Antiviral Drugs Flashcards
What are come of the biological characteristics of viruses?
- obligate intracellular parasites
- no cell wall or plasma membrane
- no metabolism- so tough to target
- few drugs block reproduction selectivity
- pharmacology focused on late symptoms
- few virus groups can be effectively treated with drugs
What are the cytopathic effects of viruses?
- host cell metabolism is hijacked
- there is a viral induced suppression of host homeostasis
- viral proteins induce lysis or apoptosis
- viral proteins trigger hose IS
- inflammatory reaction kills host
- ** all involve the lytic cycle- generation of new virus
- virus can become latent- the host cell survives
Describe the characteristics of Herpes simplex virus
- neurotrophic
- complex dsDNA viruses- at least 8 members
- HSV-1 is cold sores, and HSV-2 is genital herpes
- chicken pox (varicella zoster) is an example of this, shingles and cyclomegalovirus as well
- transmitted by close contacts
- latent infection
What is the life cycle of the HSV?
- lytic cycle in epithelial cells - 80 genes in a cascade
- viral progeny spread to sensory neurons
- retrogradely transported to the cell body
- latent- circular episomal DNA (nucleosome)
- no immune signature
- no cytotoxic effect
- stress related reactivation
- anterograde transport
- shingles - varicella zoster, rash and pain ( neuralgia)
What is the replication process of herpes simplex virus?
- viral DNA enters the nucleus and circularizes
- immediate early genes- use host RNA polymerase (2-4 hr post infection)
- host transcription factors
- VP16 viral activator
- binds host cell factor that activates OCT1 (host)
- IEG trigger early genes
- E proteins control viral DNA replication
- DNA replication initiates late genes- viral structure and assembly
What is the main antiviral drug that is used to treat HSV? How does it work?
- main antiviral is acyclovir
- synthetic nucleoside analog
- viral thymidine kinase converts to acyclo-GMP
- Acyclo-GTP inhibitor of viral DNA polymerase
- viral DNA chain termination
- treatment of genital herpes, shingles, cold sores and chicken pox
- oral or intravenous
What is famciclovir used to treat?
HSV-1, HSV-2, and VSC - prodrug of 6-deoxypenciclovir. 1st pass metabolism converts to penciclovir
What is penciclovir and what is it used to treat?
guanosine analog, used to tx HSV. Topical formulation
What is docosanol and what is it used to treat?
inhibitor of fusion of HSV-1 virus with host cell- topical formulation
Cyclomegalovirus is a major problem in _______ patients
immunocompromised
organ transplantation
CMV can lead to what?
liver failure, colitis and retinitis (inflammation of the retina)
What is ganciclovir and how does it work?
- used to treat CMV
- analog of acyclovir: x 20-100 more effective against CMV
- targets specific protein kinase phosphotransferase UL97
What is valganciclovir and how does it work?
- used to treat CMV
- prodrug of ganciclovir
- oral admin
What is foscarnet and how does it work?
- used to treat CMV
- reversible inhibitor of viral DNA/RNA polymerases
- CMV infection and resistant HSV, range of SE
What family of virus family does HIV fall under?
retrovirus family - (+) sRNA virus
What makes HIV so infective?
- has a fast replication and can infect multiple times (there can be multiple viruses going into one cell)
- reverse transcriptase - error prone- can lead to drug resistance
- latent infection- via viral integrase enzyme
- can lead to AIDS
- spreads via blood/fluid transfer (HIV viruses completely integrate into the DNA cells- can be used to transfer DNA from one cell to another one)
What kind of cells does HIV invade?
helper T cells, as well as macrophages and dendritic cells
What are the targets of HIV once they get into the helper cells and macrophages?
- targets are CD4 receptors and chemokine co-receptors (CCR5 and CCR4)
- loss of CD4+ cells
What is lost when HIV invades helper T cells and macrophages ?
cell mediated immunity is lost
-90% of patients progress to AIDS within 10-15 years
What is the origin of HIV in NA?
- started by eating monkey meat- this is the way that HIV first spread to humans , as it originated from monkeys
- a single individual from haiti visited africa and transferred the virus back to haiti
- haiti has dirty blood donating programs- transferred the blood amongst the haitian people
- american visitors came to haiti, got infected, and transferred it back to the US
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are analogs of what part of the cell?
native ribosides- they lack the 3’ hydroxyl
- gets incorporated into viral DNA once phosphorylated to triphosphate by hose enzymes
The lack of the 3’ hydroxyl leads to what?
DNA chain termination
- the drug affinity is more than the HIV reverse transcriptase
Why is there toxicity associated with NRTIs?
due to inhibition of mitochondrial DNA polymerase
What does HAART stand for?
highly active anti-retroviral therapy
Zidovudine treats what and is an analog of what nucleotide?
- tx HIV
- pyrimidine analog, converted to triphosphate by cellular enzymes
- good penetration across BBB
How is zidovudine toxic to bone marrow?
- inhibits DNA polymerase- gamma in mitochondria
What is abacavir? (NRTIs)
- guanosine analog- t1/2 1.5 hr
- resistance develops slowly
- hypersensitivity reactions can be severe. Higher risk of MI
What is lamivudine? (NRTIs)
- cytosine analogue
- good bioavailability and unaffected by food
- t1/2 is 2.5 hr
- recommended in pregnant women
- inhibits RT in HIV and HBV
- does not inhibit tDNA or bone marrow
What is emtricitabine? (NRTIs)
fluor-derivative of lamivudine- inhibits RT in HIV and HBV - long intracellular half life of 39 hr makes OD tx feasible. Good bioavailability and unaffected by food
What is tenofovir? (NRTIs)
acyclic analogue of adenosine. Long half life allows OD dosing. GI complaints and renal dysfunction contraindicated
What is the action of non nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)
- non competitive inhibitors if HIV-1 reverse transcriptase
- no activation required
- no effect on bone marrow or mitochondrial DNA polymerase
What is efavirenz (NNRTIs)
- once daily tx w/o food
- metabolized by CYP3A4 and CYP2B6. CNS SE. Some severe, such as psychosis. Skin rash. Avoid in pregnancy. Indued CYP3A4
What is nevirapine (NNRTIs)
- good oral bioavailablilty and not food dependent
- metabolized by CYP3A isoforms. Recommended in pregnancy. Severe rash can occur. Liver toxicity. Can induce CYP 3A4 system
HIV protease inhibitors reversibly inhibit what?
HIV aspartyl protease
- also prevents proteolysis of viral polyprotein
- prevents maturation of viral particles
- non-infectious virus produced
What are the pharmacokinetics of HIV protease inhibitors?
- poor oral bioavailability
- substrates for CYP 3A4 isozyme of cut p450
- substrates for P-glycoprotein multidrug efflux pump in endothelial cells of the brain - restricts access to CNS
- binds to plasma PRO - alpha1 acid glycoprotein
What are the adverse effects of HIV protease inhibitors?
- parasthesia, nausea, vomiting and diarrhea
- diabetes phenotype
- fat redistribution
What are the most common adverse effects associated with lopinavir?
GI adverse effects are the most common
What are the most common adverse effects of ritonavir?
- diarrhea, nausea, taste perversion, vomiting, anemia, increased hepatic enzymes, increased triglycerides
- required refrigeration, takes with meals
What are the drug interactions of HIV proteases inhibitors associated with?
- associated with the inhibition of CYP isozymes
What is the mechanism of action of HIV integrate inhibitors?
the inhibitors block the ability of the integrates to integrate into the host DNA
What is dolutegravir? (HIV integrate strand transfer inhibitors)
metabolized by UGT1A1 and CYP3A. Inhibits renal transported OCT2 and so contraindicated with dofetilide and metformin. Rash and hypersensitivity can form
What is raltegravir (HIV integrase strand transfer inhibitors)
metabolized by UGT1A1. Does not interact with the Cytp450 system. Antacids should be used with caution. Severe hypersensitivity and rash can occur
- this is the most common one
What is the viral fusion inhibitor class of HIV drugs?
- enfuvirtide is an example
- HIV protein gp41 mediates cell fusion
- 36 amino acid peptide binds to p41
- given subcutaneously
- used typically as salvage therapy - for multi drug resistant HIV
How does maraviroc work?
- specifically binds to host CCR5 (V3 loop)- this it is only effective against HIV-1 tropic for CCR5.
- contraindicated in renal impairment. Caution required with hepatic problems- substrate for CYP3A4. Resistance linked to mutations in gp120 protein
What is flu A carried in?
aquatic birds and domestic birds
What is more severe - flu A or B?
Flu B
Why is influenza resistant to drugs?
there is no RNS proof reading
Influenza is a ____ virus
(-) ssRNA
Influenza virus attacks ____
epithelial cells
Hemagglutinin (Hag) binds to _____ sugars on cells
sailic acid
Neuramidase cleaves ____ residues to release the virus
sailic
What does the protein channel M2 modulate?
pH
Describe the influenza virus life cycle?
- Hag binds to cell surface
- Mediates endocytosis of the particle
- M2 regulates uncoating
- M2 also controls Hag processing
- Release of particles from buds requires neuraminidase
What enzyme is viral neuraminidase?
glycoside hydrolase enzyme
Zanamivir (inhale), oseltamivir (oral) - works effectively as a ____ treatment against the spread of infection in flu A and B. What is the main problem with this however?
prophylaxis
- main problem is that it needs to be taken within 6-12 hours after contact with the virus
What are the 2 drugs that act as inhibitors of viral uncoating?
amantadine and rimantadine
What is the action of inhibitors of viral uncoating?
- block the M2 channel
- precent acidification of viral particle
- stop release of viral genome and uncoating
- early therapy is effective against influenza A
What are the potential complications of the hepatitis B virus?
- hepatitis, cirrhosis, and carcinoma
Hepatitis B is a dsDNA virus, but still used ______
reverse transcriptase
How is hepatitis B transferred?
blood-blood transfer
What happens to the DNA of the hepatitis B virus if the infection becomes persistent ?
get a covalently closed circular DNA
Hepatitis C is a _____ virus
(-) ssRNA
What is the transmission of hepatitis C?
blood-blood transmission
treats only those with a chronic infection
What is interferon treatment used for? How does it work?
- used for a chronic hepatitis infection only
- interferon alpha 2a/2b
- raises cell resistance - antiviral state
- innate induction of interferon by high levels of dsRNA or foreign RNA
- elevates MHC1- presentation of cytotoxic CD8 T cells
- increases p53- leading to apoptosis
What drug class is typically used as an anti-HBV drug?
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
What does NRTIs do to the the HBV virus?
causes DNA chain termination
What are the 2 NRTIs that are used to treat HBV? What is it usually combined with?
- lamivudine, tenofovir
- typically combined with interferons
What is the standard therapy as an anti-HCV drug? How does it work?
- ribavirin is the standard therapy in combination with peg interferon alpha
- inhibits capping of viral mRNA and viral RNA dependent RNA polymerase - also inhibits HIV and influenza
How do protease inhibitors act against HCV? What are the two drugs that fall into this class?
- inhibits NS3/4A protease that cleaves HCV- encoded poly-proteins
- there are numerous SE and interactions with other drugs that are metabolized by CYP 3A
- examples are boceprevir and telaprevir
What is the main polymerase inhibitor that is used to treat HCV? How does it work?
- sofosbuvir
- inhibits HCV NS5B RNA-dependent RNA polymerase, Combined with ribavirin and peg interferon alfa. Very expensive
