Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, reduce the likelihood of dementia, heart failure, mortality from cardiovascular disease. There are many classes of antihypertensives. Among the most important and most used drugs are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, beta blockers. Which type of medication to use for hypertension has been the subject of several large studies and resulting national guidelines; the fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack and heart failure. Patient age, associated clinical conditions and end-organ damage play a part in determining dosage and type of medication administered.
The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, cost. The choice of more expensive agents, where cheaper ones would be effective, may have negative impacts on national healthcare budgets; as of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people, an ACE inhibitor is recommended by NICE in the UK for those under 55 years old. Diuretics help the kidneys eliminate excess water from the body's tissues and blood. Loop diuretics: bumetanide ethacrynic acid furosemide torsemide Thiazide diuretics: epitizide hydrochlorothiazide and chlorothiazide bendroflumethiazide methyclothiazide polythiazide Thiazide-like diuretics: indapamide chlorthalidone metalozone Xipamide Clopamide Potassium-sparing diuretics: amiloride triamterene spironolactone eplerenoneIn the United States, the JNC8 recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACE inhibitors, or angiotensin II receptor antagonists.
There are fixed-dose combination drugs, such as ACE thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as as some newer drugs; this is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus promoted by the drug industry. Calcium channel blockers block the entry of calcium into muscle cells in artery walls. Dihydropyridines: amlodipine cilnidipine clevidipine felodipine isradipine lercanidipine levamlodipine nicardipine nifedipine nimodipine nisoldipine nitrendipine non-dihydropyridines: diltiazem verapamilJNC8 recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACE inhibitors, or angiotensin II receptor antagonists for all patients regardless of age or race.
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to -2. ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor. Captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril trandolapril benazeprilA systematic review of 63 trials with over 35,000 participants indicated ACE inhibitors reduced doubling of serum creatinine levels compared to other drugs, the authors suggested this as a first line of defense; the AASK trial showed that ACE inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACE inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status. However, ACE inhibitors should not be a first-line treatment for black hypertensives without chronic kidney disease.
Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE thiazide combinations. Notable side effects of ACE inhibitors include dry cough, fatigue, headaches, loss of taste and a risk for angioedema. Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors. Azilsartan candesartan eprosartan irbesartan losartan olmesartan telmisartan valsartan FimasartanIn 2004, an article in the BMJ examined the evidence for and against the suggestion that angiotensin receptor blockers may increase the risk of myocardial infarction; the matter was debated in 2006 in the medical journal of the American Heart Association.
To date, there is no consensus on whether ARBs have a tendenc
Blood is a body fluid in humans and other animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells. In vertebrates, it is composed of blood cells suspended in blood plasma. Plasma, which constitutes 55% of blood fluid, is water, contains proteins, mineral ions, carbon dioxide, blood cells themselves. Albumin is the main protein in plasma, it functions to regulate the colloidal osmotic pressure of blood; the blood cells are red blood cells, white blood cells and platelets. The most abundant cells in vertebrate blood are red blood cells; these contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and increasing its solubility in blood. In contrast, carbon dioxide is transported extracellularly as bicarbonate ion transported in plasma. Vertebrate blood is bright red when its hemoglobin is oxygenated and dark red when it is deoxygenated.
Some animals, such as crustaceans and mollusks, use hemocyanin to carry oxygen, instead of hemoglobin. Insects and some mollusks use a fluid called hemolymph instead of blood, the difference being that hemolymph is not contained in a closed circulatory system. In most insects, this "blood" does not contain oxygen-carrying molecules such as hemoglobin because their bodies are small enough for their tracheal system to suffice for supplying oxygen. Jawed vertebrates have an adaptive immune system, based on white blood cells. White blood cells help to resist parasites. Platelets are important in the clotting of blood. Arthropods, using hemolymph, have hemocytes as part of their immune system. Blood is circulated around the body through blood vessels by the pumping action of the heart. In animals with lungs, arterial blood carries oxygen from inhaled air to the tissues of the body, venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled.
Medical terms related to blood begin with hemo- or hemato- from the Greek word αἷμα for "blood". In terms of anatomy and histology, blood is considered a specialized form of connective tissue, given its origin in the bones and the presence of potential molecular fibers in the form of fibrinogen. Blood performs many important functions within the body, including: Supply of oxygen to tissues Supply of nutrients such as glucose, amino acids, fatty acids Removal of waste such as carbon dioxide and lactic acid Immunological functions, including circulation of white blood cells, detection of foreign material by antibodies Coagulation, the response to a broken blood vessel, the conversion of blood from a liquid to a semisolid gel to stop bleeding Messenger functions, including the transport of hormones and the signaling of tissue damage Regulation of core body temperature Hydraulic functions Blood accounts for 7% of the human body weight, with an average density around 1060 kg/m3 close to pure water's density of 1000 kg/m3.
The average adult has a blood volume of 5 litres, composed of plasma and several kinds of cells. These blood cells consist of erythrocytes and thrombocytes. By volume, the red blood cells constitute about 45% of whole blood, the plasma about 54.3%, white cells about 0.7%. Whole blood exhibits non-Newtonian fluid dynamics. If all human hemoglobin were free in the plasma rather than being contained in RBCs, the circulatory fluid would be too viscous for the cardiovascular system to function effectively. One microliter of blood contains: 4.7 to 6.1 million, 4.2 to 5.4 million erythrocytes: Red blood cells contain the blood's hemoglobin and distribute oxygen. Mature red blood cells lack a nucleus and organelles in mammals; the red blood cells are marked by glycoproteins that define the different blood types. The proportion of blood occupied by red blood cells is referred to as the hematocrit, is about 45%; the combined surface area of all red blood cells of the human body would be 2,000 times as great as the body's exterior surface.
4,000–11,000 leukocytes: White blood cells are part of the body's immune system. The cancer of leukocytes is called leukemia. 200,000 -- 500,000 thrombocytes: Also called platelets. Fibrin from the coagulation cascade creates a mesh over the platelet plug. About 55% of blood is blood plasma, a fluid, the blood's liquid medium, which by itself is straw-yellow in color; the blood plasma volume totals of 2.7–3.0 liters in an average human. It is an aqueous solution containing 92% water, 8% blood plasma proteins, trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, fatty acids, removes waste products, such as carbon dioxide and lactic acid. Other important components include: Serum albumin Blood-clotting factors Immunoglobulins lipoprotein particles Various
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
A generic drug is a pharmaceutical drug that has the same chemical substance as the drug, developed and innovated. Generic drugs are allowed for sale after the expiry of the patent of the original drugs; because the active chemical substance is the same, the medical profile of generics is believed to be equivalent in performance. The generic drug has the same active pharmaceutical ingredient as the original, but it may differ in characteristics such as manufacturing process, excipients, color and packaging. Although they may not be associated with a particular company, generic drugs are subject to government regulations in the countries in which of the drug. A generic drug must contain the same active ingredients as the original brandname formulation; the U. S. Food and Drug Administration requires generics to be identical to or within an acceptable bioequivalent range of their brandname counterparts, with respect to pharmacokinetic and pharmacodynamic properties. Biopharmaceuticals, such as monoclonal antibodies, differ biologically from small molecule drugs.
Biosimilars have active pharmaceutical ingredients that are identical to the original product and are regulated under an extended set of rules, but they are not the same as generic drugs as the active ingredients are not the same as those of their reference products. In most cases, generic products become available after the patent protections, afforded to a drug's original developer, expire. Once generic drugs enter the market, competition leads to lower prices for both the original brandname product and its generic equivalents. In most countries, patents give 20 years of protection. However, many countries and regions, such as the European Union and the United States, may grant up to five years of additional protection if manufacturers meet specific goals, such as conducting clinical trials for pediatric patients. Manufacturers, wholesalers and drugstores can all increase prices at various stages of production and distribution. In 2014, according to an analysis by the Generic Pharmaceutical Association, generic drugs accounted for 88% of the 4.3 billion prescriptions filled in the United States."Branded generics" on the other hand are defined by the FDA and NHS as "products that are either novel dosage forms of off-patent products produced by a manufacturer, not the originator of the molecule, or a molecule copy of an off-patent product with a trade name."
Since the company making branded generics can spend little on research and development, it is able to spend on marketing alone, thus earning higher profits and driving costs down. For example, the largest revenues of Ranbaxy, now owned by Sun Pharma, came from branded generics. Generic drug names are constructed using standardized affixes that distinguish drugs between and within classes and suggest their action; when a pharmaceutical company first markets a drug, it is under a patent that, until it expires, the company can use to exclude competitors by suing them for patent infringement. Pharmaceutical companies that develop new drugs only invest in drug candidates with strong patent protection as a strategy to recoup their costs to develop the drug and to make a profit; the average cost to a brand-name company of discovering and obtaining regulatory approval for a new drug, with a new chemical entity, was estimated to be as much as $800 million in 2003 and $2.6 billion in 2014. Drug companies that bring new products have several product line extension strategies they use to extend their exclusivity, some of which are seen as gaming the system and referred to by critics as "evergreening", but at some point there is no patent protection available.
For as long as a drug patent lasts, a brand-name company enjoys a period of market exclusivity, or monopoly, in which the company is able to set the price of the drug at a level that maximizes profit. This profit greatly exceeds the development and production costs of the drug, allowing the company to offset the cost of research and development of other drugs that are not profitable or do not pass clinical trials. Large pharmaceutical companies spend millions of dollars protecting their patents from generic competition. Apart from litigation, they may reformulate a drug or license a subsidiary to sell generics under the original patent. Generics sold under license from the patent holder are known as authorized generics. Generic drugs are sold for lower prices than their branded equivalents and at lower profit margins. One reason for this is that competition increases among producers when a drug is no longer protected by patents. Generic companies incur fewer costs in creating generic drugs—only the cost of manufacturing, without the costs of drug discovery and drug development—and are therefore able to maintain profitability at a lower price.
The prices are low enough for users in less-prosperous countries to afford them. For example, Thailand has imported millions of doses of a generic version of the blood-thinning drug Plavix from India, the leading manufacturer of generic drugs, at a cost of 3 US cents per dose. Generic drug companies may receive the benefit of the previous marketing efforts of the brand-name company, including advertising, presentations by drug representatives, distribution of free samples. Many drugs introduced by generic manufacturers have been on the market for a decade or more and may be well known to patients and providers, although under their branded name. India
Excretion is a process by which metabolic waste is eliminated from an organism. In vertebrates this is carried out by the lungs and skin; this is in contrast with secretion, where the substance may have specific tasks after leaving the cell. Excretion is an essential process in all forms of life. For example, in mammals urine is expelled through the urethra, part of the excretory system. In unicellular organisms, waste products are discharged directly through the surface of the cell. During life activities such as cellular respiration, several chemical reactions take place in the body; these are known as metabolism. These chemical reactions produce waste products such as carbon dioxide, salts and uric acid. Accumulation of these wastes beyond a level inside the body is harmful to the body; the excretory organs remove these wastes. This process of removal of metabolic waste from the body is known as excretion. Green plants produce carbon water as respiratory products. In green plants, the carbon dioxide released during respiration gets utilized during photosynthesis.
Oxygen is a by product generated during photosynthesis, exits through stomata, root cell walls, other routes. Plants can get rid of excess water by guttation, it has been shown that the leaf acts as an'excretophore' and, in addition to being a primary organ of photosynthesis, is used as a method of excreting toxic wastes via diffusion. Other waste materials that are exuded by some plants — resin, latex, etc. are forced from the interior of the plant by hydrostatic pressures inside the plant and by absorptive forces of plant cells. These latter processes do not need added energy, they act passively. However, during the pre-abscission phase, the metabolic levels of a leaf are high. Plants excrete some waste substances into the soil around them. In animals, the main excretory products are carbon dioxide, urea, uric acid and creatine; the liver and kidneys clear many substances from the blood, the cleared substances are excreted from the body in the urine and feces. Aquatic animals excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution.
In terrestrial animals ammonia-like compounds are converted into other nitrogenous materials as there is less water in the environment and ammonia itself is toxic. Birds excrete their nitrogenous wastes as uric acid in the form of a paste. Although this process is metabolically more expensive, it allows more efficient water retention and it can be stored more in the egg. Many avian species seabirds, can excrete salt via specialized nasal salt glands, the saline solution leaving through nostrils in the beak. In insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is transported into the tubule, which transports the wastes to the intestines; the metabolic waste is released from the body along with fecal matter. The excreted material may be called ejecta. In pathology the word ejecta is more used. UAlberta.ca, Animation of excretion Brian J Ford on leaf fall in Nature
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s