• Zidovudine, RetrovirR (AZT, Azidothymidine)
• Zalcitabine, HIVIDR (dideoxycytidine, ddC)
• Didanosine, VidexR, ddI
• Stavudine, ZeritR, d4T

Zidovudine

(Retrovir  R, Apo-Zidovudine  R, Novo-AZT   R (AZT, Azidothymidine, 3'-Azido-3'-deoxythymidine)

Overview

• First and most important drug for palliation of AIDS
• Active against HIV-1 and other mammalian retroviruses

Mechanism of action

• Decreases reverse transcriptase activity in cultured cells at 0.013 mcg/mL
• Inhibits replication of HIV-1 virus
  • Exogenously infected cells -- at 0.02 to 1.3 mcg/mL
  • Requires higher concentrations in chronically infected cells
• Some activity against human lymphotrophic virus type 1 (HTLV-1)

AZT is phosphorylated to the triphosphate form by host cell enzymes and then the AZT-TP is incorporated into the new DNA chain and inhibits further elongation.

Therefore, the target is the reverse transcriptase, which prefers AZT-TP to the normal thymidine triphosphate.

Prodrug that must be phosphorylated

• Phosphorylated to triphosphate by cellular enzymes
• inhibits viral RNA-directed DNA polymerase (transcriptase)
  • - Triphosphate binds more strongly to viral than eukaryotic DNA polymerase
• DNA chain termination
  • - azidothymidine triphosphate can be incorporated into DNA
  • - Nucleotides cannot be added to modified 3'-position
• Mammalian DNA polymerases
  • - Alpha-DNA polymerase relatively resistant to incorporating azido-TP
  • - Gamma DNA polymerase in mitochondria does incorporate -- source of toxicity? (Rang et al. 95, p38)
• Activity enhanced by --
  • acyclovir, interferon, dideoxyadenosine, granulocyte-macrophage colony stimulating factor, neutralizing antibody, and other newer drugs
• Activity decreased by --
  • thymidine and ribivarin
  • (?) competition for phosphorylation, thus decreasing activation(?)

Resistant strains

• Isolated from AIDs patients treated 6 months or more
• Still sensitive to dideoxycytidine and foscarnet

Pharmacokinetics

• PO -- F=60-65% (60-80% [Rang'95,p750])
• Peak concentration 30 to 90 minutes.
• Wide distribution
• Usual dosage is 200 mg q4h!! continuously!!

Adverse effects

• Prophylactive use -- minor, reversible adverse effects
• Higher dose, long term use -- effects significant and serious
• Hematologic
  • Current rates less than these as doses have been reduced
  • Granulocytopenia and anemia in up to 45% of patients
    • - Risk factors increase probability
  • Anemia may occur --
    • - 2 to 4 weeks into therapy
    • - 6 weeks into therapy more common
    • - 30% require transfusions.
    • - Granulocytopenia occurs after 6 to 8 weeks
    • - Monitor hematologic parameters q2w.
  • Other occur sometimes
    • - Gastrointestinal disturbances, paresthesia, skin rash, insomnia, fever, headaches, abnormalities of liver function
    • - Myopathy
    • - Confusion, anxiety, depression, and flu-like syndrome
  • Drug interaction -- increased risk
    • - Drugs that inhibit glucuronyl transferase => acetaminophen, aspirin, indomethacin, probenecid
      Probenecid has action here in addition to effect on renal tubular secretion.
    • - Renal excretion -- Probenecid slows

Clinical uses

• Patients with AIDS -- reduces
  • opportunistic infections, e.g., Pneumocystis carinii pneumonia
  • stabilizes weight
  • reduces HIV-associated thrombocytopenia
  • stabilizes HIV-associated dementia
  • reduces viral burden
• HIV positive patients before onset of AIDS
  • Delays progession of disease by 12-18 months
  • May not increase median survival time beyond typical 3 yrs from diagnosis
• HIV-positive mothers
  • reduces risk of transmission to fetus by 66%
• After specific exposure to HIV virus
  • Recommend giving zidovudine, but benefit not proven
• Final value -- not certain

Zalcitabine

HIVIDR (dideoxycytidine, ddC)

• New drug
• Similar conceptually to zidovudine
• Reverse transcriptase inhibitor
• Activated in T cell different path than zidovudine
• Dose related neuropathy
• Can worsen after stop therapy
• Used in combination with zidovudine in late AIDS

Nevirapine

• Non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT);
• one of several drugs in this category.
• Unlike nucleoside analogs, these drugs do not need to be phosphorylated to be active;
• rather they bind to RT and inactivate the enzyme in a non-com petitive fashion. Nevirapine has been shown to bind directly to a 3-dimensional pocket near to the active site within the RT enzyme molecule