In order to achieve its effect, a drug must first be administered in a suitable dosage form at an appropriate site. It must be absorbed effectively from the site of administration and distributed in the body to reach its site of action. After its action, for the termination of its effect, the drug must be metabolized, and metabolites must be excreted from the body.
Absorption is the entry of the drug molecules into the blood via the mucous membranes of the alimentary or respiratory tracts or from the site of injection.
Distribution is the movement of the drug molecules between the water, lipid and protein constituents of the body.
Metabolism is the process of alteration in the structure of the drug molecule in the body and
Excretion is the removal of the original drug molecule or its metabolites from the body. Collectively the term elimination is used for the process of metabolism and excretion of the drug.
The process of absorption, distribution, metabolism, and excretion require the passage of the drug across cell membranes. These membranes consist of a bimolecular layer of lipid molecules, coated with a protein layer on each surface. The cell membrane also has small pores and active transport systems.
The ability of the drug to cross this membrane depends on its chemical and physical properties. The chemical structure of a drug determines whether a drug will be more fat-soluble or water-soluble. In addition, a certain reactive portion of the molecule, or functional groups are responsible for the interaction of the drug with the tissue receptors. The drug may cross body membranes by the following mechanisms.
- Passive transfer: Simple Diffusion, Filtration
- Specialized Transport : Active transport, Facilitated diffusion, Pinocytosis
Passive transfer means that a drug or substance is taken up across a membrane without the need for energy. Simple diffusion requires no energy and depends on the difference in concentration of the drug on either side of the membrane. Both fat-soluble and water-soluble molecules of small size may cross the membrane by simple diffusion. The term Filtration is used when a porous membrane exists which allows the flow of substances of a certain size only, with the larger molecular sizes being blocked. The glomerular membrane of the kidney is an example of a filtering membrane.
Active Transport of a drug refers to a situation when the drug is moved against a concentration gradient, by the use of energy. A facilitated diffusion is a unique form of transport in which drug attaches to a special ‘carrier’ which facilitates the diffusion of the drug across the membrane, and then releases the drug. In this process, the drug is not chemically altered, and the carrier is again free to facilitate further drug transfer. Pinocytosis is the ability of cells to surround and engulf small droplets. This process is of importance in the uptake of large molecules. Cell plasma membrane is not a fixed structure, but dynamic one in which the various components are mobile.
Drug Absorption: Most drugs are given orally, and they must pass through the gut wall to enter the bloodstream. Whether the drug is applied locally or is administered systemically, there are five main factors which determine its fate in the body which are molecular weight, chemical stability, lipid solubility, the degree of ionization and pharmaceutical formulation of the drug. Each drug has its own characteristic physicochemical profile which governs its fate in the body.
Substances with high molecular weight are not usually absorbed intact except in minute quantities. They may also be altered by enzymatic action. Unstable drugs are inactivated in the gastrointestinal tract .if a drug is to be absorbed from any part of the gastrointestinal tract, including the mouth, it is necessary for it to pass through cell membranes.Thus it must first pass through the cells of the mucous membrane of the gut, and then into the circulation either directly via the capillaries or indirectly via the lymphatic channels. As cell membranes are lipid in nature, the degree and rate of penetration of the drug through them is dependent to a large extent on the lipid solubility of drug.
Absorption via Gastrointestinal Tract: Absorption of nearly all drugs from any site in the gastrointestinal tract is by passive diffusion. For most drugs, the proximal small intestine with its large surface area is the major site of absorption. Acidic drugs can be absorbed from the stomach they are usually absorbed faster when they reach duodenum. Basic drugs are usually absorbed only in the intestine, their absorption is delayed if taken with food and trapped in the stomach until the pyloric sphincter opens.
In oral administration, three processes precede absorption: Disintegration, Disaggregation and Dissolution. The disintegration of the solid dosage form (Tablet and Capsules) into granules, the disintegration rate is dependent on the dosage form. Disaggregation of the granules forms fine particles and Dissolution rate depends upon the particle size, of the drug material and the surrounding pH. On these three processes depends the ultimate absorption and bioavailability of the drug.
Absorption via parenteral sites: Drugs when injected intravenously (IV) are rapidly distributed, as they reach bloodstream directly without crossing any membranes. The factors that influence the rate of absorption from intramuscular (IM) and subcutaneous (SC) injection sites are drug concentration, the solubility of the drug and local blood flow. Absorption of IM and SC injections usually occurs by simple diffusion in the direction of the concentration gradient from the injection site to the plasma or lymph. The dosage formulation can also affect absorption from parenteral sites for example drugs in aqueous solutions are usually absorbed more rapidly than drugs in suspension. Often drugs are suspended in certain vehicles like oils, to reduce their rate of absorption and provide a prolonged action.
Absorption via lungs: Drugs presented in the correct form to the trachea and lungs are absorbed by simple diffusion. However, lipid-soluble compounds diffuse most readily.
Absorption via Topical sites: Drugs are usually applied to the skin for their topical effects. Absorption of most of the drugs through the intact skin is poor, as the keratinized epidermis behaves like a barrier. However, the underlying dermis is quite permeable to many drugs, and significant absorption can occur if the skin is abraded or denuded. The extent of absorption through the skin is proportional to the lipid solubility of the drug and the surface area to which the drug is applied. Absorption can enhance by dissolving the drug in an oily base, vigorous massaging of the area, occlusive dressing or simultaneously applying a keratin softening agent.
Drug Distribution: After a drug has been absorbed into the circulatory system; its distribution in the body is governed by a number of factors. Drug distribution describes the process which transports a drug to its site of action, to other storage sites in the body, and to organs of metabolism and excretion. As the distribution of a drug is ultimately dependent on its ability to cross cellular membranes, thus lipid soluble drugs tend to distribute more widely in the body compared to lipid insoluble drugs. Considering the highly permeable nature of the capillary endothelium (except brain capillaries), almost all organs (except CNS) can be affected by a given drug. The initial distribution of a drug is primarily dependent on the cardiac output and the local blood flow in various body organs. Thus highly perfused organs like the heart, liver, kidney and brain receive the largest amount of drug immediately after absorption. The main factors which govern the distribution of a drug are:
- Physicochemical characteristics of the drug
- Route of drug administration
- Binding to plasma proteins
- Regional blood flow
- The availability of active transport systems
- Special compartments and barriers
Drug Metabolism: Termination of drug effect, also termed as drug elimination involves two processes; metabolism, mainly in the liver and kidneys and excretion of unchanged drug and /or its metabolites by the kidneys, gut, lungs, sweat glands, breasts and salivary glands. Some drugs are excreted from the body unchanged, but the majority of them are metabolized in the body. These metabolic conversions, firstly render the compound more suitable for excretion by the liver and kidney, and secondly, play a role in determining the effective concentration of the drug in the body. The term ‘biotransformation’ is used interchangeably with the metabolism of drugs. Drug metabolism mainly occurs predominantly in the liver by way of hepatic microsomal enzyme systems. These consist of a group of enzymes located on the smooth endoplasmic reticulum of liver cells.
Drug Excretion: Drugs can be excreted in their unchanged form or as metabolites by several routes including kidneys, lungs and intestine and to a lesser extent by sweat, salivary and mammary glands. Among these, the most important excretion channel for the majority of drugs is the kidney.
Renal Excretion: Three major processes are involved in the excretion of drugs by the kidneys Glomerular Filtration, Tubular secretion and Tubular reabsorption. The first two processes remove drugs from plasma, whereas the third process retains drugs in the body by returning them to plasma. The net excretion of the drug, therefore, depends on the sum total of three processes.
Biliary Excretion: Excretion in the bile is a relatively minor route of elimination of un-metabolized drugs, but it is a major route of elimination of drug metabolites, particularly water-soluble conjugates. Drugs are actively secreted in the bile, and passed into the intestines, from where they may be either re-absorbed or lost in the faeces. Drugs that are unabsorbed from the gut, or secreted into the gastrointestinal tract by the bile, salivary glands and digestive glands are excreted in the faeces.
Pulmonary Excretion: This route of excretion is important primarily for gaseous and volatile liquid general anaesthetics, which can be excreted from the bloodstream across the alveolar membrane into the expired air. Excretion of drugs in sweat, saliva, milk and gastric juice is mainly by passive diffusion of non-ionized form. Some drugs are transferred to the suckling infant in breast milk in significant amounts. Hence, drug use by breastfeeding mother should be restricted to the minimum.
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