Safety Information

Different medications can interact with each other and cause what is known as drug interactions, which can occur with almost all drugs. Such interactions could occur at any stage while the drug is present within the body. These interactions could either reduce or increase the effect of other drugs, or could produce a different, new effect. Drug interactions can occur in any pharmacokinetic (PK) process, including absorption, distribution, metabolism, and excretion. All these PK processes are important and it is therefore crucial that patients should consult a physician or pharmacist about the possible interactions that may occur between drugs and with certain foods to avoid undesirable effects (Karch and Lasagna, 1975).

There are many occasions when drugs may interact with each other in absorption - one such has been observed with the antihyperlipidemic agent colestipol (Colestid®), which interacts with other medications by decreasing their absorption and thus reducing their effect as their concentrations in the plasma are lowered.(Bays and Dujovne, 1998) Also, iron-containing products which are used for treatment of certain types of anemia can decrease absorption of other drugs, and so it is recommended these drugs are used at least two hours apart. In addition, some types of food may interact with certain medications. For example, calcium-containing foods such as milk and cheese can chelate and form large complex molecules with the antibiotic group tetracyclines, preventing their absorption in the gastrointestinal tract (GIT) and rendering them ineffective in combating infection (Schmidt and Dalhoff, 2002).

The second phase of pharmacokinetics in which medications may interact with each other is the distribution phase. Many drugs are bound to proteins in the plasma, such as albumins and globulins. Protein-bound drugs are not effective and the free plasma concentration of a drug is the active one. Bound and unbound forms of a drug exist in balance with each other and portions of the bound drug are released from their proteins as the free unbound drugs get involved in the rest of the pharmacokinetic processes, including excretion. What can happen is that some drugs may displace other drugs from their proteins, increasing their free unbound concentration in the plasma - leading to adverse effects and signs of toxicity under a normal dosage regimen. For example, the anticoagulant agent warfarin (Coumadin®) is a highly protein-bound drug (97%), meaning that only 3% of the dose is active for biological effects. The widely used antipyretic agent aspirin can displace warfarin from plasma proteins, leading to serious bleeding. Thus, it is very important to be vigilant about this fact, responding by either providing a different antipyretic agent that does not displace warfarin or by adjusting the warfarin dose (lowering the dose) to prevent serious side effects (Zibaeenezhad et al., 2004, Ageno et al., 2012, Pranckeviciene et al., 2013).

The metabolism is one of the most important pharmacokinetic processes and can have great involvement in drug-drug or drug–food interactions. The liver produces many enzymes that are mainly responsible for deactivating xenobiotic agents, including the medications we use. Many drugs can alter liver enzymes by either increasing their expression or lowering their expression and production. The best known drugs that induce liver enzymes are the antibiotic drug rifampicin (Rifampin®) and the antiepileptic agent phenytoin (Dilantin®) (Lehtinen et al., 2013, Yamashita et al., 2013). Well-known and widely used drugs that are liver enzyme inhibitors include the antibiotics erythromycin (Ery-Tab®) and azithromycin (Zithromax®), and the antifungal ketoconazol (Nizoral®). A controversial drug–drug interaction related to induction of microsomal liver enzymes is that observed with the co-administration of antibiotics and contraceptives. Antibiotics reduce the level of the contraceptives and thus they may fail to prevent pregnancy (Shah et al., 2009, Smith et al., 2012, Quinney et al., 2013).

The last stage of pharmacokinetics at which drug interactions may occur is the excretion phase. This could happen when the transporters or the mechanisms by which a drug is excreted are the same for another drug that is concomitantly administered, leading to a delay in the excretion of one of the drugs and increasing its concentration in the body, which can result in toxicity and side effects. An example of such interaction is that observed when aspirin and the anticancer drug methotrexate (Treauzall®) are co-administered (Tracy et al., 1992, Bannwarth et al., 1996, Iqbal et al., 1998, Vakily et al., 2005).