A Guide To Drug-Drug Interactions In Podiatry

Robert G. Smith, DPM, MSc, RPh, CPed

   Precipitant drugs that act as binding agents, such as cholestyramine (Questran, Bristol-Myers Squibb) and colestipol (Colestid, Pfizer), can impair the bioavailability of object drugs. Thus, an impairment of the bioavailability of the object drug results in a reduction of therapeutic effect of the object drug. The amount of a medication that is absorbed from the gut may be increased or decreased by drugs that increase stomach pH. Interactions affecting the rate of absorption are generally insignificant unless the patient must achieve therapeutic plasma levels quickly as in the case of analgesics. Conversely, interactions affecting the extent of absorption may affect the efficacy of a drug.

   Once absorbed, most drugs bind to plasma proteins that are specific for some aspect or structural feature of the drug. The term, volume of distribution, commonly describes the extent of drug distribution to tissues relative to the plasma volume.

   Drug metabolism refers to enzyme-mediated structured modification to a drug that changes its biological activity and/or water solubility. Drug metabolism occurs as a result of enzymatic reactions on the medications that result in metabolites that may be active or rendered inactive. The gastrointestinal wall, lungs, liver and blood possess enzymes that metabolize drugs.6-8

   Metabolism via the smooth endoplasmic reticulum of the liver is the first step in the elimination of many drugs.6,8 Drug metabolism by the liver occurs through one or both biotransformation reactions that are classified as either Phase I or Phase II reactions.7 Phase I reactions modify the drug by using oxidation, hydrolysis and reduction. These modifying reactions create a more polar and highly water-soluble drug molecule for elimination by the kidneys.

   Phase II reactions modify the drug pharmacologically to an inactive form via conjugation resulting in glucuronides, acetates and sulfates. This occurs via the formation of a covalent linkage between a functional group appearing on the parent drug as a result of phase I metabolism and endogenously derived glucuronic acid, sulfate, glutathione, amino acids or acetate.6,9 The kidneys may now eliminate this new drug metabolite.

   Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either reduced activity of the enzyme or increased activity of the enzyme referred to as enzyme induction (see “Understanding How Drugs Affect Enzymes” at the right).

   Metabolism and elimination are responsible either separately or together for drug inactivation. Without these two pharmacokinetic functions, drugs would continuously circulate through our bodies, interacting with various body receptors and interrupting important physiological processes.13 Drugs are either eliminated directly or converted into metabolites that are subsequently excreted.

   Removal of a drug from the body may occur by a number of routes, the most important being through the kidney into the urine. Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Drugs that have the same active transport mechanism can compete for excretion in the kidney tubules. Active secretion into the renal tubules is an important route of elimination for some drugs. Other routes of elimination for drugs from the body include sweat, tears, breast milk or expired air. Some drugs are excreted in the bile as water-soluble conjugates. Bacteria in the gut can break down these conjugates to liberate the free drug, which can then be reabsorbed.

   Pharmacodynamic interactions are due to competition at receptor sites or activity of the interacting drugs on the same physiological system. There is no change in plasma concentrations of interacting drugs. When patients concurrently take medications with similar pharmacodynamic effects, this may result in an additive pharmacologic excessive response and possible drug toxicity. Conversely, drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs. The pharmacodynamic consequences precipitated by drug-drug interactions may or may not closely follow pharmacokinetic drug changes.

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