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IHO Week 6 - WLB > Microbiology Case 2: HIV Drugs - Regal > Flashcards

Microbiology Case 2: HIV Drugs - Regal Flashcards

1
Q

What are some general concepts to keep in mind with HIV treatment?

A
  • Goal is fully undetectable levels of virus
  • The lower the viral RNA can be driven, the lower the rate of accumulation of drug resistant mutants will be & the longer the therapeutic effect will last
  • Maximally inhibit viral replication
  • To achieve maximal and durable suppression of viral RNA, drug combinations and patient compliance are required
  • Resistance testing recommended before starting therapy
  • Monitor HIV RNA levels (viral load) and CD4+ cell count
    • increased viral load may indicate development of drug resistance
  • Use drug combinations
    • but avoid contraindicated drug combinations (lists available)
  • Think about drug interactions
  • Encourage compliance
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2
Q

What is the MOA of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?

A
  • Competitively inhibit reverse transcriptase
    • in cytosol
  • Can be incorporated into viral DNA chain
    • the inhibitor binds to the DNA chain and terminates the production of DNA
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3
Q

What do NRTIs require to become active?

A

Phosphorylation by cellular enzymes to the triphosphate form

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4
Q

What are the four NRTI drugs that we need to know?

A
  1. Zidovudine (Azidothymidine or AZT)
  2. Lamivudine
  3. Emtricitabine
  4. Abacavir
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5
Q

What are the general adverse effects of NRTIs?

A
  • Potentially fatal syndrome of lactic acidosis with hepatic steatosis
    • probably due to mitochondrial toxicity
  • Associated with fat redistribution and hyperlipidemia
    • skinny arms and a fat trunk
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6
Q

What is unique about Zidovudine compared to the other NRTI drugs?

A
  • granulocytopenia and anemia in up to 45% of treated patients
    • hematological monitoring at 2 week intervals
  • CNS disturbances:
    • severe headache
    • nausea
    • insomnia
    • malaise
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7
Q

What is unique about Lamivudine & Emtricitabine compared to the other NRTI drugs?

A
  • Probably best tolerated of the NRTIs
  • Also active against Hepatitis B
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8
Q

What is unique about Abacavir compared to the other NRTI drugs?

A
  • hypersensitivity reactions can be a problem
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9
Q

What is the MOA of Nucleotide Reverse Transcriptase Inhibitors (NRTI)?

A
  • Same as Nucleoside Reverse Transcriptase Inhibitors:
    • Competitively inhibit reverse transcriptase
      • in cytosol
    • Can be incorporated into viral DNA chain
      • the inhibitor binds to the DNA chain and terminates the production of DNA
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10
Q

What is the difference between a nucleotide and a nucleoside?

A

Nucleotides are phosphorylated nucleosides.

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11
Q

What is the one Nucleotide Reverse Transcriptase Inhibitor drug that we need to know?

A

Tenofovir

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12
Q

What are adverse side effects of Tenofovir?

A
  • Most common:
    • N/V
    • Diarrhea
    • potential for renal failure
  • Potentially fatal syndrome of lactic acidosis with hepatic steatosis
    • probably due to mitochondrila toxicity
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13
Q

What is the MOA of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)?

A
  • Bind directly to the reverse transcriptase at a site distinct from that of the NRTI
    • enzyme cannot produce viral DNA
  • Does not require phosphorylation for activity
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14
Q

What are the two Non-Nucleoside Reverse Transcriptase Inhibitor drugs that we need to know?

A
  • Efavirenz
  • Etravirine
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15
Q

Is there cross resistance with NNRTIs and NRTIs and protease inhibitors?

A

NO

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16
Q

What are adverse side effects of NNRTIs?

A
  • Varying levels of GI intolerance
  • Skin rash
  • Drug interactions
    • metabolized by and can affect hepatic cyp450

can be inducers, inhibitors, or mixed inducers/inhibitors of enzyme

17
Q

What is unique about Efavirenz compared to the other NNRTIs?

A
  • Once daily dosing
  • CNS effects
    • vivid dreams
    • nightmares
    • hallucinations
18
Q

What is unique about Etravirine compared to the other NNRTIs?

A
  • Rash
  • Nausea
  • Peripheral neuropathy
19
Q

What is the MOA of Protease Inhibitors?

A
  • Prevent protease action required for maturation of the fully assembled virus
    • prevent post-translational cleavage of the Gag-Pol polyprotein
      • prevent the processing of viral proteins into functional conformations
      • without cleavage, virus is not infectious
    • inhibit HIV protease activity and prevent HIV replication in vitro
  • Active against viral strains resistant to reverse transcriptase inhibitors
20
Q

What are the three Protease Inhibitor drugs that we need to know?

A
  • Atazanavir
  • Ritonavir
  • Darunavir
21
Q

What are the potential adverse side effects of Protease Inhibitors?

A
  • GI disturbances
  • Hepatotoxicity
  • Hyperglycemia and insulin resistance
  • Dyslipidemia
  • Cardiac conduction abnormalities
  • Peripheral lipoatrophy and central fat accumulation
  • Metabolized by and inhibit hepatic CYP3A4
22
Q

What is Ritonavir boosting?

A
  • Giving low doses of Ritonavir (a protease inhibitor) in addition to other PIs
  • Why?
    • it is a potent inhibitor of CYP3A4
    • with CYP3A4 inhibited by Ritonavir, it increases the serum concentrations of other protease inhibitors
    • decreases the dosage and frequency of other PIs
23
Q

What is the name of the pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins and can also act as a booster of protease inhibitors (but is not a protease inhibitor itself)?

A

Cobicistat

24
Q

What is the MOA of Fusion Inhibitors?

A
  • binds to gp41 and prevents the conformational change required to facilitate fusion of the viral and host cell membranes
25
Q

What is the one Fusion Inhibitor drug that we need to know?

A

Enfuvirtide (T-20)

26
Q

What are potential adverse side effects of Enfuvirtide?

A
  • High incidence of local reactions with pain, erythema, induration, nodules, & cysts
    • SubQ administration x2 daily
  • Systemic hypersensitivity rare
  • Maybe a higher incidence of bacterial pneumonia
27
Q

What is the MOA of Integrase Inhibitors?

A
  • By binding integrase, it inhibits strand transfer
    • stops final step of provirus integration
28
Q

What is the one Integrase Inhibitor drug that we need to know?

A

Raltegravir

29
Q

What are the potential adverse side effects of Raltegravir?

A

Fewer drug-drug interactions that PI or NNRTI based regimens.

30
Q

What is the MOA of CCR5 Antagonist?

A
  • Binds specifically and selectively to host CCR5
    • prevents HIV-1 binding to receptor
    • virus is not able to gain entry into the host cell
31
Q

What is the one CCR5 Antagonist drug that we need to know?

A

Maraviroc

32
Q

What are adverse side effects of Maraviroc?

A
  • Pyrexia (fever)
  • Rash
  • Postural dizziness
  • No evidence yet of increased risk of malignancy or infection.
33
Q

What is HAART treatment?

A
  • Highly Active Antiretroviral Therapy
    • therapy with reverse transcriptase inhibitors (RTIs) in combination with protease inhibitors (PIs)
34
Q

What is the major adverse side affect associated with HAART?

A
  • HAART associated lipodystrophy
    • wasting of subcutaneous fat
    • central adiposity
    • hyperlipidemia, insulin resistance, and diabetes mellitus
35
Q

How common is HAART associated lipodystrophy?

A
  • Estimated to affect 25-50% of patients
  • Most often seen with use of NRTIs + PI
    • but also see with single NRTI treatment
36
Q

Why is compliance with antiretroviral therapy a challenge?

A
  • High number of pills
  • Adverse side effects of therapy
  • Fixed dose combinations are becoming available, but are less flexible in terms of dosage requirement.
37
Q

Why are most antiretroviral drugs used in combination or as “drug cocktails”?

A

High mutation rate of reverse transcriptase

(HIV loves to mutate)

***Best way to avoid drug resistance.

IHO Week 6 - WLB (8 decks)

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