Protease Inhibitors and other HIV drugs

Question 1

Class

Answer 1

Inhibit the protease that cleaves the long precursors into the proteins needed for the viral core and thus prevent new waves of infection.

Mutation and development of resistance is common. Always used in combo w/reverse transcriptase inhibitors for tx of HIV. Most have poor bioavailability and are metabolized by CYP3A4.

St. Johns Wart is very bad with these!

SE: altered body fat distribution: buffalo hump with truncal obesity with facial and peripheral atrophy. Insulin resistance/hyperglycemia, inc serum cholesterol (dont combine with statins), spontaneous bleeding in hemophilia A and B.

Question 2

Atazenavir

Answer 2

1. DOC due to less SE and once a day dosing
2. NO cross-resistance with other protease inhibitors
3. Less effect on lipoproteins
4. inhibits CYP3A4, increases bilirubin due to inhibition of UGT
5. Rash, nausea

Question 3

Darunavir

Answer 3

1. Very safe and efective, now drug of second choice
2. Rash, nausea, diarrhea
3. HA and bad dreams may occur

Question 4

Ritonavir

Answer 4

1. Inhibits CYP3A4-many interactions, will inhibit metabolism of other protease inhibitors so it is often added in subtherapeutic dose to increase bioavailability but to reduce ritonavir SE.
2. SE: N/V/D, weakness, burning or tingling around mouth and in periphery and elevated liver enzymes
3. Contains alcohol, can get disulfiram like effect if taken with metronidazole.

Question 5

Saquinavir

Answer 5

1. Bioavailability is low; soft gel has better absorption. Levels increase if taken with grapefruit juice or ritonavir.
2. CYP3A4 metabolism, man interactions
3. SE: GI effects and rhinitis

Question 6

Amprenavir

Answer 6

1. Well absorbed orally, oral solution contains propylene glycol, do not give with disulfiram or metronidazole.
2. Inhibits CYP3A4
3. SE: N/D/V, paresthesias and rash, may cause stevens johnson syn

Question 7

Tipranavir

Answer 7

1. Non-Peptidic protease inhibitors, may work in HIV resitant to other protease inhibitors. Given in conjuction with ritonavir (see ritonavir) and also food increases abosorption.
2. Should not be combined with drugs metabolized by CYP3A4 that have narrow therapeutic range, or induces of CYP3A4

Question 8

Enfuviritide

Answer 8

1. MOA: fusion inhibitor, binds to gp41 subunit of viral envelope and prevents conformational change required for membrane fusion and subsequent viral entry into target cells.
2. Kinetics: no cross resistance with other antiretroviral agents, SubQ injection
3. SE: increased likelihood of bacterial pneumonia, especially i other risk factors present, injection site rxns, hypersensitivity rxns are rare but requre discontinuation.

Question 9

Maraviroc

Answer 9

1. MOA: inhibits fusion of virus by binding to the CCR5 receptor of the CD4 tcell inhibiting strains that use this coreceptor to enter the cell. Only used in pts with CCR5 tropic HIV when other tx is not effective
2. SE: generally safe and well tolerated, rash is most common

Question 10

Raltegravir

Answer 10

1. MOA: integrase inhibitor- blocks the integrase enzyme needed for viral replication, inhibiting transfer of viral DNA to host cell DNA. Used in Tx resistant pts where other drugs are no longer working.
2. SE: N/V/D and HA