The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

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A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceTable 27-4: Common Substrates of 3A4 and 2D6 Isoenzymes3A4 SubstratesBenzodiazepinesCisapride (Propulsid)MacrolidesMethadoneRisperidoneQuinidineSildenafil (Viagra)2D6 SubstratesBeta blockersTricyclic antidepressantsSSRIsHaloperidolLovastatin (Mevacor)Simvastatin (Zocor)Atorvastatin (Lipitor)Cerivastatin (Baycol)Fluvastatin (Lescol)Pravastatin (Pravachol)Dosage Adjustments for the SSRIsAs a class, the SSRIs have varying inhibitory effects on CYP450 isoenzymes, with far-reachingimplications. Most of the research is still ongoing and interactions reported between an individualSSRI 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 inhibitsCYP2D6. Fluvoxamine (Luvox) inhibits all of the major isoenzymes and possibly also CYP2C9; asa result of this, it appears to have the greatest propensity for drug-drug interactions theoreticallyand most probably clinically, as well. Despite its potent inhibition of the cytochrome P450CYP2D6 isoenzyme, paroxetine (Paxil) may be regarded as the least problematic with regard tointeraction potential from a clinical standpoint in comparison to fluoxetine (Prozac) orfluvoxamine (Luvox). 7The SSRIs have a wide therapeutic window, without the danger of overdosing that exists withthe TCAs. Nonetheless, as a general rule with the SSRIs and TCAs, doses are started low andbuilt up gradually; initial doses should be decreased 50% to 66% and then increased graduallyuntil the desired response is obtained. 8SSRIs and nefazodone have been reported to increase serum levels of protease inhibitors, particularlythrough inhibition of CYP3A4; the clinical significance of this interaction needs furtherclarification. Before starting ritonavir, doses of most neuroleptics should be decreased and suchpatients monitored closely; this is in anticipation of ritonavir-induced CYP inhibition that mayincrease levels of such neuroleptics. The other protease inhibitors—indinavir, nelfinavir,saquinavir and amprenavir as well as the NNRTIs efavirenz, nevirapine and delavirdine—havemuch fewer effects on psychotropic drugs but may also inhibit CYP3A4 isoenzymes.Pimozide (Orap) and triazolam (Halcion) are contraindicated with the protease inhibitors. 1All 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. 4558U.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau
A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceCYP2D6 inhibition by SSRIs when coadministered with opiate drugs such as codeine andhydrocodone results in lack of conversion to active form and a significant decrease in narcoticefficacy, and should be avoided. 426 picasAs a general rule, two underlying mechanisms cause clinically significant drug interactions amongthese 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 theiradverse effects. The other involves psychotropic agents that increase the adverse effects or limitthe efficacy of protease inhibitors. Most of the currently available, newer antidepressant agentsare substrates for cytochrome P450 enzyme system isoenzymes.Substrates can simply be described as substances that are amenable to the action of enzymes inthis cytochrome P450 enzyme system of the liver. A drug or chemical substance can have any oneof three relationships to the CYP450 enzyme system; it can be a substrate, an inducer, or aninhibitor. Inhibitors of the CYP system are medications or chemical substances, including herbalremedies, which may cause a decrease in the volume of enzymes produced by this system reducingthe 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 areadministered concomitantly with other agents—such as the PIs, the NNRTIs, or othernonantiretroviral agents which may also be substrates, inducers or inhibitors of these enzymes—drug accumulation can occur, leading to potentially dangerous and sometimes unpredictabletoxicities. 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 HIVdisease) and erythromycin will cause a decrease in the clearance of such drugs as citalopram(Celexa), terfenadine, midazolam (Versed), and triazolam (Halcion) (specifically mentioned inthe February 2001 DHHS Guidelines for Treatment of HIV in Adults and Adolescents), leading tocardiac arrhythmias and sudden and unexplained deaths.XXVIIU.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau 559
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DedicationA Clinical Guide to Suppo
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Lynn A Jansen, RN, PhDAssistant Res
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TABLE OF CONTENTSPart IChapter 1Cha
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IChapter 1.26 picasHIV and Palliati
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IA Clinical Guide to Supportive and
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A Clinical Guide to Supportive and
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IIIChapter 3.Assessment of Physical
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Chapter 6.26 picasPulmonary Symptom
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Chapter 8.26 picasOral ProblemsDavi
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Chapter 9.26 picasDermatologic Prob
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Chapter 10.26 picasPsychiatric Prob
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Chapter 11.26 picas Substance Use P
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Chapter 14.26 picasCulture and Care
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Chapter 15.26 picasSpecial Populati
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Chapter 17.26 picasEthical IssuesLy
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Chapter 18.26 picasLegal and Financ
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Chapter 19.Palliative 26 picas Care
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Chapter 23.26 picas Medical Care in
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Chapter 25.26 picas Prevention of S
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The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

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