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87 Cards in this Set
- Front
- Back
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What type of organism are viruses?
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obligate intracellular organisms
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therapeutic index
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drug's ability to selectively target the virus or bacteria instead of the host
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What is the only way to eradicate or control viral infections?
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vaccines
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DNA viruses
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adenovirus
herpes hepatitis B |
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RNA viruses
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Hepatitis A
Hepatitis C HIV influenza MMR Polio rabies RSV |
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Where do most people with HIV live?
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Sub Saharan Africa
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nucleoside reverse transcriptase inhibitors mechanism of action
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cellular enzymes convert NRTIs to the active triphosphate which is a competitive inhibitor of HIV reverse transcriptase and terminator of viral DNA synthesis
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What is the function of HIV reverse transcriptase
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transcribes viral RNA into double stranded DNA which is integrated into the host cell DNA (CD4 T lymphocytes)
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selectivity
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greater affinity for viral RT than human DNA polymerase
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Zidovudine (AZT, retrovir)
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thymidine nucleoside analog
1st NRTI used against HIV SE: bone marrow suppression: anemia, neutropenia increased levels of MCV |
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Didanosine (DDI, videx)
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adenine analog
take on empty stomach acid decreases absorption used against HIV SE: pancreatitis peripheral neuropathy |
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lamivudine
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cytosine analog
used against both HIV and HBV: dual infection excellent absorption, distribution, long half life, renally eliminated, well tolerated resistance develops easily for both HIV (not a bad thing for HIV) and HBV |
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emtricitabine
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cytosine analong
HIV and HBV very similar to lamivudine longer half life DARKENING SKIN PIGMENTATION |
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stavudine
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thymidine analgog
antagonism with AZT SE: peripheral neuropathy |
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Abacavir
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guanine analog
hepatically metabolized long half life SE: hypersensitivity reaction SE diminish with time do not rechallenge HLA-B5701 genetic screening |
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tenofovir
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nucleotide of adenosine monophosphate
unlike other NRTIs already phosphorylated tx: HIV and HBV prodrug: Tenofovir DF, oral, converted by serum esterases SE: nephrotoxicity (fanconi syndrome) |
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nucleotide reverse transcriptase inhibitors mechanism of action
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cellular enzymes convert NRTIs to the active triphosphate which is a competitive inhibitor of HIV reverse transcriptase and terminator of viral DNA synthesis
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nucleotide reverse transcriptase inhibitors side effects
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mitochondrial toxicity
-inhibit mitochondrial DNA gamma polymerase by NRTIs -mitochondria: energy powerhouse of the cell, have own DNA that is replicated by mtDNA polymerase -damage results in lactic acidosis lipoatrophy hepatic steatosis: fatty liver due to increased utilization of TG myopathy peripheral neuropathy pancreatitis nephrotoxicity |
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adenosine analogs
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didanosine
tenofovir |
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cytosine analogs
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zalcitabine
lamivudine emtricitabine |
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guanine analogs
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abacavir
amdoxovir |
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thymine analogs
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zidovudine
stavudine |
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non-nucleoside reverse transcriptase inhibitors drug names
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nevirapine
efavirenz delavirdine |
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non nucleoside reverse transcriptase inhibitors mechanism
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inhibit HIV RT by directly binding to the enzyme and altering the position of critical amino acids within the catalytic site. Thus preventing viral DNA synthesis.
synergistic with NRTIs |
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nevirapine
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metabolized by liver
enzyme induction of CYP3A4 drug interactions: enzyme induction can result in subtherapeutic concentrations of other hepatically metabolized drugs interferes with methadone and protease inhibitors, SE: rash, hepatitis (monitor LFTs, caution in HCV, risk if CD4 <250) |
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efavirenz
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most efficacious drug to date for HIV
half-life 40-50 hours (qd dosing) hepatically metabolized drug interactions: induction and inhbition induction predominates methadone protease inhibitors SE: rash CNS- dizziness, vivid dreams, inability to concentrate increased LFT teratogenic false + urine for THC |
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Protease inhibitors class toxicity
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lipodystrophy syndrome
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protease inhibitors structure and mechanism of action
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structure: peptide like
MOA: competively binds to HIV protease active site thus inhibiting the enzymes ability to form mature viral proteins |
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Ritonavir
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never used as single protease inhibitor due to side effects and drug interactions, but rather used for its enzyme inhibition properties to boost levels of other PI. Now the standard of care used in combo with other PI
one of the most potent liver enzyme inhibitors known, many drug interactions. SE: increase triglycerides and Cholesterol, drug induced hepatitis |
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fosamprenavir
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structure: peptide that contains sulfa moiety
prodrug of amprenavir, converted in gut boosted with ritonavir SE: rash |
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kaletra (lopinavir/ritonavir)
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1st co-formulated PI
-prevent viral resistance -overcome existing resistance -all antiviral activity due to lopinavir taken with food, BID hepatically metabolize (CYP P450 3A4) |
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atazanavir
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PI
QD favorable lipid profile taken with food SE: rash, hyperbilirubinemia: 7-10% develop jaundice |
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ritonavir side effects
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PI used for drug induced hepatitis
increase triglycerides and cholesterol |
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tipranavir
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Protease inhibitor
used for drug resistance SE: liver toxicity rash: contains sulfonamide moiety |
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Darunavir
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newest PI
used for PI resistance must be boosted with ritonavir SE: skin rash (sulfa) well tolerated |
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protease inhibitors and other drugs
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all PIs are hepatically metabolized by CYP 450 3A4
all are inhibitors of CYP 450 3A4 but ritonavir is a very potent CYP450 3A4 inhibitor as well as 2D6 with many drug interactions low dose ritonavir is almost universally prescribed with other PI, therefore drug interactions are inevitable |
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Protease inhibitors class side effects
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lipodystrophy syndrome
-fat redistrobution -wasting of face, butt -weight gain in abdomen, buffalo hump, lipomas 3 main components of lipodystrophy: DM: impaired glucose tolerance and insulin resistance fat redistrobution: lipoatrophy, truncal adiposity hyperlipidemia: cardiovascular disease |
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fusion inhibitors: mechanism of action
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36AA synthetic peptide that inhibits the fusion of HIV virus to CD4 cell membrane receptor.
Blocks transfer of viral RNA into host CD4 cell. |
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fusion inhibitor side effects
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BID SC injections-> injection site reactions
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fusion inhibitor drug names
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efuvirtide
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efuvirtide
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fusion inhibitor
difficult to prepare very expensive |
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maraviroc: mechanism and important facts
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entry inhibitor
mechanism: CCR5 co-receptor antagonist, prevents HIV from entering cells requires tropism assay- expensive used in "salvage therapy" hepatically metabolized by CYP3A4- drug interactions |
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Anti-Herpetic drugs
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acyclovir
famciclovir valacyclovir ganciclovir foscarnet cidofovir valganciclovir |
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Hepatitis B drugs
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interferon
lamivudine adefovir tenofovir emtricitabine entecavir |
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Hep C drugs
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pegylated interferon
ribaviron |
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influenza drugs
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amantadine
rimantadine oseltamivir zanamivir |
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Herpes
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80 known viruses
8 infect humans lifelong latent infection 25% + for HSV2 HSV 1 (oral), 2(genital), VZV persist indefinitely in dorsal nerve root or cranial nerve ganglia |
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Varicella zoster virus
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latent infection
outbreak in dermatome around ribcage |
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Acyclovir
structure pharmacokinetics: SE: |
guanine nucleoside analog
Tx: HSV 1, 2, VZV poor bioavailability short half-life (1-2 hours) renal excretion good tissue distribution SE: well tolerated |
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Acyclovir mechanism of action and selectivity
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cellular uptake by virus infected cells-> activated by phosphorylation by viral thymidine kinase.
ACV monophosphate is then converted by cellular enzymes to ACV-PPP-> inhibits viral DNA polymerase selective for virally infected cells the affinity for viral TK is 200x greater than for mammalian TK |
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Acyclovir uses
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HSV 1, 2, VZB
immunocompetent: encephalitis, neonatal infection, shingles immunocompromised: HSV 1, 2, VZV, CMV, disseminated to lungs, liver, eyes, CNS, GI |
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famciclovir
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prodrug of penciclovir
100X less potent than acyclovir but much higher intracellular concentrations and longer half-life metabolized by esterases in the liver, intestinal lumen and plasma to penciclovir greater bioavailability than penciclovir ACV resistant HSV are also resistant to famciclovir |
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mechanism of action of penciclovir and acyclovir
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cellular uptake by virus infected cells-> activated by phosphorylation by viral thymidine kinase.
ACV monophosphate is then converted by cellular enzymes to ACV-PPP-> inhibits viral DNA polymerase selective for virally infected cells the affinity for viral TK is 200x greater than for mammalian TK |
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valacyclovir
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valine ester of acyclovir
prodrug (lake famciclovir) enzymatically cleaved in the liver and intestines to form ACV-> enhanced bioavailability better bioavailability than ACV QD-BID dosing |
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cytomegalo virus
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opportunistic infection
disease is rare in immunocompetent most of us have been exposed as children |
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ganciclovir
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used to treat: HSV 1, 2, VZV, CMV
guanine nucleoside analog phosphorylated by viral TK in HSV infected cells phosphorylated by phosphotransferase in CMV infected cells IV QD dosing Renally eliminated-monitor renal function SE: bone marrow suppression, teratogenic |
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valganciclovir
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valine ester of ganciclovir
produg converted by intestinal and hepatic esterases to GCV good bioavailability oral dosing-> more GI SE |
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foscarnet
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used against all herpes viruses including ACV and GCV resistant
unlike GCV, foscarnet has a much greater affinity for herpes virus DNA polymerase than mammalian DNA polymerase so no bone marrow suppression structure: inorganic pyrophosphate analog, different from all other anti-herpetic drugs mechanism: unique inhibits cleavage of pyrophosphate form deoxynucleotide triphosphate by inhibiting viral polymerase, thus preventing the formation of the phosphate backbone of viral DNA IV only 90% renally excreted sequestered in bone- half life of days-weeks SE: nephrotoxicity (50% of patients, saline hydration before) electrolyte wasting neurotoxicity anemia infections genital ulcerations |
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foscarnet mechanism
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mechanism: unique
inhibits cleavage of pyrophosphate from deoxynucleotide triphosphate by inhibiting viral polymerase, thus preventing the formation of the phosphate backbone of viral DNA |
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cidofovir
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nucleoTide analog
structure: Cytosine analog (monophosphorylated) inhibits viral DNA polymerase at concentrations much lower than would be needed to inhibit mammalian DNA polymerase spectrum: all herpes, even resistant pharmacokinetics: renal elimination, long half-life SE: nephrotoxicity, give probenecid and IV hydration to prevent toxicity |
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probenecid
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prevents renal tubular secretion of cidofovir therefore protecting kidneys from nephrotoxicity
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Hepatitis B
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# 1 cause of chronic liver disease worldwide
10-15% of HIV patients are coinfected with HBV |
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Hepatitis B serology
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HBsAG: chronic infection
HBsAB: immunity by exposure or immunization |
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lab values used to monitor hepatitis B liver damage
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1. HBV-DNA (hep. B viral load)
2. Liver function tests (alanine aminotransferase) 3. liver histology (biopsy) |
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Why is hepatitis B incurable?
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because it is integrated into the host's genome (like HIV, but different from hepatitis C)
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What is the common factor between HIV and HBV
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they both use reverse transcriptase and integrate viral DNA into the host genome
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What is the goal for Hepatitis B
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vaccinate all newborns and everyone to eradicate the disease
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What is the risk of developing chronic HBV after infection?
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5-10% develop chronic infection
but they are at risk for cirrhosis or hepatocellular carcinoma (death or liver transplant) 90% develop immunity that leads to clearance of the infection and lifelong protection |
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How is Heptatis B treated
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pegylated interferon (HCV)
HIV/HBV medications 1. lamivudine: high rate of resistance after 1 year monotherapy 2. tenofovir 3. emtricitabine other nucleoside analogs 1. adefovir: NtRTI, like tenofovir, activity against lamivudine resistant HBV, developed for HIV but too toxic 2. entecavir requires lifelong treatment |
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lamivudine
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drug used for HIV and HBV
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tenofovir and emtricitabine
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used for co-infected HIV/HBV
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entecavir
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guanine analog
mechanism: inhibit HBV DNA polymerase preventing DNA/RNA synthesis TX: epivir resistant HBV no use in HIV SE: severe acute exacerbation of HBV with discontinuation |
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hepatitis C virus
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does not integrate into the host genome-> curable
#1 reason for liver transplant |
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factors that promote hepatits C progression and severity
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alcohol: doubles risk of cirrhosis
>40 yo at time of infection HIV co-infection male chronic HBV co-infection |
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meaning of Heptatis C antibodies
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HCV infects cell
HCV proteins expressed on surface of hepatocytes antibodies to HCV proteins are produced by host HCV antibodies do not convey immunity- simply a marker of exposure |
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hepatitis C infection risk
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Injecting drugs use
transfusion transplant from infected donor occupational exposure iatrogenic (unsafe injection) birth to HCV infected mother sex with infected partner |
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How do HBV and HCV infection differ in most exposures
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most exposed to HCV are unable to clear the virus and progress to chronic disease
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Treatment of hepatitis C
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pegylated interferon and ribavirin
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HCV-RNA
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measure of viral load to determine if they have active infection and the likelihood of response to infection
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goals for hepatitis C treatment
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viral eradication: undetectable HCV-RNA 48 weeks after tx
histologic and clinical: delay fibrosis and progression to cirrhosis prevent hepatic decompensation prevent hepatocellular carcinoma |
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pegylated interferon
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interferon: natural proteins made by mammalian cells in response to stimuli like viral infections
attachment of polyethylene glycol increases the half life of interferon and the duration of therapeutic activity administered 1x/week subcutaneously vs. 3x/week for interferon SE: not tolerated well -flulike depression and other psych SE thyroid dysfunction anorexia hair loss bone marrow suppression sleep disturbances |
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ribavirin structure and MOA
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guanine analog
interferes with viral RNA and DNA synthesis exhibits greater affinity for viral polymerase enzymes than mammalian |
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ribavirin spectrum and SE
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narrow therapeutic index
HCV, RSV SE: anemia, teratogenic |
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HCV
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no vaccine
no protective antibodies most patients have disease progression over years can be treated but takes 1 year tx with interferon and ribavirin |
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influenza vaccine
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made from antigens representing influenza A and B
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treatment of influenza
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zanamivir(relenza)
oseltamivir (tamiflu) |
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mechanism of zanamivir and oxeltamivir
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used to treat influenza
viral neuraminidase inhibitors (essential viral enzyme responsible for releasing virus from infected cells) activity against both A and B but tx must be initiated within 48 hours, treat for 5 days |
