Antivirals

Question 1

HIV Protease Inhibitors (“-navir”)

1. Mechanism:
2. Toxicity:

Answer 1

Assembly of virions depends on HIV-1 protease (encoded by the pol gene) which cleaves the polypeptide products of HIV mRNA into their functional parts.
Protease inhibitors prevent maturation of new viruses

Resistance: results from mutation in the HIV protease gene

Toxicity: hyperglycemia, nausea, diarrhea, lipodystrophy (increased total and LDL-cholesterol and triglycerides, decreased HDL)

Ritonavir: inhibition of CYP3A4 which can produce toxic levels of other drugs

Rifampin (potent CYP/UGT inducer) is contraindicated with protease inhibitors because it can decrease protease inhibitor concentration

Indinavir: nephropathy, hematuria, elevated bilirubin
Ritonavir + Rifampin = drug induced hepatitis

Question 2

Nuceloside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Nucleosides: Abacavir (ABC), Didanosine (ddI), Emtricitabine (FTC), Lamivudine (3TC), Stavudine (d4T), Zidovudine (ZDV - formerly known as AZT)

Nucleotides: Tenofovir (TDF)

Answer 2

HIV antiviral

Triphosphates competitively inhibit nucleotide binding to reverse transcriptase
When incorporated into viral DNA, nascent chains are terminated due to the absence of a 3’-OH.
Nucleosides must be phosphorylated in the host cell by nucleoside kinase to be active

Zidovudine is administered to pregnant women to decrease the risk of transmission to the fetus

Toxicity: bone marrow suppression (administer G-CSF and EPO), peripheral neuropathy, nausea, fatigue.

Nucleosides: lactic acidosis (mitochondrial toxicity - drugs inhibit mitochondrial DNA polymerase)
ZDV: anemia
ddI: pancreatitis

Tenofovir: hepatomegaly and Fanconi syndrome

Question 3

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Drugs: Delavirdine, Efavirenz, Nevirapine

Answer 3

HIV antiviral

Bind to reverse transcriptase at site different from NRTIs; do not require phosphorylation to be active.

Toxicity: Rash and hepatotoxicity
Delavirdine: contraindicated in pregnancy, hepatotoxicity, TEN, SJS
Efavirenz: contraindicated in pregnancy, nightmares

Question 4

Integrase Inhibitors (Raltegravir)

Answer 4

HIV antiviral

Inhibits HIV genome integration into the host cell chromosome by reversibly inhibiting HIV integrase

Toxicity: elevates the creatine kinase

Pharmacokinetics: cleared by glucuronidation in the liver; no CYP450 involvment

Question 5

Fusion Inhibitors

1. Enfuvirtide
2. Maraviroc

Answer 5

HIV antiviral

1. Binds gp41 which inhibits viral entry into host cells (viral fusion).
   Toxicity: skin reaction at injection site (drug is injected subcutaneously)
2. Binds CCR-5 on surface of T-cells and monocytes which inhibits interaction with p120. Not effective against CXCR-4 tropic HIV

Question 6

Interferons

1. IFN-α
2. IFN-β
3. IFN-γ

Answer 6

Mechanism of IFN-α: Inhibit viral replication and viral protein synthesis

1. Chronic hepatitis B and C, Kaposi sarcoma, Hairy cell leukemia, Condyloma acuminatum, Renal cell carcinoma, Malignant melanoma
2. Multiple sclerosis
3. Chronic granulomatous disease

Toxicity: neutropenia, myopathy

Question 7

Acyclovir

1. Clinical use:
2. Mechanism:
3. Toxicity:

Answer 7

1. HSV, VSV, and weak activity against EBV
2. Guanosine analog that is monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells
   The triphosphate potently inhibits viral DNA polymerase → since since acyclovir has no 3’-OH, incorporation into DNA results in chain termination
3. Generally well tolerated. Oral administrations can result in GI distress and headache. IV administration can cause renal dysfunction

Question 8

Valacyclovir

Answer 8

a prodrug form of acyclovir that is converted to acyclovir during first-pass hepatic metabolism. Oral administration yields serum concentrations of acyclovir 3-5 fold greater than those achieved after oral acyclovir

Question 9

Ribavirin

Answer 9

HCV antiviral

A synthetic nucleoside inhibits synthesis of guanine nucleotides (GMP) by competitively inhibiting inosine monophosphate dehydrogenase

Toxicity: hemolytic anemia, teratogen

Question 10

Telaprevir, Boceprevir, Simeprevir

Answer 10

HCV Protease Inhibitors
Inhibit viral replication by inhibiting NS3/4A serine protease

Inducers of CYP3A4 (rifampin) significantly decrease serum concentration

Contraindicated for use with drugs that depend on CYP3A4 that have potential for toxicity at elevated levels

Question 11

Sofosbuvir

Answer 11

HCV Polymerase Inhibitor
Nucleotide analog that inhibits HCV RNA-dependent RNA polymerase acting as a chain terminator

Do not use as a monotherapy