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Drug Interaction 'Pearls': Looking at the Big Picture

by Diane B. Crutchfield, D.Ph., C.G.P.

Geriatric Times March/April 2001 Vol. II Issue 2

(Part I of this article, "Drug Interaction 'Pearls': Asking the Right Questions," appeared in the January/February issue of Geriatric Times, p9-Ed.)

In last month's column, we looked at how lifestyle, diet and over-the-counter (OTC) medications may affect drugs in the elderly. In this column, we will explore problems with drug-drug interactions.

A few essential facts about drug interactions should be understood in order to determine which interactions are likely to impact your patients. Drug interactions are typically characterized as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions are those in which one drug alters the rate or extent of absorption, distribution, metabolism or excretion of another drug. Pharmacodynamic interactions involve a change in a patient's response to a drug induced by another drug.

Pharmacological interactions may be difficult to identify. Concurrent use of two or more drugs with either synergistic or antagonistic effects are examples of this type of interaction.

Drugs can interact at various locations in the body. The most well-studied site of drug interactions is the liver, which metabolizes many medications. The enzymes responsible for hepatic drug metabolism are components of the cytochrome P450 (CYP) system, and an understanding of this system provides the key to understanding the significance of many interactions. The cytochrome P450 enzyme system has several key features (Cadieux, 1999). Among them:

In addition to looking for pharmacokinetic and pharmacodynamic drug interactions, we must also be aware of the need to consider the pharmacology of the individual agents and how they impact the efficacy of each other.

Residents in long-term care facilities are frequently sent to the hospital and return to the facility with new medication orders in addition to an order to "continue previous meds at nursing home." Mr. B, a 78-year-old male, returned to the facility with an order for ciprofloxacin (Cipro) for seven days and instructions to continue previous meds, which included chronic warfarin (Coumadin) therapy. The International Normalized Ratio (INR) was elevated to 4.1 by the third day at the facility. After several adjustments of warfarin dose, the antibiotic course was completed and the patient was stabilized.

Pearl No. 1

Don't forget to ask about previous medications the patient has been taking. I have frequently seen ciprofloxacin given with an antacid to avoid gastrointestinal upset, or the antacid has been continued routinely as requested in the order for continuing previous medications. Ciprofloxacin binds with the aluminum- or magnesium-containing antacid, and there is a reduction in drug levels of 50% to 90%. The binding interaction is also seen with other fluoroquinolones, but not to the extent as with ciprofloxacin. The outcome is an essentially untreated infection that is very expensive in terms of the drug's cost and a negative outcome for the patient.

On numerous occasions, I have found patients with diagnoses of dementia and Parkinson's disease (PD) receiving a typical antipsychotic and carbidopa/levodopa (Sinemet). They are receiving a dopamine antagonist (antipsychotic) and carbidopa/levodopa to increase dopamine. In addition, the typical antipsychotic will contribute to Parkinson-like extrapyramidal symptoms.

Pearl No. 2

Ideally, atypical agents should be used, but keep in mind that there are still patients who have been on typical antipsychotics for many years. Another issue that comes to mind is whether the patients have been properly diagnosed with PD or whether the chronic use of antipsychotics has led to their movement disorder.

Another example is the use of acetylcholinesterase inhibitors, such as donepezil (Aricept), with anticholinergic medications. Drugs with central anticholinergic properties are pharmacologic opposites of the acetylcholinesterase inhibitors and should be avoided. Examples include benztropine (Cogentin), trihexyphenidyl (Artane) and strongly anticholinergic antidepressants. It should also be noted that another potential interaction exists with donepezil and some selective serotonin reuptake inhibitor antidepressants. SSRIs that are potent inhibitors of the CYP2D6 isoenzyme, such as fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil) and possibly sertraline (Zoloft), inhibit the metabolism of donepezil and can cause severe gastrointestinal side effects.

One question that you could always count on getting correct on state board exams is whether aspirin and warfarin can be given together. I now pity the unfortunate nurse who calls the cardiologists to inform them about this "deadly" interaction! Low-dose aspirin is now commonly used with warfarin, keeping a close watch on INR values and evaluating the benefit to risk.

Pearl No. 3

Stay abreast of current clinical practice with the understanding that "managed interactions" do exist and are not detrimental to the patient.

Reports now indicate that routine use of acetaminophen also increases the risk of bleeding for patients taking warfarin. Traditionally, patients on anticoagulants have been encouraged to take acetaminophen instead of aspirin. Again, if the patient is managed on a routine dose of acetaminophen and warfarin, then the potential problem should be noted, but a significant change in INR can be avoided as long as the patient does not suddenly increase or decrease the acetaminophen dose (Hylek et al., 1998). Remember to advise against the nonprescription use of nonsteroidal anti-inflammatory drugs with warfarin.

Order of administration of medications plays a role in the potential for a drug interaction. For example, a patient taking cimetidine (Tagamet) can be started on warfarin without great concern. If, however, the patient is stable on warfarin and then starts taking cimetidine, which is also now available OTC, there is cause for very close monitoring of INR values and clinical monitoring. This interaction results in a gradual increase in hypoprothrombinemia over one to two weeks.

Do not assume that medications within the same class have the same interactions. Cimetidine is known to have several drug interactions that are not seen with other H2 antagonists, such as the warfarin interaction described above. The same is true for SSRIs.

Pearl No. 4

We should use caution when interpreting drug interactions based on computer software alone, since some programs only recognize class interactions. Tools are convenient and helpful, but a basic understanding of pharmacology is invaluable to the physician, pharmacist or nurse.

Another point to remember is that not all interactions occur immediately, so the possibility of a drug interaction cannot be discounted if it occurs a few weeks after a medication change.

Pearl No. 5

Medications known as enzyme inducers stimulate the hepatic microsomal metabolism of a variety of drugs by inducing specific isoenzymes. The enzyme induction may take several days to weeks. Drugs commonly known as inducers include rifampin (Rifadin), phenobarbital, carbamazepine (Tegretol) and phenytoin (Dilantin). Use of these agents with narcotic analgesics, for example, may result in decreased analgesic efficacy or withdrawal symptoms.

Conclusion

Many of the examples given include cases with the use of narrow therapeutic index drugs, which increases the significance of the interaction even more-particularly for the geriatric population. I hope that these pearls have provided information that you can apply in your practice setting to avoid drug interactions in our elderly population.

Dr. Crutchfield is president of Pharmacy Consulting Care, an independent consultant pharmacy practice located in Knoxville, Tenn.

References

Cadieux RJ (1999), Antidepressant drug interactions in the elderly: understanding the P-450 system is half the battle in reducing risks. Postgrad Med 106(6):231-249.

Hylek E, Heiman H, Skates SJ et al. (1998), Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 279(9):657-662 [see comment].

Further Reading

Goldberg RM, Mabee J, Mammone M et al. (1994), A comparison of drug interaction software programs: applicability to the emergency department. Ann Emerg Med 24(4):619-625.

Hansten PD, Horn JR (1997), Hansten and Horn's Drug Interactions Analysis and Management. Vancouver, Wash.: Applied Therapeutic Inc.

Slyk MP (2000), Drug interactions: the pharmacist's forte? Consult Pharm 15(1):85-92.