17. Anti-viral Chemotherapy Flashcards
What is the virus particle?
Slide 3
Has lipoprotein envelope
Core proteins (capsid)
RNA or DNA core
Surface proteins
What are viruses?
Small obligate intracellular parasites
Contain nucleic acid core surrounded by a protein capsid; with an envelope
Attach to host cell receptors then enter cell by endocytosis or penetration
Use hosts mechanisms of replication cause viruses can’t themselves
Assemble virions within the host cell, released during cell lysis (nonenveloped viruses) or budding (enveloped viruses)
Slides 4-7
What are viral infections?
Can’t be lytic (destroy host), latent (no signs or symptoms for long time), chronic (when virus buds from host cell, infection can be chronic)
Can be awaited from humans, animals or environment; through direct contacts or environmental routes
Characterized by incubation period
Can spread to other tissues
Slides 8-10
What are the 8 things to do to treat viral infections?
- Block viral attachment to cells
- Block in coating of virus
- Inhibit viral DNA/RNA synthesis
- Inhibit viral protein synthesis
- Inhibit specific viral enzymes
- Inhibit viral assembly
- Inhibit viral release
- Stimulate host immune system
Slides 9-10
How do you treat respiratory virus infections?
Treatments exist for influenza types A and B, and respiratory syncytial virus (RSV)
Immunization against influenza virus is the preferred approach (annual flu shot)
Slides 12-13
What are neuraminidase inhibitors?
3 drugs
Oseltamivir
Zanamivir
Peramivir
Neuraminidase removes sialic acid receptors from viral particles and from cell surface, preventing self aggregation and gluing to infected cell surface
These 3 drugs inhibit neuraminidase of influenza A and B viruses, and prevent release of new virions
Slides 14-19
What do each of the 3 neuraminidase inhibitors do;
Oseltamivir
Zanamivir
Peramivir
Oseltamivir- orally active prodrug, hydrolyzed by the liver to its active form
AE: GI discomfort and headache
Zanamivir- inhaled or intranasal, or intravenous, avoid inhaled or intranasal with respiratory diseases or asthma
Peramivir- new neuraminidase inhibitor, intravenous only
AE: diarrhea & neutropenia
Oseltamivir and zanamivir are effective and safe for prophylaxis after exposure to and for treatment of influenza A and B
Slides 15-19
What is avian flu?
Uncoating inhibitors amantadine and rimantadine may have activity against some avian strains of influenza, but not against most of H5N1 subtype strains which caused avian flu outbreaks
Oseltamivir has been active against avian strains of influenza in animal studies (option for H5N1)
Zanamivir has been active in animal models, not studied in human infection with influenza
Slide 19
What are viral uncoating inhibitors?
2 drugs
Amantadine
Rimantadine
Block the viral membrane matrix protein M2 (H+ ion channel)
Both orally administered for influenza A virus only
Both reported to be effective for prophylaxis and treatment of susceptible strains of influenza A
Resistance has increased substantially
Amantadine is effective in some Parkinson’s
Neither recommended anymore
Slides 20-21
What is ribavirin?
Synthetic guanosine analog, effective against RNA and DNA viruses
For treating severe RSV infections in infants and young children, and testing influenza
Effective in chronic hepatitis C infections
Inhibits GTP formation, viral mRNA capping, and thereby inhibits viral protein synthesis
Oral, intravenous, aerosol
Slide 22
How do we treat hepatic viral infections?
Hepatitis B and C are most common for chronic hepatitis, cirrhosis, hepatocellular carcinoma
Chemotherapy is available for hepatitis B and C
Other drugs for HBV infection; adefovir, entecavir, telbivudine, tenofovir
What is interferon (IFN)?
Mode of action, adverse effects
Mode of action: induction of host cell enzymes that inhibit viral RNA translation, degradation of viral RNA, and stimulation of immune system
Peg-IFN-α-2a and peg-IFN-α-2b once weekly dosing, pegylatipn slows absorption, decreases clearance and provides higher serum concentrations
Administered intralesionally, subcutaneously, or IV
Adverse effects: flu like symptoms, bone marrow suppression, neurotoxicity, autoimmune disorders
What is lamivudine?
Mode of action, what it treats
Mode of action: inhibits both HBV DNA polymerase and HIV reverse transcriptase
Absorbed orally, well tolerated
For treatment of HBV and HIV infections
Slide 26
How do you treat HCV infection?
After HCV enters the hepatocyte, the viral genome is released from the nucleocapsid and then, an HCV polyprotein is translated
Polyprotein is cleaved by cellular and viral proteases to yield structural and non structural proteins
Several antivirals targeting NS3/NS4A protease, NS5B polymerase and NS5A protein involved in HCV replication and assembly are available
Slides 27-28
What are the 4 different kinds of drugs for HCV treatment?
NS3/NS4A protease inhibitors:
Paritaprevir, grazoprevir, voxilaprevir, glecaprevir
Previr = NS3/NS4
NS5B polymerase inhibitors:
Sofosbuvir, dasabuvir
Buvir = NS5B
NS5A replication complex inhibitors;
Ledipasvir, ombitasvir, elbasvirasvir, velpatasvir
Asvir = NS5A
Ribavirin: used for chronic HCV in combo with IFN or DAAs
Slide 28
How do you treat herpes virus infections (HSV)?
Herpes simplex virus types 1 (oral) and 2 (genital)
Most infections are asymptomatic (latent phase)
Drugs are effective only during acute phase of infections, can’t prevent reoccurrences
Acyclovir, valacyclovir, famciclovia, penciclovir, ganciclovir, foscarnet
Slides 29-34
What is acyclovir?
Modes of action, adverse effects
Drug of choice for HSV1, HSV2, and VZV
Analog of endogenous substrate deoxyguanosine
Most common use is for treatment of genital herpes infections
Competitively inhibits dGTP for viral DNA polymerases, binds to DNA template causing termination of premature viral DNA, traps viral DNA polymerase on terminated DNA chain
Admin using IV oral or topical
Adverse effects: local irritation (topical), headache/GI upset (oral), renal dysfunction (IV)
Slides 30-33
What is HIV?
Attaches CD4+ cells
Contains a reverse transcriptase to make cDNA
Viral cDNA copy is integrated into host genome and form provirus
Inactivates CD4+ cells leading to deficient cell mediated immunity
Releases (buds off) without killing host cell
Use combinations of drugs to suppress HIV replication and to restore a degree of immuno-competency in host
Known as HAART (highly active antiretroviral therapy)
Slides 36-58
What is 1st section of anti HIV agents: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)?
Prodrugs, analogs if native nucleosides or nucleotides
Convert to triphosphates in the cell
Preferentially incorporated into viral DNA to terminate its elongation
Zidovudine (AZT)- converted by mammalian thymidine kinase time triphosphate, decreases viral load and increases CD4+ cells
Toxic to bone marrow, headaches
Didanosine, zalcitabine, lamivudine, abacavir, emtricitabine, tenofovir
Slides 41-44
What is 2nd section of anti HIV agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs)?
Highly selective, non competitive inhibitors of HIV-1 reverse transcriptase (lack affinity against HIV-2)
Don’t require activation by cellular enzymes
Lack of effect on bone marrow, lack of cross resistance with NRTIs
Can have resistance, drug interactions, hypersensitivity reactions
Nevirapine- used with other antiretroviral drugs (subs AZT), causes rash, fatal hepatotoxicity, induces CYP3A4 enzymes
Efavirenz- activity against HIV-1, used into in conbo with other HIV agents
Slides 45-48
What is 3rd section of anti HIV agents: protease inhibitors?
Selective reversible inhibitors of HIV aspartyl protease (for formation of reverse transcriptase, protease, integrase, and proteins) and block viral maturation
Are synergetic with NRTIs and NNRTIs
AE: GI intolerance, disturbances in glucose and lupus metabolism
Avoid using inducers of CYP isozymes of cytochrome P450 (rifampin, barbiturates, carbamazepine)
Ritonavir- inhibits cytochrome P450 isozymes (CYP3A4) causes drug drug interactions
Saquinavir, atazanavir, indinavir, Darunavir
Slides 49-54
What is 4th section of anti HIV agents: viral entry inhibitors?
Enfuvirtide- viral fusion inhibitor
Binds gp41 and prevents conformational changes that occur when HIV fuses with host cell membrane
Enfuvirtide/maraviroc- CCR5 antagonist
Slides 55-56
What is 5th section of anti HIV agents: integrase inhibitors?
Raltegravir- HIV1 integrase strand transfer inhibitors (InSTI), inhibits HIV1 strains resistant to multiple anti viral agents
Resistance occurs in people not taken any other fully active drugs
Dolutegravir/elvitegravir- 2 newly approved integrase inhibitors for HIV treatment
Slides 57-58
