Antivirals

Question 1

Acyclovir

Answer 1

• Uses: HSV and VZV; some EBV infections
• MOA: inhibits DNA polymerase by chain termination
  
  • Viral thymidine kinase phosphorylates acyclovir, a guanosine analog → Acyclo-GMP that is then phophorylated by host enzyme → Acyclo-GTP that is incorporated into growing strand of viral DNA → chain termination
• AEs:
  
  • Oral: headache, diarrhea, nausea, vomiting
  • IV: transient renal dysfxn

Question 2

Valacyclovir

Answer 2

• Same as acyclovir, but has greater oral bioavailability

Question 3

Ganciclovir

Answer 3

• Uses: CMV
• Analog of acyclovir
• MOA: inhibits viral DNA polymerase, since it is incorporated into viral DNA → chain termination
• AEs:
  
  • Neutropenia
  • Carcinogenic
  • Teratogenic

Human thymidine kinase has a higher affinity for ganciclovir than acyclovir, which is why ganciclovir has worse AEs

Question 4

HAART Protocol

Answer 4

<!--StartFragment-->

** 3 drugs: 2 NRTIs that serve as the “backbone,” and a protease inhibitor, nNRTI, or integrase inhibitor that serves as the “base**<!--EndFragment-->

Question 5

<!--StartFragment-->

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

<!--EndFragment-->

Answer 5

• Analogs of native ribosides (all missing 3’ OH)
• Enter cells and are phosphorylated to triphosphate analog, which is preferentially incorporated into the viral DNA
• Since there is no 3’ OH present, the DNA chain cannot be formed → termination of DNA chain elongation (i.e. reverse transcriptase inhibition)

<!--EndFragment-->

Question 6

Tenofovir

Answer 6

• Class: NRTI
• <!--StartFragment-->MOA: acyclic nucleoside phosphonate analog of adenosine 5’monophosphate
  • It is converted by cellular enzymes to adenosine diphosphate, which inhibits the reverse transcriptase
• Pharmacokinetics:
  
  • Can cross the blood-brain barrier
  • Long half-life → once-daily dosing
  • Recovered unchanged in the urine
• AEs:
  
  • GI complaints: nausea, diarrhea, and bloating
  • Rash
  • Black box warning: (when used w/ other antiretrovirals)
    
    • Lactic acidosis
    • Hepatomegaly w/ steatosis

<!--EndFragment-->

Question 7

Emtricitabine

Answer 7

• <!--StartFragment-->Class: NRTI
• MOA: cytosine analogue that inhibits both HIV and HBV reverse transcriptase
• Orally active (bioavailability 93%)
• Pharmacokinetics:
  
  • Plasma half life = 10 hours
  • Intracellular half life = 39 hours (long)
  • Eliminated essentially unchanged in the urine
• Common AEs:
  
  • Headache
  • Diarrhea, nausea
  • Rash
• Less common AEs:
  
  • Hyperpigmentation of the soles and palms
  • Lactic acidosis
  • Fatty liver
  • Hepatomegaly

<!--EndFragment-->

Question 8

<!--StartFragment-->

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)<!--EndFragment-->

Answer 8

• General MOA: Bind reverse transcriptase at a site adjacent to the active site → conformational ∆ → enzyme inhibition
• Major advantages:
  
  • Don’t effect host blood-forming elements
  • No cross resistance with NRTIs
• Common AEs:
  
  • Rash
  • Hepatotoxicity

<!--EndFragment-->

Question 9

Efavirenz

Answer 9

• <!--StartFragment-->Class: NNRTI
• MOA: Binds reverse transcriptase → inhibition of RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication
  
  • Does not require intracellular phosphorylation for antiviral activity
  • Treatment with efavirenz in combination w/ NRTIs → ⇡CD4 counts and ⇣viral load
  • Comparable to that seen with PIs in combination with NRTIs
  • Makes it the preferred NNRTI on DHHS guidelines
  • Oral administration and well distributed
  • Binds to plasma albumin at therapeutic doses
  • Crosses blood-brain barrier
  • Should be avoided in pregnant women (teratogenic)
• Pharmacokinetics:
  
  • Half-life > 40 hours → once-daily dose
  • Extensively metabolized to inactive products
  • CYP450 enzymes inducer
  • May ⇣ concentrations of drugs that are substrate of CYP450
• AES:
  
  • Dizziness
  • Headache
  • Vivid dreams
  • Loss of concentration
  • Rash

<!--EndFragment-->

Question 10

Protease Inhibitors (PIs)

Answer 10

• <!--StartFragment-->General MOA: reversible inhibitors of the HIV aspartyl protease, the enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes (e.g., protease, integrase, reverse transcriptase)
• Pharmacokinetics:
  
  • Poor oral bioavailability
  • All are potent substrates (and inhibitors) of CYP3A4 isozymes of CYP450
  • Extensive metabolism → little unchanged excretion in urine
• AES:
  
  • Paresthesias
  • Nausea, vomiting, diarrhea
  • Hypertriglyceridemia
  • Hyperglycemia
  • Hypercholesterolemia

<!--EndFragment-->

Question 11

<!--StartFragment-->

Ritonavir<!--EndFragment-->

Answer 11

• <!--StartFragment-->Used as a pharmacokinetic enhancer or “booster” of other protease inhibitors
• Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir administration (at low doses) increases the bioavailability of the second protease inhibitor, often allowing for longer dosing intervals

Question 12

<!--StartFragment-->

Lopinavir<!--EndFragment-->

Answer 12

<!--StartFragment-->

Lopinavir has very poor intrinsic bioavailability, which is substantially enhanced by including a low dose of ritonavir in the formulation.

<!--EndFragment-->

Question 13

Truvada

Answer 13

= Tenofovir + Emtricitabine

Question 14

Atripla

Answer 14

= Tenofovir + Emtricitabine + Efavirenz

Question 15

<!--StartFragment-->

Enfuviritide<!--EndFragment-->

Answer 15

• <!--StartFragment-->Class: **Fusion inhibitor **(<!--StartFragment--> interfere with binding, fusion, and entry of an HIV virion into CD4 cells)<!--EndFragment-->
• MOA: <!--StartFragment-->Enfurvitide blocks gp41 conformational change which prevent virions from fusing with CD4 cells.<!--EndFragment-->
• Enfuviritide is not used in treatment-naïve patients because of toxicity and difficulties in drug administration
• It is approved for therapy of treatment-experienced patients with evidence of viral replication despite ongoing antiretroviral drug therapy
• Must be given subcutaneously because it is a peptide
• Most of the adverse effects are related to the injection, including pain, erythema, induration, and nodules, which occur in almost all patients.

<!--EndFragment-->

Question 16

Oseltamivir

Answer 16

• (Tamiflu)<!--StartFragment-->
• Class: Neuraminidase inhibitor
• MOA: Oseltamivir mimics the sialic acid receptor that is the substrate for NA → Interference with the release of progeny virus from infected host cell → no cell to cell spread of infection
• Only one round of infection is possible → ⇣severity of infection
• If given within 36-48 hours of onset, the ⇣the illness by 1-2 days, ⇣severity, and also appear to prevent secondary bacterial PNA and otitis media
• The earlier they are given, the more effective they are
• Does not interfere with immune response to influenza vaccine<!--StartFragment-->
• Adverse effects:
  
  • GI discomfort and nausea (can be alleviated by taking the drug with food)
  • Bronchospasm in patients with asthma and COPD (precaution)

<!--EndFragment-->

​

<!--EndFragment-->