Physiological Pharmaceutics

102 Physiological Pharmaceuticspeak plasma concentration and area under the plasma concentration-time curve of thenifedipine, but not its metabolite. The increased absorption of these drugs also produced asignificantly higher heart rate. Lying down decreased the rate of gastric emptying whencompared to sitting, and a combination of sitting and standing produced the most rapidgastric emptying 102 .Drug-induced effects on gastric emptyingDrugs contained within the formulations may also alter gastric motility. For exampleadrenergic agonists, particularly ß 2-agonists such as salbutamol, delay gastric emptying. Inasthmatic subjects an variable quantity of the inhaled drug may be swallowed, and henceeven though the drug is not taken by the oral route, it may still have an effect on the gastricemptying of other drugs. Tricyclic antidepressants and some anti-Parkinsonian drugsdepress gastrointestinal motility. Dopaminergic antagonists e.g. domperidone, andcholinergic agonists e.g. bethanechol, enhance gastric motor activity.GASTRIC pH AND ENTERIC COATINGSIn the past, the pH chosen by most formularies to represent the conditions in the stomachis 1.0 (100 mM HCl). However, there is some evidence that the basal gastric pH can besurprisingly high. It has been reported that 35% of humans have a resting gastric pH of 6or above 103 . Less than 2% of the human subjects had a resting pH below 1.5. Basal gastricpH in normal healthy students is around 1.8, but occasional cases of achlorhydria are seen.Meals markedly alter the pH, which can increase to 3–5 after eating, particularly if the mealcontains large amounts of easily digested protein.These variations in pH will be especially important when developing productsdesigned to be gastro-resistant, e.g. enteric coatings for acid-labile or potentially irritantdrugs. In these cases gamma scintigraphy may be combined with in vivo pH measurementto investigate the efficiency and operation of the enteric coating. In a study whichadministered both radiolabelled pH radiotelemetry capsules and radiolabelled entericcoated naproxen tablets to fed subjects 72 , it was found that the pH remained below 2 withinthe stomach, except for a transient rise after food. Five tablets disintegrated in the smallintestine approximately 1.2 h after gastric emptying, 1 disintegrated in the stomach at pH1.1 and 1 tablet remained intact in the stomach for 9 h.DRUG/FORMULATION INDUCED ULCERATIONAcute and/or chronic lesions on the gastric mucosa may result from the ingestion of alcohol,and some drugs such as anti-inflammatory drugs, reserpine, histamine and caffeine.Salicylates are often reported to produce dyspepsia and gastric ulcers due to theirwidespread use. A single dose of 2 aspirin tablets produced haemorrhaging in the stomachof normal volunteers within 1 hour of ingestion, continued intake (2 tablets every 6 hours)resulted in gastric erosions in all subjects and duodenal erosions in 50% of the subjects 104 .Patients who require aspirin on a regular basis should take enteric coated or adequatelybuffered preparations.ANIMAL MODELS FOR GASTRIC EMPTYINGDogs are widely used to assess the absorption of drugs. However, the drug absorptionprofiles differ quite considerably from those in humans, and this is a particular problemwhen attempting to obtain useful data for either sparingly water-soluble drugs or sustainedrelease preparations.