HIV drugs Flashcards Preview

IHO week 6 and Final > HIV drugs > Flashcards

Flashcards in HIV drugs Deck (28)
1

o resistance - change in AA of gp41

o binds gp41 to prevent conformational change needed for binding to CCR5 or CXCR4 - virus can no longer enter

o injection administration - not a first line drug for this reason

Fusion inhibitors

2

o inhibits CCR5 R → virus can’t bind and can’t enter cell

o If virus uses CXCR4 the drug will not function - can be a form of resistance

o would need to do tropism testing in order to determine if the virus is using CXCR4 rather than CCR5

Chemokine receptor inhibitors

3

o pro-drug → phosphorylated into active form → inhibit RT or incorporate into viral DNA as it is being made →inhibit production of the dsDNA

o host cellular enzyme does the phosphorylating - the enzyme converting nucleoside to nucleotides

o competitive inhibitor

o Occurring in cytosol (where reverse transcriptase is)

NucleoSide reverse transcriptase inhibitors

4

o Nucleotide has been phosphorylated

o Skip first step of nucleoside reverse transcriptase inhibitors

o Need to do some more phosphorylating (drug is a monophosphate)

NucleoTide reverse transcriptase inhibitors

5

o Bind directly to reverse transcriptase but at different site than NRTI

o Don’t need to be phosphorylated to be active

o Allosteric inhibitor - binds and stops the reverse transcriptase

o If HIV becomes resistant to NRTI, it might not have resistance to these because they function in different places

non-nucleoside reverse transcriptase inhibitors

6

o works in the cytosol (maybe the nucleus)

o blocks integrase to prevent forming the pro-virus

integrase inhibitors

7

o Inhibits cleaving of polyprotein - needed for survival

o bind the active site of the protease

o cannot splice gag-pol-env polyprotein → proteins cannot be used → virus cannot be infectious

o does nothing for the cell that is infected already - does not inhibit the provirus

 cell can cause apoptosis of other CD4+ T cells, but no virus particle production occurs

protease inhibitors

8

o prevents metabolism of other protease inhibitors to promote their concentration in the blood

 called a “booster”

 used in conjugation with other protease inhibitors

Ritonavir

9

Why are drugs used in combination?

o Reverse transcriptase makes a lot of mistakes - high mutation rate

o Typically use triple cocktail of different classes of drugs

o AZT used in combination now because of this high rate of mutation - want to prevent resistance

 reason AZT is no longer used alone

10

Toxicities of NRTIs:

- mitochondrial toxicity and lactic acidosis

11

Toxicities of Non-NRTIs/

- rash, GI, drug interactions

12

Toxicities of protease inhibitors?

o Drug interactions

o Peripheral lipoatrophy and central fat accumulation = fat distribution

 skinny arms and a fat gut

13

Whats the difference between nucleosides and nucleotides?

nucleotides have one or more phosphate groups

nucleoSide = Smaller (no phosphates)

14

4 nucleoside reverse transcriptase inhibitors:

Zidovudine (Azidothymidine or AZT)

Lamivudine

Emtricitabine

Abacavir

15

Side fx:

• granulocytopenia and anemia in up to 45% of treated patients (hematological monitoring at 2 week intervals).

• CNS disturbances: severe headache, nausea, insomnia, malaise

Zidovudine (Azidothymidine or AZT)

16

-Probably best tolerated of the NRTIs

-Also active against Hepatitis B

Lamivudine

Emtricitabine

17

NRTI associated with hypersensitivity rxn:

Abacivir

18

nucleoTide RTI

nausea, vomiting, diarrhea

renal failure

lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity

Tenofovir

19

2 NNRTIs:

Efavirenz

Etravirine

20

NNRTI

Once daily dosing

CNS effects (vivid dreams, nightmares and hallucinations)

Efavirenz

21

NNRTI

Rash, nausea, peripheral neuropathy

Etravirine

22

3 protease inhibitors:

Atazanavir

Ritonavir

Darunavir

23

General AE of protease inhibitors?

• GI disturbances

• Hepatotoxicity

• Hyperglycemia and insulin resistance

• Dyslipidemia

• Cardiac conduction abnormalities

• Peripheral lipoatrophy and central fat accumulation

• Metabolized by and inhibit hepatic CYP3A4

24

used at lower doses to increase the serum concentrations of other protease inhibitors

decrease the dosage frequency of other PIs

potent inhibitor of CYP3A4 which is the cytochrome that metabolizes a number of the other PIs and decreases their effectiveness.

Ritonavir

25

36 amino-acid synthetic peptide that binds to gp41 and prevents the conformational change

Fusion inhibitor

Enfuvirtide

26

Integrase inhibitor

Fewer drug drug interactions than PI or NNRTI

Raltegravir

27

Binds specifically and selectively to host CCR5

Pyrexia, rash, postural dizziness

Maraviroc

28

• Estimated to affect 25-50% of patients
• Wasting of subcutaneous fat
• Central adiposity
• Hyperlipidemia, insulin resistance and diabetes mellitus.
• Most often seen with use of NRTIs + PI, but also seen with single NRTI treatment

HAART associated lipodystrophy

(Highly Active AntiRetroviral Therapy)