (e.g., tobbacco or marijuana alone or mixed with heroin) or 'chased' (originating from 'chasing the dragon' - inhaling the vapors of the heated drug). Smoking and chasing have negligible risk of bacterial or viral transmission and the risk of overdose is lessened compared to injecting, but they still retain much of the 'rush' of injecting as the effects of the drug occur very

rapidly. Chasing is a far safer way to use heroin than injecting, with the best option being to use new aluminum foil, first passing a cigarette lighter flame over both sides to help sterilize it. Swallowing tends to be the safest and slowest method of ingesting drugs. It is safer as the body has a much greater chance to filter out impurities. As the drug comes on slower, the effect tends to last longer as well, making it a favorite technique on the dance scene for speed and ecstasy. People rarely take heroin orally, as it is converted to morphine in the stomach and its potency is reduced by more than 65% in the process. However, it is well known that oral bioavailability of opioids is heavily dependent on the substance, dose, and patient in ways that are not yet understood.[6] Pills like benzodiazepines are best swallowed as they have chalk or wax fillers in them. These fillers won't irritate the stomach, but pose serious health risk for veins or nasal membranes. Shebanging involves spraying the dissolved drug into the nose to be absorbed by the nasal membrane. Shafting, or rectal ingestion, relies on the many veins in the anal passage passing the drug into the blood stream quite rapidly. Some users find that trading off some of the 'rush' for fewer health risks is a good compromise. Shafting usually involves about 1.5 ml of fluid mixed with the drug. Women have the added option of shelving, where drugs can be inserted in the vagina. This is similar to the rectum, in that there are many blood vessels behind a very thin wall of cells, so the drug passes into the bloodstream very quickly. Care should be taken with drugs such as amphetamine that may irritate the sensitive lining of the rectum and vagina.

In medicine a catheter is a tube that can be inserted into a body cavity, duct or vessel. Catheters thereby allow drainage, injection of fluids or access by surgical instruments. The process of inserting a catheter is catheterization. In most uses a catheter is a thin, flexible tube ("soft" catheter), although in some uses it is a larger, solid tube ("hard" catheter). A catheter left inside the body, either temporarily or permanently, may be referred to as an indwelling catheter. A permanently inserted catheter may be referred to as a permcath. The ancient Syrians created catheters from reeds. "Katheter" originally referred to an instrument that was inserted such as a plug. The word "katheter" in turn came from "kathiemai" meaning "to sound" with a probe. The ancient Greeks

inserted a hollow metal tube through the urethra into the bladder to empty it and the tube came to be known as a "katheter". Contents * 1 Uses * 2 Inventors * 3 Materials * 4 Interventional procedures * 5 References * 6 See also * 7 External links Uses Placement of a catheter into a particular part of the body may allow: * draining urine from the urinary bladder as in urinary catheterization, e.g., the Foley catheter or even when the urethra is damaged as in suprapubic catheterisation. * drainage of urine from the kidney by percutaneous nephrostomy[1] * drainage of fluid collections, e.g. an abdominal abscess * administration of intravenous fluids, medication or parenteral nutrition with a peripheral venous catheter * angioplasty, angiography, balloon septostomy, balloon sinuplasty, catheter ablation. Often the Seldinger technique is used. * direct measurement of blood pressure in an artery or vein * direct measurement of intracranial pressure * administration of anaesthetic medication into the epidural space, the subarachnoid space, or around a major nerve bundle such as the brachial plexus * subcutaneous administration of insulin or other medications, with the use of an infusion set and insulin pump * A central venous catheter is a conduit for giving drugs or fluids into a largebore catheter positioned either in a vein near the heart or just inside the atrium. * A Swan-Ganz catheter is a special type of catheter placed into the pulmonary artery for measuring pressures in the heart. * A Touhy borst adapter is a medical device used for attaching catheters to various other devices. * A Quinton catheter is a double or triple lumen, external catheter used for hemodialysis. Inventors The modern application of the catheter was in use at least by 1868 when Dr. N.B.Sornborger patented the Syringe and Catheter (patent #73402) with features for fastening it to the body and controlling the depth of insertion.

David S. Sheridan was the inventor of the modern disposable catheter in the 1940s. In his lifetime he started and sold four catheter companies and was dubbed the "Catheter King" by Forbes Magazine in 1988. He is also credited with the invention of the modern "disposable" plastic endotracheal tube now used routinely in surgery. Prior to his invention, red rubber tubes were used, sterilized, and then re-used which often led to the spread of disease and also held a high risk of infection. As a result Mr Sheridan is credited with saving thousands of lives. In the early 1900s, a Dubliner named Walsh and a famous Scottish urinologist called Norman Gibbon teamed together to create the standard catheter used in hospitals today. Named after the two creators, it was called the Gibbon-Walsh catheter. The Gibbon catheter and the Walsh catheter have been described and their advantages over other catheters shown. The Walsh catheter is particularly useful after prostatectomy for it drains the bladder without infection or clot retention. The Gibbon catheter has largely removed the necessity of emergency prostatectomy. It is also very useful in cases of urethral fistula. A simple procedure such as dilatation of the urethra and passage of a Gibbon catheter often causes the fistula to close. This catheter is also of use in the treatment of urethral stricture and, as a temporary measure, in the treatment of retention of urine caused by carcinoma of the prostate Benjamin Franklin invented a flexible Catheter for his brother who had a bladder stone. Materials A range of polymers are used for the construction of catheters, including silicone rubber latex and thermoplastic elastomers. Silicone is one of the most common choices because it is inert and unreactive to body fluids and a range of medical fluids with which it might come into contact. On the other hand, the polymer is weak mechanically, and a number of serious fractures have occurred in catheters. It is widely used, for example, in breast implants where failures by rupturing of the silicone shell are well attested. It is also used in Foley catheters where fractures have been reported, often requiring surgery to remove the tip left in the bladder.

List of medical inhalants

* 1 Drugs and therapeutic agents administered by inhalation o 1.1 Anaesthetics o 1.2 Anti-Asthmatics/Bronchodilators o 1.3 Anti-Hypertensives o 1.4 Antimicrobials o 1.5 Pulmonary surfactants o 1.6 Miscellaneous Drugs and therapeutic agents administered by inhalation Anaesthetics * Desflurane * Enflurane * Ether * Halothane * Isoflurane * Methoxyflurane * Nitrous oxide * Sevoflurane Anti-Asthmatics/Bronchodilators * Albuterol * Arformoterol * Beclomethasone * Bitolterol * Budesonide * Budesonide/Formoterol * Ciclesonide * Cromolyn * Dexamethasone * Epinephrine * Flunisolide * Fluticasone * Fluticasone/Salmeterol * Formoterol * Ipratropium * Ipratropium/Albuterol * Isoetharine * Isoproterenol * Levalbuterol * Metaproterenol * Mometasone

* Nedocromil * Nitric oxide * Pirbuterol * Procaterol * Racepinephrine (racemic epinephrine) * Salmeterol * Terbutaline * Tiotropium * Triamcinolone Anti-Hypertensives * Amyl nitrite * Iloprost Antimicrobials * Pentamidine * Ribavirin * Tobramycin * Zanamivir Pulmonary surfactants * Beractant * Calfactant * Colfosceril * Exosurf * Poractant Miscellaneous * Aromatic ammonia * Dornase alfa * Heliox * Insulin * Methacholine * Nicotine * Sodium chloride


By Gankidi Raghavender ZSMU


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