Tips for Managing Multiple Medication Use

James Thew_AdobeStock

SPECIAL REPORT: POLYPHARMACY

With great power comes great responsibility.” That quote is best known in terms of the fictional character Spider-Man, but dates to the early 19th century.

Regardless of the origin, it is quite applicable to prescribers. The principles and resources in this article should elucidate why and how the quote applies to prescribing medications to our patients. (Interested readers are encouraged to review the references for deeper discussions of these principles.)

First Principle

The prescriber has the potential to change the biology of their patient by the drugs they prescribe. Changing the biology of the patient is how most drugs treat disease.

How many variations on human biology can drugs produce? Quadrillions based on the number of drugs on the market and using up to just 5 in combination. In a simple scenario, starting with only 600 drugs and using up to 5 in combination can yield 650 billion different possible combinations.¹

This article intentionally uses the phrase multiple medications rather than polypharmacy because the latter term conveys a negative connotation. Importantly, there are many good reasons for a patient to be taking multiple medications.

Similarly, drug-drug interactions (DDIs) are also not necessarily bad. They may be planned and beneficial. Every instance in which a prescriber uses a second drug to augment the efficacy or improve the tolerability of a first drug is a planned DDI.

First Principle in Practice

Clinical scenarios can help put this first principle into perspective.

Case 1. “Anthony” had treatment-resistant schizophrenia that had been in remission, particularly for positive symptoms, for several years with clozapine. After he developed anxiety symptoms, the treating clinician added buspirone starting at 15 mg/day in 3 equally divided doses and then increasing to 30 mg/day.

Because his anxiety was not improving, Anthony went to the hospital and was admitted to a psychiatric unit by another team of psychiatrists. They added an antidepressant and consulted an internist for the patient’s complaints of “wheezing.” The internist added theophylline.

Lessons learned. There are many facets to this case.² The patient went from 1 to 4 medications over the course of 2 weeks. In addition, the buspirone was maintained although it had not worked; the clinician could have increased the amount to the maximum recommended dose or declared the drug to be a treatment failure and stopped the buspirone. Not following this approach (ie, adjusting the dose or declaring a treatment failure) contributes to needless multiple medication use.

Although theophylline would not be used today, it reflects the silo approach to treatment by the internist. This patient was hospitalized for increasing anxiety and insomnia, which are common adverse effects of theophylline. The internist was treating the patient’s respiratory system and not considering the whole patient.

Case 2. “Charlie” was being treated by 4 different clinicians: His primary care physician was treating him for pain with codeine, his cardiologist was treating his hypertension with metoprolol, his psychiatrist was treating his depressive disorder with paroxetine, and his infectious disease specialist was treating his bronchitis with erythromycin.³

The questions that should be asked are: Do these medications interact? If so, how does the patient appear as a result?

The answer to the first question is yes—4 times. First, codeine requires biotransformation to morphine to be effective for pain relief. This biotransformation is mediated by the drug-metabolizing enzyme cytochrome P450 (CYP) 2D6. Second, metoprolol requires biotransformation by the same CYP enzyme to be eliminated from the body. Third, paroxetine inhibits CYP2D6. Fourth, paroxetine requires biotransformation by CYP3A4 to be eliminated from the body. Erythromycin inhibits CYP 3A4.

Regarding the second question, how does the patient look as a result of these interactions? Due to CYP2D6 inhibition, he remains in pain despite the codeine, and his increased levels of metoprolol can cause fatigue. Due to CYP3A4 inhibition, his paroxetine levels increase, which can cause apathy and decreased libido. Each interaction can make the patient look more depressed.

Lessons learned. Drugs do not interact because of who prescribed them or their therapeutic class (particularly psychiatric medications). Instead, they interact based on their pharmacodynamics (their action on the body) and their pharmacokinetics. The results of such interactions are not necessarily dramatic (eg, sudden death) but instead can present in multiple ways that blend into everyday clinical practice.

Second Principle

Prescribers need to consider all the drugs patients are taking in terms of their pharmacodynamics and pharmacokinetics, because that is how they interact. The equation (Figure 1) is a foundation for understanding how most drugs produce a clinical response, both desired and undesired.

Figure 1. Understanding the Clinical Response

The ability of a drug to bind and have an effect (eg, agonism, antagonism, inverse agonism) on a site of action gives it the potential to produce an effect. This is the first variable in the equation. However, the drug must occupy a sufficient number of those sites to produce the effect. This is determined by the second variable in the equation, drug concentration.

Nevertheless, the interindividual variability among patients can influence the nature or the magnitude of the drug’s effect. That is the third variable in the equation. The 4 major causes of variability are genetics (including epigenetics), age, disease, and internal environment (ie, what patients are consuming, including drugs). The third variable(s) affects either the first and/or second 2 variables in the equation to determine the drug’s effect in a specific patient.

Although drugs can be classified in 4 ways, only 2 are relevant to prescribing (Figure 2).

Figure 2. Four Ways to Categorize Drugs

Caveat. Psychiatric medications (particularly the so-called atypical antipsychotics) affect multiple sites of action over a relatively narrow concentration range of approximately 5- to 20-fold. As the concentration of these drugs increases, they begin to affect their lower affinity targets such that the effects they produce also change.

For example, at its lowest concentrations, quetiapine affects α-1 adrenergic and histamine-1 receptors, but to function as an antipsychotic, the concentration must be 20 times higher. Thus, low doses (25-100 mg) can aid with sleep, whereas higher doses (500-750 mg) are needed to treat psychosis.

Third Principle

In addition to being aware of all prescribed medications, clinicians need to be aware of any illicit drugs, over-the-counter drugs, and nutraceuticals the patient is taking. That is a tall order but can be aided by ensuring the patient is receiving all their medications by a single pharmacy or pharmacy chain, as they will have a record of the medications and will cross-check them for interactions.

Electronic medical records and states’ drug monitoring systems and their usefulness is a vast topic beyond the scope of this paper; it is important to note that these systems, including those used by pharmacies, have limitations.

For instance, they may be set for sensitivity and hence will over alert and waste a clinician’s time. Or they may be set for specificity and hence will under alert. Thus the prescriber/clinician is the final arbiter because they are monitoring the patient and the clinical response, which is the summation of the variables in the aforementioned equation.

Fourth Principle

The more medication the patient is taking, the more likely they are to be taking a combination that is unique to them.⁴ Similarly, patients receiving psychiatric medications are at higher risk of taking multiple medications than those who are not taking psychiatric medications, even when one adjusts for the age of the patient.⁵

Fifth Principle

Be disciplined when prescribing and avoid falling into the trap of adding more medications when one fails to perform as expected. Use the scientific method and sequential therapeutic trials to determine what is most appropriate for each patient.⁶

That means stopping the failed medication when a trial does not work, unless a combination trial (which is generally a planned DDI) is warranted. If that combination trial fails, stop it and move to another therapeutic trial including nonpharmacological treatments.

Sixth Principle

If a patient is not doing well and is taking multiple medications, look at the multiple medications as a potential cause. Perhaps they are not doing well because they are taking those drugs rather than despite their taking them.³

Seventh Principle

Be familiar with each medication’s package insert, particularly in terms of the drug’s pharmacodynamics and pharmacokinetics as well as how the agent might interact with other drugs. Package inserts are easily available on the internet.^7,8

Concluding Thoughts

These 7 principles provide clinicians with an introduction to the issues that should be considered as part of prescribing single as well as multiple medications for a patient. However, this is just the beginning; there are 12 additional considerations for minimizing unintended and adverse DDIs.⁹

Similarly, it is important to reflect and record the results of therapeutic drug monitoring (which is woefully underutilized in psychiatry) and genetic testing (which may be overused and misused in psychiatry).^10,11 Genetics are useful because they help determine factors such as drug metabolism, but phenoconversion can occur so that the patient is functionally not what their genetics would predict.

For this and other reasons, genetic testing in psychiatry is in its infancy and has limitations. Therapeutic drug monitoring assists by determining the functional capability and adherence of the patient with the dosing recommendation.

Follow the Hippocratic oath and first do no harm. Remember, the benefit of the treatment should outweigh its tolerability and safety concerns. Be knowledgeable and disciplined when prescribing medication, because prescribing medication is a great power that comes with great responsibility.

Dr Preskorn is a professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine-Wichita. He has been a principal investigator at the site level on all antipsychotic and antidepressant medications approved in the United States over a 25-year period.

Dr Preskorn has disclosed that he has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker’s bureau for Alkermes, BioXcel Therapeutic, Eisai Co, Ltd, Janssen, Lyndra Therapeutics, Otsuka Pharmaceutical, Co Ltd, Sunovion Pharmaceuticals Inc, and Usona Institute. All clinical trial and study contracts were with, and payments made to, The University of Kansas Medical Center Research Institute, a research institute affiliated with the University of Kansas School of Medicine-Wichita.

A complete list of references is available at psychiatrictimes.com/view/references-tips-for-managing-multiple-medication-use.