Physiological Pharmaceutics

166 Physiological Pharmaceuticsthe colonic lumen which therefore alters luminal pH, resulting in changes in the rate ofabsorption of drugs from the lumen. As a result the effectiveness of colonic delivery may beunpredictable in patients with constipation or diarrhoea. The increased rate of transit wouldalso be responsible for the premature voiding of sustained release formulations, and wouldalso be expected to alter the sieving function of the colon. Diarrhoeal diseases are knownto cause decreased gut transit time, and hence incomplete metabolism, of pro-drugs such assulphasalazine. To date, however, little detailed information exists in the literatureconcerning the effect of motility disorders on colonic delivery.RECTAL ADMINISTRATION OF DRUGSThe rectal route of drug administration offers several advantages, includinga) a relatively large dosage form can be accommodated in the rectumb) the rectal route is safe and convenient for elderly and young patientsc) drug dilution is minimized as the residual fluid volume is lowd) the rectum is generally emptye) absorption adjuvants have a more pronounced effect than in the upper gastrointestinaltractf) degradative enzymes in the rectal lumen are at relatively low concentrationsg) therapy can easily be discontinuedh) first-pass elimination of drug by the liver is partly avoidedThe rectal route is often used when administration of dosage forms by mouth isinappropriate, for example, in the presence of nausea and vomiting, in unconscious patients,if upper gastrointestinal disease is present which could affect the absorption of the drug, orif the drug is unpleasant tasting or acid-labile.Drug absorption and avoidance of first-pass metabolismSeveral factors have to be overcome for a drug to be absorbed after rectal administration.If the drug is administered as a suppository, melting or liquefaction of the base has to occurand the degree of this will partly determine the spreading of the dose through the rectum.The drug must then dissolve in the limited rectal fluid available, which has been estimatedto be between 1 and 3 ml. The amount of drug available for absorption can be furtherreduced by degradation by luminal contents, adsorption to luminal contents anddefaecation. The drug must then diffuse across the unstirred water and mucous layersadjacent to the epithelium.Drugs may be absorbed across the epithelial cell or via tight junctions, and it isbelieved that only passive transport occurs. Venous return from the colon and upper rectumis via the portal vein to the liver. If a drug is delivered to the upper part of the rectum, itis transported into the portal system (Figure 7.10), and is therefore subject to first passmetabolism in the liver. The only way of avoiding first-pass metabolism is to deliver the drugto the lower part of the rectum. This simple principle is complicated by the presence ofanastomoses which do not allow a precise definition of the areas which drain to the portaland systemic circulation. A 100% increase in the availability of lignocaine wasdemonstrated when administered rectally rather than orally, and it was calculated that themean fraction of the rectally administered dose escaping first-pass metabolism was 57% 113 .Other drugs with high first pass metabolism, such as salicylamide and propranolol, did notdemonstrate as large an increase in bioavailability when administered rectally. However, thismay be due to incomplete absorption since these drugs exhibited a much largerbioavailability when administered rectally rather than orally to rats 114 .