Pharmacokinetics. Fig. 2. First-order elimination for a drug (A) administered by the intravenous route showing elimination over time.
technology (gas GC, or liquid ► HPLC) coupled to ► mass spectrometry (MS). This is because of the complex nature of the matrix (blood (or brain tissue extracts in animals)) to be analysed; the need for high sensitivity to detect low drug concentrations (10~6 to 10~9g) and the long time-point data. Blank or t =0 samples taken before administration are important in determining a baseline and ensure data integrity with such complex sample matrices. There is currently considerable interest in the use of very high sensitivity LC-MS-MS for micro dosing studies, which are seen as a promising alternative to animal experimentation.
Population pharmacokinetics is the study of sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. This methodology seeks to identify the measurable patho-physiologic factors that cause changes in the dose-concentration relationship and the extent of these changes. The industry standard software for population pharmacokinetics analysis is NONMEM.
A basic tenet of clinical pharmacokinetics is that the magnitudes of both desired response and toxicity are functions of the drug concentration at the site(s) of action (Rowland and Tozer 1995). Using this definition, "therapeutic failure'' results when either the concentration of the drug at the site of action is too low, giving ineffective therapy, or is too high, producing unacceptable toxicity. For example, in drug treatment services, relapse and a return to illicit drug use has been frequently observed when the maintenance dose of ► methadone is too low to stop opioid withdrawal symptoms or ► craving for heroin. The concentration range in between these limits, the range associated with "therapeutic success'' is often regarded as the "therapeutic window or range'' (Fig. 3). However, these definitions are sometimes difficult to interpret for drugs that are not controlled by pharmaceutical regulations (► cocaine or ► cannabis or, ► MDMA) or are difficult to apply to drugs consumed without restriction (► alcohol and ► nicotine).
In practice, the measurement of a drug in the body is usually determined in blood or urine, because measurement of the drug concentration at the site of action is not easily achievable.
For some drugs with variable pharmacokinetics such as Warfarin (Coumadin), biological monitoring is required to ensure that the blood concentration of the drug is strictly maintained within the therapeutic window (normal reference range, Fig. 3). Warfarin used for preventing thrombosis and embolism (abnormal formation and migration of blood clots) interacts with
Pharmacokinetics. Fig. 3. Pharmacokinetic parameters describing a typical plasma concentration-time profile after an oral administration. Cmax maximum concentration; fmax many common medications and some foods. Its activity has to be monitored by frequent blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken. Other compounds, for example, clozapine have a risk of serious side effects. ► Clozapine is used principally in treating
► schizophrenia and also for reducing the risk of suicide in patients with chronic risk for suicidal behavior. Plasma concentration of clozapine and norclozapine need to be measured regularly in order to assess adherence to the dosing regime, prevention of toxicity, and in dose optimization.
The discipline of pharmacokinetics is concerned with the quantitation of the mechanisms of ► absorption. The process by which a drug enters the blood stream;
► distribution of an administered drug; the rate at which a drug action begins; the duration of the effect; the ► metabolism of the drug in the body and; the effects and routes of ► excretion of the drug and its metabolites. These processes together are commonly referred to as ADME (Jacobs and Fehr 1987). More recently biophar-maceutics has emerged as a new body of science that links traditional pharmacokinetics with pharmaceutics and the acronym LADME (http://en.wikipedia.org/wiki/ Pharmacokinetics) has been used to describe the processes studied by biopharmacists. Essentially adding the term "► Liberation" to the well recognized ADME acronym.
In order for a drug to exert its pharmacological effect, it must first gain entry into the body, be absorbed into the blood stream and transported to the site of action (usually in the brain for CNS active drugs). The intensity of effect of a drug is governed by two major factors:
• The concentration of drug at the site of action in the body; and
• The sensitivity of the target cells (i.e., the magnitude of their response to a given concentration of drug).
The concentration of drug at the site of action in the body at any given time after administration is determined by both the size of the dose and the pharmacokinetics of the substance.
Biopharmaceutics has brought to the fore the importance of the physicochemical properties of a drug, the dosage form (or design) and the route of administration, all of which are key parameters when considering drug "Liberation.'' Once administered, the drug must be liberated from its dosage form. Tablets and capsules may require disintegration (forming smaller particles) before dissolution and entry into the systemic circulation can occur. Similarly, the delivery of drug particulates into the lung from passive inhaler products is only achieved after "Liberation" of the drug from the formulation during inhalation activation. The science of drug formulation design has rapidly grown over the last decade and is a thriving discipline.
Drug dissolution usually occurs in the stomach and is dependent upon gastric activity. Many factors influence the dissolution of tablets and capsules, including particle size, chemical formulation, the inclusion of inert fillers, and the outer coating of the tablet. It is not unusual, therefore for proprietary or generic preparations of a drug to have different dissolution characteristics and produce a range of plasma concentrations after oral administration. Dissolution characteristics of a dosage form are thus important considerations when interpreting pharmacokinetic data.
As explained above, the extent and rate of absorption of a substance depends on the chemical properties of the drug itself and the way in which it is administered. The rate of absorption depends on the concentration of the drug, its degree of lipid solubility, the surface area of absorption, and the diffusion distance (i.e., the number of membranes it must cross before it reaches the bloodstream). Peak plasma concentration-time is the most widely used time to Cmax; AUC area under the curve.
general index of absorption rate; the slower the absorption, the longer period of time to reach peak plasma concentration.
There are four principle methods of drug administration: oral/ingestion, across mucous membranes, by inhalation, and by parenteral process (injection).
Oral (by swallowing): Drugs taken orally are generally absorbed primarily in the small intestine rather than in the stomach. The ► benzodiazepines comprise a large family of lipophilic drugs. ► Diazepam for instance, is rapidly absorbed, with peak concentration occurring within an hour for adults and, as quickly as, 15-30 min in children (Jenkins 2008). This route is characteristically slow and may be delayed by the presence of food in the digestive tract. The oral route may be ineffective for certain drugs because the acidity of the stomach renders them ineffective. Heroin provides a good example of the latter phenomenon. Drug users looking for an immediate or intense effect or "rush," avoid the oral route. Nonlipo-philic (nonionized) compounds such as ► alcohol, readily cross cell membranes by passive diffusion and are easily and rapidly absorbed from the gut, particularly on an "empty" stomach.
Transmucosal Absorption: Mucous membranes (that form the moist surfaces that line the mouth, nose, eye sockets, throat, rectum and vagina, etc) are thinner, have a greater blood supply and, are more permeable (lack keratin) compared with the epidermis (skin). For these reasons, absorption across mucus membranes is rapid and drugs (especially lipophilic compounds) are effectively absorbed into the bloodstream. ► Nicotine in the form of chewing tobacco and buprenorphine placed sublin-gually (under the tongue) is successfully absorbed through the mucous membranes of the mouth. Drugs can be administered rectally including aminophylline, a drug used in the treatment of bronchial asthma and tribromoethanol, an anesthetic. Drugs can also be absorbed by insuffalation (sniffing, snorting), which allows ► cocaine, ► ketamine amylnitrite and tobacco stuff to be absorbed across the mucous membranes of the nose and sinus cavities. Nasal administration (a preferred route for users of illicit substances) enables rapid absorption into the cerebrospinal fluid (CSF) and hence, the cerebral circulation. After nasal administration, the concentration of some drugs in the CSF may be higher than in plasma (Calvey 2007).
Inhalation: In the case of inhalation, a drug is absorbed into the bloodstream across the alveolar membranes of the lung. This occurs in gas form (e.g., the vapors of solvents), in fine liquid drops (heroin or cocaine), or in fine particles of matter suspended in a gas
(e.g., aerosols or the smoke from tobacco or cannabis). For many drugs, inhalation is the most rapid method of absorption into the general circulation. Glue "sniffing" is actually an incorrect description; technically, glue vapors are inhaled and absorbed via the linings of the lung.
Parenteral (Injection): The term "parenteral" denotes those pathways through which drugs are injected directly into the body. There are three principle parenteral routes: subcutaneous, intramuscular, and intravenous. Subcutaneous injection ("skin popping'' to street users) involves injecting the drug under the skin. The rate of absorption from the site of injection is slower than the intravenous injection, but faster than the oral route. Intramuscular injection involves deeper penetration of the drug into the body tissue. The drug is injected either in solution or in suspension directly into the muscle mass, where it is slowly absorbed into the bloodstream. Intravenous injection (popularly known as "mainlining") involves the direct injection of the drug into the veins. It is one of the fastest ways of getting a drug into the bloodstream and also allows relatively large amounts of a drug to be administered at one time. Intravenous drug administration poses the highest risk of toxicity and overdose (Wolff 2005).
Kinetics of Absorption The oral absorption of drugs often approximates first-order kinetics, especially when given in solution. Under these circumstances, absorption is characterized by an absorption rate constant, Ka, and a corresponding half-life. ► First-order kinetics depend on the concentration of only one reactant and a constant fraction of the drug in the body that is eliminated per unit time. The rate of absorption is proportional to the amount of drug in the body.
Sometimes a drug is absorbed essentially at a constant rate, called zero-order absorption. ► Zero-order kinetics is described when a constant amount of drug is absorbed (or eliminated) per unit time but the rate is independent of the concentration of the drug (Fig. 4). Zero-order kinetics explains the way in which alcohol is handled in
Pharmacokinetics. Fig. 4. Schematic representation of the absorption of a drug by zero-order kinetics.
the body and several other drugs at high dosage concentrations, such as phenytoin and salicylate (Neligan 2009).
The pharmacokinetic parameter linked to the passage of a drug into the systemic circulation is known as ► Bio-availability. It is a measurement of the amount of active drug that reaches the general circulation and is available at the site of action (although this parameter is difficult to establish for CNS active drugs, due to the need to cross the blood-brain barrier). It is expressed as the letter F.
It is assumed that a drug given by the intravenous route will have an absolute bioavailability of 100% or 1 (F = 1), while drugs given by other routes usually have an absolute bioavailability of less than one. F, is often calculated as the proportion of drug that reaches the systemic circulation after oral compared to IV administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The formula for calculating F for a drug administered by the oral route (p.o.) is given below.
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