Pharm Exam 3 Antiviral Drugs

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Acyclovir

-Anti-Herpes Therapy
-Mechanism of action: taken up by ALL host cells, but phosphorylated to monophosphate by virus-encoded thymidine kinase, so ONLY infected cells affected
-converted to TRIPHOSPHATE by host cell enzymes
-leads to competitive viral DNA polymerase inhibition

Acyclovir Resistance

-Absence of partial production of viral thymidine kinase
-Altered thymidine kinase specificity
-Altered viral DNA polymerase

Acyclovir pharmacokinetics

HSV-1>HSV-2>VZV>Cytomegalovirus
-Poor oral bioavailability, bioavailabil. decreases with increased doses
-good body fluid penetration
-topical application--> decreased effectiveness
-eliminated UNCHANGED in urine

Acyclovir adverse effects

-Nausea, diarrhea
-Rash
-Headache
-Renal insufficiency and neurotoxicity with IV formulation

Valacyclovir

Anti-Herpes
-prodrug of acyclovir- converted rapidly and completely via enzymatic hydrolysis
-better oral bioavailability than acyclovir
-similar adverse effects to acyclovir
Clinical use:
-as effective as acyclovir for HSV
-BETTER than acyclovir for VZV treatment

Examples of anti-influenza drugs

-Amantadine (Symadine)- NO longer used due to resistance
-Rimantadine (Flumadine)- NOT used due to resistance
-Osetalmivir (Tamiflu)
-Zanamivir (Relenza)

Oseltamivir

-Inhibitor of Influenza A and B NEURAMINIDASES- causes conformational change within enzyme's active site
-RESISTANCE due to mutations of hemagglutinin or neuraminidase
- Rapid absorption and activation by esterases in GI
tract and liver
- Cleared by the kidneys
• Adverse effects
- GI upset
• Clinical use
- Prophylaxis in those who cannot receive vaccine
- Early treatment . decrease symptoms by 1-2 days

Zanamivir

- Inhibitor of Influenza A and B neuraminidases .causing a conformational change within the enzyme's active site
• Resistance
- Mutations to hemagglutinin or neuraminidase
• Those variants have reduced infectivity and virulence
- Resistance has not been documented in immunocompetent hosts
• Pharmacokinetics
- Low oral bioavailability . available as oral inhalant
• Adverse effects
- Wheezing, Bronchospasm
• Clinical use
- Prophylaxis in those who cannot receive vaccine
- Early treatment . decrease symptoms by 1-3 days

Ribavirin

Used for RSV Treatment and Hepatitis Tx
• Mechanism of action:
- Inhibits both RNA and DNA viruses secondary to alterations of cellular nucleotide pools and inhibits viral messenger RNA synthesis
• No documented resistance
• May decrease morbidity in some children
• Adverse effects
- Transient wheezing and rash (aerosolized)
- Increased bilirubin, anemia, and rigors (systemic)
- Teratogenic

What can be used for Anti-Hepatitis Therapy?

-Ribavirin
• NRTIs
- Lamivudine
- Adefovir
- Entecavir
- Telbivudine
- Tenofivir
• Interferon

Interferon alfa

• Naturally occurring proteins produced by host
cells in response to viral infections

Interferon alfa-2b

• Produced by recombinant DNA technology
- Stimulates the body's immune system to fight off the virus
• Induction of gene transcription
• Inhibits cellular growth
• Alters the state of cellular differentiation
• Interferes with oncogene expression
• Alters cell surface antigen expression
• Increases phagocytic activity of macrophages
• Augments cytotoxicity of lymphocytes
• Clinical use
- Hepatitis B
- Hepatitis C
• Requires dosing adjustment in renal insufficiency
• Black Box Warning
- DC therapy if patient develops severe pulmonary symptoms, autoimmune disorders, worsening hepatic function, psychiatric symptoms, ischemia, or infectious disorders

Fusion Inhibitors (FI)

• Prevent HIV from entering healthy CD4+ cells
- Block proteins on the surface of HIV or on the
CD4+ cell by binding to glycoprotein-41
• These proteins are required for the virus to gain entry
into the cell (e.g. fuzeon)

Fusion Inhibitor Pharmacokinetics

• Twice daily subcutaneous injections
• Does NOT affect the metabolism of other antivirals requiring the CYP system
- No reported DDI
• NO dose adjustments needed for renal or mild-moderate hepatic dysfunction

How does Fusion Inhibitor Resistance develop?

• Amino acid substitutions resulting in loss of
activity
• Give in combination with other antivirals to
decrease resistance

Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Incorporates into the DNA of the virus
- Must be converted to triphosphate inside host cell by host
cell kinases
- Inhibiting the replication process and terminating the DNA
chain
- Cannot create new virus
• Some examples
- Emtricitabine
- Lamivudine
- Zidovudine
- Didanosine
- Stavudine

NRTI Pharmacokinetics

• Well absorbed
- Zidovudine- food slows absorption
- Didanosine- take 30 minutes before or 2 hours after food
- Stavudine- NOT affected by food
• Does require intracellular phosphorylation
• Renally excreted

NRTI Adverse Effects

• Anemia
• Granulocytopenia/ bone marrow suppression
• Myopathy
• Neuropathy
• Pancreatitis
• Steatosis
• lipoatrophy
• Lactic acidosis (with or without hepatomegaly)

NRTI Resistance

• Two mechanisms of resistance
- Impaired incorporation into viral DNA
- Removed from viral DNA
• Thymidine analog mutation removes NRTI from DNA .
conformational change to reverse transcriptase
- Causes a break in DNA chain . DNA unable to continue
elongation
• Mutations occur over time
- More than 1 mutation needed to cause resistance
• Except M184V mutation -> resistance with single mutation

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Stops HIV production within the host cell
- Binds directly onto the reverse transcriptase, preventing the conversion of RNA to DNA
• Examples
- Nevirapine
- Efavirenz
- Rilpivirine
- Delavirdine mesylate
- Etravirine

NNRTI Pharmacokinetics

• MUCH variability amongst individual NNRTIs
• Well absorbed
- NOT altered by food
• Does NOT require intracellular phosphorylation to be active
• No activity against host cell DNA polymerase
• Crosses placenta and concentrated in breast milk
• Metabolized by CYP enzymes
• Varying DDIs

NNRTI Resistance

• Highly susceptible to resistance
- Single mutation affecting binding site
• Do NOT use as monotherapy
• Cross resistance between NNRTIs

Protease Inhibitors (PIs)

• Prevent HIV from being assembled and released from the infected CD4+ cell
• Some examples
- Amprenavir
- Indinavir sulfate
- Saquinavir
- Ritonavir
- Nelfinavir

Protease Inhibitor Pharmacokinetics

• High interindividual variability
• Highly protein bound
• Hepatic clearance
• P-glycoprotein efflux pump substrate
- Limits concentration in the brain
• CYP 3A4 substrates
- Often given with low dose ritonavir

Protease Inhibitor Resistance

• Mutations in the enzymatic active site
- Multiple mutations needed for high-level resistance
• Secondary mutations distant from active site
• Resistant to 1 PI . resistance to ALL Pis
- More mutations increase likelihood of crossresistance
- Secondary resistance decreases likelihood of longterm
response

Integrase Inhibitors (IIs)

• Prevents the transport and attachment of
proviral DNA to host-cell chromosomes
- Inhibiting transcription of viral proteins and the assembly of virus particles
• Example
- Raltegravir (Isentress®)

Integrase Inhibitor Pharmacokinetics

• Rapid oral absorption
- Not affected by food
- Antacids decrease absorption
• Protein bound
• P-glycoprotein substrate
- Minimal CNS penetration

Integrase Inhibitor Resistance

• Mutations exist to viral integrase gene
- 2 clinical trials have demonstrated decreased
susceptibility

Chemokine Receptor Antagonists
(CRAs)

• Selectively binds to a chemokine coreceptor
(CCR5) that is partly responsible for the
binding and then fusion of HIV to CD4 cells
- The interaction between CRA and coreceptor
blocks HIV interaction and inhibits fusion
• Example
- Maraviroc (Selzentry®)

Chemokine Receptor Antagonist Pharmacokinetics

• Protein bound
• Metabolized via CYP3A4
- MUST be dose adjusted when given with other inhibitors or inducers
• P-glycoprotein substrate
- Minimal CNS penetration
• Resistance has been observed
- Unknown mechanism

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