Physiological Pharmaceutics

Pulmonary drug delivery 227Lung permeabilityThe alveolar epithelium and the capillary endothelium have a very high permeability towater, most gases and lipophilic substances. There is an effective barrier however for manyhydrophilic substances of large molecular size and for ionic species. The alveolar type 1 cellshave tight junctions, effectively limiting the penetration of molecules to those with a radiusof less than 0.6 nm. Endothelial junctions are much larger, with gaps of the order of 4 to6 nm. Clearance from the alveoli by passage across the epithelium bears an approximateinverse relationship to the molecular weight. The normal alveolar epithelium is almosttotally impermeable to proteins and small solutes, for example the half-time for turnover ofalbumin between plasma and the alveolar compartment is of the order of 36 hours 1 . Themicrovascular endothelium, with its larger intercellular gaps, is far more permeable for allmolecular sizes and there is normally an appreciable leak of protein into the systemiccirculation.Lung mucusA thin fluid layer called the mucous blanket, 5 µm in depth, covers the walls of the entirerespiratory tract (Figure 10.5). This barrier serves to trap foreign particles for subsequentremoval and prevents dehydration of the surface epithelium by unsaturated air taken induring inspiration.There are about 6000 tracheo-bronchial glands in man, with an average of one cellper square millimetre of surface area. The ratio of goblet cells to ciliated cells is 1 to 5 inthe large airways and 1 to several hundred in the bronchioles. The mucus largely originatesfrom the vagally innervated, submucosal glands, with a smaller contribution from gobletcells. Within the gland, distal serous cells secrete a watery fluid, whereas the mucus cells nearthe neck secrete a gel. It is speculated that the secretions of the serous cells help in themovement of the swollen gel to the surface. Although the mucus producing cells are undervagal control and can be regulated by cholinergically mediated drugs, goblet cells dischargemucus without physiological stimulation.The main component of nasal mucus appears to be a mucopolysaccharide complexedwith sialic acid. Mucus contains 2–3% mucin, 1–2% electrolytes, and the remainder water.Tracheo-bronchial mucus has viscoelastic properties and it averages 5% solids, includingFigure 10.5 The mucociliaiy escalator