• blocks viral M2 protein (an ion channel in viral membrane)
• this leads to prevention of viral uncoating

• prophylactically against A (Asian) influenza
  • within 48 hrs of onset of symptoms
• may also be used in vaccination, which is preferred

• mutation of M2 protein

Cause cross resistance to rimantadine

• CNS effects (CI: CNS abnormality)
  • anxiety
  • hallucinations
  • insomnia
  • difficulty concentrating
• CI: pregnancy, children

Especially worry about elderly

• enter CNS
• excreting in urine without metabolism
  • toxicity increased in renal failure

• longer half life than amantidine
• extensive metabolism
  • dosage adjust for severe liver dysfunction, esp. elderly
• less renal excretion, but still dose adjust for renal failure
• less enters CNS, so less CNS toxicity than amantidine
• toxicity mainly GI
• CI: pregnancy

• interference with DNA implies possible mutagenicity

1. decrease neruoamidase activity
2. leads to decreased cleavage of sialic acid residues
3. decreased activation of cellular R bound to viral hemagglutin
4. decrease release of new virus from infected cells
5. decrease spread
   • shorten disease by 1-2 days
   • decrease complications of bacterial LRT infection

• relatively nontoxic, but still CI in pregnancy
• in children, neuropsyc abnormalities

• changes in neuroaminidase or hemagglutin, but rare

• oseltamivir: oral
• zanamivir: via inhalation (poor bioavailability)
  • beware of serious bronchospasm toxicity
  • CI: preexisting lung disease

1. metabolized via cellular enzymes to 5-triphosphate derivative
2. this will inhibit viral mRNA and DNA replication as well as inhibit IMP DH, GTP formation, viral RNA polymerase

• RSV in infants as aerosol
• Hep C virus with IFN orally

• bone marrow toxicity
• hemolytic anemai
• pulmonary deterioration
• CI: pregnancy (teratogenic)
• caution: renal impairment

• mechanism: nucleoside RTI's
  1. thymidine analog phosphorylated by host thymidine kinase to triphosphate
  2. incorperated into DNA of HIV via viral reverse transcriptase
  3. terminates viral DNA chain because of unusual linking positin, 3'-OH on sugar, is blocked by azido group
  4. AZT triphosphate (specificity for reverse transcriptase) inhibits reverse transcriptase as well by competing for thymidine triphosphate for binding enzyme
  5. AZT monophospate inhibits normal phosphorylation of thymidine phosphate and DNA synthesis in bone marrow (THIS CAUSES TOXICITY)

• bone marrow depression
• anemia
• neutropenia
• confusion (penetrate CNS)
• dosage adjust: renal and liver disease
• lactic acidosis

We can reduce toxicity via bone marrow stimulating factors.

Remember, this is due to ability to inhibit DNA synthesis

• penetrates CNS and inhibits viral prolif. in CNS
• extensive interaction with drugs given concurrently
  • excreted as inactive glucoronide (so must compete with other drugs glucoronidated)

• decrease affinity of mutant form of reverse transcriptase
• enzymatic removal of AZT from DNA complex

Some cross resistance with some RT inhibitors

• mechanism: nucleoside RTI analgous to AZT
  1. inhibit viral RT
  2. incorporated into DNA as ddA-triphosphate
  3. leads to DNA chain termination
• very little cross resistances between two drugs

• peripheral neuropathy
• pancreatitis (esp. with alcoholics)
• lactic acidosis

• occasionally see recipricol changes in sensitivity of reverse transcriptase to ddI and AZT
  • will have mutation in RT sequence which makes virus resistant to one drug while remaining susceptible to another (ping pong effect)

• mechanism: like ddI
• toxicity (dose limiting)
  • neuropathy
  • pancreatitis
  • lactic acidosis
  • less marrow toxicity
• indication- HIV, hep B in reducing risk of liver cancer

1. binding noncompetitively with reverse transcriptase, but at a different site for NRTI's
   • not phosphorylated, so do not compete with normal nucleoside triphosphates, are not incorperated into DNA
2. directly inhibit reverse transcriptase and viral DNA polymerase

• if given alone, emergence of resistance is rapid (must give with other anti HIV drugs)
• beware of cross resistance among NNRTI's (common)

1. decreases protease activity
2. decrease cleavage of viral GAG, GAG POL
3. decrease viral maturation, proliferation, and infectivity
   • decrease for death rate from AIDS
   • decrease HIV mRNA to minimally detectable levels (but virus still prolif. in CD4 cells)

Best works with RTI's families

• interfere with P450 drug metabolism or other drugs
  • drug interactions likely
• combined with low dose ritnavir, which blocks P450 enzymes

• inhibits CYP3A4 often combined with other PI's to permit reduce dosing scheduling

• entry and fusion inhibotrs
  • Maraviroc
  • Enfuvirtide
• integrase inhibitors- Raltegravir

• no single aents
• tx aggressively with drug combination once CD4 dips below 350
• first treatment: 2 NRTI's plus either NNRTI or PI with retinovir
• do not discontinue tx and then resume after pause
• if possible, avoid antiretroviral therapy during first trimester of pregnancy
• give drugs regularly, adhering to strict dosage schedule as prescribed
  • otherwise get virus breakthroughs, therapeutic failures and emergence of resistant strains

• insulin resistance and DM
• hyperlipidemia
• increase in MI

could be disease related

1. analog of deoxyribose of guanosine is selective for phosphorylated by herpes TK
2. via cellular enzymes form acyclovir triphosphate which competes with dGTP for viral DNA polymerase
   • inhibits DNA polymerase in infected cells preferentially
   • incorperated into viral DNA where it terminates DNA chains

• HSV-1 and 2 (NOT curative)
  • herpes encephalitis
  • early tx reduce transmission of virus, severity and duration of chicken pox, reduces pain of shingles, promotes healing of rashes, but neurological sequalae may persist but occur later
  • genital herpes (oral)- viral infections recur after cessation of tx
• VZV (chicken pox)

acyclovir: mechanism of resistance and solution to it

• resistance mechanism
  • lower TK levels
  • enzyme mutation with altered drug affinity
• solution- virus may be still be sensitive to foscarnet or cidofovir (dont require viral TK)

• mechanism- prodrug of acyclovir, so same mechanism after metabolism
• has greater bioavailability, making it more advantageous for post herpetic neuralgia

1. prodrug of penciclovir
2. activated by viral TK to penciclovir triphosphate
3. inhibits viral DNA polymerase
4. converted to drug with poor availability (so available as topical cream)

1. guanosine analog that inhibits viral DNA polymerase by competeing with dGTP
   • phosphorylated by HSV viral PK
   • phosphorylated by CMV deoxyguanosine kinase
2. incorperated into DNA and inhibits viral DNA polymerase

• CMV
  • CMV retinitis
  • CMV pneumonitis, esophagitis, colitis

• bone marrow suppression
• neutropenia

Increased toxicity when used with AZT, so may need to stop AZT or reduce ganciclovir dose

• failure to phosphorylate drug (but CMV may still respond to foscarnet or cidovovir, and you can use ganciclovir with foscarnet)

1. cytidine monophosphate analog form triphsophate
2. compete with dCTP for viral DNA polymerase
3. incorperated into viral DNA
4. inhibits viral DNA synthesis preferentially

No need for TK for activation since it is already a nucleotide, so if TK mutation causing resistance in acyclovir and ganciclovir, cidofovir is still active.

• nephrotoxicity
• can reduce by giving probenicid concurrently (reduce tubular secretion, extending half life)

• nephrotoxicity
  • tx with hydration and electorlytes
• little bone marrow suppression

• not cross resistant to acyclovir or AZT because it does not require activation by TK

1. inorganic phosphate analog compete with pyrophosphate binding site of viral polymerase
   1. prevents cleave of pyrophosphate from triphosphates
   2. inhibits DNA polymerase
   3. prevents viral DNA synthesis
   4. inhibits HIV reverse transcriptase (but too toxic for use)

• pegIFN alpha 2b and PegIFN alpha 2a combined with ribavirin

• hep C
• hairy cell leukemia
• Kaposi sarcoma

• influenza
  • amantadine
  • rimantidine
  • oseltamivir
  • zanamivir
• other RNA viruses
  • Ribavarin

• nucleoside RTI's
  • Zidovudine (AZT)
  • Didanosine (ddI)
  • Lamivudine
• nucleotide RTI- Tenofovir
• NNRTI
  • Nevirapine
  • Efavirenz
  • Delvaridine
• HIV protease inhibitors- Ritonavir
• entry and fusion inhibitors
  • maraviroc
  • enfuvirtide
• integrase inhibitor- raltegravir

• Herpes and varicella
  • Acyclovir
  • Valacyclovir
  • Famciclovir
• CMV
  • Ganciclovir
  • Valganciclovir
  • Cidofovir
  • Foscarnet
• Hep B and C
  • IFN