Biopharmaceutics Venkateswarlu Pdf

[Jacqualine Henington]

Thetherapeutic response of a drug is normally dependent on an adequate concentration of the drug being achieved and then maintained at the site or sites of action of the drug. In the case of systemically acting drugs it is generally accepted for clinical purposes that a dynamic equilibrium exists between the concentration of drug in blood and the concentration of drug at its site(s) of action. It means that a linear relationship exists between the drug level in blood and drug concentration at the site of action. Therefore, drug concentration at the site of action can be predicted from blood concentration of drug.

Strictly, the concentration of drug in plasma water (i.e., protein free plasma) is a more accurate index of drug concentration at the site(s) of action than is the concentration of drug in whole plasma since a drug may often bind in a reversible manner to plasma protein. Only drug that is unbound (which is free and is dissolved in plasma water) can pass out of the plasma through the capillary endothelium and reach other body fluids and tissues and finally to its site(s) of action. However, to measure the concentration of an unbound drug in plasma water requires more complex and sensitive assay methods than to measure the total concentration of both unbound and bound drug in plasma.

However, it should be realized that this simplification may not always be valid. Indeed one should not draw inferences about the clinical effects of a drug from its plasma concentration until it has been established that the two are consistently correlated. The concentration of a drug in plasma depends on numerous factors. These includes the

Fig. 1.1 shows the factors that influences the concentration of drug in blood. In case of I.V. bolus, the total dose of the drug administered reaches the circulation immediately. Where it undergoes the processes of protein binding, distribution, metabolism, renal excretion and elimination by all possible routes. After reaching the systemic circulation, the drug reaches its site(s) of action by the process of distribution, elicits its pharmacological action as long as the drug concentration in blood is above the minimum therapeutic level.

In case of extravascular administration of a drug in suitable dosage form, additional factors such as release of drug from dosage form and absorption of drug from the site of administration influences the concentration of drug in blood.

It follows that there are two aspects of drug absorption that are important in clinical practice, namely, the rate of absorption and the extent of absorption. Simply because a certain dose of a drug is being administered to a patient, there is no guarantee (except for intravenous administration) that all of that dose will reach the systemic circulation. The fraction of an administered dose of the drug that reaches the systemic circulation in unchanged form is known as bioavailable dose. The relative amount of an administered dose of a particular drug that reaches the systemic circulation intact and the rate at which this occurs is known as bioavailability. Bioavailability is thus concerned with the rate and extent at which the intact form of a particular drug appears in the systemic circulation following extravascular administration of the drug. The bioavailability exhibited by a drug is thus very important in determining whether a therapeutically effective concentration is achieved at the site(s) of action or not.

Hence, according to the definition of bioavailability, an administered dose of a particular drug in an oral dosage form will be 100% bioavailable only if the drug is completely released from the dosage form into the solution in the gastrointestinal fluids. The released drug must also be completely stable in the solution in the gastrointestinal fluids and all the drug must pass through the gastrointestinal barrier into the mesenteric circulation without being metabolized. Finally, the entire absorbed drug must pass into the systemic circulation without being metabolized on passing through liver. Thus any factor which adversely effects either the release of the drug from the dosage form, its dissolution in the gastrointestinal fluids, its stability in the gastrointestinal fluids, its permeation through and stability in the gastrointestinal barrier or its stability in the hepatic portal circulation will influence the bioavailability exhibited by that drug from the dosage form in which it was administered.

Many factors have been found to influence the time course of a drug in the plasma and thereby its concentration at the site(s) of action. These include the foods eaten by the patient, the effect of the disease state on drug absorption, the age of the patient, the site(s) of absorption of the administered drug, co-administration of other drugs, the physical and chemical properties of the administered drug, the type of dosage form, the composition and method of manufacture of the dosage form and the size of dose and frequency of administration of the dosage form. Thus, a given drug may exhibit differences in its bioavailability if-

3. it is given by the same route of administration and in the same dosage form, but formulation and methods of manufacture of the dosage form are different, e.g. different formulations of an aqueous suspension of a given drug administered by the peroral route.

The variability by a drug in bioavailability from different formulations of the same type of dosage form or from different types of dosage forms etc., can cause the patient to be under or over medicated. The result may be a therapeutic failure or serious adverse effects, particularly in the case of drugs that have a narrow therapeutic indices.

The study of the various factors that can affect aforesaid processes and the application of this knowledge to obtain the expected therapeutic effect from a drug product when it is used by a patient is known as biopharmaceutics.

The absorption process is developed in the biological system for getting required organic and inorganic chemicals (nutrients) into the systemic circulation to maintain life. Drugs are absorbed into the systemic circulation by the same processes that are meant for the absorption of nutrients. A majority of drugs are administered orally and vast majority of orally administered drugs are intended to be absorbed from the gastrointestinal tract. The study of absorption of drugs from the GIT enables us to understand the mechanisms of absorption.

In order to understand the numerous factors that can potentially influence the rate and extent of appearance of an intact drug into the systemic circulation, a schematic illustration of the steps involved in the release and gastrointestinal absorption of a drug from tablet is presented in Fig. 2.1. It is evident from this figure that the rate and extent of appearance of the intact drug into the systemic circulation depends on a succession of rate processes.

The slowest step in the series of rate processes that controls the overall rate and extent of appearance of intact drug in the systemic circulation is called the rate-limiting step. The particular rate-limiting step may vary from drug to drug. Thus for a drug which exhibits a very poor aqueous solubility, the rate at which the drug dissolves in the gastrointestinal fluids is often the slowest step and therefore exhibits a rate-limiting effect on the drug bioavailability. In contrast, for a drug having a high aqueous solubility its dissolution rate will be rapid and the rate at which the drug crosses the gastrointestinal membrane will be the rate-limiting step.

The gastrointestinal tract (GIT) is a highly specialized region of the body whose primary functions involves the processes of secretion, digestion and absorption. Since all nutrients needed by the body, with the exception of oxygen, must first be ingested orally, processed by the GIT, and then made available for absorption into the blood stream, the GIT represents an important barrier and interface with the environment.

Fig. 2.2 illustrate the gross functional anatomy of the GIT. The liver, gallbladder, and pancreas, although not part of the gut, have been included since these organs secrete materials vital to the digestive and certain absorptive functions of the gut. The lengths of various regions of the GIT (mean values )are presented in Table 2.1. The small intestine, comprising the duodenum, jejunum and ileum, represents more than 60% of the length of the GIT, which is consistent with its primary digestive and absorptive functions. In addition to the daily food and fluid intake, the GIT and associated organs secrete about 8 liters of fluids per day. Of this total, between 100 and 200 ml of stool water is lost per day, indicating an efficient absorption of water throughout the tract.

A common anatomical feature of the entire GIT is its four concentric layers. Beginning with the luminal surface, these are the mucosa, submucosa, muscularis external and serosa. (Fig. 2.3) The three outer layers are similar throughout most of the tract; however, the mucosa has distinctive structural and functional characteristics at different regions of the GIT and is most important with respect to the absorption of drugs from the lumen of the gastrointestinal tract.

2. Lamina propia lies between the basement membrane and the muscularis mucosa, which contains connective tissue, blood and lymph vessels that carry the absorbed materials into the general circulation.

3. Muscularis mucosa which is a relatively thin layer of muscle fibres. These mucosae are highly specialized in each organ of the gastrointestinal tract, facing a low pH in the stomach, absorbing a multitude of different substances in the small intestine, and also absorbing specific quantities of water in the large intestine. Reflecting the varying needs of these organs, the structure of the mucosa can consist of invaginations of secretory glands (e.g., gastric pits), or it can be folded in order to increase surface area (examples include villi and plicae circulares).

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