Managing polypharmacy Walking the fine line 24 Current VOL. 2, NO. 2 / FEBRUARY 2003 p SYCHIATRY Current p SYCHIATRY between help and harm Steven F. Werder, DO o no harm” is the first rule of medicine, Assistant professor yet 106,000 Americans die each year from Departments of psychiatry and internal medicine properly prescribed and correctly taken Sheldon H. Preskorn, MD medications.1 In some cases, the cause of death is known and Professor and chairman “D Department of psychiatry and behavioral sciences can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the University of Kansas School of Medicine Wichita number of medications a patient is taking, even after control- ling for underlying diseases.2 In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symp- Drug combinations often represent toms: • Patients with affective and psychotic disorders are com- ‘uncontrolled experiments,’ with monly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more unknown potential for toxic effects. than one class), anxiolytics, antihistamines, and anti- Yet, combination therapies often cholinergics. • Patients with posttraumatic stress disorder may take are used in managing psychiatric selective serotonin reuptake inhibitors, buspirone, tra- zodone, antipsychotics, mood stabilizers, benzodi- disorders. These authors provide azepines, beta blockers, and opiates. • Multiple-drug regimens are used in treating other practical tools for prescribing multiple medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep dis- drugs as safely as possible. orders, and epilepsy. The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being VOL. 2, NO. 2 / FEBRUARY 2003 25 Managing polypharmacy Box 1 opment of multiple drug-resistant Mycobacterium tuber- POLYPHARMACY: culosis, and adding pyridoxine prevents isoniazid- MANY DRUGS, MANY DEFINITIONS induced neurotoxicity. This example illustrates two pre- scribing principles: • using multiple drugs can help achieve an intended oly, from the Greek word polus (many, much) and therapeutic goal Ppharmacy, from the Greek word pharmakon (drug, • adding one drug can prevent a known side effect poison) literally means many drugs or, alternatively, much of another drug. 3 poison. The word polypharmacy first appeared in the Another example is the therapeutic management of medical literature in 1959 in the New England Journal of congestive heart failure, in which five drug classes—an 4 Medicine and in the psychiatric literature in 1969 in an angiotensin-converting enzyme (ACE) inhibitor, a diuret- 5 article citing its incidence at a state mental hospital. ic, a digitalis glycoside, a beta blocker, and an aldosterone Many definitions have been used to describe and antagonist—are used in various combinations. All play a define polypharmacy, both qualitatively and quantitatively. role in improving cardiac function and reducing morbidity Monotherapy is drug treatment with one drug. and mortality. Sometimes treatment with two drugs is referred to as Using combination drug therapy can also generate co-pharmacy, while treatment with three or more drugs cost benefits, such as by adding a drug to delay or inhibit is referred to as polypharmacy. Minor polypharmacy the metabolism of an expensive principal drug. For exam- refers to treatment with two to four drugs, while major ple, adding diltiazem—a cytochrome P450 (CYP) 3A4 polypharmacy refers to treatment with five or inhibitor—to cyclosporine—which is metabolized by CYP 6 more drugs. 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of treated, sometimes while being mistaken for patient psy- cyclosporine’s narrow therapeutic index.) chopathology. As a prescriber, you are in a unique position to Contratherapeutic polypharmacy occurs when a patient tak- recognize and prevent interactions that can occur when ing multiple drugs experiences an unexpected or unintended patients are treated with two or more medications. This arti- adverse outcome. cle defines polypharmacy, describes its consequences, preva- lence, and risk factors, and offers an eight-step strategy with Settings for polypharmacy two mnemonics to help you avoid adverse events when pre- Polypharmacy occurs in five principal prescribing situations: scribing multiple-drug regimens. • treatment of symptoms • treatment of multiple illnesses What is polypharmacy? • treatment of phasic illnesses, such as many affective, Many definitions have been used to describe polypharmacy anxiety, seizure, and neurodegenerative disorders (Box 1).3-6 The most common definition is the use of five or • preventing or treating adverse effects of other drugs more drugs at the same time in the same patient.7 Although • attempting to accelerate the onset of action or augment polypharmacy often has a pejorative connotation, using five the effects of a preceding drug. or more drugs may be therapeutic or contratherapeutic. As described above, diseases such as tuberculosis and Therapeutic polypharmacy occurs, for example, when expert congestive heart failure, with well-understood causes and panels or researchers in carefully controlled clinical trials rec- pathophysiologies, are often treated with multiple therapeu- ommend using multiple medications to treat specific dis- tic drug combinations. However, the causes of many psychi- eases. For example, the five-drug combination of isoniazid, atric disorders and syndromes are less well-understood, rifampin, ethambutol, pyrazinamide, and pyridoxine is ther- which makes prescribing drug combinations more difficult. apeutic in initial tuberculosis treatment. More is better in this It may be that treating less well-understood diseases is a risk case because four antibiotics are needed to prevent the devel- factor for contratherapeutic polypharmacy. continued on page 29 26 Current VOL. 2, NO. 2 / FEBRUARY 2003 p SYCHIATRY Current p SYCHIATRY continued from page 26 Most individuals Table 1 who are prescribed five POLYPHARMACY WITH TWO OR MORE MEDICATIONS or more drugs are tak- ing unique drug com- Description Example 8 binations. These het- Two or more drugs from the same Two nonsteroidal anti-inflammatory erogeneous regimens drug category drugs (NSAIDs), two ACE inhibitors, represent “an uncon- or two phenothiazines trolled experiment,” with effects that cannot Use of multiple medications across Use of multiple CNS medications, as in be predicted from stud- therapeutic classes multiple antidepressants, antipsychotics, ies in the literature.9 or anticonvulsants Tables 1, 2, and 3 describe how contra- An inappropriate or unnecessary Inappropriate prescription due to therapeutic polyphar- medication is prescribed to a patient relative or absolute contraindications macy may occur with taking other medication Inappropriate prescription due to combinations of any weak or no indication number of drugs, Prescription of an exceedingly high dose The maximum recommended dose may be whether five or more to a patient taking other medication functionally exceeded to a serious degree if by the classic definition a drug with a narrow therapeutic index (e.g., or only two. For exam- amitriptyline) is combined with one that ple, contratherapeutic blocks its metabolism (e.g., fluoxetine) polypharmacy may occur when a patient is Two or more drugs sharing Anticholinergic toxicity due to combining a given the mood-stabi- similar toxicities low-potency phenothiazine antipsychotic and lizing drugs valproate a tertiary amine tricyclic antidepressant and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous: Other examples of potentially dangerous drug combina- • Carbamazepine is oxidized by arene oxidase to CBZ tions include those associated with torsades de pointes, which 10,11-epoxide, which is hydrolyzed by epoxide hydro- may occur with certain combinations of antihistamines, antide- lase to CBZ 10,11-dihydroxide. The metabolite CBZ pressants, antipsychotics, antivirals, antibacterials, antifungals, 10,11-epoxide has both ther- antiarrhythmics, and promotility agents. apeutic and toxic effects. • In monotherapy, the ratio of carba- Drug-drug interactions mazepine to CBZ 10,11-epoxide is Contratherapeutic In a drug-drug interaction, the presence of 10:1, with CBZ 10,11-epoxide having a polypharmacy may one drug alters the nature, magnitude, or shorter half-life than carbamazepine. occur with five duration of the effect of a given dose of • However, when carbamazepine and val- or more drugs another drug; the interaction may be either proate are taken as co-pharmacy, valproate therapeutic or adverse, depending on the blocks the hydrolysis of CBZ 10,11-epoxide or with only two desired effect. A drug-drug interaction may by inhibiting epoxide hydrolase, so that the be intended or unintended and is deter- ratio of carbamazepine to CBZ 10,11- mined by pharmacokinetics and pharmacodynam- epoxide becomes 2:1. Higher concentra- ics rather than by therapeutic class. tions of the epoxide metabolite con- Most available drug information describes the effects of tribute to neurotoxicity. individual drugs used alone (monopharmacy). Information VOL. 2, NO. 2 / FEBRUARY 2003 29 Managing polypharmacy Table 2 HOW PHARMACODYNAMICS MAY CAUSE ADVERSE