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Pharmacology (Topic C) > 6. Antiretroviral agents. > Flashcards

6. Antiretroviral agents. Flashcards

1
Q

What is the MOA of Nucleotide Reverse Transcription Inhibitors (NRTIs).

A

Nucleotide Reverse Transcriptase Inhibitors (NRTIs) also known as HAART (highly active antiretroviral therapy) are nucleotides + nucleosides that lack an OH group necessary for 3’ → 5’ phosphodiester bond formation → chain termination. Nucleoside NRTIs need P-ation by cellular enzymes to be active. Generally, analogs of the same purine/pyrimidine bases (i.e. two cytosine analogs) are not given together.

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2
Q

List the 1st line NNRTIs.

A
  1. Efavirenz
  2. Nevirapine
  3. Delaviridine
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3
Q

List the 2nd line NNRTIs.

A
  1. Ertavirine
  2. Rilpivirine
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4
Q

List the NRTIs.

A
  1. Lamivudine
  2. Tenofovir
  3. Zidovudine - AKA azidothymidine, ZDV or AZT
  4. Stavudine
  5. Didanosine
  6. Abacavir
  7. Emitricitabine
  8. Zalcitabine - cytosine analog, withdrawn in Europe
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5
Q

List the protease inhibitors.

A
  1. Indinavir
  2. Ritonavir
  3. Saquinavir
  4. Atazanavir (newer, least metabolic effects)
  5. Others: Darunavir, Lopinavir, Tipranavir, Indinavir, Nelfinavir, Fosamprenavir.

Most have the “-avir” suffix (remember “guinevere”-based Sketchy scene)

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6
Q

List the integrase inhibitors.

A
  1. Raltegravir
  2. Elvitegravir
  3. Dolutegravir
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7
Q

List the fusion inhibitors.

A
  1. Enfuviritide
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8
Q

List the entry inhibitors.

A
  1. Maraviroc
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9
Q

What are the side effects of NRTIs?

A
  1. Mitochondrial toxicity - all
  2. Lactic Acidosis - all
  3. Lipodystrophy - zidovudine and stavudine
  4. Peripheral Neuropathy - lamivudine, stavudine, didanosine
  5. Headache, Fatigue, GI issues, Liver dysfunction - all
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10
Q

What are the indications for Lamivudine?

A

Lamivudine is a cytosine analog used for Hepatitis B treatment.

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11
Q

What are the side effect of Lamivudine?

A

This is the least toxic, but also least effective NRTI.

  1. Peripheral Neuropathy
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12
Q

What are the indications for Tenofovir?

A

Tenofovir is the only nucleotide NRTI (no P-ation required) and is used for Hepatitis B.

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13
Q

What are the indications of Zidovudine?

A

Zidovudine is used for HIV in pregnancy + breastfeeding to prevent vertical transmission as well as infant prophylaxis.

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14
Q

What are the side effects of Stavudine?

A
  1. Peripheral Neuropathy
  2. Also myelosuppression, but not as bad as AZT.
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15
Q

What are the side effects of Didanosine?

A
  1. Pancreatitis - dose-dependent.
  2. Peripheral Neuropathy - especially ↑ risk if with stavudine.
  3. also hyperuricemia and liver dysfunction.
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16
Q

What are the side effects of Abacavir?

A
  1. Hypersensitivity - type IV → delayed rash; HLA-B57:01 assoc.
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17
Q

What are the side effects of Emtricitabine?

A
  1. Palmoplantar Hyperpigmentation
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18
Q

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

A

NNRTIs directly bind HIV reverse transcriptase → allosteric inhibition of DNA polymerase activity.

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19
Q

What are the side effects of NNRTI’s?

A

common in NNRTIs:

  1. Flu-like Symptoms: abrupt onset
  2. Hepatic failure: abdominal pain, fever, jaundice (within 6 wks of start)
  3. Skin Rash: sometimes more severe, as Stevens-Johnson syn.
  4. Drug Interactions: CYP450 induction + inhibition
  5. Teratogenicity: both delavirdine and efavirenz
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20
Q

What is the mechanism behind NNRTIs resistance?

A

Resistance is only active for HIV-1; resistance to 1st gen NNRTIs by point mutation in some strains.

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21
Q

What are the side effects of Efavirenz?

A
  1. CNS effects: dizziness, drowsiness, headache, psychosis, insomnia, nightmares
  2. Teratogenicity
  3. CYP450 induction and inhibition
22
Q

What is the MOA of Protease inhibitors?

A

Protease Inhibitors inhibit HIV aspartate proteases (encoded by POL gene) necessary for cleavage of HIV polyprotein gene products (no similar protease in humans → selectivity).

23
Q

What is the MOA of Entry Inhibitors?

A

Entry Inhibitors binds to T-cell surface protein CCR5 → blocks HIV env-encoded gp120 from co-binding CD4/CCR5 during viral entry into cell (does not work for HIV strains with CXCR4 instead of CCR5).

24
Q

What is the MOA of Fusion inhibitors?

A

Fusion Inhibitors block env-encoded viral gp41, which normally facilitates HIV fusion to T cells.

25
Q

What is the MOA of Integrase Inhibitors?

A

Integrase Inhibitors block pol-encoded viral integrases, which normally allow integration of viral DNA into host genome.

26
Q

What are the indications for Integrase inhibitors?

A

known as cART (combined anti-retroviral therapy)

  1. HIV-related symptoms - of HIV opportunistic infections / HBV coinfection
  2. CD4+ count <200 - definite indication, but <350 also recommended
  3. Viral load > 5000 - 10,000 / ml
  4. Pregnancy - all except efavirenz (teratogen)
  5. Prophylaxis in exposed medical staff
  6. Children - more aggressive tx bc of faster progression
  7. Sexual Partners
27
Q

What are the side effects of Zidovudine?

A
  1. Myelosuppression - causing anemia and neutropenia
  2. Lipodystrophy - redistribution of fat from limbs to trunk
  3. Headaches
  4. Asthenia
  5. Myalgia and myopathy
  6. Peripheral neuropathy
28
Q

What are the indications for Emtricitabine?

A

Emtricitabine a cytosine analog (a newer form of lamivudine) which is also effective against hepatitis B.

29
Q

What is the mechanism behind integrase inhibitor resitance?

A

Resistance happens via pol mutation (affects efficacy of NRTIs, NNRTIs, PIs and integrase inhibitors).

30
Q

What are the side effects of integrase inhibitors?

A
  1. Rhabdomyolysis - rare; seen as ↑ creatine kinase
31
Q

NNRTIs is also part of which therapy?

A

Also part of “HAART” therapy.

HAART = highly active antiretroviral therapy.

32
Q

What are the side effects of Delavirdine?

A
  1. Teratogenicity
  2. CYP450 induction and inhibition
33
Q

What are the indications for Nevirapine?

A

Single dose intrapartum ↓ vertical transmission 50%.

34
Q

What are the kinetics like for Nevirapine?

A

Penetrates CNS well (others do not) → worse CNS effects!

35
Q

What are the side effects of Nevirapine?

A

Moderate CYP450 induction

36
Q

What are the side effects of Maraviroc?

A
  1. HA, dizziness
  2. Orthostatic hypotension
  3. Airway infections
  4. Allergic
  5. Liver disorders
  6. Increased malignancy
37
Q

What is the mechanism behind protease inhibitors resistance?

A

POL gene mutation → resistant proteases

38
Q

What is the mechanism behind Entry inhibitors resistance?

A

via env mutation

39
Q

What are the side effects of protease inhibitors?

A
  1. Hyperglycemia - via insulin resistance; can → diabetes
  2. Dyslipidemias - TAGs and LDL ↑
  3. Lipodystrophy - ↑ fat on back/abdomen, ↓ on face/limbs
  4. CYP450 Inhibition - worst with ritonovir
  5. Interactions: rifampin CYP induction will ↓ protease inhibitor levels; use rifabutin instead!
40
Q

What is the mechanism behind fusion inhibitors resistance?

A

via env mutation

41
Q

How is maraviroc metabolized?

A

Metabolized by CYP3A4

42
Q

What are the side effects of Enfuviritide?

A

Enfuvirtide is a polypeptide, administered subcutaneously. It is well tolerated, but may cause local reactions, HA, nausea, bacterial pneumonia?

43
Q

What are the indications for Enfurviritide?

A

They are used for multidrug-resistant cases.

44
Q

What are the side effects of Indinavir?

A
  1. Nephrolithiasis - within days of starting; ↓ by hydration
45
Q

What are the side effects of Ritonavir?

A

Worst CYP inhibition among protease inhibitors. Can be used to ↑ levels of other CYP-metabolized protease inhibitors!

46
Q

What are some important remarks about Saquinavir?

A

Saquinavir is the oldest, least toxic and has↓ oral availability.

47
Q

What are the kinetic parameters of Raltegravir?

A
  1. Raltegravir is given orally
  2. Metabolized by glucuronide conjugation
48
Q

What are the side effects of Raltegravir?

A

Chelates bivalent cations, generally well tolerated, but GI, HA, dizziness, rashes may occur.

49
Q

What are the side effects to Elvitegravir?

A

Elvitegravir has similar sfx to raltegravir; given with CYP inhibiting “booster” (ritonavir or cobicstat).

50
Q

What are the side effects of Dolutegravir?

A
  1. Severe HS rxns
  2. Insomnia
  3. Headache
51
Q

What are the indications of Dolutegravir?

A

Known as cART (combined anti-retroviral therapy)

  1. HIV-related symptoms - of HIV opportunistic infections / HBV coinfection
  2. CD4+ count <200 - definite indication, but <350 also recommended
  3. Viral load > 5000 - 10,000 / ml
  4. Pregnancy - all except efavirenz (teratogen)
  5. Prophylaxis in exposed medical staff
  6. Children - more aggressive tx bc of faster progression
  7. Sexual Partners

Pharmacology (Topic C) (20 decks)

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