Therapeutics ID Nieto Flashcard

Zidovudine (AZT): MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

Didanosine: MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

Lamivudine: MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

Zalcitabine: MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

Stavudine: MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

Abacavir: MOA

Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI)

 

Dideoxynucleoside Analog

  • Inhibition of reverse transcriptaste –> prevents conversion of the viral RNA genome into a double-stranded copy prior to integration into the cell genome
  • Inhibitor AND substrate for reverse transcriptaste enzyme
  • Selective toxicity (minimal affinity for DNA polymerase)
  • Binding to the enzyme-template-primer
  • Affinity is higher than natural substrate (dNTPs)

 

NRTIs Resistance

  • Associated with point mutations –> highest level is 4-5 amino acid substitutions
  • AZT resistance –> decreased affinity for deoxynucleoside triphosphate binding site
  • AZT-resistant virus is cross-resistant only to NRTIs with N3 and with other deoxythymidine analogs (Stavudine)

NRTIs: ADME

A: PO, Didanosine has low and variable absorption (acid labile), high fat/high protein meals slow zidovudine absorption

D: low plasma protein binding, well distributed into tissues and cells, penetration into the CNS and CSF

M: rapidly cleared (triphosphate lasts longer), Didanosine –> liver, AZT –> liver (glucuronidation)

E: renal

NRTIs: AE

1. Bone Marrow Toxicity

  • neutropenia, anemia
  • reversible and dose-dependent
  • AZT metabolites (monophosphate) inhibits hematopoietic cells growth
  • inhibition of mitochondrial DNA synthesis, decreased expression of the erythropoietin receptors, decreased globin mRNA synthesis

2. Peripheral Neuropathy

  • Most NRTIs (except AZT)
  • painful, sensorimotor neuropathy
  • slow onset (2 months)
  • symptoms: tingling, burning, pain at rest
  • resolves after termination of therapy
  • related to mitochondral DNA synthesis

3. Myopathy

  • serious in AZT therapy
  • long lasting and debilitating
  • AZT – muscle mitochondrial toxin – interferes with oxidative phosphorylation and respiratory chain activity

4. Pancreatitis

  • mainly associated with didanosine
  • progressive abdominal pain, nausea, vomiting, and deviation of serum amylase

5. Hepatic Toxicity

  • AZT and didanosine: hepatomegaly with fatty degeneration of the liver
  • metabolic acidosis
  • Inhibition of mitochondrial DNA synthesis –> reduction of DNA polymerase gamma (mitochondrial DNA synthesis), with an increase of lactic acid production

Nevirapine: MOA

Non-Nucleoside Analog Reverse Transcriptase Inhibitor (NNRTI)

 

  • Allosteric inhibition of enzyme function –> binds to a non-catalytic binding site of the enzyme –> causes conformational change of the catalytic site –> locks enzyme in this position so it cannot bind with the natural substrate
  • Non-competitive Inhibition
  • No phosphorylation needed

 

Delavirdine: MOA

Non-Nucleoside Analog Reverse Transcriptase Inhibitor (NNRTI)

 

  • Allosteric inhibition of enzyme function –> binds to a non-catalytic binding site of the enzyme –> causes conformational change of the catalytic site –> locks enzyme in this position so it cannot bind with the natural substrate
  • Non-competitive Inhibition
  • No phosphorylation needed

Efavirenz: MOA

Non-Nucleoside Analog Reverse Transcriptase Inhibitor (NNRTI)

 

  • Allosteric inhibition of enzyme function –> binds to a non-catalytic binding site of the enzyme –> causes conformational change of the catalytic site –> locks enzyme in this position so it cannot bind with the natural substrate
  • Non-competitive Inhibition
  • No phosphorylation needed

NNRTIs: ADME

A: nevirapine not impaired by food, antacids, or didanosine, delavirdine decreased by food and didanosine

D: highly lipophilic, binds to plasma proteins

M: extensively

E: Nevirapine and Delavirdine renal, Efavirenz feces and renal

NNRTIs: AE

  • Low toxicity
  • Skin rashes: maculopapular
  • HA, fatigue, GI, complaints, and hepatic enzyme elevation

NNRTIs: Effect on CYP450 enzymes

Efavirenz and Nevirapine INDUCES CYP3A4

Delavirdine INHIBITS CYP450

Amprenavir: MOA

Protease Inhibitor

  • Transition-State Mimetics
  • Prevents post-translational processing of core proteins and budding

Ritonavir: MOA

Protease Inhibitor

  • Transition-State Mimetics
  • Prevents post-translational processing of core proteins and budding

Indinavir: MOA

Protease Inhibitor

  • Transition-State Mimetics
  • Prevents post-translational processing of core proteins and budding

Nelfinavir: MOA

Protease Inhibitor

  • Transition-State Mimetics
  • Prevents post-translational processing of core proteins and budding

Saquinavir: MOA

Protease Inhibitor

  • Transition-State Mimetics
  • Prevents post-translational processing of core proteins and budding

Protease Inhibitors: ADME

A: Indinavir, ritonavir, and nelfinavir have good PO; saquinavir has low PO (high calorie, high fat meal required for good absorption)

D: Highly bound to plasma protein

M: CYP450

E: renal

Protease Inhibitors: AE

  • GI disturbances
  • Hemorrhage (hemophilia pts)
  • Hypertriglyceridemia, glucose intolerance, and abnormal fat distribution

Maraviroc (Selzentry): MOA

CCR-5 Co-Receptor Antagonist

 

Entry Inhibitor

 

Maraviroc (Selzentry): ADM

A: good PO

D: > 70% bound to plasma proteins

M: n-dealkylation, hydroxylation

Maraviroc (Selzentry): AE, Drug Interactions

  • Upper respiratory tract infections
  • Rash
  • Cough
  • Abdominal pain
  • Dizziness
  • Pyrexia

Drug Interactions: CYP3A4 substrate

Raltegravir (Isentress): MOA

Integrase Inhibitor

 

Inhibits insertion of viral DNA into human DNA

Raltegravir (Isentress): PK

Rapidly Absorbed (not affected by food)

 

No drug interactions due to CYP450 metabolism

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