November 30, 1999
Patients receiving palliative care for HIV disease have the potential for numerous drug interactions, given the complex drug regimens used to treat both early as well as advancing HIV disease. It is estimated that at any point, up to 50% of patients in palliative care may still be recipients of highly active antiretroviral therapy (HAART) which often comprises protease inhibitors (PIs) along with other antiretroviral agents, namely the nucleoside reverse transcriptase inhibitors (NRTIs, or nukes) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs, or non-nukes). All protease inhibitors as well as all currently available NNRTIs are metabolized by the cytochrome P450 (CYP) isoenzymes and are therefore expected to be involved in a large number and variety of drug-drug interactions.
As providers attempt to palliate advancing HIV disease, they may need to administer to patients -- along with antiretroviral agents -- medications for pain; insomnia; anorexia/weight loss; fatigue/weakness; GI disturbances including nausea, vomiting, diarrhea, dysphagia, odonophagia and reflux esophagitis; dyspnea; pruritis; fever; anxiety/depression; confusion/dementia; and a host of other symptoms. All of these medications may need to be administered in the presence of other co-morbid conditions such as hepatitis; PI-associated complications such as hypertriglyceridemia, hyperglycemia, lipodystrophies and HIV-associated nephropathies; and the opportunistic infections that are the hallmark of advanced HIV disease. It is therefore neither surprising that drug-drug as well as drug-disease interactions become paramount considerations as patients advance into palliative care, nor that optimizing therapy in these situations can become exceedingly complex and overwhelming.
This chapter will describe drug-disease, drug-food and drug-drug interactions likely to be encountered in symptom management of advanced HIV disease as practiced during palliative care of patients. The chapter also highlights the clinical significance of these interactions and offers strategies to avoid or circumvent many of them. Tables 27-1 through 27-13 (PDFs) offer detailed information about the drug interactions and circumvention strategies discussed in the text, as follows:
Application of basic pharmacokinetic principles can be useful for circumventing clinically relevant drug-drug interactions in the management of advanced HIV disease. Pharmacologically, there are two broad classes of drug interactions:
Interactions are described as pharmacokinetic when the action of one drug alters the serum concentration of another drug by altering any of the following processes: drug Liberation, Absorption, Distribution, Metabolism and Excretion (the LADME system). Pharmacokinetics is the study of the processes of drug action through these various processes.
In advanced HIV disease and AIDS, possibilities abound for pharmacokinetic drug interactions. For instance, any circumstance that alters gastric pH can affect the absorption of many drugs. This is particularly important for patients receiving palliative care, many of whom may have hypochlorhydria which is common in advanced HIV disease and can lead to suboptimal absorption of pH-dependent medications such as ketoconazole (Nizoral), itraconazole (Sporonox) and indinavir (Crixivan). Since fluconazole (Diflucan) is readily absorbed independent of gastric pH, it is often the azole of choice when an azole antifungal is indicated for the treatment of several opportunistic infections.
Pharmacodynamic interactions are those interactions that may alter the overall clinical response expected from use of the drugs, by altering the efficacy and often toxicity of the drugs. The interaction could be synergistic and mostly positive (e.g., the positive antiretroviral response seen when zidovudine is combined with lamivudine). Conversely, it can be antagonistic and mostly negative (e.g., the additive bone marrow suppression caused by combining zidovudine and ganciclovir; nephrotoxicity caused by combining cidofovir (Vistide) and amphotericin B (Fungizone); or the neuropathy caused by stavudine (Zerit) combined with didanosine (Videx, Videx-EC).
Drug interactions can arise as a result of changes due to HIV disease itself. As persons with HIV disease advance in their illness, oral absorption of foods and drugs is often compromised due to changes in gastric pH that accompany HIV enteropathy, a syndrome that describes the effect of advanced HIV disease on the gastrointestinal (GI) system. Diarrhea tends to be common in HIV disease and may result from a variety of causes: GI disturbance following side effects of several of the most commonly used antiretroviral agents; presence of concurrent opportunistic organisms; and bacterial, protozoal and viral infections that tend to be more common as the disease advances and the immune system weakens. The occurrence of diarrhea -- especially if frequent and poorly controlled, as in patients with cryptosporidiosis -- can jeopardize absorption of all drugs because of the decreased transit time and may cause drug regimens to be less efficacious. This will lead subsequently to less than optimal clinical outcomes, and in some instance may predispose the patient to subtherapeutic drug levels that may herald the emergence of resistant strains of the virus in patients still taking antiretroviral agents.
People with HIV in palliative care are more likely to be susceptible to adverse events than people in the early stages of HIV disease. For example, patients in palliative care are more likely to have allergic reactions to sulfonamides and other drugs. Another physiological component of advancing HIV disease is malabsorption, which is the hallmark of enteropathy and predisposes the patient to changes in body weight that often reflect changes in the volume as well as distribution of both fat and muscle tissue. This in turn may affect the efficacy of drugs with dose-related efficacy, for example, the agents used in the treatment of tuberculosis and mycobacterium avium complex (MAC). Also frequently reported at this stage of illness are decreases in serum albumin, which in turn may alter the efficacy of drugs such as phenytoin when used in the management of patients with toxoplasmosis or sulfamethoxazole when used both as treatment and in the prophylaxis of patients with pneumocystis carinii pneumonia (PCP).
Other changes also occur in drug metabolism with advancing disease. These include changes due to HIV-related biliary disease or to hepatitis -- frequently a concomitant infection in this population, especially patients who were injection drug users (IDUs). These conditions may make it necessary to adjust both the doses and the dosing intervals of drugs that are mostly metabolized through the liver, such as rifampin, isoniazid and ketoconazole, and to be selective in the choice of such medications. Changes in the renal elimination of drugs also occur with advancing disease and can be especially important for renally cleared antiretrovirals such as zidovudine, lamivudine, didanosine, zalcitabine and stavudine, antiviral agents such as ganciclovir and cidofovir, antifungal agents such as amphotericin B, and antibacterial agents such as the aminoglycosides.
Changes in immune status that may affect drug responses to antimycobacterial medications (such as the tuberculostatics) or management of opportunistic infections such as MAC have frequently been reported in patients with advanced disease. As a general rule, there is an increased incidence of drug toxicity as well as drug sensitivity in patients with HIV -- for example, with use of the neuroleptics (chlorpromazine and prochlorperazine) -- which may necessitate a decrease from usually recommended doses in order to avoid toxicity.
Signs of Drug-Drug Interaction in a Patient With HIV Disease
As a general rule, patients experiencing exaggerated toxicities on usual doses of medications or manifesting treatment failure in the absence of factors such as resistance or poor adherence/compliance may be suffering from an unidentified drug-drug interaction. A careful review of the patient's medication profile is necessary in order to monitor for such drug interactions. Clinicians should become familiar with the agents most often associated with significant drug-drug interactions and with the measures to circumvent these interactions when necessary.
Regimens with enzyme inducers such as rifampin or enzyme inhibitors such as ritonavir should be noted and checked against a list of other agents metabolized by those same enzyme pathways (see Table 27-14, PDF, Advice to Patients: Red Flag Medications, at the end of this chapter). Fortunately, the majority of drug-drug interactions are minor in nature and do not require extensive changes to the patient's drug regimen. However, the minority of drug interactions that can be clinically important can offset treatment goals and outcomes in patients if unrecognized or unaddressed, leading to patients receiving suboptimal levels of various drugs and so to treatments failing, often due to emergence of drug-resistant strains of the virus.
Drug-Food Interactions of Clinical Significance
It is well established that the presence or absence of food or certain beverages can significantly affect the bioavailability of a number of medications. A variety of mechanisms including changes in pH, formation of unabsorbable cation complexes, increased solubility of drugs and interference with gut metabolism as well as a decrease in the motility of the gut may be at play. Table 27-1 (PDF) lists some of the more common food-drug interactions with antiretroviral agents.1
Interactions Involving Azole Antifungals, Didanosine and Other Drugs
Interactions of significance with azole antifungals, didanosine and other drugs used to alleviate HIV-related disorders are presented in this section, along with strategies to circumvent the interactions. For more detailed guidance, consult the most recent package inserts of ketoconazole and the various drugs.
Ketaconazole (Nizoral) and itraconazole (Sporonox) with gastric acid-reducing agents: Increase in gastric pH (due to agents such as antacids, H2 antagonists, proton-pump inhibitors and non-enteric-coated formulations of didanosine) impairs absorption of ketoconazole, whose absorption is optimal when gastric pH is low. When prescribed together, didanosine and ketoconazole must be taken two hours apart or an alternative antifungal agent should be used.2
Measures to increase gastric acidity for azole bioavailability: Administration of acidic beverages such as 240 ml of orange juice, tomato juice, ginger ale, grapefruit juice or cola drinks in the presence of achlorhydria of advanced HIV disease will enhance azole biovailability, especially for ketoconazole. When hypochlorhydria is severe, each 200 mg of ketoconazole should be dissolved in 4 ml of 0.2N hydrochloric acid. A straw should be used to avoid contact with teeth.
PIs and NNRTIs with azoles: As a general rule, use of ketoconazole with PIs and NNRTIs is not advised due to a large number of potentially significant drug-drug interactions. Fluconazole (Diflucan) is preferred. (See Tables 27-2, PDF and 27-3, PDF.)
Ketoconazole and other drugs: Rifampin decreases activity of both drugs; INH decreases effect of ketoconazole; terfenadine and cisapride (both now removed from the market) lead to ventricular arrhythmias and concurrent use should be avoided.
Didanosine: Didanosine buffered formulations usually cause problems of absorption for medications whose absorption are pH-sensitive. Didanosine can decrease absorption of itraconazole, ketoconazole, dapsone and delavirdine (Rescriptor) because of increased gastric pH. It can also decrease absorption of the quinolones and tetracyclines by chelation of these antibiotics with the calcium and magnesium ions contained in the buffer.
Oral fluoroquinolones: With oral fluoroquinolones, patients should avoid dairy products, elemental minerals and heavy nutritional supplements; take fluoroquinolones two hours before or six hours after these items.
Drug-Drug Interactions Due to the Cytochrome P450 Enzyme System
The cytochrome P450 (CYP) enzyme system is a group of mixed function monooxygenases located on the smooth endoplasmic reticulum of cells throughout the body, primarily the liver. In humans, there are more than 20 different cytochrome enzymes, eight of which are responsible for the metabolism of almost all clinically useful medications. These eight enzymes are designated as CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Though they are somehow related and share many general features, each is unique in the substrates for which it is specific and so metabolizes only specific drugs and substances.3 The P450 enzymes involved in drug metabolism are found not only in the liver, but also in the kidneys, lungs, brain, small intestine and placenta.
Enzymes of the CYP450 system are responsible for the oxidative metabolism of a large and varied number of compounds including, most importantly, the antiretroviral agents (PIs and NNRTIs), several drugs used in the management of opportunistic infections in advancing HIV disease, many of the newer serotonin-specific reuptake inhibitors (SSRIs) and other psychotropic agents, endogenous substances such as steroids and prostaglandins, environmental toxins, and dietary components. The primary role of the isoenzymes in drug metabolism is to make the drugs more water-soluble and less fat-soluble, so that biliary excretion will take place. As a result of this, actions of these enzymes can affect the amount of active drug in the body at any given time. Such changes can be positive, enhancing efficacy, or negative, enhancing toxicity and adverse events.4
Role of the Cytochrome P450 3A4 (CYP3A4)
CYP3A is both the most abundant and clinically significant family of cytochrome P450 enzymes. The CYP3A consists of three major enzymes, CYP3A4 being the one most commonly associated with drug interactions. The most notable inducers of CYP3A4 include the glucocorticosteroids, rifampin, carbamazepine, phenobarbital, phenytoin, nevirapine and efavirenz. Notable CYP3A4 inhibitors include erythromycin, clarithromycin, Biaxin (but not azithromycin), ketoconazole, verapamil, and grapefruit juice among others.
Ritonavir (Norvir) is the most potent inhibitor of the CYP3A4 system when compared to all the other PIs and indeed to all other drugs, generally. Indinavir and nelfinavir exhibit the same level of inhibition while saquinavir and amprenavir appear to be the least likely to inhibit CYP3A4. Among the NNRTIs, delavirdine is a potent irreversible inhibitor of this enzyme and is presently the only drug that has been shown to affect levels of ritonavir, increasing its Area Under the Curve (AUC) by 60% in patients maintained on a regimen of ritonavir 600 mg twice daily.5
Recent studies have shown that both ritonavir and nelfinavir can act as inducers as well as inhibitors. Though this feature is not completely understood, affinity studies show that these two compounds bind with such high affinity that it becomes impossible for other agents to attach to the enzyme; hence inhibiting access to the enzymes while inducing their own metabolism.
Drug Interactions With Ritonavir and Other Substrates of the CYP3A4 System
In relation to CYP3A4, there are a number of clinically significant drug-drug interactions with which providers must become conversant. For the past several years, ritonavir (Norvir), the powerful inhibitor of enzymes of the cytochrome P450 system, has been used to boost levels of other PIs, mostly saquinavir (Fortovase), indinavir (Crixivan) and amprenavir (Agenerase).
More recently, another PI, lopinavir, was added to this list of boosted PIs. Ritonavir and lopinavir were combined together into a powerful boosted PI combination (Kaletra) that takes advantage of ritonavir's inhibition of the CYP3A enzyme system to increase levels of lopinavir up to ten times its normal AUC. This combination can eradicate with a ten-fold increase in potency, for the most part overcoming PI resistance in heavily experienced patients. Results from the few studies so far completed indicate that the profile of drug-drug interactions and drugs that should be avoided for ritonavir are mostly the same for the combination of lopinavir and ritonavir (Kaletra).1
There have been reports of excessive drops in blood pressure following introduction of ritonavir into the therapy of a hypertensive subject stabilized on a calcium channel blocker such as verapamil. Other drugs to watch out for include the proarrhythmic agents that undergo extensive first-pass metabolism such as terfenadine, astemizole and cisapride. Others include the HMG-C0A reductase inhibitors -- drugs that are frequently prescribed for patients on antiretroviral therapy who develop lipid abnormalities -- as well as triazolam and midazolam, often used to alleviate anxiety or to treat insomnia.
Drug-Drug Interactions Between Psychotropics and Antiretroviral Agents
Several of the medications used to treat mood and anxiety disorders are substrates of the cytochrome P450 enzyme system and as such are prone to interact with protease inhibitors and other drugs used for the treatment of opportunistic infections or the several degenerating neurological disorders that may accompany advancing HIV disease. Some of these psychotropic medications may be either substrates, inducers or inhibitors of this same system. For patients receiving these medications concomitantly, the need for awareness and closer monitoring regarding drug-drug as well as drug-disease interactions of significance has been heightened. Recently, these concerns, though not limited to people with HIV, have been exacerbated by the reports of sudden cardiac deaths due to unexpected ventricular arrhythmias (torsades des pointes) in patients on some antipsychotic medications, who were concomitantly receiving some of the newer antihistamines (terfenadine, astemizole), some of the newer SSRIs, some of the newer antiarrhythmics (amiodarone, sotalol, fleicanide), some macrolides (erythromycin) and some newer quinolones. The purpose of this section of the discussion is to clarify some of the issues associated with drug-drug interactions of clinical significance between the antiretroviral agents and drugs used in psychiatry.
Specific Interactions Between Some Antidepressants, Antipsychotics and Antiretroviral Agents
Why do interactions occur among some antidepressants, antipsychotic agents and antiretroviral agents? Clinicians prescribing drugs for patients with HIV must be aware of the important potential for interactions that exists between some of the PIs (especially ritonavir) and non-nucleoside antiretroviral agents (especially efavirenz) and psychotropic drugs. Protease inhibitors have varying degrees of inhibition of the cytochrome P450 enzyme system responsible for most of the oxidative metabolism that occurs in the liver. Ritonavir in particular is one of the most potent inhibitors of the various P450 isoenzymes, especially CYP2D6 and CYP34A which are responsible for metabolizing the benzodiazepines, some neuroleptics and both the SSRI and triclyclic antidepressants.
Tables 27-2 (PDF), 27-3 (PDF) and 27-4 (PDF) give highlights of these ritonavir interactions and classifications of substrates, inducers and inhibitors of the CYP450 enzyme system. Patients on PIs who are receiving tricyclic antidepressants (TCAs) should have their dosages reduced by 50% to 66% initially, with close monitoring of blood levels to establish a safe and effective dose.6
Dosage Adjustments for the SSRIs
As a class, the SSRIs have varying inhibitory effects on CYP450 isoenzymes, with far-reaching implications. Most of the research is still ongoing and interactions reported between an individual SSRI and the P450 system may differ from one source to the other. Fluoxetine (Prozac, Serafem) and its metabolite appear to inhibit CYP2D6 and CYP3A4, while paroxetine inhibits CYP2D6. Fluvoxamine (Luvox) inhibits all of the major isoenzymes and possibly also CYP2C9; as a result of this, it appears to have the greatest propensity for drug-drug interactions theoretically and most probably clinically, as well. Despite its potent inhibition of the cytochrome P450 CYP2D6 isoenzyme, paroxetine (Paxil) may be regarded as the least problematic with regard to interaction potential from a clinical standpoint in comparison to fluoxetine (Prozac) or fluvoxamine (Luvox).7
The SSRIs have a wide therapeutic window, without the danger of overdosing that exists with the TCAs. Nonetheless, as a general rule with the SSRIs and TCAs, doses are started low and built up gradually; initial doses should be decreased 50% to 66% and then increased gradually until the desired response is obtained.8
SSRIs and nefazodone have been reported to increase serum levels of protease inhibitors, particularly through inhibition of CYP3A4; the clinical significance of this interaction needs further clarification. Before starting ritonavir, doses of most neuroleptics should be decreased and such patients monitored closely; this is in anticipation of ritonavir-induced CYP inhibition that may increase levels of such neuroleptics. The other protease inhibitors -- indinavir, nelfinavir, saquinavir and amprenavir as well as the NNRTIs efavirenz, nevirapine and delavirdine -- have much fewer effects on psychotropic drugs but may also inhibit CYP3A4 isoenzymes.
Pimozide (Orap) and triazolam (Halcion) are contraindicated with the protease inhibitors.1
All SSRIs can cause additive serotonergic effects when combined with MAO inhibitors, selegiline, sibutramine, tryptophan, sumatriptin, nefazodone, venlaxafine, fenfluramine, dexfenfluramine, tramadol and St. John's wort.4
CYP2D6 inhibition by SSRIs when coadministered with opiate drugs such as codeine and hydrocodone results in lack of conversion to active form and a significant decrease in narcotic efficacy, and should be avoided.4
As a general rule, two underlying mechanisms cause clinically significant drug interactions among these groups. One involves the alteration of the hepatic metabolism of some psychotropic agents, leading to an increase or decrease of their therapeutic effect or causing an increase in their adverse effects. The other involves psychotropic agents that increase the adverse effects or limit the efficacy of protease inhibitors. Most of the currently available, newer antidepressant agents are substrates for cytochrome P450 enzyme system isoenzymes.
Substrates can simply be described as substances that are amenable to the action of enzymes in this cytochrome P450 enzyme system of the liver. A drug or chemical substance can have any one of three relationships to the CYP450 enzyme system; it can be a substrate, an inducer, or an inhibitor. Inhibitors of the CYP system are medications or chemical substances, including herbal remedies, which may cause a decrease in the volume of enzymes produced by this system reducing the metabolism of such drugs and thereby increasing their levels.
This is the basis for the use of ritonavir as a PI enhancer in dual protease regimens. The SSRIs, for instance, and nefazodone are inhibitors of many CYP450 isoenzymes. When such agents are administered concomitantly with other agents -- such as the PIs, the NNRTIs, or other nonantiretroviral agents which may also be substrates, inducers or inhibitors of these enzymes -- drug accumulation can occur, leading to potentially dangerous and sometimes unpredictable toxicities. Inhibitors of the CYP450 enzymes such as the azole antifungals, namely ketoconazole, itraconazole and to a much lesser extent fluconazole (hence making it the most desirable in HIV disease) and erythromycin will cause a decrease in the clearance of such drugs as citalopram (Celexa), terfenadine, midazolam (Versed), and triazolam (Halcion) (specifically mentioned in the February 2001 DHHS Guidelines for Treatment of HIV in Adults and Adolescents), leading to cardiac arrhythmias and sudden and unexplained deaths.
Interactions Between HAART Drugs and Other Drugs Used by Patients With Advancing HIV Disease
Clinicians should become familiar with these interactions of clinical significance between antiretroviral drugs and ancillary drugs needed to manage the many complications of advancing HIV disease. Providers should avoid drug combinations likely to result in potentially serious interactions. Table 27-5 (PDF) provides a detailed list of the drug interaction studies in the presence of ritonavir, the most potent CYP-modifying protease inhibitor, while Tables 27-6a (PDF) and 27-6b (PDF) offer clinical monitoring highlights and counseling tips for patients using drugs that may prolong the QTC interval.
Drug Interactions Involving Amprenavir (Agenerase) and Vitamin E
One capsule of amprenavir (Agenerase) contains 109 international units (IUs) of vitamin E. The daily dose of eight capsules of amprenavir, taken twice daily which adds up to 1,200 IUs, has been established as the minimum toxic dose (MTD); this is the smallest dose that has been found to be harmful when taken over a period of time. The manufacturer, Glaxo-Wellcome, notes in the package insert that people taking amprenavir should not take any extra vitamin E. High doses of vitamin E can create problems because vitamin E is a blood thinner and so can cause problems with other blood thinners such as warfarin (Coumadin), vitamin K or clotting factors. One woman on long-term warfarin experienced intracranial bleeding less than a week after starting amprenavir. People taking low-dose aspirin daily to prevent heart attacks as well as people on herbal blood thinners like ginger, garlic, feverfew, ginseng and ginkgo biloba should also be careful with the extra vitamin E in amprenavir. Symptoms of vitamin E toxicity (which is ordinarily rare) include spontaneous nosebleeds, cuts that will not stop bleeding and bruises acquired easily.9
Effects of Concomitant Medications on QTC Prolongation
Torsades des pointes is a serious form of cardiac arrhythmias which has been associated with reports of sudden death within the last several years. Like many other drugs, several of the medications reported to cause torsades des pointes are metabolized by CYP3A, a specific member of the cytochrome P450 enzyme system responsible for a larger percentage of these degradation reactions. Tables 27-6a (PDF) and 27-6b (PDF) offer clinical monitoring parameters as well as baseline counseling tips for patients receiving such drugs.
Table 27-7 (PDF) highlights HIV-related drugs with overlapping toxicities. Table 27-8 (PDF) lists some of the most significant drug interactions with agents used in the treatment of Pneumocystis carini pneumonia,10 the most common opportunistic infection at the point of AIDS diagnosis for most patients with HIV disease.
Selected Enzyme Inducers of the CYP System
Table 27-2 (PDF) lists agents that are inducers of the CYP system, which are discussed here in greater detail.
It should be noted that ritonavir is both an inducer and inhibitor of the CYP system; it is presently one of the most potent inhibitors known; it also induces CYP1A2, the enzyme system responsible for the metabolism of theophylline and caffeine. Other notable inducers of this system are rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine, nelfinavir, indinavir, efavirenz and nevirapine. Both ritonavir and nevirapine are autoinducers which means that they will induce enzymes that hasten their own metabolism as well. As a result of this, manufacturers of these agents suggest that treatment be initiated with doses that are slowly escalated within the first two weeks of treatment (always consult the manufacturers' most recent package inserts for additional information, updated drug-drug interactions listings and other drug information).
Selected Enzyme Inhibitors of the CYP System
Table 27-3 (PDF) lists agents that are inhibitors of the CYP system, which are discussed here in greater detail.
As a potent inhibitor of CYP3A both in vitro and in vivo, ritonavir significantly increases the area under the curve (or, serum concentrations) of drugs that are eliminated primarily through this enzyme system, especially the other protease inhibitors such as saquinavir, indinavir, amprenavir and lopinavir. These increases range from 77% to twenty-fold in humans and constitute the basis for the boosted PI regimens that have been shown to increase plasma levels and in many instances are able to improve efficacy of salvage regimens in advancing disease.
Administering reduced dosages of both PIs reduces pill burden and improves tolerability, while food and hydration requirements as well as the incidence of crystalluria due to indinavir are significantly reduced. By the same mechanism, enzyme inhibition causes levels of drugs such as clarithromycin, ketoconazole and rifabutin to be greatly increased, leading to unexpected toxicities and adverse events; concomitant administration of these agents should therefore be avoided.
Other Ritonavir Drug-Drug Interactions of Clinical Significance
Since ritonavir is also an inducer of several other metabolizing enzymes such as CYP1A4, glucoronyl transferase and possibly CYP2C9 and CYP2C19, the magnitude of ritonavir interactions is difficult to predict especially for drugs metabolized by multiple enzyme systems or drugs that have a low intrinsic clearance by CYP3A, such as methadone. Enzyme induction, first recognized in the 1940s, occurs when hepatic blood flow is increased or the synthesis of more CYP450 enzymes is stimulated. In early animal models of enzyme induction, phenobarbital was found to increase liver weight in a dose-dependent manner. Liver biopsies in human patients taking anticonvulsants on a chronic basis showed up to a 52% increase in liver size. Enzyme induction is influenced by age and liver disease. As a general rule, subjects older than 60 years of age tend to have decreased capacity for enzyme induction, as shown by reports of differential induction of drug metabolism in such elderly, compared to younger subjects, following exposure to polycyclic aromatic hydrocarbons in cigarette smoke.3
Other Drug Interactions
Drug Interactions With Herbal Products
Use of herbal remedies, multiple vitamins, and mineral and dietary supplements is extremely common among all patient populations surveyed. In one U.S. survey of adults who regularly take prescription medications, 18.4% reported concurrent use of at least one herbal product or high dose vitamin. In another study, 61.5% of patients who used conventional therapies did not disclose use of other remedies to their health care provider.11
Anecdotal experience from questions asked of people with HIV at our busy outpatient clinic suggests that the use of such remedies is reasonably high among this population, particularly as patients advance in their illness and shift into palliative care. In a survey of 515 users of herbal remedies in the U.K., 26% of patients would consult their general practitioner for a serious adverse reaction associated with a conventional over-the-counter medicine, but not for a similar reaction from an herbal remedy. It seems that most patients still do not quite regard herbal remedies as medications.
Another reason patients may not disclose their use of herbal remedies, even if the remedies cause severe adverse effects, is that patients are afraid of censure.12 Health providers must therefore ask patients about their use of herbs in a relaxed manner that is nonjudgmental; it has been shown in several studies that disapproval will ensure that patients conceal any such use in the future. Such patients should be involved in a partnership in which providers share whatever information is available about the herbal product, including the lack of information on drug interactions and the need for open communication on both sides about the use of all such remedies. All such formulations, the reasons for their use, dosages, brand and manufacturer should be documented in patient charts and updated from time to time.
Interactions With St. John's Wort
This commonly used, over-the-counter antidepressant herbal product induces cytochrome P450 3A enzymes and as a result has been shown in several studies to decrease significantly levels of all of the protease inhibitors and, most probably also, the NNRTIs currently available in the market. In one study, indinavir trough levels decreased 81% when concomitantly given with St. John's wort.13 The DHHS guidelines of February 2002 recommend that St. John's wort not be taken by patients on PI antiretroviral medications.1
An increased risk of serotonin syndrome has also been reported in patients who mix St. John's wort with certain SSRIs, namely trazodone (Desyrel), paroxetine (Paxil), sertraline (Zoloft) and nefazodone (Serzone).4, 14
Reports also have been made of decreased serum concentrations of drugs such as digoxin, theophylline, cyclosporine and phenprocoumon when combined with St. John's wort.11 At the present time, many reports of herb-drug interactions are sketchy and lack proper pharmacokinetic studies to substantiate them; nonetheless, health care providers should counsel patients on the need always to form a partnership in the use of these remedies and if possible to avoid unnecessary herbal and unproven remedies that can lead to undesirable drug-herb interactions.
Significant Induction Interactions: Cigarette Smoking, Benzodiazepines, Rifampin and Narcotic Analgesics
Similar to theophylline, the inducing effects of smoking are associated with decreased drowsiness in patients taking diazepam and chlordiazepoxide. In a comprehensive in-hospital drug surveillance program comparing 2274 nonsmokers, light smokers and heavy smokers receiving benzodiazepines, smokers generally required larger doses of benzodiazepines to achieve a sedative and/or anxiolytic effect.15
Rifampin is one of the most powerful inducers of the cytochrome P450 enzyme system and can impair the efficacy of some benzodiazepines based on this activity. When co-administered with rifampin to ten healthy volunteers in a double-blind cross-over study, the AUC of midazolam was decreased 96% while the hypnotic effects were nonexistent in all ten subjects. Similar studies with triazolam and rifampin gave similar results, with markedly decreased effects of triazolam in the presence of rifampin based on standardized psychomotor tests.
It is also well known that rifampin, like benzodiazepines, increases the rate of metabolism of many opioids and may induce withdrawal symptoms in patients.16
Drug Interactions of Clinical Significance Involving Warfarin
The anticoagulant effects of warfarin, as measured by increases in prothrombin time, have been reported to be increased two-fold by the presence of fluconazole (Diflucan) and three-fold by ketoconazole (Nizoral). Clearances of both isomers of warfarin were reduced even by doses of fluconazole as low as 100mg/day for seven days.17
Numerous other reports tend to substantiate the effects of erythromycin in enhancing the hypoprothrombinemic effects of warfarin when given in combination. Two-fold increases in prothrombin time were reported after seven days but there have been few reports of bleeding complications.The clinical relevance of this interaction depends on a number of factors such as age of patient, concurrent drug therapy, rate of clearance of warfarin and ability to transfer drug metabolism to other non-inhibited pathways. This interaction has not been observed with azithromycin; as with erythromycin, caution is advised with clarithromycin therapy in this setting.
Omeprazole, another drug commonly used by patients for palliative care, has been shown to inhibit the metabolism for warfarin, an interaction that is most likely mediated by CYP3A4. This interaction is usually observed after several days of taking omeprazole, is dose-related, and may not necessarily abate upon discontinuation of the agent. Lansoprazole (Prevacid) appears not to have this interaction and offers a comparable alternative treatment.18
As a general rule, patients with clotting disorders, those awaiting surgical procedures, and those on anticoagulant therapy should be cautioned against the use of herbs such as garlic, papaya, ginseng (Pannax species), Devil's claw (Harpagophytum procumbens), Danshen (Salvia mittiorhiza), ginkgo (Ginkgo biloba), Don quai (Angelica sinensi).11 Where patients insist on continuing with these medications along with their herbal remedies, their bleeding times should be more closely monitored. Since most of these herbs interfere with platelet aggregation, not the coagulation cascade, they will neither affect prothrombin time, partial thromboplastin (PTT) nor the international normalized ration (INR). It is also worthy to note that since many herbal substances contain anticoagulant substances, patients on warfarin should as a precautionary measure, have their INRs measured within seven days of starting any herbal remedy.
Drug Interactions of Clinical Significance Involving HMG-CoA Reductase Inhibitors (Statins)
Recent medical and lay literature has raised a number of concerns regarding adverse events with the HMG-CoA group of cholesterol-lowering agents, culminating in the removal of at least one product, cerivastatin (Baycol), from the U.S. market following reports of rhabdomyolysis (destruction of skeletal muscle, leading to renal failure) and myopathy. Clinically significant drug interactions occur with the statins when these agents, all of which are substrates to the CYP450 enzyme system and so are amenable to the action of these enzymes, are combined with other drugs that cause muscle damage or drugs that interact to give rise to increased statin plasma levels resulting from inhibition of statin metabolism.
Numerous interactions between statins metabolized by CYP3A and several CYP3A inhibitors, including the protease inhibitors, the azole antifungals, grapefruit juice, and kaolin/pectin (especially lovastatin) have been reported.4 DHHS guidelines specifically suggest avoiding combinations of protease inhibitors and simvastatin (Zocor) and lovastatin (Mevacor), with fluvastatin (Lescol) and atorvastatin (Lipitor) as alternatives that must be used with caution.1 Fibrates such as gemfibrizol may cause myopathy when used alone and also in combination with most of the statins, with the exception of fluvastatin (Lescol). An increased incidence of myopathy has been reported when niacin is combined with lovastatin but not with fluvastatin, pravastatin or simvastatin.19
Despite the increased risk of adverse events, providers are sometimes compelled to continue statin therapy in order to ward off serious cardiovascular sequalae. In such circumstances, patients should be counseled to report immediately any signs or symptoms of myopathy such as muscle pain, calf tenderness or muscle weakness.
Significant Induction Interactions: Estrogens and Corticosteroids
Estrogens and corticosteroids are substrates to the cytochrome P450 enzyme system, hence remain susceptible to the action of these enzymes and can be changed or metabolized by them or by substances that act as inducers or inhibitors on CYP450 enzymes. Protease inhibitors such as nelfinavir or ritonavir, which can act both as inducers and inhibitors of the CYP450 enzyme system, have been shown to increase the degradation of ethinyl estradiol, a major component of oral contraceptive pills.20 Women with HIV taking these PIs should receive additional or alternative contraceptive methods in order to ensure full protection.
As a result of the recent decreases in the estrogen and progestin concentrations of oral contraceptives, reports of unintended pregnancies and episodes of breakthrough bleeding seem to be on the rise.16 Reports of clinically significant drug interactions secondary to enzyme induction have implicated phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone and rifampin.21-24 Such reports have not been made for gabapentin, lamotrigine, topiramate and valproate. When such interactions are suspected, a higher dose oral contraceptive containing 50 mg ethinyl estradiol, medroxyprogesterone or a non-hormonal alternative method of contraception is usually recommended.
Corticosteroids, which often remain the mainstay of management of diseases that occur in palliative care of advanced HIV infection, have their clearances increased in a similar fashion to the estrogens by the same agents, when administered concomitantly. Patients receiving steroids for chronic diseases should be monitored for exacerbation of symptoms in these situations and the necessary dosage adjustments made.24
Drug Interactions Between Illicit Drugs and Antiretroviral Agents
Interactions between drugs of abuse and other treatment modalities that may be offered in palliative care, including antiretroviral agents, occur against a background of related events and conditions that vary by individual patient. Though patients differ, most patients with longstanding substance use will suffer from comorbid conditions that will significantly affect their response to the therapies offered to them at all stages of their HIV disease. It is well established that the abuse of psychoactive substances not only causes a significant number of accidents, but often is associated with other medical problems and comorbid conditions as shown in Table 27-9 (PDF).25 For example, excessive alcohol intake places a patient at risk for various adverse events and conditions including peripheral neuropathy and pancreatitis, cirrhosis, malignancies and psychiatric disorders. Any of these events and conditions can exacerbate the occurrence as well as the severity of drug-drug and drug-disease interactions, especially as HIV disease advances and patients begin to receive palliative care.
Most Commonly Used Illicit Substances and Their Interaction With Antiretroviral Agents
Recent reports in the literature have brought more attention to the life-threatening interactions, including deaths, that occurred when protease inhibitors were combined with illicit drugs such as ecstasy (MDMA) and GHB (gamma hydroxy butyrate).26
Although PIs have dramatically improved the prognosis for many people living with HIV, PIs are associated with numerous adverse effects including increases in serum glucose, triglycerides, lipodystrophy, hepatitis, nephrolithiasis and a large variety of GI side effects.27 In addition to the drug interactions previously discussed, protease inhibitors can cause serious adverse reactions and interactions when administered in combination with other substances, including illicit drugs, whose metabolism may be altered as a result of the inhibitory effects of the PIs on the cytochrome P450 enzyme system.
Illicit substances most commonly abused include cocaine, marijuana, methamphetamine, ecstacy (MDMA, or methylenedioxymethamphetamine), heroin, methadone, ketamine, crystal and GHB (gamma hydroxy butyrate). As a result of the myriad side effects that can follow use of these substances (see Table 27-10, PDF), combining any of these substances with PIs especially increases the likelihood of an overdose due to one of these agents, particularly ecstasy.
Cocaine has been reported to increase the speed at which HIV replicates, while combination of the protease inhibitors with marijuana increases levels of tetrahydrocannabinoids in the blood. Because combination of methamphetamine with ritonavir (Norvir) causes an increase in the potency of ritonavir, two-fold or three-fold, the likelihood of overdose with methamphetamine is increased. Concomitant use of ketamine in the presence of the protease inhibitors causes hepatitis. Ritonavir decreases plasma levels of heroin by 50%.
The potency of methadone is decreased in the presence of ritonavir, indinavir (Crixivan) and nevirapine (Viramune), while methadone increases the potency of ritonavir by 50%. Nevirapine was demonstrated to reduce plasma methadone levels and to precipitate opiate withdrawal in patients who were maintained on methadone for narcotics addiction.28 More recent studies have reported decreases in the amount of stavudine (Zerit) and didanosine (Videx) absorbed from the digestive tract into the bloodstream in the presence of methadone. Table 27-10 (PDF) provides highlights of the side effects that may be exacerbated by the use of ecstasy (MDMA), a powerful street drug recently associated with fatal drug interactions when administered concomitantly with ritonavir.29
Drug Interactions Between Opioid Analgesics and Protease Inhibitor Antiretroviral Agents
Since most opiates are substrates of the CYP450 enzyme system, when they are co-administered with cytochrome P450 enzyme inhibitors such as the protease inhibitors erythromycin and clarithromycin, marked increases in serum levels can occur. Patients should be monitored for over-sedation and initial dosages should be decreased by 50%. Patients abusing opiate drugs are at risk of toxicity if they concomitantly take these agents, and should be counseled appropriately.30Table 27-11 (PDF) lists metabolic pathways of frequently abused drugs potentially affected by co-administration with the protease inhibitors.26
Table 27-12 (PDF) offers an extensive and exhaustive listing of potential drug-drug interactions involving medications that may be applied therapeutically to various organ systems during palliative as well as early care of HIV disease.
Table 27-13 (PDF) presents a list of red-flag medications that should be discussed in counseling patients before prescribing. With the increasing complexity of HIV therapy, the potential for drug interactions for patients in both active and palliative care is exceedingly high. Health care providers must be committed to constantly monitoring their patients and applying strategies to minimize and/or circumvent harmful drug-drug interactions.
With more than 30 new medications approved by the FDA each year for use in our therapeutic armamentarium, the recognition and management of drug interactions has become an ongoing challenge. While some pharmacokinetic and pharmacodynamic interactions can be favorable and clinically useful, many have the potential to be detrimental or to even lead to life-threatening toxicities and/or therapeutic failures. Providers must, therefore, become familiar with the fundamental issues involved in drug-drug interactions, especially with the red-flag medications -- usually the drugs in the patient's regimen that are enzyme inducers or inhibitors, have a narrow therapeutic index, or have specific absorption requirements -- as well as with other medications that require close patient monitoring and avoidance of certain groups of drugs.
It is equally important that patients become active partners in their own care. Patients must understand that many potential drug-drug interactions can be circumvented, as long as providers are made aware of all the medications and herbal remedies a patient is taking. Providers may want to photocopy Table 27-14 (PDF), Advice to Patients: Red Flag Medications, for discussion with patients receiving active and/or palliative care therapies for HIV disease.
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