Protease Inhibitors

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These drugs inhibit the activity of HIV protease. This enzyme, which is required for the production of a mature infectious virus, cleaves the gag-pol polyprotein into structural proteins and active enzymes. The phar-macokinetic parameters of the protease inhibitors are listed in Table 51.5.

The protease inhibitors are used in the multidrug therapy of HIV infection. Resistance to the HIV protease inhibitors results from mutations in the protease gene and perhaps the cleavage sites of gag-pol. Although different protease mutations tend to be associated with resistance to individual drugs, resistance to one protease inhibitor is often associated with a less than optimal response to other agents of this class. Indinavir, ritonavir, and lopinavir require more mutations to lose their effectiveness than do the other protease inhibitors.

All protease inhibitors can produce nausea, vomiting, diarrhea, and paresthesia. Drug-induced hyper-glycemia and insulin resistance may precipitate the onset of diabetes mellitus or worsen existing cases. Protease inhibitors may also cause hypercholester-olemia and hypertriglyceridemia. Liver enzymes may be increased, and hepatic toxicity may occur at high doses. Fat redistribution is common and can manifest as central fat accumulation, peripheral wasting, buffalo hump at the base of the neck, breast enlargement, and/or lipomas.

Protease inhibitors may increase the risk of bleeding in hemophiliacs. These drugs should be used with caution in patients with diabetes, lipid disorders, and hepatic disease. Dosage adjustment may be necessary.

Protease inhibitors interact with a large number of drugs because they are metabolized by and inhibit CYP3A4. Ritonavir is the most potent inhibitor of CYP3A4, with indinavir, amprenavir, and nelfinavir being much less potent and saquinavir the least potent. When given as part of a combination therapy, the protease inhibitors affect plasma levels of NNRTIs as well as each other (Tables 51.4 and 51.6). Many drugs interact with protease inhibitors by inhibiting or inducing their metabolism; similarly, protease inhibitors inhibit or induce the metabolism of numerous drugs (Table 51.7).

TABLE 51.5 Pharmacokinetic Properties of Selected Protease inhibitors3

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