Enzyme Inhibitors - Protease Inhibitors (PIs)

The third type of enzyme inhibitor is the protease inhibitor, also called PI. These medications treat both HIV-1 and HIV-2 in combination with at least one reverse transcriptase inhibitor in order to prevent resistance from occurring. PIs also tend to increase the therapeutic effects of other antiretroviral medications. 

Prototype and Other Medications

Ritonavir—Classification: Protease Inhibitor

The prototype for the protease inhibitors is ritonavir. Multiple protease inhibitors are currently available including saquinavir, bortezomib, atazanavir, and darunavir.​​​​​​​

Expected Pharmacologic Action

Protease is an enzyme that breaks up large polyproteins into smaller proteins so that the HIV virus can continue maturing and growing. The protease inhibitors prevent this change and thus keep the HIV virus harmless and in an immature state. The protease inhibitors work at the very end of the HIV replication cycle. When a protease inhibitor is combined with one or more nucleotide reverse transcriptase inhibitors, or NRTIs, these medications are quite effective in decreasing the replication of the HIV virus. If a client is taking a protease inhibitor by itself, the virus easily develops resistance to all protease inhibitors, so it is important that different types of HIV medications are combined in order to prevent the occurrence of resistance to single medications. 

Adverse Drug Reactions

The protease inhibitors have a number of adverse effects in common. These include hyperglycemia and increased risk for diabetes; fat redistribution causing thin extremities, face, and buttocks; increased abdominal fat; gynecomastia; and buffalo hump, which is a fat accumulation between the shoulder blades. Other adverse effects include increased cholesterol and triglyceride levels, which may lead to atherosclerosis and cardiovascular disease, and reduced bone density, which may lead to osteoporosis and liver toxicity. In addition, each protease inhibitor has its own set of adverse effects. For ritonavir, the gastrointestinal symptoms of nausea, vomiting, diarrhea or constipation, heartburn, and abdominal pain are common. 

Interventions

When administering a protease inhibitor, it is important to monitor baseline and periodic blood glucose testing, and to give any prescribed antidiabetic medications, as well as teach the client about lifestyle modifications for diabetes as appropriate. Also, monitor for fat redistribution effects and each client’s response to them. Monitor cholesterol and triglyceride levels, and give prescribed anti-cholesterol medications, except those with statins, which are contraindicated. Monitor bone density tests for reduced density and administer medications to increase bone density if prescribed, such as bisphosphonates and others. Also, monitor baseline and periodic serum transaminase and other liver tests and watch for signs of liver toxicity such as abdominal pain, anorexia, or jaundice. For clients taking ritonavir, monitor for and report persistent gastrointestinal effects and monitor clients’ weight for any weight loss.

Administration

The protease inhibitors are all available for oral administration. Each medication in this group has its own separate administration requirements. For ritonavir, give the medication twice daily with food or a snack for the best absorption. Giving it with food also tends to decrease gastrointestinal effects and problems with altered taste, another side effect of this medication. 

Client Instructions

Advise clients who take a protease inhibitor to report increased thirst, food intake, or urination, which could be signs of diabetes. Tell clients that fat redistribution may occur and, if appropriate, consult with the provider about the injection of a substance that corrects the loss of facial fat. Reinforce the increased risk for cardiovascular disease and the need to have a lipid profile drawn every few months. Instruct clients to increase their intake of calcium and vitamin D to increase weight-bearing exercise, and advise clients not to smoke. Also, advise clients to comply with liver function testing and to report to the provider increased abdominal pain, anorexia, or jaundice. Clients taking ritonavir should also be instructed to report persistent gastrointestinal symptoms. Also, advise them to notify the provider before taking any new over-the-counter or prescribed medications due to multiple interactions.

Safety Alert

Reinforce to clients the effect protease inhibitors have on their cholesterol and triglyceride levels and the related increased risk for heart disease. Clients should maintain a strict schedule for having their lipid profile drawn to monitor these values. Evaluation of these levels should be done every 3 to 4 months, and increases reported to the provider. Clients can also take an active part in preventing heart disease by eating a healthy diet, exercising at least three times a week, and taking a fibrate antilipemic medication that lowers cholesterol. Due to the deleterious effect these medications can have on the liver, liver function tests should also be closely monitored. 

Contraindications and Precautions

Contraindications to protease inhibitors include resistance to any protease inhibitor, pancreatitis, and lactation. Also, see the interactions section for medications that are contraindicated to take with any protease inhibitor. Use caution when giving protease inhibitors to clients who have liver disorders or elevated liver enzymes, diabetes mellitus, elevated cholesterol, or renal insufficiency. Also, use caution when giving these medications to clients who have hemophilia because protease inhibitors cause an increased risk of bleeding in these clients. 

Interactions

The protease inhibitors all interact adversely with many medications. They inhibit P 450, so all PDE5 inhibitors, such as sildenafil, should be given in reduced dosages. Certain medications are contraindicated due to the possibility of toxic levels. These include the benzodiazepines: alprazolam, triazolam, and midazolam; also, the ergot alkaloid, ergotamine, and the anti-cholesterol medications, simvastatin and lovastatin. In addition, the herb St. John’s wort and antiseizure medications, such as phenobarbital, phenytoin, and carbamazepine, decrease levels of protease inhibitors. Also, ritonavir decreases levels of oral contraceptives containing ethinyl estradiol. In contrast, it greatly increases levels of rifabutin, ketoconazole, clarithromycin, and desipramine, so dosages of these medications must be reduced. For an overview of the protease inhibitor prototype, click the button to access a medication information table.