Anti-retrovirals

Question 1

Generally, what is HAART?

Answer 1

Highly Active Anti-retroviral Therapy

Three antiretrovirals from at least two different classes

Question 2

Outline an example of general HAART treatment

Answer 2

Typically two nucleoside reverse transcriptase inhibitors NRTIs

Combined w/ a third from either:

- integrase stand transfer inhibitor (INSTI)
- non-nucleoside reverse transcriptase inhibitor (NNRTI) 
- protease inhibitor (PI) w/ pharmacokinetic enhancer (cobicistat or ritonavir)

Question 3

What is the suffix used to identify the integrase strand transfer inhibitor-based (INSTI) regimens?

Answer 3

• gravir

Question 4

What is the suffix used to identify protease inhibitor (PI)-based regimens?

Answer 4

• navir

Question 5

What is the MOA of integrase inhibitors (INSTI)?

Answer 5

Inhibit viral integrase —> prevent insertion of processed viral DNA ends into host DNA –> prevent transfer of viral DNA in to host DNA

Question 6

What type of action do integrase inhibitors (INSTI) have on viruses?

Answer 6

Time dependent action

Virustatic

Question 7

What is an ADR of concern w/ INSTIs?

Answer 7

Depression and suicidal ideations

Question 8

What is the MOA of nucleoside reverse transcriptase inhibitors (NRTIs)?

Answer 8

Inside cell –> host cell kinases —> NRTI phosphorylated –> 5’-trisphosphate derivative –> 5’-trisphosphate NRTI incorporated into growing viral DNA —-> chain termination

Compete w/ host cellular triphosphate substrate for proviral DNA synth by viral-dependent DNA polymerase

Inhibit host cell DNA polymerase

Question 9

What type of action do NRTIs have against viruses?

Answer 9

False substrates of nucleotides, namely guanine and cytosine

Can also be for adenine or thymine

Virustatic

Time-dependent

Question 10

What are some interesting facts about NRTIs? (BBB? Excretion?)

Answer 10

Cross BBB + distribute into CSF = HIV hides here

Orally active

Renal excretion

Question 11

What is tenofovir?

Answer 11

NRTI

Is is a prodrug converted to an active diphosphate (phosphorylated twice) form by CD4 cell kinases

Question 12

How are NRTIS metabolised?

Answer 12

alcohol dehydrogenase

glycuronyl transferase

Metabolites are renally excreted

Question 13

What are some ADRs seen in NRTI use?

Answer 13

Peripheral neuropathy

lactic acidosis with hepatic steatosis with/without pancreatitis

Question 14

Discuss how non-nucleoside reverse transcriptase inhibitors (NNRTIs) work

Answer 14

Do not require intracellular phosphorylation for activity

Non-competitively bind (directly) to reverse transcriptase = direct inhibition –> conformational change –> altered efficiency of enz catalytic site –> dec viral DNA synth

Question 15

What is an example of a synergistic combination in HAART therapy?

Answer 15

NRTIs and NNRTIs = synergistic inhibition of HIV replication

NNRTIs also synergistic w/ PI in HIV

Question 16

What type of action doe NNRTIs have on viruses?

Answer 16

Virustatic

Question 17

Outline the metabolism and F of NNRTIs

Answer 17

Good bioavailability = Highly lipophilic

Extensively metabolised = faecal and renal excretion

Question 18

What kind of effect do protease inhibitors (PI) on viruses?

Answer 18

Virustatic

Question 19

What is the MOA of PI?

Answer 19

Inhibit proteases responsible for cleaving viral precursor proteins –> inhibit maturation and replication of HIV

Extensive CYP450 metabolism