Physiological Pharmaceutics

2 Physiological PharmaceuticsINTRODUCTIONAll living things are made of cells—small individually functional units which, in higherorganisms, are organised into collections called tissues. A typical cell consists largely ofcytoplasm, an aqueous liquid in which a wide range of biochemical processes occur. Thecytoplasm is held as an intact unit by a cell membrane, which surrounds it and prevents itfrom mixing with its surroundings. Depending on the cell type and function, a number ofother structures may be present, particularly a nucleus, in which the cell genetic informationis stored in the form of DNA. Provision must be made for the supply and retention ofsubstrates from extracellular sources and for the secretion of waste products that wouldotherwise accumulate in toxic amounts. The outer membrane of the cell must thereforeallow penetration of some substances and not others, i.e. it must be selectively permeable.This is one of the most important features of the cell membrane.Organs and tissues are collections of cells surrounded by specialised cell structurescalled epithelia, which can be thought of as the organ’s ‘outer membrane’ in an analogousfashion to the membrane that surrounds the individual cell. Like cell membranes, they notonly bound the organ, but also are the site for a wide range of transport, barrier andsecretory processes which vary widely with the particular organ. Many epithelia protectorgans from hostile environments (for example the skin or the contents of the stomach) andsuch cells generally have a rapid turnover and numerous barrier features.In order for a drug to reach a site of action it must pass from an ‘external’ site (forexample the surface of the skin or the small intestine) to an ‘internal’ site (the bloodstreamor the cytoplasm of a particular cell group). In doing so it will have to pass through anumber of tissues and epithelia, either by going through the cells themselves (and thuspenetrating their plasma membranes) or by finding pathways between the cells. Overcomingthese barriers to absorption is one of the most important considerations in the drug deliveryprocess, and requires a detailed knowledge of the structure and behaviour of the cellmembranes and epithelial tissues.THE PLASMA MEMBRANEThe plasma membrane retains the contents of the cell and acts as a permeability barrier.That is, it allows only certain substances to enter or leave the cell, and the rate of entry isstrictly controlled. Early researchers recognised that hydrophobic materials entered cellseasily and proposed that an oily or ‘lipoidal’ layer was present at the cell surface. Gorter andGrendel in 1925 estimated the thickness of this layer by extracting the oily membrane fromerythrocytes with acetone and spreading it as a monomolecular film in a Langmuir trough 1 .By measuring the film area and calculating the surface area of the original red cells (chosensince their geometry is reasonably constant), they concluded that exactly two layers ofmolecules were present at the interface, and proposed a lipid bilayer as the major cellmembrane element. We now know that their experiment was subject to a considerablenumber of errors 2 , but fortunately these cancelled out in the final analysis and hence theyobtained the correct answer by the wrong route. Electron micrographs indicate a doublelayered lipid membrane with bands approximately 3 nm in width and an overall thicknessof between 8 to 12 nm. Although this is consistent with the lipid bilayer view, electronmicrographic evidence was held in doubt for many years due to the difficulty of preparingthe samples and the possibility of artefacts at so small a scale.Subsequent discovery of the incorporation of proteins and polysaccharides led to thefluid mosaic model of Singer and Nicholson 3 . This model tended to suggest that themembrane was a sea of tightly packed phospholipids interspersed with proteins, leading toa rather ill-defined mixed membrane. However, studies during the last decade havedemonstrated that the membrane is a highly organised structure; proteins in specific