Chapter 5

How to manage potential drug interactions

I. Introduction to drug interactions

Q. What are the different types of drug interactions?

A.

There are different types of pharmacodynamic drug interactions:

• Additive (same response as the sum of the two drugs individually)
• Synergistic (greater response)
• Antagonistic (less of a response).

Examples include: additive effects when two or more drugs with similar pharmacodynamic effects are given together resulting in excessive response and possible toxicity; synergistic effects where the effects of two drugs taken together is greater than the sum of their separate effect at the same dose and; antagonistic effects where drugs with opposing therapeutic effects may reduce the response to one or both drugs. For instance, nonsteroidal anti-inflammatory drugs (NSAIDs) that increase blood pressure may inhibit the anti-hypertensive effects of angiotensin-converting enzyme (ACE) inhibitors when given together (Hansten & Horn 2003).

    Synergistic drug interaction: The effect of two or more drugs when administered together is greater than if the drugs were given separately; may produce responses equivalent to over dosage. For example, patients with hypertension do not respond adequately with one drug must take combination drugs (Meredith & Elliott 1992).

Q. How are drug–drug/food interactions rated according to how much of an impact it makes?

A. Table 5.1 classifies the rating of drug interactions.

Q. What is the relative importance of drug interactions in dentistry?

A. Many drug interactions are usually harmless or go clinically unnoticed; many of those which are potentially harmful occur in only a small percentage of patients given the interacting drugs. Results of the interaction differ among ­individuals and may be more serious in one patient than another. The drugs most often involved in serious interactions are those with a small therapeutic index, such as phenytoin and those where the dose must be carefully controlled according to the response, as with anticoagulants, antidiabetics and antihypertensives. The elderly and patients with impaired renal and liver function are especially prone to drug interactions.

Table 5.1 Rating of drug interactions.

Q. When does a drug interaction show clinically?

A. It depends. Factors that must be taken into account include the drugs half-lives, the dosages that are being administered and the mechanism of metabolism. For example, if the offending drug takes a long time to accumulate, the interaction may be delayed several days. However, if the patient is receiving a large dose of the drug, the interaction may occur more rapidly. Also, if the patient is not getting the expected response from the drugs then a drug–drug interaction could be suspected.

Q. Explain the cytochrome P450 enzyme interactions?

A. Few drugs are eliminated from the body unchanged in the urine. Most drugs are metabolized or chemically altered to a less lipid-soluble compound which is more easily eliminated from the body. One way of metabolizing drugs involves alteration of groups on the drug molecule via the cytochrome P450 enzymes. These enzymes are found mostly in the liver, but can also be found in the intestines, lungs, and other organs. Each enzyme is termed an isoenzyme, because each derives from a different gene. There are more than 30 cytochrome P450 enzymes present in human tissue.

Q. How does one drug interact with another drug via the cytochrome P450 enzymes?

A. The substrate is a drug that is metabolized by a specific CYP450 isoenzyme. An inhibitor is a drug that inhibits or reduces the activity of a specific CYP450 isoenzyme. An inducer is a drug that increases the amount and activity of that specific CYP450 isoenzyme.

Q. When does a drug interaction occur via the cytochrome P450 enzymes?

A. Drug interactions can occur when a drug that is metabolized and/or inhibited by these cytochrome enzymes is taken concurrently with a drug that decreases the activity of the same enzyme system (e.g., an inhibitor). The result is often increased concentrations of the substrate. Another scenario is when a substrate that is metabolized by a specific cytochrome enzyme is taken with a drug that increases the activity of that enzyme (e.g., an inducer). The result is often decreased concentrations of the substrate.

    Some substrates are also inhibitors for the same enzyme, probably due to competitive inhibition of enzyme activity. Some inhibitors affect more than one isoenzyme and some substrates are metabolized by more than one isoenzyme (Weinberg, 2002).

Q. What are common drug–drug interactions that occur with the cytochrome P450 isoenzymes that are significant in dentistry?

A. Table 5.2 lists common drugs (related to drugs the patient is taking and dental medications prescribed to the patient) that are metabolized (substrate) by specific cytochrome P450 isoenzymes and the drugs that inhibit (inhibitor) or ­accelerate (inducer) the specific isoenzyme causing a drug interaction. Please note: only commonly encountered drugs used in dentistry are listed. There are many more drugs involved in the cytochrome P450 isoenzyme metabolism. Please refer to Hersh & Moore, 2004 and Cupp & Tracey, 1998 for more details.

Table 5.2 Substrates (drugs) metabolized by specific isoenzymes.

Q. Which are the most abundant cytochrome enzymes in humans?

A. The CYP3A isoenzymes make up about 30% of all cytochromes in the liver.

Q. Why is it important to know about substrates and inhibitors and how are the tables used?

A. Inhibitors are drugs prescribed by the dentist that can interfere with a substrate or a drug already taken by the patient. Tables 5.3 and 5.4 are used to look up a drug that you are prescribing to see if it is an inhibitor or an inducer of an isoenzyme. If it is found on the table then determine which isoenzyme is affected and then go to Table 5.2 to see if the patient is taking a drug that is metabolized by that isoenzyme.

    If the dentist prescribes a drug that could inhibit the metabolism of the above substrate (look under the correct CYP isoenzyme) then possibly there is a drug interaction that could result in toxicity (elevated plasma levels) of the substrate. It is necessary to check on the list to avoid this problem. For example, if the patient is taking atorvastatin for cholesterol problems and an antibiotic is needed because of a dental infection and the patient is allergic to penicillin, clarithromycin (Biaxin) should not be prescribed because according to the table, clarithromycin is a potent inhibitor of atorvastatin, resulting in toxic plasma levels of the statin drug. If it is appropriate prescribe clindamycin or azithromycin (Zithromax). Remember that azithromycin is not metabolized by the CYP isoenyzmes so that there are less drug interactions. Table 5.3 lists common inhibitors of the above substrates.

Table 5.3 Inhibitors (drugs) of specific cytochrome P450 isoenzymes: the drugs listed on the right side inhibit the specific isoenzyme on the left side of the table.

Table 5.4 Inducers (drugs) of the CYP450 isoenzymes.

Hersh & Moore 2004.

Q. What could happen if the patient is taking alprazolam (Xanax) for anxiety and is prescribed clarithromycin or erythromycin?

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