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Major toxicities and concerns with the HIV protease inhibitor - Lopinavir

GI adverse effects are the most common


Major toxicities and concerns with the HIV protease inhibitor
- Ritonavir

Diarrhea, nausea, taste perversion, vomiting, anemia, increased hepatic enzymes, increased triglycerides

Requires refrigeration; take with meals; chocolate milk improves the taste


What drug classes should not be administer with any protease inhibitor

Antiarrhythmics, ergot derivatives, antimycobacterial drugs, benzodiazepines, barbiturates, anticoagulants, herbal supplements

**linked to inhibition of CYP isozymes


Describe HIV integrase inhibitors - mechanism of action

Integrase binds to viral DNA & catalytically processes 3' ends.

Integrase joins viral and cellular DNA.

Raltegravir blocks strand transfer.

Degradation or recombination and repair.


Describe the HIV integrase strand transfer inhibitor - Dolutegravir

-metabolized by UGT1A1 and CYP3A
-inhibits renal transporter OCT2 and so contraindicated with dofetilide and metformin
-rash and hypersensitivity can occur


Describe the HIV integrase strand transfer inhibitor - Elvitegravir

-requires boosting
ex. cobicistat (inhibitor of CYP3A4)


Describe the HIV integrase strand transfer inhibitor -

-metabolized by UGT1A1
-Does not interact with Cyt p450 system
-Antacids should be used with caution
-Severe hypersensitivity and rash can occur


Describe viral fusion inhibitor

-new class
-HIV protein gp41 mediates cell fusion
-36 amino acid peptide binds to gp41
-given subcutaneously
-expensive - 25,000 p.a.
-salvage therapy - for multi drug resistant HIV


Describe the co-receptor inhibitor: Maraviroc

-specifically binds to host CCR5 (V3 loop) - thus 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


Describe the influenza virus

-Flu A and B most common
-Flu A carried in aquatic birds - domestic birds
-Flu A most severe
-No RNA proof-reading - drug resistance
-Spanish flu (type A) pandemic 1918-1919 - 40-100 million died


Describe the key proteins of the influenza virus

-(-)ssRNA virus
-aerosol passage
-attack epithelial cells
-Hemagglutinin (Hag) binds to silica acid sugars on cells
-Neuraminidase cleaves sailic residues to release virus
-M2 ion channel - proton channel that modulates pH


Influenza virus life cycle

-Hag binds to cell surface
-Mediates endocytosis of particle
-M2 regulates uncoating
-M2 also controls Hag processing
-Release of particles from buds requires neuraminidase


Describe neuraminidase inhibitors

-viral neuraminidase - glycoside hydrolase enzyme
-cleave glycosidic linkages on neuraminic (sailic) acid
-permits release of viral particle from host cell
-Zanamivir (inhale); Oseltamivir (oral) - effective prophylaxis and against spread of infection in flu A and B
-Problem - needs to be taken within 6-12 hours**


List 2 inhibitors of viral uncoating



Describe Amantadine and Rimantadine (inhibitors of viral uncoating)

-Block M2 channel
-Prevent acidification of viral particle
-Stop release of viral genome and uncoating
-Early therapy effective against influenza A


Describe Hepatitis B Virus (HBV)

-most common form (of hepatitis?)
-hepatitis, cirrhosis, carcinoma
-dsDNA virus (but uses reverse transcriptase)
-blood-blood transfer
-2 billion people infected (type B)
-acute liver damage
-vaccination possible
-persistent infection - cccDNA (covalently closed circular)


Describe hepatitis C virus

-(-)ssRNA virus
-Difficult to detect symptoms
-blood-blood transmission
-200 million infected
-treatment in patients likely to exhibit cirrhosis


Describe interferon treatment

-chronic 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 to cytotoxic CD8 T cells
-Increases p53 - apoptosis
-Subcutaneous injection: 4-6 months


Describe anti-HBV drugs

-use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
-DNA chain termination
-Combined with interferon


Ribavirin is an anti-HCV drug

-guanosine analogue
-inhibits capping of viral mRNA and viral RNA-dependent RNA polymerase - also inhibits influenza/HIV-1
-hemolytic anemia and range of other side effects
-contraindicated in pregnancy, kidney disease and vascular disease

*Standard therapy now ribavirin plus peg interferon alfa


Describe the protease inhibitors that work as anti-HCV drugs

-inhibit NS3/4A protease that cleavers HCV-encoded poly-proteins
-numerous side effects and drug: drug interactions
-CYP3A interactions
-Contraindicated with statins and rifampin

ex. Boceprevir - combined with ribavirin and peginterferon
ex. Telaprevir
ex. Sofosbuvir - inhibits HCV NS5B RNA-dependent RNA polymerase
-combined with ribavirin and peg interferon alfa
-very expensive


____ and ____ use reverse transcriptase (RT)