Avoiding common drug−drug interactions

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.