MG - infectious diseases and oncology 7

Antiviral agents

lytic infection

host cell bursts upon infections

rapid distribution through the population

often harmful to host acutely

poli/ebola

persistent or chonic infection

virus is released slowely

host cell does not always die

host cell can divide, allows virus communication

infection can persist for years without symptoms

HIV/Hepatitis B and C

latent infection

virus does not reproduce continuously

genetic material is incorporated into the host genome

virus genes pass into daughter cells after division

long, symptom-free periods

Varizella zoster virus

targets of the antiviral drug

virostatic

only effective against replicating viruses

attacking targets specific for the virus

HIV

human immunodeficiency virus

• progressive failure of the immune system

• infects immune cells by direct killing resulting in the cell-mediated immunity being lost

• sexually tranmissted infection

treatment

• combinational therapy with antiretroviral drugs

• progression to AIDS increasingly rare

• with no detectable viral load there is no chance of passing through sex

abacavir, zidocudine

anti-HIV (nucleoside/nucleotide HIV reverse transcriptase inhibitors)

MOA: inhibition of the RNA virus replication by reversible inhibition of viral HIV reverse transcriptase. in addition there are analogues of pecursors of the natural purines and pyrimidines involved in DNA transcription initiated by the virus

resistance: rapid development (combinational therapy!) due to mutations affecting the drug binding site

SE: often severe

• neutropenia anemia, GI, headache, insomnia, myalgia/myositis, pancreatitis

efavirenz, vevirapine

anti-HIV(non-nucleoside HIV reverse transcriptase inhibitor)

MOA: binding directly to HIV-1 reverse transcriptase

resistance: point mutations resulting in reduced binding

PK: enzyme inducers(CYP) resulting in a lot of IA

SE: rashes, nausea, vomiting, abdominal pain, headache, depression , hepatotoxicity

atazanavir, ritonavir

anti-HIV(HIV protease inhibitor)

MOA: blockade of the active site of the viral protease, but there is no effect on virus activity in host cells

resistance: mutations affecting the amino acid sequence of the HIV protease

PK: inhibitor of CYP3A4(also metabolized by)

SE: GI, lipodystrophy syndrome, hepatic dysfunction, nephrolithiasis, pancreatitis, paraesthesiae

dolutegravir, raltegravir

anti-HIV(HIV integrase inhibitors)

MOA: specific viral integrase, mainly used in resistant cases

Resistance: mutations in the viral integrase, cross resistance

PK: no CYP effect

SE: GI, headache, rashes

maraviroc

Anti-HIV (CCR5 inhibitor)

MOA: selective binding to receptor for several cytokines, used in individuals who have already received another antiretroviral treatment

resistance: uncommon but there can be changes in the viral envelope

SE: nausea, diarrhea, anorexia, malaise, rashes, depression, insomnia, headache

lenacapavir

anti-HIV(capsid inhibitor)

MOA: binding directly to the interfase disturbing essential steps of viral replication

indications: HIV with multidrug resistance or patient does not tolerate others. pre-exposure prophylaxis

SE: relatively mild

resistance: very rare but can develop

issue: relatively expensive

acyclovir, ganciclovir, valaciclovir, valganciclovir

nucleoside inhibitors of viral DNA polymerase

MOA: guanosine analogues, active against many DNA viruses, inhibition of viral DNA synthesis and polymerase

indications(acyclovir)

• herpes simplex

• varicella zoster infection

• prophylaxis in immunocompromised patients

resistance: alterations in viral DNA polymerase (mainly in immunocompromised)

SE: severe local phlebitis at infusion site, nausea, vomiting, abdominal pain, diarrhea, rashes, headache, nephrotoxicity(acyclovir), bone marrow suppression(ganciclovir)

foscarnet

non-nucleoside inhibitors of viral DNA polymerase

MOA: binds to the DNA polymerase inhibiting the DNA chain elongation, does not rely on intracellular activation

indications: CMV, HSV in AIDS

SE: nausea, vomiting, diarrhea, neutropenia, headache, tremor, dizziness, mood disturbances, nephrotoxicity

interferon a

MOA: cytokines produced by virus-infected cells resulting in the increase of mRNA translation with a decrease in viral replication and increase in viral clearance

SE: headache, myalgia, fever, rigors, fatigue, anorexia, depression, bone marrow suppression, unmaking or exacerbation of autoimmune conditions

indications: chronic viral hepatitis

• AIDS related Kaposi’s sarcoma

• hairy cell leukemia

  • recurrent or metastatic renal cell carcinomas

sofosbuvir

direct acting antiviral agent against hepatitis C

MOA: inhibits the HCV RNA polymerase

SE: flu-like symptoms, fever, cold shivers, skin rash, puritus

sofosbuvir/velpatasvir

common combination used for HCV

the addition is an inhibitor of viral replication

entecavir, tenofovir, disoproxil, ribavirin

nucleoside and nucleotide analogues

MOA: differences among the agents

• entecavir: inhibits the viral enzyme reverse transcriptase

• tenofovir: nucleotide analogue that inhibits the reverse transcriptase

• ribavirin: nucleoside analogue, inhibits ciral RNA synthesis

SE: GI, cough, headache, dizziness, insomnia, fatigue, rashes

amantadine

M2 channel inhibitor

used in the treatment of influenza

MOA: active only against influenza A

• inhibits the transmembrane M2 ion channel which permits proton entry reuding the intracellular replication

SE: livedo reticularis, CNS(impulse control disturbances), orthostatic hypertension, withdrawal syndrome

oseltamivir, zanamivir

neuraminidase inhibitors (influenza treatment)

MOA: inhibit the neuraminidases of both A and B, effective in resistant cases

SE: GI, headache, fatigue, insomnia, bronchospasm(zanamivir due to inhalational administration)

pavilizumab

humanized monoclonal antibody

MOA: reduces the ability of respiratory syncytial virus cells to replicate and infect cells

SE: mild (fever and injection site reactions)

what is the main reason of using combinational therapy against HIV

to counteract the rapid development of resistance

what is the mechanism of action of maraviroc

CCR5 inhibitor