Protease inhibitors

Protease inhibitors

Protease inhibitors are drugs that act against the enzyme HIV pro-tease, preventing it from dividing a larger viral precursor protein into the active smaller enzymes that the HIV virus needs to fully mature. The result is an immature, noninfectious cell. Drugs in this group include:

·                 amprenavir

·                 atazanavir

·                 darunavir

·                 fosamprenavir

·                 indinavir sulfate

·                 lopinavir and ritonavir

·                 nelfinavir mesylate

·                 ritonavir

·                 saquinavir mesylate

·                 tipranavir.

Pharmacokinetics

Protease inhibitors may have different pharmacokinetic proper-ties.

Active and inactive

Amprenavir is metabolized in the liver to active and inactive metabolites and is minimally excreted in urine and stool.

·                 Atazanavir is rapidly absorbed and is metabolized in the liver by the CYP3A. The drug is excreted mainly through stool and urine.

·                  Darunavir is well absorbed when taken with food and highly protein-bound. It’s metabolized in the liver and excreted in stool.

·                  Fosamprenavir is well absorbed and highly protein-bound. It’s rapidly metabolized by CYP3A4 and it is unknown how it is ex-creted.

P-450 at it again

Lopinavir is extensively metabolized by the liver’s cytochrome P-450 system; ritonavir acts as an inhibitor of lopinavir. This com-bination drug’s antiviral activity is due to lopinavir.

Availability unknown

Nelfinavir’s bioavailability (the degree to which it becomes avail-able to target tissue after administration) isn’t determined. Food increases its absorption. It’s highly protein-bound, metabolized in the liver, and excreted primarily in stool.

Broken into five…

Ritonavir is well absorbed, metabolized by the liver, and broken down into at least five metabolites. It’s mainly excreted in stool, with some elimination through the kidneys.

…and seven

Indinavir sulfate is rapidly absorbed and moderately bound to plasma proteins. It’s metabolized by the liver into seven metabo-lites. The drug is excreted mainly in stool.

Highly bound

Saquinavir mesylate is poorly absorbed from the GI tract. It’s widely distributed, highly bound to plasma proteins, metabolized by the liver, and excreted mainly by the kidneys.

Tipranavir has limited absorption, but its bioavailability in-creases when it’s taken with a high-fat meal. It’s metabolized by the chromosome P-450 and excreted mostly unchanged in stool.

Pharmacodynamics

All of these drugs inhibit the activity of HIV protease and prevent the cleavage of viral polyproteins.

Pharmacotherapeutics

Protease inhibitors are used in combination with other antiretrovi-ral agents for the treatment of HIV infection.

Drug interactions

Protease inhibitors may interact with many drugs. Here are some common interactions.

The action of saquinavir may be reduced by phenobarbital, phenytoin, dexamethasone, and carbamazepine.

Blockers beware!

·                 Ritonavir may increase the effects of alpha-adrenergic blockers, antiarrhythmics, antidepressants, antiemetics, antifungals, anti-lipemics, antimalarials, antineoplastics, beta-adrenergic blockers, calcium channel blockers, cimetidine, corticosteroids, erythro-mycin, immunosuppressants, methylphenidate, pentoxifylline, phenothiazines, and warfarin.

§    Indinavir sulfate inhibits the metabolism of midazolam and tria-zolam, increasing the risk of potentially fatal events such as car-diac arrhythmias.

§    Didanosine decreases gastric absorption of indinavir sulfate; these drugs should be administered at least 1 hour apart.

§    Rifampin markedly reduces plasma levels of most protease in-hibitors, including atazanavir.

§    Nelfinavir may greatly increase plasma levels of amiodarone, er-got derivatives, midazolam, rifabutin, quinidine, and triazolam.

§    Lopinavir and ritonavir are used in combination because of their positive effects on HIV RNA levels and CD4 counts. When given together, ritonavir inhibits the metabolism of lopinavir, leading to increased plasma lopinavir levels.

§    Carbamazepine, phenobarbital, and phenytoin may reduce the effectiveness of nelfinavir.

§    Protease inhibitors may increase sildenafil levels, resulting in sildenafil-associated adverse reactions, including hypotension, vi-sion changes, and priapism.

§    Atazanavir shouldn’t be given with drugs also metabolized by the CYPA3A pathway, such as HMG-CoA reductase inhibitors (in-cluding lovastatin, simvastatin, and atorvastatin). Concurrent use may increase the risk of myopathy and rhabdomyolysis.

Interval issues

Drugs that prolong the PR interval, such as calcium channel blockers (including diltiazem) and beta-adrenergic blockers (in-cluding atenolol), should be used cautiously with atazanavir be-cause atazanavir may also prolong the PR interval.

Atazanavir shouldn’t be given with benzodiazepines, such as mi-dazolam and triazolam, because of the potential for increased se-dation or respiratory depression.

Atazanavir shouldn’t be given with ergot derivatives, such as er-gotamine and dihydroergotamine, because of the potential for life-threatening ergot toxicity resulting in peripheral vasospasm and ischemia of the extremities.

St. John’s wort may reduce plasma levels of atazanavir and darunavir.

Tipranavir and sulfonyureas administered together may result in hypoglycemia.

Indinavir and ritonavir may increase plasma nelfinavir levels. (See Adverse reactions to protease inhibitors.)