Psychotropic Drug Interactions with Antiretroviral Medications



Psychotropic Drug Interactions with Antiretroviral Medications


Philip A. Bialer

Kyle S. Kato

Vassilios Latoussakis



With the Food and Drug Administration (FDA) approval and release of saquinavir in December of 1995, and the subsequent approval and release of two more protease inhibitors in early 1996, the age of highly active antiretroviral therapy (HAART) transformed the medical management of patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The early 1990s also brought a more complete understanding of the way medications were metabolized, particularly the process of oxidative metabolism by the cytochrome P (CYP) 450 enzyme system. When reports of serious interactions between two relatively benign medications such as erythromycin and terfe- nadine surfaced, the importance of more complete knowledge of the pharmacokinetics of commonly used medications became clear. Possibly for more than any other type of patient, the practitioner treating those with HIV infection or AIDS needs to be very aware of the potential for drug–drug interactions because of the large number of medications often prescribed by multiple providers that these patients could be taking. This chapter examines the drug–drug interactions, reported and potential, that are most likely to be encountered by patients being dually treated for HIV and mental health problems.


Basic Pharmacology

To fully understand how drugs interact, it will be helpful to review some basic pharmacologic principles and mechanisms. First, the clinician must differentiate between pharmacodynamic and pharmacokinetic interactions. Pharmacodynamic interactions refer to one drug’s influence on another drug’s effect at the intended receptor site. For example, the opioid agonist methadone blocks the effects of administered heroin by occupying all available opioid receptors. Pharmacokinetic interactions refer to the effect of one drug on the movement throughout the body of another drug—meaning absorption, distribution, metabolism, or excretion of the drug. Although drug–drug interactions affecting any of these steps can produce serious
results, there has been increasing attention on interactions involving drug metabolism; this chapter focuses primarily on these interactions.

Phase I metabolism, in which drugs are oxidized, is mainly mediated by the CYP450 system. Although most drugs are inactivated during this process, some have pharmacologically active metabolites and some prodrugs must be oxidized before they become active. There are over 40 CYP450 enzymes found in humans that may be involved in metabolizing both endogenous and exogenous materials, but only 6 of these enzymes are responsible for 90% of drug metabolism: 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. After oxidation, some drugs may be excreted in the bile or feces, but most undergo phase II metabolism or conjugation for excretion in the urine. Glucuronidation accounts for most phase II metabolism and is mediated by uridine 5′-diphosphate glucuronosyltransferase (UGT) enzymes. As with CYP450 enzymes, there are many UGTs, but UGT2B7 accounts for the majority of glucuronidation. Some drugs, such as lorazepam, oxazepam, temazepam, lamotrigine, valproate, nonsteroidal anti- inflammatory agents, most opiates, and zidovudine are primarily metabolized by UGT enzymes without undergoing any oxidation. CYP450 enzymes and UGTs are found throughout the body, but primarily in the liver and gut wall.1

Some drug–drug interactions occur when the metabolic process is either inhibited or induced. Metabolic inhibition leads to a prolonged pharmacologic effect and may lead to drug toxicity. In the case of a prodrug that must be metabolized to be effective, inhibition may have an opposite effect and lead to inactivity. Inhibition usually occurs when two drugs have an affinity for a particular metabolic enzyme, with the more tightly bound drug inhibiting the other, and occurs fairly quickly. Metabolic induction usually involves the synthesis of more metabolic proteins, making more sites available for metabolism and thus increasing the rate of drug inactivation. The induction process takes longer to occur than inhibition and may lead to subtherapeutic levels of a drug. For patients on HAART, this can have an extremely negative impact if subtherapeutic levels of one drug allow for the development of viral drug resistance. Both phase I and phase II enzymes can be inhibited or induced.1


Taking a Drug History

In approaching a patient with respect to drug–drug interactions, the first step is to determine all of the medications that a person is taking. This includes prescriptions drugs, over-the-counter medications, supplements, alternative medications, nonprescription psychoactive substances, and foods. Because these patients may be taking a large number of medications, they are not always fully aware of all the names and dosages, so it is helpful to have them bring their medications to the office and/or get corroborating information. In addition to antiretrovirals, patients with HIV disease or AIDS are most often taking additional medications for intercurrent infections and other medical problems, prophylaxis against opportunistic infections, and nutritional supplements or herbal remedies; any one of these may have potential interactions with psychotropics. A large proportion of patients in this population also have past and current histories of substance use, and some illicit drugs can have potentially serious interactions with AIDS medications and psychotropics. One should try to obtain this information in a nonthreatening way so the patient can be educated about these dangers.


Protease Inhibitors

All protease inhibitors (PIs) are metabolized primarily by CYP3A4, and all PIs can competitively inhibit 3A4 metabolism to some degree.2 However, ritonavir is by far the most potent inhibitor of 3A4 among the PIs and has caused the most concern about potential drug–drug
interactions (Table 16.1). The triazolobenzodiazepines alprazolam, midazolam, and triazolam are metabolized by 3A4, and coadministration with ritonavir can lead to higher serum levels of these drugs, with resulting oversedation and respiratory distress. Other psychotropics that are substrates for 3A4 include trazodone, fluvoxamine, and nefazodone, and coadministration of these drugs with ritonavir can result in toxicity. After several weeks, ritonavir can also induce 3A4 metabolism and actually decrease the efficacy of the psychotropic medications already mentioned.








TABLE 16.1 Antiretrovirals: Metabolism, CYP450 Enzyme Inhibition, and Induction
















































































































































Drug Metabolism Site(s) Enzyme(s) Inhibited Enzyme(s) Induced
Protease Inhibitors      
Amprenavir (Agenerase) 3A4 3A4b None known
Indinavir (Crixivan) 3A4 3A4a None known
Lopinavir/ritonavir (Kaletra) 3A4 3A4,a 2D61 3A4, UGT (phase II)
Nelfinavir (Viracept) 3A4, 2C19 3A4,c 1A2, 2B61 ?2C9
Ritonavir (Norvir) 3A4, 2D62 3A4,a 2D6,a 2C9,a 2C19,a 2B61 3A4,a1A2,b 2C9,b 2C19,
      UGT
Saquinavir (Invirase) 3A4 3A4c None known
Non-nucleoside Reverse      
Transcriptase Inhibitors (NNRTIs)      
Delavirdine (Rescriptor) 3A4, 2D6, 2C9,2 2C192 3A4,a 2C9,1 2C19,1 2D61 None known
Efavirenz (Sustiva) 3A4, 2B6 3A4,a 2C9,1 2C19,1 2B61 3A4,b 2B6c
Nevirapine (Viramune) 3A4, 2B6 None known 3A4,b 2B6b
NRTIs      
Abacavir (Ziagen) Alcohol dehydrogenase,    
  UGT None known None known
Didanosine (ddI, Videx) Purine nucleoside    
  phosphorylase Unknown Unknown
Emtricitabine (Emtriva) Full recovery in urine and    
  feces None known None known
Lamivudine (3TC, Epivir) Minimal metabolism None known None known
Stavudine (d4T, Zerit) Not yet known None known None known
Tenofovir (Viread) Renal 1A2a None known
Zalcitabine (ddC, Hivid) Renal    
Zidovudine (AZT, Retrovir) UGT 2B7, CYP450 b5   None known
1Inhibited in vitro.
2Minor pathway.
aPotent (bold type).
bModerate.
cMild.
This table was adapted from two tables by the same authors. Reprinted with permission from Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, 2e (Copyright 2003). Washington, DC: American Psychiatric Publishing, Inc.; and Psychosomatics, Washington, DC: American Psychiatric Publishing; 2004.

Ritonavir is also a moderately potent inhibitor of CYP2D6, which is the primary metabolic enzyme for many psychotropic medications. Therefore it is necessary to monitor serum tricyclic antidepressant levels in patients taking both of these drugs and to monitor carefully for side effects in patients taking selective serotonin reuptake inhibitors (SSRIs) and most
neuroleptics. Ritonavir also inhibits 2C9 and 2C19 and induces 1A2, 2C9, and 2C19 (Table 16.1). Ritonavir can have multiple effects on the CYP450 enzyme system, so it is imperative to review the specific contraindications and warnings for any patient taking this medication before prescribing additional medications. The clinician must also remember that Kaletra is composed of lopinavir and ritonavir, although the lower dose of ritonavir in this formulation may preclude some of the potential drug–drug interactions. Similarly, ritonavir must always be given along with the newly approved tipranavir so the same cautions and contraindications apply for this drug.

Because all of the PIs are CYP3A4 substrates, medications that inhibit or induce this enzyme can also cause potentially serious interactions (Table 16.2). Nefazodone is a potent CYP3A4 inhibitor and can result in PI toxicity. Carbamazepine, phenobarbital, St. John’s wort, and phenytoin are inducers of 3A4 and can potentially decrease PIs to subtherapeutic serum levels. Chronic alcohol use can also induce CYP3A4.


Non-Nucleotide Reverse Transcriptase Inhibitors

The non-nucleotide reverse transcriptase inhibitors (NNRTIs) bind directly and noncompetitively to the reverse transcriptase enzyme to inhibit it and prevent viral replication. They are commonly a component of HAART. Delavirdine may be the least used of the NNRTIs, but it is important to know that it is a potent inhibitor of CYP3A4, 2C9, 2C19, and 2D6 and can interact with many of the same medications as ritonavir. Nevirapine is more commonly used and induces 3A4.3 Case reports and clinical experience have demonstrated an increased rate of metabolism of methadone among patients taking nevirapine, requiring an upward adjustment of the methadone dose.4 Efavirenz has more complex effects on the CYP450 system by both inhibiting and then inducing 3A4. It also has some inhibitory effects on 2C9, 2C19, 2D6, and 1A2, resulting in a drug interaction profile similar to that of ritonavir (Table 16.1). Patients on methadone maintenance taking efavirenz may also need their dose adjusted upward.


Nucleoside Reverse Transcripase Inhibitors, Fusion Inhibitors

These nucleoside reverse transcriptase inhibitors (NRTIs) are analogs of the nucleotide building blocks of DNA and RNA and inhibit the reverse transcriptase enzyme by being incorporated into the viral DNA at a key point, thus preventing viral replication. None of these drugs are metabolized by the CYP450 system, but they undergo metabolism by intra-cellular enzymes and/or glucuronidation. Zidovudine (AZT) is metabolized by UGT2B7, and some UGT inhibitors, such as valproate and methadone, have been reported to increase serum levels of AZT, resulting in toxicity. Otherwise, there do not appear to be any other potential interactions between this class of drugs and psychotropic medications. The fusion inhibitor enfuvirtide also has no significant CYP450 or UGT interactions.








TABLE 16.2 Psychotropic Medications That Are Potent Inhibitors or Inducers of CYP3A4

















3A4 Inhibitors 3A4 Inducers
Nefazodone Carbamazepine
Fluvoxamine Phenytoin
  Phenobarbital
  St. John’s wort



Other Medications used in HIV Treatment

Although it is not within the scope of this chapter to examine the drug–drug interactions of all the possible medications a patient with HIV disease or AIDS could be taking, there are a few instances in which special precautions should be taken. Given for intercurrent infections such as community-acquired pneumonia, clarithromycin (Biaxin) is a potent CYP3A4 inhibitor and can cause increased serum levels of many of the same medications as ritonavir, such as the triazolobenzodiazepines. Azithromycin (Zithromax) is a mild CYP3A4 inhibitor and can probably be used safely with most psychotropics. Patients may be taking antifungal agents for oral thrush. Of these, both ketoconazole (Nizoral) and itraconazole (Sporanox) are potent CYP3A4 inhibitors. Ketoconazole (Diflucan) has moderate 3A4 inhibition activity, so psychotropics metabolized by this enzyme should be used in lower doses or not at all. Patients with HIV disease or AIDS may be at higher risk for the development of tuberculosis. Two antituberculosis drugs, rifampin and rifabutin, are potent CYP3A4 inducers that may result in lower serum levels of psychotropics metabolized by 3A4 when these drugs are coadministered. Of particular concern would be withdrawal reactions among patients taking methadone.

Fortunately, most of the other nonantiretroviral medications that patients with HIV disease and AIDS may be taking, such as acyclovir, atovaquone (Mepron), or sulfamethoxazole/ trimethoprim (SMX/TMP; Bactrim) have no psychotropic drug interactions reported.

The remainder of the chapter examines the metabolism of psychotropics and the ways specific drugs may interact when given to patients receiving HAART. Table 16.3 summarizes the interactions.


Anxiolytics and Sedative Hypnotics

Three benzodiazepines—lorazepam, temazepam, and oxazepam—undergo glucuronidation primarily, have no active metabolites, and are associated with few drug–drug interactions. They have no drug interactions with antiretrovirals. They may also be preferred for patients who have compromised liver function from hepatitis C, a common comorbidity in HIV-infected patients.

The other benzodiazepines are metabolized by CYP3A4. Triazolam, alprazolam, and midazolam are the most sensitive to inhibition of this enzyme and should be used with extreme caution by patients taking medications that are potent or moderate inhibitors. Clonazepam, diazepam, estazolam, and flurazepam may also be affected by CYP3A4 inhibition. The anxiolytic buspirone is also primarily metabolized by CYP3A4, so its serum levels will be affected by 3A4 inhibitors and inducers. Diphenhydramine and hydroxyzine are antihistamines that are sometimes used as anxiolytics; neither of these has reported interactions with antiretrovirals.

There are mixed reports regarding the safety of concurrently prescribing PIs and zolpidem, which is partially metabolized by CYP3A4. Ritonavir inhibits zolpidem metabolism 22% less than it inhibits triazolam metabolism.5 There were no drug interactions reported between zaleplon or chloral hydrate and antiretroviral medications (Table 16.3).

Among the barbiturates, phenobarbital induces 3A4 as well as other CYP450 enzymes and may decrease serum concentration and antiviral efficacy of the PIs or the NNRTIs. Its use is not recommended for patients receiving HAART. There are no drug interactions reported between other barbiturates and antiretrovirals.


Antidepressants

Antidepressant side effects and a patient’s profile should be considered before medication selection. Decreased side effects lead to improved adherence to medication treatment. Common side effects of PIs and SSRIs include nausea, vomiting, fatigue, and sexual dysfunction; a



different antidepressant class may be preferred for patients experiencing these side effects. Although weight gain related to mirtazapine use may be problematic among patients with lipodystrophy and other antiviral-related metabolic abnormalities, the sedating effects of mirtazapine may be helpful in the patient complaining of insomnia. The energizing effects of bupropion may be helpful among patients who experience fatigue from their HIV treatment. The SSRIs undergo extensive oxidative metabolism usually by several CYP450 enzymes, so if one of them is inhibited, others will take over. Thus SSRIs can be given safely along with most antiretrovirals, with the possible exception of ritonavir. Some cases of serotonin syndrome have been reported when fluoxetine was given to patients taking ritonavir.6 Antiretroviral toxicity should also be monitored among patients taking fluvoxamine because it is a moderate CYP3A4 inhibitor (Tables 16.2 and 16.3).








TABLE 16.3 Antiretroviral/Psychotropic Drug—Drug Interactions



























































































































































































































































































































































































































































































































































































































































































































































  Protease Inhibitors NNRTI
  Amprenavir Atazanavir Indinavir Nelfinavir Ritonavir Saquinavir Delavirdine Efavirenz Nevirapine
Mood Stabilizers                  
Lithium + + + + + + + + +
Carbamazepine ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++
Gabapentin + + + + + + + + +
Lamotrigine + + + + ++ + + + +
Oxcarbazepine ++ ++ ++ ++ ++ ++ ++ ++ +
Topiramate + + + + + + + + +
Valproate + + + + + + + + +
Antidepressants                  
Tricyclics ++++ ++++ +++ +++ ++++ +++ ++++ +++ ++
Duloxetine + ++ + ++ +++ + ++ ++ +
Venlafaxine + ++ ++ + ++ + ++ + +
Citalopram + + + + + + + + +
Escitalopram + + + + + + + + +
Fluoxetine ++ ++ ++ ++ +++ ++ +++ ++ ++
Fluvoxamine +++ +++ +++ +++ ++++ +++ +++ +++ +++
Paroxetine + + + + +++ + ++ + +
Sertraline + + + + +++ + ++ + +
Bupropion ++ ++ ++ ++ +++ ++ ++ ++ ++
Mirtazapine + + + + ++ + + + +
Nefazodone ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
Trazodone ++ ++ ++ ++ +++ ++ +++ ++ ++
Antipsychotics                  
Haloperidol + + + + ++ + + ++ ++
Thioridazine ++ ++ ++ ++ +++ ++ ++ ++ +
Pimozide +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++
Clozapine +++ +++ +++ +++ ++++ +++ +++ +++ +
Olanzapine + ++ + ++ +++ + ++ ++ +
Risperidone ++ ++ ++ ++ +++ ++ ++ ++ +
Aripiprazole ++ ++ ++ ++ +++ ++ ++ ++ +
Quetiapine ++ ++ ++ ++ +++ ++ ++ ++ +
Ziprasidone ++ ++ ++ ++ +++ ++ ++ ++ +
Opioid Agonists                  
Methadone ++ ++ ++ ++ +++ ++ ++ ++ +
Buprenorphine + + + + + + + + +
LAAM + + + + + + + + +
Erectile Dysfunction Treatment                  
Sildenafil +++ +++ +++ +++ ++++ +++ +++ +++ +
Tadalafil +++ +++ +++ +++ ++++ +++ +++ +++ +
Vardenafil +++ +++ +++ +++ ++++ +++ +++ +++ +
Anxiolytics/Hypnotics                  
Benzodiazepines + + + + + + + + +
Lorazepam, oxazepam, temazepam ++++ ++++ ++++ +++ +++++ ++++ ++++ ++++ ++
Triazolam, alprazolam, midazolam ++ +++ +++ ++ ++ +++ ++ +++ +++
Zolpidem ++ +++ +++ ++ ++ +++ ++ +++ +++
Stimulants                  
Atomoxetine + + + + + + + + +
Dextroamphetamine + + + + + + + + +
Modafinil ++ ++ ++ ++ +++ ++ ++ ++ ++
Herbals                  
Echinacea +++ +++ +++ +++ +++ +++ +++ +++ +++
Garlic ++ ++ ++ ++ ++ +++ ++ ++ ++
Ginseng, ginkgo +++ +++ +++ +++ +++ +++ +++ +++ +++
Kava                  
St. John’s wort +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
Substances of Abuse                  
Alcohol +++ +++ +++ +++ +++ +++ +++ +++ +++
Cannabis ++ +++ ++ +++ +++ ++ + + +
Cocaine +++ +++ +++ +++ ++++ ++++ ++++ +++ ++
Crystal methamphetamine ++ ++ ++ ++ ++++ ++ +++ +++ +
GHB +++ +++ +++ +++ ++++ +++ +++ +++ +
Ketamine +++ +++ +++ +++ ++++ +++ +++ +++ +
MDMA ++ ++ ++ ++ ++++ ++ +++ +++ +
Phencyclidine (PCP) +++ +++ +++ +++ ++++ +++ +++ +++ +
+Coadministration is considered safe; no significant interactions have been reported.
++Use with some caution; interactions of unclear clinical significance have been reported or are theoretically of small risk.
+++Use with moderate caution; interactions have occasionally been reported or are theoretically possible.
++++Use with extreme caution; clinically significant interactions have frequently been reported or are theoretically likely; relatively contraindicated.
+++++Coadministration is absolutely contraindicated.

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Aug 28, 2016 | Posted by in PSYCHIATRY | Comments Off on Psychotropic Drug Interactions with Antiretroviral Medications

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