which can, in many respects, be envisioned more accurately as the actions of the body on an administered drug. It includes studies of the mechanisms of drug absorption, distribution, metabolism, and excretion; onset of action; duration of effect; biotransformation; and effects and routes of excretion of the metabolites of the drug. Pharmacokinetics determine how rapidly and for how long the drug will apear at the target organ.
. the degree to which a drug or other substance becomes available to the target tissue after administration. A measure of the amount of drug that is actually absorbed from a given dose. the degree to which a drug or other substance becomes available to the target tissue after administration. Clinical pharmacology The degree to which a drug is available to a target tissue after administration which, for oral drugs, reflects the rate and extent of GI tract absorption; BA is the in vivo presence of a substance in a form that allows it to be metabolized, serve as a substrate, bind a specific molecule, or participate in biochemical reactions. For dietary supplements, herbs and other nutrients in which the route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed.Bioavailability is defined slightly differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food and Drug Administration regulations.Bioaccessibility is a concept related to bioavailability in the context of biodegradation and environmental pollution. A molecule (often a persistent organic pollutant) is said to be bioavailable when "[it] is available to cross an organism’s cellular membrane from the environment, if the organism has access to the chemical."
Absorption parameters : gastrointestinal track.
BioequivalenceIn determining bioequivalence, for example, between two products such as a commercially-available Brand product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects, generally healthy individuals but occasionally in patients. Serum/plasma samples are obtained at regular intervals and assayed for parent drug (or occasionally metabolite) concentration. Occasionally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled corticosteroids), then pharmacodynamic endpoints rather than pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), and absorption lag time (tlag). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics.In addition to data from bioequivalence studies, other data may need to be submitted to meet regulatory requirements for bioequivalence. Such evidence may include:1. analytical method validation2. In vitro-in vivo correlation studies(IVIVC)
Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product.Generic drug : a medication sold under its generic name ; usully legal only after the patent has expired or if no patent was issued for the substance . Generic drugs are usually less expensive than proprietry medication .
Anti-convulsants : a drug that relieves or prevent convulsions, A type of drug given to prevent seizures ,some patients with migrines can be treated effectively with an anti-convulsants. ( conulsions : an involuntry contraction or series of contraction of the voluntry muscles ).Anti-coagulants : substance that prevents coagulation of blood .Corticosteroids : Cardio-active drug :
the ratio between the dosage of a drug that causes a lethal effect and the dosage that causes atherapeutic effect.Medical Dictionarytherapeutic index n. The ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relativesafety of the drug for a particular treatment.Quantitatively, it is the ratio given by the lethal or toxic dose divided by the therapeutic dose.In animal studies, the therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50).Lethality is not determined in human clinical trials; instead, the dose that produces a toxicity in 50% of the population (TD50) is used to calculate the therapeutic index.While the lethal dose is important to determine in animal studies, there are usually severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the lethal/toxic threshold than the dose taken to elicit the therapeutic effect.
Examples of biological half-livesWaterThe biological half-life of water in a human is about 7 to 14 days. It can be altered by behavior. Drinking large amounts of alcohol will reduce the biological half-life of water in the body. This has been used to decontaminate humans who are internally contaminated with tritiated water (tritium). Drinking the same amount of water would have a similar effect, but many would find it difficult to drink a large volume of water. The basis of this decontamination method (used at Harwell) is to increase the rate at which the water in the body is replaced with new water.AlcoholThe removal of ethanol (drinking alcohol) through oxidation by alcohol dehydrogenase in the liver from the human body is limited. Hence the removal of a large concentration of alcohol from blood may follow zero-order kinetics. Also the rate-limiting steps for one substance may be in common with other substances. For instance, the blood alcohol concentration can be used to modify the biochemistry of methanol and ethylene glycol. In this way the oxidation of methanol to the toxic formaldehyde and formic acid in the (human body) can be prevented by giving an appropriate amount of ethanol to a person who has ingested methanol. Note that methanol is very toxic and causes blindness and death. A person who has ingested ethylene glycol can be treated in the same way. complex kineticsMetalsThe biological half-life of caesium in humans is between one and four months. This can be shortened by feeding the person prussian blue. The prussian blue in the digestive system acts as a solid ion exchanger which absorbs the caesium while releasing potassium ions.For some substances, it is important to think of the human or animal body as being made up of several parts, each with their own affinity for the substance, and each part with a different biological half-life (physiologically-based pharmacokinetic modelling). Attempts to remove a substance from the whole organism may have the effect of increasing the burden present in one part of the organism. For instance, if a person who is contaminated with lead is given EDTA in a chelation therapy, then while the rate at which lead is lost from the body will be increased, the lead within the body tends to relocate into the brain where it can do the most harm.Polonium in the body has a biological half-life of about 30 to 50 days.Caesium in the body has a biological half-life of about one to four months.Mercury (as methylmercury) in the body has a half-life of about 65 days.Lead in bone has a biological half-life of about ten years.Cadmium in bone has a biological half-life of about 30 years.Plutonium in bone has a biological half-life of about 100 years.Plutonium in the liver has a biological half-life of about 40 years.
MeSH definition : an abbreviations derived from MEDICAL SUBJECT HEADINGS , the list of medical terms used by NATIONAL LIBRARY OF MEDICINE ( NLM ) for its computerized system of storage and retrivel of published medical reports , this system is also used for indexing medical reference published in the monthly and annual volumes of index medicus …16000 terms .
AUC (area-under-the-curve): This is the overall amount of drug in the bloodstream after a dose. AUC studies are often used when researchers are looking for drug-drug or drug-food interactions. The way to get an AUC involves collecting many blood samples (usually every one or two hours) right after a person takes a dose up until the next dose is due. In each blood sample, the concentration of the drug is measured with a machine (discussed later). Then all the drug concentrations are put onto a graph based on the time after the dose that they were collected. A curve is made by connecting the points on the graph. The AUC for that drug is then calculated as the area under this drug concentration curve. An AUC study contains a lot of information about PK. It is probably the best way to understand how people handle a drug (PK).Cmax (maximum concentration): This is the highest concentration of drug in the blood that is measured after a dose. Cmaxusually happens within a few hours after the dose is taken. The time that Cmaxhappens is referred to as Tmax. For some antiretroviral drugs, a high Cmax is thought to increase the risk of side effects from the drug.Cmin or trough (pronounced "troff")(minimum concentration): This is the lowest concentration of the drug in the blood that is measured after a dose. It happens right before a patient takes the next usual dose. It is not known for certain, but many people in the HIV community believe that keeping the trough concentration (Cmin) above a certain level is especially important for anti-HIV activity.
Cmax , The maximum drug concentration. The maximum concentration of drug in the plasma is a function of both the rate and extent of absorption. Cmax will increase with an increase in the dose, as well as with an increase in the absorption rate. 3. Tmax , The time at which the Cmax occurs. The Tmax reflects the rate of drug absorption, and decreases as the absorption rate increases.
Area under first moment curve (AUMC) : plasma drug concentration x time after dosing versus time after drug administration.Mean resident times (MRT) : it is used for linear and non-linear systems.
Lipophilic drug :Hydrophilic drug :
2/12/2013PHARMACOLOGYINTRO DEFINATION Zulcaif Ahmad 1
2/12/2013TOPIC1) Bioavailability2) Bioequivalence3) Therapeutic index4) Plasma half life5) Dose response curve6) Area under curve (AUC)7) Volume of distribution 2
2/12/2013PHARMACOKINETICS Pharmakon ( drug ) Kinetics ( motion ) Definition : The actions of the body on an administered drug ( dose concentration ). It involves drug absorption , distribution , metabolism and elimination . 3
2/12/2013 Pharmacokinetics conc. vs timeConc.(mg/L) 0.0 0 25 Time (h) 5
2/12/20131) BIOAVAILABILITY In pharmacology, bioavailability is a measurement of the rate and extent to which a drug reaches the systemic circulation It is denoted by the letter f Bioavailability is the ratio of the area calculated for oral route of administration to the intravenous route of administration. In pharmacology, bioavailability (BA) is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non- intravenous routes of administration. 6
2/12/2013For a non-intravenous drug , it is less than 100% because of : 1) Absorption Parameters. 2)First-pass elimination. Bioavailability is the drug proportion that actually reaches systemic circulation . 7
2/12/20132) BIOEQUIVALENCE Relationship between 2 preparations of the same drug at same dose in same form with similar bioavailability. OR The relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability. 9
2/12/2013 Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards." 10
2/12/20133) THERAPEUTIC INDEX The difference between the minimum therapeutic and minimum toxic concentrations of a drug. Therapeutic index represents the safety of a drug. Drugs having low therapeutic index include: Anticonvulsants, lithium, anticoagulants, corticosteroids and cardio active drugs. 12
2/12/2013 therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies). the ratio between the dosage of a drug that causes a lethal effect and the dosage that causes therapeutic effect. Medical Dictionary : The ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relative safety of the drug for a particular treatment. 13
2/12/20134) PLASMA HALF LIFE The duration of action of a drug is known as its half life. This is the period of time required for the concentration or amount of drug in the body to be reduced by one-half. Drug can be eliminated from the body, or it can be translocated to another body fluid compartment such as the intracellular fluid or it can be destroyed in the blood after it is reduced to half life. The removal of a drug from the plasma is known as clearance and the distribution of the drug in the various body tissues is known as the volume of distribution. Both of these pharmacokinetic parameters are important in determining the half life of a drug. Here is the symbol to represent the half-life: t½ 14
2/12/2013 The biological half-life or elimination half- life of a substance is the time it takes for a substance (for example a metabolite, drug, signaling molecule, radioactive nuclide, or other substance) to lose half of its pharmacologic, physiologic, or radiologic activity , as per the MeSH definition. Biological half-life is an important pharmacokinetic parameter . 15
2/12/20135) DOSE-RESPONSE CURVE A dose–response curve is a simple X–Y graph relating the magnitude of a stressor ( e.g. amount of drug ) to the response of receptor. The measured dose (usually in milligrams, micrograms, or grams per kilogram of body- weight for oral exposures or milligrams per cubic meter of ambient air for inhalation exposures) is generally plotted on the X axis and the response is plotted on the Y axis. The dose–response relationship , describes the change in effect on an organism caused by differing levels of exposure (or doses) to a stressor (usually a chemical) after a certain exposure time. This may apply to individuals (e.g.: a small amount has no significant effect, a large amount is fatal), or to populations (e.g.: how many people or organisms are affected at different levels of exposure). Studying dose response, and developing dose response models, is central to determining "safe" and "hazardous" levels and dosages for drugs, potential pollutants, and other substances to which humans or other organisms are exposed. These conclusions are often the basis for public policy. Dose–response relationships generally depend on the exposure time and exposure route (e.g., inhalation, dietary intake); quantifying the response after a different exposure time or for a different route leads to a different relationship and possibly different conclusions on the effects of the stressor under consideration. 17
2/12/20136) AREA UNDER CURVE (AUC) The area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration The area under the plasma (serum, or blood) concentration versus time curve (AUC) has a number of important uses in pharmacokinetics. The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs (ClT). 18
2/12/2013 AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much - how long a drug stays in a body. The AUC measured after administration of a drug product is an important parameter in the comparison of drug products. These bioequivalence or bioavailability studies can be analyzed by comparing AUC values. Drug AUC values can be used to determine other pharmacokinetic parameters, such as clearance or bioavailability, F. Similar techniques can be used to calculate area under the first moment curve (AUMC) 20
2/12/20137) VOLUME OF DISTRIBUTION Volume of distribution is the measure of the apparent space in the body available to contain the drug. Volume of distribution relates the amount of drug in the body to the concentration of drug in blood or plasma . Formula for volume of distribution is , total amount of drug in the body divided by drug blood plasma concentration. It is not a real but a theoretical volume. if VD is greater, it shows that the drug is more diluted than it should be (in the blood plasma), meaning more of it is distributed in tissue (i.e. not in plasma). It is defined as the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing. 21
2/12/2013 Volume of distribution may be increased by renal failure (due to fluid retention) and liver failure (due to altered body fluid). Conversely it may be decreased in dehydration. 22