Steven F. Werder, DO

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

A temporal relationship is all that is required, although preexisting conditions and events clearly related to other causes are not usually considered adverse events.

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

‘Uncontrolled experiments.’ Drug combinations often are “uncontrolled experiments” with unknown potential for toxic effects.¹² Studies have linked polypharmacy and DDIs as well as DDIs and AEs:

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

DDI risk is increasing over time as the number of medications used to treat psychiatric patients has grown. For example, 3.3% of patients discharged between 1974 and 1979 from the National Institute of Mental Health Biological Psychiatry Branch were taking 3 or more medications, compared with more than 40% of patients discharged between 1990 and 1995—a 12-fold increase.¹⁵

Box 2

 

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

Table 1

LISTEN: 6 tips to minimize DDI risk

L	Listeach drug’s name and dosage in the patient’s chart and in a note given to the patient.
I	Each drug should have a clear indication and well-defined therapeutic goal; discontinue any drug not achieving its goal
S	Make the regimen as simple as possible, with once- or twice-daily dosing.
T	When possible, treat multiple symptoms with a single drug, rather than multiple symptoms with multiple drugs
E	Educatepatients about polypharmacy, DDIs, and adverse events; assess all medications—including vitamins, minerals, herbs, dietary supplements, nonprescription products—and address potential DDIs
N	Avoid prescribing medications with a narrow therapeutic window.

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

Mood stabilizer	Drug interactions
Carbamazepine	↑plasma clomipramine, phenytoin, primidone
	↑risk of neurotoxic side effects and confusional states with lithium
	Alters thyroid function with anticonvulsants
	↓anticoagulant concentrations and↑bleeding risk
	↓oral contraceptive reliability; can cause false-negative pregnancy tests
	↑metabolism and may ↓efficacy of cancer chemotherapy (docetaxel, estrogens, paclitaxel, progesterone, cyclophosphamide)
	↑aprepitant, granisetron metabolism and ↓efficacy
	↑glipizide, tolbutamide metabolism
Lithium	NSAIDs (ibuprofen, indomethacin, piroxicam) and COX-2 inhibitors ↑plasma lithium
	ACE inhibitors ↑plasma lithium
	Calcium channel blockers and carbamazepine ↑lithium neurotoxicity
	SSRIs ↑diarrhea, confusion, tremor, dizziness, and agitation
	Acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate ↓plasma lithium
	Metronidazole ↑lithium toxicity
	Encephalopathic syndrome possible with haloperidol
Lamotrigine	↑concentration of carbamazepine’s epoxide metabolite
	Carbamazepine, phenytoin, phenobarbital ↓plasma lamotrigine 40% to 50%
	↑plasma sertraline
	↓plasma valproic acid 25%; valproic acid doubles plasma lamotrigine and ↑rash risk
Topiramate	↑valproic acid concentrations 11%; valproic acid ↓plasma topiramate 14%
	↑plasma phenytoin up to 25%; phenytoin, carbamazepine ↓plasma topiramate by 40% to 48%
	↓digoxin bioavailability
	↓oral contraceptive efficacy
Valproic acid	↑plasma phenobarbital, primidone
	↓phenytoin clearance, volume distribution and ↑breakthrough seizure risk
	↑serum concentration of antiepileptics, such as lamotrigine; absence status possible with clonazepam
↑= Increases ↓= Decreases
ACE = angiotensin-converting enzyme; COX = cyclooxygenase
NSAIDs = nonsteroidal anti-inflammatory drugs; SSRIs = selective serotonin reuptake inhibitors
Source: References 17, 21-25

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

 

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

Drug brand names

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Disclosure

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

A temporal relationship is all that is required, although preexisting conditions and events clearly related to other causes are not usually considered adverse events.

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

‘Uncontrolled experiments.’ Drug combinations often are “uncontrolled experiments” with unknown potential for toxic effects.¹² Studies have linked polypharmacy and DDIs as well as DDIs and AEs:

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

DDI risk is increasing over time as the number of medications used to treat psychiatric patients has grown. For example, 3.3% of patients discharged between 1974 and 1979 from the National Institute of Mental Health Biological Psychiatry Branch were taking 3 or more medications, compared with more than 40% of patients discharged between 1990 and 1995—a 12-fold increase.¹⁵

Box 2

 

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

Table 1

LISTEN: 6 tips to minimize DDI risk

L	Listeach drug’s name and dosage in the patient’s chart and in a note given to the patient.
I	Each drug should have a clear indication and well-defined therapeutic goal; discontinue any drug not achieving its goal
S	Make the regimen as simple as possible, with once- or twice-daily dosing.
T	When possible, treat multiple symptoms with a single drug, rather than multiple symptoms with multiple drugs
E	Educatepatients about polypharmacy, DDIs, and adverse events; assess all medications—including vitamins, minerals, herbs, dietary supplements, nonprescription products—and address potential DDIs
N	Avoid prescribing medications with a narrow therapeutic window.

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

Mood stabilizer	Drug interactions
Carbamazepine	↑plasma clomipramine, phenytoin, primidone
	↑risk of neurotoxic side effects and confusional states with lithium
	Alters thyroid function with anticonvulsants
	↓anticoagulant concentrations and↑bleeding risk
	↓oral contraceptive reliability; can cause false-negative pregnancy tests
	↑metabolism and may ↓efficacy of cancer chemotherapy (docetaxel, estrogens, paclitaxel, progesterone, cyclophosphamide)
	↑aprepitant, granisetron metabolism and ↓efficacy
	↑glipizide, tolbutamide metabolism
Lithium	NSAIDs (ibuprofen, indomethacin, piroxicam) and COX-2 inhibitors ↑plasma lithium
	ACE inhibitors ↑plasma lithium
	Calcium channel blockers and carbamazepine ↑lithium neurotoxicity
	SSRIs ↑diarrhea, confusion, tremor, dizziness, and agitation
	Acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate ↓plasma lithium
	Metronidazole ↑lithium toxicity
	Encephalopathic syndrome possible with haloperidol
Lamotrigine	↑concentration of carbamazepine’s epoxide metabolite
	Carbamazepine, phenytoin, phenobarbital ↓plasma lamotrigine 40% to 50%
	↑plasma sertraline
	↓plasma valproic acid 25%; valproic acid doubles plasma lamotrigine and ↑rash risk
Topiramate	↑valproic acid concentrations 11%; valproic acid ↓plasma topiramate 14%
	↑plasma phenytoin up to 25%; phenytoin, carbamazepine ↓plasma topiramate by 40% to 48%
	↓digoxin bioavailability
	↓oral contraceptive efficacy
Valproic acid	↑plasma phenobarbital, primidone
	↓phenytoin clearance, volume distribution and ↑breakthrough seizure risk
	↑serum concentration of antiepileptics, such as lamotrigine; absence status possible with clonazepam
↑= Increases ↓= Decreases
ACE = angiotensin-converting enzyme; COX = cyclooxygenase
NSAIDs = nonsteroidal anti-inflammatory drugs; SSRIs = selective serotonin reuptake inhibitors
Source: References 17, 21-25

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

 

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

Drug brand names

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Disclosure

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

A temporal relationship is all that is required, although preexisting conditions and events clearly related to other causes are not usually considered adverse events.

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

‘Uncontrolled experiments.’ Drug combinations often are “uncontrolled experiments” with unknown potential for toxic effects.¹² Studies have linked polypharmacy and DDIs as well as DDIs and AEs:

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

DDI risk is increasing over time as the number of medications used to treat psychiatric patients has grown. For example, 3.3% of patients discharged between 1974 and 1979 from the National Institute of Mental Health Biological Psychiatry Branch were taking 3 or more medications, compared with more than 40% of patients discharged between 1990 and 1995—a 12-fold increase.¹⁵

Box 2

 

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

Table 1

LISTEN: 6 tips to minimize DDI risk

L	Listeach drug’s name and dosage in the patient’s chart and in a note given to the patient.
I	Each drug should have a clear indication and well-defined therapeutic goal; discontinue any drug not achieving its goal
S	Make the regimen as simple as possible, with once- or twice-daily dosing.
T	When possible, treat multiple symptoms with a single drug, rather than multiple symptoms with multiple drugs
E	Educatepatients about polypharmacy, DDIs, and adverse events; assess all medications—including vitamins, minerals, herbs, dietary supplements, nonprescription products—and address potential DDIs
N	Avoid prescribing medications with a narrow therapeutic window.

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

Mood stabilizer	Drug interactions
Carbamazepine	↑plasma clomipramine, phenytoin, primidone
	↑risk of neurotoxic side effects and confusional states with lithium
	Alters thyroid function with anticonvulsants
	↓anticoagulant concentrations and↑bleeding risk
	↓oral contraceptive reliability; can cause false-negative pregnancy tests
	↑metabolism and may ↓efficacy of cancer chemotherapy (docetaxel, estrogens, paclitaxel, progesterone, cyclophosphamide)
	↑aprepitant, granisetron metabolism and ↓efficacy
	↑glipizide, tolbutamide metabolism
Lithium	NSAIDs (ibuprofen, indomethacin, piroxicam) and COX-2 inhibitors ↑plasma lithium
	ACE inhibitors ↑plasma lithium
	Calcium channel blockers and carbamazepine ↑lithium neurotoxicity
	SSRIs ↑diarrhea, confusion, tremor, dizziness, and agitation
	Acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate ↓plasma lithium
	Metronidazole ↑lithium toxicity
	Encephalopathic syndrome possible with haloperidol
Lamotrigine	↑concentration of carbamazepine’s epoxide metabolite
	Carbamazepine, phenytoin, phenobarbital ↓plasma lamotrigine 40% to 50%
	↑plasma sertraline
	↓plasma valproic acid 25%; valproic acid doubles plasma lamotrigine and ↑rash risk
Topiramate	↑valproic acid concentrations 11%; valproic acid ↓plasma topiramate 14%
	↑plasma phenytoin up to 25%; phenytoin, carbamazepine ↓plasma topiramate by 40% to 48%
	↓digoxin bioavailability
	↓oral contraceptive efficacy
Valproic acid	↑plasma phenobarbital, primidone
	↓phenytoin clearance, volume distribution and ↑breakthrough seizure risk
	↑serum concentration of antiepileptics, such as lamotrigine; absence status possible with clonazepam
↑= Increases ↓= Decreases
ACE = angiotensin-converting enzyme; COX = cyclooxygenase
NSAIDs = nonsteroidal anti-inflammatory drugs; SSRIs = selective serotonin reuptake inhibitors
Source: References 17, 21-25

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

 

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

Drug brand names

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Disclosure

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 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 cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

 

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Description	Example
Two or more drugs from the same drug category	Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines
Use of multiple medications across therapeutic classes	Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants
An inappropriate or unnecessary medication is prescribed to a patient taking other medication	Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication
Prescription of an exceedingly high dose to a patient taking other medication	The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine)
Two or more drugs sharing similar toxicities	Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism	Examples
One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug	Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension
One drug has an action that increases the potential for an adverse event of a co-prescribed drug	Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

 

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

Mechanism of interaction of two or more drugs	Two or more drugs interact where …	Examples
One negatively affects the other’s absorption		Use of tetracycline with substances containing calcium
One negatively affects the other’s distribution		Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level
One negatively affects the other’s metabolism	One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity	Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration
	One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity	Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal
	One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance	Combination of carbamazepine and valproate
One negatively affects the other’s elimination		Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion)

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

Psychiatric disorders	Medications being taken
Schizophrenia	Cardiovascular agents
Bipolar disorder	Antipsychotics
Depression	Mood stabilizers
Borderline and other personality disorders	Antidepressants
Substance abuse (including tobacco habituation)	Self-medication with aspirin
Neurologic disorders	Demographic variables
Mental retardation	Age 65 or older
Dementia	Ethnicity (Caucasian, African-American)
Chronic pain, facial pain	Female gender
Headache (including migraine)	Psychosocial variables
Insomnia	Lower socioeconomic status
Epilepsy	Inner-city residence
Medical disorders	Lower level of education
Chronic diseases, multiple diseases	Unemployment
Obesity	Self-medication
Diabetes	Concealed drug use
Chronic hypertension
Coronary artery disease

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

 

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.