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Nursing Pharmacology: Antiviral Drugs
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Protease Inhibitors
Antiretroviral Drugs Used in Treating HIV Infection
→Protease Inhibitors
Metabolism:
Antiretroviral protease inhibitors are metabolized by the cytochrome P450 hepatic and intestinal microsomal metabolizing system.3,4
The primary isoform responsible for metabolism is CYP3A4, except for nelfinavir, although its major metabolite is dependent on CYP3A4.
Protease inhibitors also inhibit CYP3A4 with the most significant inhibitory effect noted with ritonavir and the least with saquinavir.
However, some protease inhibitors including amprinavir and ritonavir can induce particular cytochrome P450 isoforms.
HIV protease inhibitors exhibit variable pharmacokinetic properties probably due to interindividual differences likely due to variation in hepatic and intestinal CYP isoform enzymatic activities.
HIV protease inhibitor half-lives range from about 2 to 10 hours, usually allowing for 12 once- to twice-daily dosing.
Since protease inhibitors may inhibit CYP3A4 or induce cytochrome
P450-mediated hepatic drug oxidation, drug-drug interactions are numerous.3,4
Examples of drug interactions include: dihydroergotamine, depridil and some benzodiazepines.8
Enhanced pharmacologic activity may be associated with amiodarone, quinidine, lidocaine (systemic effects), tricyclic antidepressants and warfarin administration.
Additional drug-drug interactions have been noted with rifampin, phenobarbital, rifabutin, dexamethasone, phenytoin, and carbamazepine.8
Accordingly,
dosage adjustments are often needed and some drug combinations may be
contraindicated.3,4
Boosting
pharmacological efficacy of some protease inhibitors may be noted when the
inhibitor is given in combination with ritonavir, taking advantage of
ritonavir-mediated CYP3A4 inhibition.
As a result of this ritonavir-caused inhibition of the cytochrome P450 isoform responsible for protease inhibitor metabolism, the other protease inhibitor's half-life is lengthened.
Extending the drug half-life permits both reduces dosing frequency and makes the development of drug resistance more difficult.3,4
Some protease inhibitors
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Ritonavir |
Saquinavir |
Amprenavir |
Side-Effect/Toxicities:
Administration of protease inhibitors, as a class, may result in nausea, diarrhea, and dyslipidemia.
Furthermore, body fat redistribution and accumulation result in central obesity, "dorsocervical" fat enlargement (Buffalo hump), peripheral and facial wasting and breast enlargement.4
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Less frequently, a cushingoid presentation may occur.4
Elevated triglycerides and low-density lipoprotein levels are associated with protease inhibitor administration.
Hyperglycemia and insulin resistance may also occur.
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In some studies (not all) administration of abacavir, lopinavir + ritonavir, fosamprenavir + ritonavir may elevate cardiovascular disease risk.
Protease inhibitors generally may induce myocardial conduction abnormalities, such as PR or QT interval prolongation (or both).
Protease inhibitor treatment related hepatitis and rarely severe hepatotoxicity have also been found.
The likelihood of hepatic adverse effects appears higher with tipranavir + ritonavir compared to other protease inhibitors.
In patients with hemophilia A or B may be at risk for increased spontaneous bleeding associated with protease inhibitor administration.4
Identified
genetic alterations resulting in resistance to protease inhibitor
antiretroviral activity frequently occur, suggesting that protease
inhibitor-based monotherapy is likely inappropriate.
Codon sites associated with extensive resistance to protease inhibitors are located at positions 10, 46, 54, 82, 84 and 90, although other mutation sites have also been identified.
Some protease inhibitors, such as darunavir and tipranavir, show enhanced virologic activity in individuals exhibiting HIV-1 resistance to other protease inhibitors.
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