Therapeutics ID Nieto Flashcard

Idoxuridine: MOA

Pyrimidine Analog

Has an Iodine group

 

Incorporation of IUdR instead of thymidine into viral DNA

DNA susceptible to strand breakage

Mutation rate is increased

Errors in subsequent RNA and protein synthesis

 

 

Trifluridine: MOA

Pyrimidine Analog

CF3 is similar in size to CH3 of Thymidine

 

Incorporation of Trifluridine instead of thymidine into viral DNA

DNA susceptible to strand breakage

Mutation rate is increased

Errors in subsequent RNA and protein synthesis

 

Incorporated into viral (and host cell) DNA

 

Vidarabine: MOA

  • Purine Derivative
  • Competes with natural substrate (Adenisone?) –> incorporated into DNA faster than natural substrate
  • Phosphorylated faster than natural substrate (Adenisone?) –> necessary for competitive inhibition of HSV DNA Polymerase
  • The deamination of vidarabine to hypoxanthine arabinoside results in an OH group where the NH2 used to be –> still has antiviral activity
  • Potent inhibitor of ribonucleotide reductase and DNA polymerase  –> interferes with viral nucleic acid replication
  • Competitive inhibition of HSV DNA Polymerase (dATP)
  • Higher Selective Toxicity compared to IUdR and Trifluridine

Acyclovir: MOA

  • Highly selective inhibitor of HSV replication
  • Activated to acyclovir monophosphate by Herpesvirus-Specific Thymidine Kinase –> faster in infected cells
  • Then it is converted to di- and triphosphate by Guanosine Monophosphate Enzyme (cell enzyme)
  • Viral DNA Polymerase competitively inhibited by acyclovir triphosphate
  • Preferential uptake of acyclovir by infected cells

Acyclovir: Resistance
Mutation in the thymidine kinase gene
Acyclovir: ADME

A: Poorly absorbed from GI

D: 15% bound to protein plasma

M: Very little

E: Kidney (glomerular filtration and tubular secretion)

 

Acyclovir: Adverse Effects

Ocular: no adverse effects

Topical: may cause irritation and burning in genital lesions

IV: phlebitis, local rxns, renal toxicity

Bone marrow toxicity at higher doses

 

Renal Toxicity: due to precipitation in renal tubules (nausea, emesis, flank pain, increasing azotemia)

 

Cimetidine and Probenecid decrease renal clearance and increase plasma concentration of Acyclovir

Penciclovir: MOA

  • Phosphorylated by Herpesvirus-Specific Thymidine Kinase
  • Then it is converted to di- and triphosphate by Guanosine Monophosphate Enzyme (cell enzyme)
  • Competitive Inhibition of Viral DNA Polymerase

Famciclovir: MOA

  • Must be cleaved for it to be active — diacetyl ester prodrug
  • Phosphorylated by Herpesvirus-Specific Thymidine Kinase
  • Then it is converted to di- and triphosphate by Guanosine Monophosphate Enzyme (cell enzyme)
  • Competitive Inhibition of Viral DNA Polymerase

Penciclovir: Resistance
Mutations in thymidine kinase — cross resistance with acyclovir
Famciclovir: Resistance
Mutations in thymidine kinase — cross resistance with acyclovir
Ganciclovir: MOA

  • Acyclic Nucleoside Analog of Guanosine
  • Converted to monophosphate and triphosphate
  • Inhibits viral DNA polymerase
  • Inhibition of the incorporation of deoxyguanosine triphosphate into elongating viral DNA — not an absolute terminator of synthesis

 

Ganciclovir: Resistance

  • Mutations that reduce the conversion to monophosphate
  • Mutations in the viral DNA polymerase

Ganciclovir: ADE

A: poor PO

D: penetrates BBB

E: 90% unchanged glomerular filtration and tubular secretion

Ganciclovir: Adverse Effects

  • Narrow Therapeutic Index
  • Granulocytopenia, Thrombocytopenia, Azoospermia, Rise is serum creatinine
  • CNS: from headache to behavioral changes to convulsion and coma
  • Infusion related phlebitis, azotemia, rash, fever, liver function test abnormalities
  • Drug interactions: drugs toxic to the bone marrow (zidovudine), nephrotoxicity (probenecid, acyclovir)

Foscarnet: MOA

  • Inorganic Pyrophosphate
  • DNA polymerase inhibitor — binds to pyrophosphate binding site — DNA polymerase cannot remove pyrophosphate from natural substrate (nucleotides)
  • Prevents elongation
  • Also inhibits reverse transcriptase

Foscarnet: Resistance
Mutations in DNA polymerase
Foscarnet: ADME

A: poor, IV has intra- and inter-patient plasma concentration variability

M: no metabolism

E: renal

 

Foscarnet: AE

  • Nephrotoxicity
  • Acute-infusion related symptoms
  • Disturbance in serum Ca2+ and phosphate levels
  • Diarrhea, vomiting

Adefovir: MOA

  • Formulated as prodrug (adefovir dipivoxil)
  • Phosphorylation not necessary since it is already phosphorylated
  • Competitive inhibitor of DNA polymerase and reverse transcriptase

 

Adefovir: AME

A: prodrug absorbed and rapidly hydrolyzed by esterases

D: low protein binding

E: unchanged, renal

Adefovir: AE

  • Dose related nephrotoxicity and tubular dysfunction
  • HA, abdominal discomfort, diarrhea, asthenia
  • Drug interactions

Lamivudine: MOA

  • Nucleoside analog
  • Potent inhibitor of HIV reverse transcriptase and DNA polymerase

Lamivudine: Resistance

Mutations in DNA polymerase

Lamivudine resistant strains are sensitive to adefovir and entecavir

Lamivudine: ADME

A: well absorbed

D: body water

M: oxidation of S — inactive metabolites

E: 70% unchanged in urine

 

Well tolerated

Entecavir (Baraclude): MOA

  • Guanosine nucleoside analog
  • No antagonism, addition, or synergy
  • Inhibits DNA polymerase
  • Efficiently phosphorylated — active triphosphate
  • Competes with natural substrate deoxyguanosine triphosphate
  • Cross resistance with other HBV agents

Entecavir (Baraclude): ADME

A: decreases with food

D: extensively distributed into tissues, minimal protein binding

M: minor phase II metabolites, no interactions with CYP450

E: kidney, unchanged (60-70%)

 

Entecavir (Baraclude): AE

  • Exacerbation of hepatitis after discontinuation of therapy
  • HA, fatigue, dizziness, nausea
  • Liver function monitoring
  • Drug interactions with ones that reduce renal function

Telbivudine: MOA

  • Synthetic thymidine nucleoside analog
  • Beta-L enantiomer of the naturally occurring nucleoside thymidine
  • Phosphorylated by cellular kinases
  • Phosphorylated telbivudine inhibits viral DNA polymerase by competing with the natural substrate
  • Cross resistance among HBV nucleoside analogs

Telbivudine: ADME

A: well absorbed

D: widely via body water into tissues, minimal protein binding

M: none

E: unchanged by urine

Telbivudine: AE

  • Well tolerated
  • Nauea, HA, vomiting
  • Influenza-like symptoms
  • Pain

Ribavirin: MOA

  • Synthetic guanosine analog (competes with guanosine) –> however, not a pyrimidine or purine analog
  • DNA polymerase inhibitor

Possible MOA

  1. alteration of cellular nucleotide pools and inhibition of viral RNA synthesis
  2. Intracellular phosphorylation by host enzymes
  3. Monophosphate form: competitor of cellular IMP dehydrogenase — interferes with GTP synthesis
  4. Triphosphate form: also inhibits GTP-dependent 5′ capping of viral mRNA

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Ribavirin: ADME

A: rapid PO, IV, aerosol

M: liver

E: renal

Ribavirin: AE

  • Well tolerated
  • Related to dose duration
  • Mild conjunctive irritation
  • Rash
  • Transient wheezing
  • Reversible deterioration of pulmonary function

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Interferon: MOA

  • Mediator of immune response
  • Interferon ;: broad spectrum, acts on virus-infected cells –> inhibits transcription and translation of RNA viruses
  • It may act by blocking synthesis of a cleaving enzyme required for viral release

Interferon: ADME, AE

  • PK not well understood
  • D: does not penetrate CSF
  • IM, IV
  • Toxicity: influenza like symptoms

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