Oral absorption of medications: clinical implications

January 2003

The Pharmacology Consult column will periodically review basic principles of pharmacology and drug therapy management. Such reviews may be beneficial reminders of why recommendations for specific drug therapy administrations may differ. This month’s column will review the principles of oral absorption, including its characteristics and its clinical implications.

Principles of drug absorption

Most medications are given orally for children and adults. Most drugs exert their pharmacologic effect and clinical benefit only after absorption from the gastrointestinal (GI) tract and systemic distribution. This process may be especially important in infants and children because of the physiologic developmental changes that occur within the first years of life. Other factors, such as the effect of food and illness (eg, diarrheal episodes) upon drug absorption, are additionally important.

Most drugs are absorbed into the systemic circulation from the small intestine. Thus, they must first proceed through the relatively harsh environment of the stomach. Medications may be orally administered in numerous pharmaceutic dosage forms – solutions, suspensions, tablets, chewable tablets, capsules and enteric-coated dosage forms, among others. All of these drugs must first dissolve, as dissolution is the rate-limiting step for drug absorption. Once dissolved, the drug must proceed to the main site for absorption—the small intestine.

Numerous factors may affect the processes of dissolution and movement to the site of absorption: pH (affecting ionization, drug solubility, and dissolution), gastric emptying time, the presence of food (retarding gastric emptying), other disease states affecting the GI tract, chemical stability of the drug at various pH values, the pharmaceutic dosage form of the drug (affecting dissolution), blood flow to the GI tract, GI tract enzymatic activity and biliary function, among others. Many of these factors are further altered in young infants, as physiologic maturation occurs. Greater differences occur in infants born preterm.

Unfortunately the clinical implications of many of these factors are not well known, because many drugs are not well studied in children (see November 2002 Pharmacology Consult). Once dissolution occurs, absorption ensues as the drug reaches the intestinal villi, where blood perfusion is high. Newborn term infants have less gastric acid production in the first few days of life as compared to older infants and children. Gastric acid production increases throughout the first week of life, although similarities to adults do not occur until approximately two years. Gastric emptying is perhaps more important to drug absorption. Maturing of gastric emptying may not occur for up to six months in term infants. These differences are greater in infants born preterm. Delayed gastric emptying may affect the extent of drug absorption, although the rate of absorption is more likely to be affected. The presence of food (Table) may affect drug absorption by decreasing gastric emptying rate (longer for the drug to reach the site of absorption), retarding drug dissolution rate, slowing movement to the site of absorption or possibly even forming complexes with the drug.

Solid food will affect drug absorption and some liquids may as well. For example, apple juice has been shown to slow gastric emptying. This is most important for drugs that are chemically unstable in the gastric environment (eg, penicillin, erythromycin). Certainly, there are exceptions to this, as some drugs are more efficiently absorbed when food is in the stomach. Additionally, it is recommended to administer some medications with food – not so much to increase absorption, but as a means to decrease nausea, diarrhea or other GI tract adverse effects.

To summarize, the rate of absorption (and possibly the extent) for many drugs may be maximized by: administering drugs as liquid formulations when possible, administering doses on an empty stomach, administering doses with water (increasing gastric emptying), and administering doses with the patient in an upright position (effects of gravity). Specific clinical benefits of these effects may be difficult to predict, however. Recommendations to administer a specific drug with or without food may result from initial clinical studies, where pharmacokinetic analysis may have revealed higher serum levels when food was given or where study protocol dictated dosing on an empty stomach. Specific clinical benefits (ie, improved outcome) may not be identified in such studies.

Concomitant disease states may also affect drug absorption. Diarrheal episodes are common in children and may substantially increase transit rate through the GI tract, potentially decreasing the extent of drug absorption. Emesis can also alter the absorption process. It is difficult to judge the extent of absorption that has occurred with a specific dose when emesis occurs after drug administration.

As discussed above, various factors can affect the rate and extent of absorption. It may be best to allow the therapeutic index of the drug and the seriousness of the disorder to be used as factors in assessing if an additional dose should be given. Alternative routes of administration may become necessary (eg, intramuscular, rectal). Some disease states affecting the GI tract (eg, inflammatory bowel disease) may also alter drug absorption, although this concept has generally not been well studied. Concerns of altered absorption may be addressed in part by administering drugs in liquid dosage forms when possible, as time necessary for dissolution is decreased.

Sequential therapy

Sequential therapy is used to describe the replacement of intravenous drug therapy with oral therapy in the treatment of various disorders, at a point relatively early on in treatment. This change in the route of administration allows significant cost savings, as oral dosage forms are less expensive, often resulting in earlier hospital discharge than previously planned, and is more convenient for the patient and clinical staff. These benefits have been shown by numerous published studies. Most of these studies have evaluated sequential antibiotic therapy in the treatment of community-acquired pneumonia, with intravenous therapy continuing for two to three days and oral therapy for an additional five to eight days. Criteria for switching to oral therapy have included, euthermia, declining leukocyte counts, normal GI tract absorption, improving symptoms and the ability to tolerate oral medications. Although most of these studies have been conducted in adults, several studies have evaluated children, with similarly good results. Antibiotics most commonly evaluated have included second- or third-generation cephalosporins and fluoroquinolones. Cefuroxime (Zinacef, GlaxoSmithKline) has been frequently evaluated, for it is available as intravenous and oral dosage forms and is commonly used in the treatment of pneumonia. Clinicians should use some caution with sequential therapy of third-generation cephalosporins, as several agents available orally may not possess adequate antibacterial activity toward Streptococcus pneumoniae (notably ceftibuten [Cedax, Biovail] and cefixime [Suprax, Lederle]).

Drug-food interactions

The accompanying table lists commonly used medications in children and the potential effects of food upon their absorption. Because this table is not complete, clinicians should consult specific drug labeling for more information. As stated above, absorption for most medications is most efficient without food in the stomach. Some drugs, however, may be better absorbed with food, and administration with food may decrease the potential for adverse effects for other drugs. Some drugs best taken on an empty stomach may be given with food if gastrointestinal adverse effects occur.

For more information:

• Mayersohn M. Principles of drug absorption. Modern Pharmaceutics, 3rd Ed., Marcel Dekker, Inc., New York, 1996, 21-73.
• Vogel F. Intravenous/oral sequential therapy in patients hospitalized with community-acquired pneumonia – which patients, when, and what agents? Drugs. 2002;62:309-17.
• Dagan R., et al. Parenteral-oral switch in the management of pediatric pneumonia. Drugs. 1994;47(Suppl 3):43-51.