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)

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)

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)

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)

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)

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)

• 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)

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

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

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

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

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

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

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

Efavirenz and Nevirapine INDUCES CYP3A4

Delavirdine INHIBITS CYP450

Protease Inhibitor

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

Protease Inhibitor

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

Protease Inhibitor

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

Protease Inhibitor

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

Protease Inhibitor

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

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

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

CCR-5 Co-Receptor Antagonist

Entry Inhibitor

A: good PO

D: > 70% bound to plasma proteins

M: n-dealkylation, hydroxylation

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

Drug Interactions: CYP3A4 substrate

Integrase Inhibitor

Inhibits insertion of viral DNA into human DNA

Rapidly Absorbed (not affected by food)

No drug interactions due to CYP450 metabolism