Physiological Pharmaceutics

20 Physiological PharmaceuticsINTRODUCTIONThe term parenteral drug delivery covers a number of administration routes, which havelittle in common other than the fact that they generally involve the use of a hypodermicneedle to inject the drug into the body. This route bypasses a number of physiologicalbarriers and hence the constraints on the composition and formulation of the medicine aremuch more rigorous than for less invasive routes such as oral or transdermal delivery.Despite this a surprising range of materials can be injected into various tissues if theappropriate precautions are taken. We will examine the constraints for specific formulationswith respect to the appropriate physiological route, but a number of general principles arecommon to all routes. The most important is that the formulation must be sterile, since themajor defence mechanisms of the body (the skin and mucous membranes) are bypassed, andso any infective agent in the formulation may cause major disease. It is not only necessaryto remove live microorganisms; parts of dead organisms can elicit an immune response, andpolysaccharides from the bacterial cell wall, known as pyrogens, can cause a substantialincrease in body temperature.The most important routes of parenteral delivery are intravenous and intramuscular,with subcutaneous being widely used for small volumes and for vaccination. There are anumber of less important routes, since it is generally possible to inject materials into virtuallyany part of the body in an attempt to gain a rapid local action. Thus we also have relativelyspecialized routes such as intrathecal, intraarticular and intracardiac.INTRAVENOUS DELIVERYPhysiologyIntravenous delivery involves the direct injection of the formulation into the venouscirculation. To understand the behaviour of intravenous drugs it is essential to consider thefunction of the circulatory system. This is shown in diagrammatic form in Figure 2.1.Although the heart is normally described as a pump, it is in fact two pumps, one of whichcirculates the blood around the tissues, and one which circulates it specifically around thelungs in a separate loop. Oxygenated blood is pumped by the left side of the heart throughthe aorta and arteries into a network of capillaries which allow transfer of oxygen andnutrients into the tissues, and remove waste products. The blood is then collected by anetwork of veins and passes into the right side of the heart. It is then passed through thepulmonary circulation into the lungs, where it loses carbon dioxide produced by tissuerespiration, and is reoxygenated. It then passes back to the left side of the heart for the cycleto repeat.Not all of the circulation from the tissues returns directly to the heart. A fraction, inparticular that which perfuses the gastrointestinal tract, is pumped to the liver first. The liverperforms a wide range of metabolic processes, but for drug delivery it can be rather moreof a hindrance since it absorbs a fraction of the drug from the bloodstream and begins thecycle of metabolism and excretion. Consequently drugs which are administered orally willvisit the liver before they have the opportunity to reach the target tissue; this effect is calledfirst pass metabolism and can remove a significant and often unpredictable fraction of thedose. When the drug is injected into a vein it passes directly into the heart, and is carriedto the tissues before passing on to the liver. Consequently first pass metabolism is avoidedand the drug has an opportunity to act on the tissues before it passes to the liver onsubsequent cycles around the circulation.The capillaries are, in general, designed to retain their contents, and so in mosttissues the capillary endothelial cells are in close contact without gaps, and a continuousbasement membrane underlies them. Capillaries of this type can allow only relativelysmall solutes, such as water, low molecular weight drugs, and small proteins (maximum