Antivirals Flashcards
What are the main drugs for HSV?
- Acyclovir
- Famciclovir
- Docosanol
What are the main drugs for CMV?
- Foscarnet
- Ganciclovir
What are the main drugs for Influenza?
- Amantadine
- Rimantadine
- Zanamivir
What are the drugs for HBV, HCV?
- Interferon
- Lamivudine (NRTI)
- Boceprevir
- Ribavarin
- Sofosbuvir
What is Herpes Simplex Virus (HSV)?
- Neurotropic
- HSV-1 (cold sores), HSV-2 (genital herpes)
- Chicken pox, singles (Varicella zoster - VZV), cytomegalovirus (CMV)
- Close contact transmission
- Latent infection
What does HSV effect?
lytic cycle in epithelial cells
viral progeny spread to sensory neurons
neurotrophic
What is Acyclovir (Zovirax)?
= drug for HSV
- synthetic nucleoside analog
- Viral thymidine kinase converts to acyclo-GMP
- Acyclo-GTP inhibitor of viral DNA polymerase
- Viral DNA chain termination
- Tx for genital herpes, shingles, cold sores & chicken pox
- oral or IV
What is Famciclovir?
= drug for HSV
- prodrug of 6-deoxypenciclovir - 1st pass metabolism converts to penciclovir
- active against HSV-1, HSV-2 & VZC
- oral or topical
What is Docosanol?
= drug for HSV
- inhibitor of fusion of HSV-1 virus with host cell.
- Topical formulation.
What is CMV?
- CMV major problem in immuno-compromised patients (organ transplantation).
- Can lead to liver failure, colitis and retinitis (inflammation of retina).
What is Ganciclovir?
= drug for CMV
- analog of acyclovir: x20-100 more effective against CMV;
- targets virus specific protein kinase phospho-transferase UL97.
- Intravenous.
What is Foscarnet?
= drug for CMV
- reversible inhibitor of viral DNA/RNA polymerases;
- CMV infection and resistant HSV;
range of side effects (intravenous only)
What are the 3 drug targets for Influenza virus?
- Hemagglutin (Hag) binds to sailic acid sugars on cells
- Neuraminidase cleaves sailic residues to release virus
- M2 ion channel - proton channel that modulates pH & regulates uncoating
What are Neuraminidase Inhibitors?
- Viral neuraminidase - glycoside hydrolase enzyme
- Cleave glycosidic linkages on neuraminic (sailic) acid to release virus
- Permits release of viral particle from host cell
What is Zanamivir?
= drug for Influenza (Neuraminidase Inhibitor)
- effective prophylaxis and against spread of infection in flu A and B (b/c inhibits virus from leaving)
- Problem - needs to be taken within 6-12 hr
(inhale)
What is Amantadine; Rimantadine?
= drugs for Influenza (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
What are Antiretrovirals?
denoting or relating to a class of drugs that inhibit the activity of retroviruses such as HIV
What are the main Antiretrovirals drugs?
- NRTIs = AZT, abacavir, lamivudine, emtricitabine;
- NNRTIs = efavirenz, nevirapine;
- Protease inhibitors = atazanavir, ritonavir;
- Fusion inhibitors = enfuvurtide, maravaroc;
- DNA strand transfer inhibitors = raltegravir
What are the Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)?
- Zidovudine (AZT)
- Abacavir
- Lamivudine
- Emtricitabine
= Antiretrovirals drugs
What are the Non Nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)?
- Efavirenz
- Nevirapine
= Antiretrovirals drugs
What are the Protease Inhibitors?
- Atazanavir
- Ritonavir
= Antiretrovirals drugs
What are the Fusion Inhibitors? What are the Co-Receptor Inhibitors?
Fusion inhibitors
- Enfuvurtide
Co-receptor
- Maravaroc
= Antiretrovirals drugs
What are the DNA Strand Transfer Inhibitors?
- Raltegravir
= Antiretrovirals drugs
What is Human Immunodeficiency Virus (HIV)?
- Reverse transcriptase - error prone - drug resistance (why we need to make new drugs)
- Latent ability - viral integrase enzyme (target for drugs)
- AIDs
- Blood/fluid transfer
- Invades CD4+
- Cell-mediated immunity lost
- No cure (need highly active anti-retroviral therapy - HAART)
What are the Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)?
- Analog of native ribosides - LACK 3’-hydroxyl leads to DNA CHAIN TERMINATION
What is Zidovudine (AZT)?
= drug for HIV (a NRTI)
- converted to triphosphate by cellular enzymes (that prevents DNA replication)
- good tissue pen. across BBB (virus does get into CNS/brain)
- toxic to bone marrow
- inhibits DNA poly-gamma in mitochondria
- often come off the drug due to: myopathy, neuropathy
What is Abacavir?
= drug for HIV (a NRTI)
- guanosine analogue; unaffected by food
- avoid alcohol
- RESISTENCE DEVELOPS SLOWLY!
- hypersensitivity rxns can be severe
- higher risk of MI
What is Lamivudine?
= drug for HIV (a NRTI)
- cytosine analogue; good bioavailability & unaffected by food
- recommended in pregnant woman!
- inhibits RT in HIV & HBV; does not inhibit mtDNA or bone marrow!
What is Emtricitabine?
= drug for HIV (a NRTI)
- fluor-derivative of lamivudine;
- inhibits RT in HIV and HBV;
- LONG INTRACELLULAR HALF-LIFE OF 39 hr makes once a day treatment feasible. !
- Good bioavailability and unaffected by food.
- ORAL formulation, with propylene glycol, CONTRAINDICATED in young children, pregnant women and renal/hepatic failure.
What are the Non Nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)?
- Non-competitive inhibitors of HIV-1 reverse transcriptase
- No activation required
- No effect on bone marrow or mitochondrial DNA polymerase
(Efavirenz, Nevirapine)
What is Efavirenz?
= drug for HIV (NNRTIs)
- once daily treatment on an empty stomach.
- Metabolized by CYP3A4 and CYP2B6. CNS side effects.
- Some severe – e.g. psychosis.
- Skin rash.
- AVOID in pregnant women.
- Induces CYP3A4.
What is Nevirapine?
= drug for HIV (NNRTI)
- good oral bioavailability and not food dependent.
- Metabolized by CYP3A isoforms.
- RECOMMENDED in pregnant women.
- Severe rash can occur.
- Liver toxicity.
- Can induce CYP3A system.
What are HIV Protease Inhibitors?
- Reversible inhibitors of HIV aspartyl protease
- Prevents proteolysis of viral polyprotein
- 1000 fold higher affinity for HIV protease
- Prevents maturation of viral particles
- Non-infectious virus produced
- Used in HAART
(Atazanavir, Ritonavir)
What are the Pharmacokinetics for HIV Protease Inhibitors?
- Poor oral bioavailability
- Substrates for CYP3A4 isozyme of cyt p450
- Substrates for P-glycoprotein multidrug efflux pump in endothelial cells of brain - restricts access to CNS
- Bind to plasma proteins – alpha1 acid-glycoprotein
*Not easy to work with; have limitations, but can combine with other drugs
What are the adverse effects of HIV Protease Inhibitors?
- Parasthesia, nausea, vomiting, diarrhea
- Diabetes phenotype
- Fat redistribution
Resistance
- Mutations of HIV protease gene
What are the specific drug toxicity issues with Atazanavir (HIV Protease Inhibitor)?
- Nausea
- Abdominal discomfort
- Headache
- Skin rash
What are the specific drug toxicity issues with Ritonavir (HIV Protease Inhibitor)?
- Diarrhea
- Nausea
- Taste perversion
- Vomiting
- Anemia
- Increased hepatic enzymes
- Increased triglycerides
- Requires refrigeration; take with meals; chocolate milk improves the taste
What are drug interactions for HIV Protease Inhibitors?
linked to inhibition of CYP isozymes
(Antiarrhythmics, Ergot Derivatives, Antimycobacterial drugs, Benzodiazepines, Barbiturates, Anticoagulants, Herbal Supplements)
What is the HIV Integrase Inhibitors mech. of action?
?
What is Raltegravir?
= 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.
What is Enfuvirdie?
= drug for HIV (Viral Fusion Inhibitor)
- HIV PROTEIN gp41 mediates cell fusion
- 36 amino acid peptide binds to gp41
- Given SC
- Expensive!!!
- SALVAGE THERAPY – for multidrug resistant HIV
What is Maraviroc?
= drug for HIV (Co-receptor Inhibitor)
- 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.
(*most HIV is for CCR4, so this isn’t perfect)
What is Hepatitis B Virus (HBV)?
- most form Hepatitis, Cirrhosis, Carcinoma
- dsDNA virus - but uses RT!!
- Blood-blood transfer
- Vaccine
- Persistent infection - cccDNA
What is Hepatitis C Virus?
- (+)ssRNA virus
- Difficult to detect symptoms
- Blood-blood transmission
- Tx in patients likely to exhibit Cirrhosis
What is the Interferon Tx?
- Chronic infection only
- Interferon alpha 2a/2b
- Raises cell resistance - ‘antiviral state’
- Elevates MHC1
- Increase p53
(normal immune response is to release interferon - to fight viral particles)
(increased antiviral cells - activate CD4+ to target these cells & lead to destruction of hepatitis & prevent spread & cirrhosis)
What are the Anti-HBV drugs?
- Use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- DNA chain termination
- Lamivudine; tenofovir
- Combined with interferon
What is Ribavirin?
= Anti-HCV drug
- Guanidine 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 preganancy, kidney disease and vascular disease.
STANDARD THERAPY now ribavirin plus peginterferon alfa
What are the Protease Inhibitors for Anti-HCV? What are the Polymerase inhibitors?
Inhibit NS3/4A protease that cleaves HCV-encoded poly-proteins. Numerous side effects and drug: drug interactions – CYP3A interactions. Contraindicated with statins and rifampin.
- Boceprevir – combined with ribavirin and peginterferon
- Telaprevir
Polymerase Inhibitor:
- Sofosbuvir - inhibits HCV NS5B RNA-dependent RNA polymerase. Combined with ribavirin and peginterferon alfa. Very expensive.
