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115 Cards in this Set

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Drug of choice for CMV?
Ganciclovir, valganciclovir
Drug of choice for HSV, VZV?
Acyclovir
Drug of choice for HBV?
IFN-α, lamivudine
Drug of choice for HCV?
IFN-α
Drug of choice for Influenza A/B?
Oseltamivir
NRTIs?
Zidovudine
Abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine
NNRTIs?
Delavirdine
Efavirenz, nevirapine, tenofovir
Protease Inhibitors?
Indinavir
Amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir
Fusion inhibitors?
Enfuvirtide
Antiherpes drugs?
Acyclovir
Ganciclovir
Cidofovir
Foscarnet
Vidarabine
Idoxuridine, Trifluridine
Fomivirsen
general MOA of antiherpes drugs?
antimetabolites bioactivated via viral or host cell kinases to form compounds that inhibit viral DNA polymerases
MOA of acyclovir?
activated to acyclovir triphosphate, which blocks viral DNA synthesis
(competitive substrate for DNA polymerase, also leads to chain termination after incorporation into viral DNA)
mechanism of resistance to acyclovir?
virus lacks thymidine kinase
(involved in the initial viral-specific phosphorylation of acyclovir)
toxic effects of parenteral acyclovir?
delirium, tremor, sezures, hypotension, nephrotoxicity
which drug is converted to acyclovir by hepatic metabolism, reaches plasma levels 3-5X greater than acyclovir, and has longer duration?
Valacyclovir
which drug is activated by viral thymidine kinase and inhibits DNA polymerase but doesn't cause chain termination?
Penciclovir
Which of the acyclovir congeners have activity against TK- strains of HSV?
none of them
MOA of docosanol?
inhibits fusion btwn HSV envelope and plasma membranes (prevents viral entry and subsequent replication)
MOA of ganciclovir?

Resistance?
guanine derivative, triphophorylated to form a nucleotide that inhibits DNA polymerases of CMV and HSV and causes chain termination.

HSV: absence of TK; CMV: mutations in viral phosphotransferase and viral DNA polmerases
Which drug has high oral bioavailability and has decreased usage of IV ganciclovir in CMV?
Valganciclovir (prodrug of ganciclovir)
Clinical use of ganciclovir and valganciclovir?
prophy and tx of CMV retinitis and other CMV infxns in immunocompromised pts
toxic effects of ganciclovir?
leukopenia, thrombocytopenia, mucositis, hepatic dysfxn, seizures
MOA of cidofovir?

Resistance?
activated by host cell kinases to diphosphate that inhibits DNA polymerases of HSV, CMV, adenovirus and HPV

mutations in DNA polymerase gene
Toxic effects of cidofovir?
Nephrotoxicity (IV administered and metabolized by kidneys, adjust dose in proportion to CrCl),

Probenicid decreases tubular secretion and reduces nephrotoxicity
MOA of Foscarnet?

Resistance?
*Does not require phophorylation for action;
Inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase

point mutations in DNA polymerase gene
Clinical use of foscarnet?
alternative prophy/tx of CMV, esp. against TK- strains
inhibits TK- HSV, esp. in AIDS pts
Toxic effects of foscarnet?
*Effects are severe*
Nephrotoxicity w/ electrolyte disturbances (esp hypocalcemia)
GU ulcers
CNS (HA, hallucinations, seizures)
Antiherpes drug that is an adenine analog, is active against HSV, VZV, and CMV, used topically for herpes keratitis, is rapidly metabolized and has marked toxicity?
Vidarabine
Toxic effects of Vidarabine?
(with systemic use)
GI upset, paresthesias, tremor, convulsions, hepatic dysfxn
Antiherpes drugs that are pyrimidine anaolgs, used topically in herpes keratitis, but are too toxic for systemic use?
Idoxuridine and trifluridine
MOA of Fomivirsen?
antisense oligonucleotide that binds mRNA of CMV, inhibiting early protein synthesis
Clinical use of Fomivirsen?
injected intravitreally for CMV retinitis
current ideal tx regimen for HIV?
tx with 3 or more anti-retroviral drugs before onset of sx, if possible
MOA of NRTIs?
activated by host kinases to triphosphates which competitively inhibit binding of natural nucleotides to dNTP binding site of rev transcriptase and also chain terminate (lack 3'-hydroxyl, preventing attachment of next nucleotide)
problem with NRTIs?
resistance emerges rapidly if used as single agents (via mutations in pol gene)
Features of Abacavir?

Toxic effects?
NRTI: guanosine analog; good oral bioavail; 12-24h 1/2 life; resistance develops slowly

Hypersensitivity rxns (sometimes fatal) in 5% of HIV pts
Which NRTI causes pancreatitis in alcoholic pts and pts with hypertriglyceridemia?
didanosine
Toxic effects of didanosine?
peripheral neuropathy
diarrhea
hepatic dysfxn
hyperuricemia
CNS effects
Which NRTI has once-daily dosing but is contraindicated in pregnancy, children, and pts with hepatic or renal dysfxn?
Emtricitabine
Toxic effects of Emtricitabine?
asthenia
GI upset
HA
hyperpigmentation of palms and/or soles
which NRTI is used in HBV infection in addition to HAART?
Lamivudine
toxic effects of Lamivudine?
usually mild; GI upset, HA, insomnia, fatigue

renal metabolism requires dosage adjustment in renal insufficiency
which NRTI penetrates most tissues, including CNS, but causes peripheral neuropathy, esp w/ co-administration of didanosine or zalcitabine?
Stavudine

(Zalcitabine also causes peripheral neuropathy)
Which NRTI has the greatest incidence of lactic acidosis w/ hepatic steatosis?
Stavudine
What type of protein is Tenofovir?

MOA?
Nucleotide

Acts like NRTIs to competitively inhibit reverse transcriptase and cause chain termination
what side effect is mutual to all NRTIs?
lactic acidosis and severe hepatomegaly with steatosis
What antiviral may inhibit the renal excretion of acyclovir and ganciclovir?
Tenofovir
names of NRTI's?
-ines and -vudines (and Abacavir)
Names of PIs?
-avirs
Toxic effects of Tenofovir?
GI upset, asthenia, HA, acute renal flr (rare) and Fanconi's syndrome (rare)
benefit of Zalcitabine?

toxic effects?
high oral bioavailability

can increase toxicity of nephrotoxic drugs, peripheral neuropathy, pancreatits, esophageal ulcers, stomatitis, arthralgias
Which NRTI is distributed to most tissues including CNS and is eliminated via hepatic metabolism and renal excretion (must reduce in pts with cirrhosis and uremic pts)?
Zidovudine
Primary toxic effect of Zidovudine?
bone marrow suppression (additive with other myelosuppressive drugs) --> anemia, neutropenia
which drugs increase the plasma levels of Zidovudine?

which drugs increase the clearance?
azole antifungals and protease inhibitors

Rifampin
MOA of NNRTIs?
Block viral nucleic acid synthesis by binding to a site on reverse transcriptase (different than the site of NRTIs) do not require activation by phosphorylation, and do not compete with nucleoside triphospates
mechanism of resistance to both NRTIs and NNRTIs?
mutations in the pol gene
NNRTIs?
Delavirdine
Efavirenz
Nevirapine
Tenofovir
What drugs decrease the blood levels of Delavirdine?

What drugs increase the blood levels?
antacids, ddI, phenytoin, rifampin, nelfinavir

azole antifungals, macrolides
Major side effects with Delavirdine?
drug interactions because it is metabolized by CYP3A4 and CYP2D6

Skin rash
Which NNRTI can be given once daily?
Efavirenz
major problem with NNRTIs?
drug interactions b/c metabolized by CYP enzymes
what should you tell a patient to do to increase the bioavailability of Efavirenz?
take with fatty foods
Toxic effects of Efavirenz?
CNS dysfxn
skin rash
elevated plasma cholesterol
teratogenic
Which NNRTI has good oral bioavailability, penetrates most tissues (CNS) and has a half-life > 24h?
Nevirapine
Which NNRTI is effective in preventing HIV vertical transmission?
Nevirapine (given as single dose to mothers at onset of labor and to neonate)
Toxic effects of Nevirapine?
skin rash
Stevens-Johnson syndrome and severe toxic epidermal necrolysis
What drugs increase the blood levels of NNRTIs?

What drugs decrease them?
cimetidine and macrolide abx

enzyme inducers (e.g. Rifampin)
MOA of PIs?
Inhibit HIV-1 aspartate protease enzyme that is used to cleave precursor polyproteins to form the final structural proteins of the mature virion core
Resistance mechanism against PIs?
multiple point mutations in pol gene
Use of PIs in AIDS are most commonly in combinations with what drugs?
Reverse transcriptase inhibitors (NNRTIs and NRTIs)
which PI has the most pronounced inhibitory effect on CYP3A4?
Ritonavir
Side effect of all PIs?
CHO and lipid metabolism disorders (hyperglycemia, insulin resistance or hyperlipidemia with altered body fat distribution)

lipid-regulating proteins have active sites similar to HIV protease and may be thus inhibited
The absorption of which PI is inhibited by fatty foods?
Amprenavir/fosamprenavir
Toxic effects of amprenavir/fosamprenavir?
GI upset, paresthesias, rash (sometimes severe)

Cross-allergenicity with sulfonamides
Which PI can be given once daily but must not be taken simultaneously with antacids?
Atazanavir
Toxic effects of Atazanavir?
GI upset, peripheral neuropathy, rash, hyperbilirubinemia, prolonged QT interval (at high dose)
Which PI is the only one NOT associated with dyslipidemias, fat redistribution or a metabolic syndrome?
Atazanavir
Which PI has more common occurrence of insulin resistance?
Indinavir
Which PI can cause hyperbilirubinemia and kidney stones, in addition to nausea, diarrhea and thrombocytopenia?
Indinavir
Which PIs are given together because one enhances the pharmacokinetics of the other by inhibiting its CYP3A metabolism?
Lopinavir/ritonavir

(ritonavir inhibits CYP3A to enhance lopinavir, can give smaller dose)
Which PI is the safest for pregnancy?
Nelfinavir
Which PI is characterized by increased oral absorption in the presence of food and a short half-life?
Nelfinavir
Adverse effects of Nelfinavir?
Diarrhea
Which drugs inhibit CYP3A4?
Amiodarone, azoles, cimetidine, erythromycin, clarithromycin, cyclosporine, diltiazem, fluoroquinolones, indinavir, ritonavir, grapefruit juice, PI's, metronidazole, quinine, SSRIs, tacrolimus
Which drugs induce or enhance the activity of CYP3A4?
Barbiturates, carbamazepine, corticosteroids, efavirenz, phenytoin, rifampin, troglitazone
Toxic effects of Ritonavir?
bitter taste, GI upset, paresthesias, elevations of liver enzymes, inhibits metabolism of many drugs
Toxic effects of Saquinavir?

How can these effects be lessened?
nausea, diarrhea, dyspepsia, rhinitis

GI effects reduced by combination with ritonavir, allowing once-daily dosing
MOA of Enfuvirtide?
binds to gp41 subunit of viral envelope glycoprotein, inhibiting fusion of viral and host cellular membranes

NOT metabolized by CYP450
Mechanism of resistance to Enfuvirtide?
mutations in env gene
Which anti-HIV drug is administered SQ with other anti-HIV drugs in patients with persistent HIV-1 replication despite ongoing therapy?
Enfuvirtide
What are the anti-influenza agents?
Amatadine/Rimantadine and Osetamivir/Zanamivir
MOA of Amantidine/Rimantidine?
prevent uncoating of Influenza A virus after penetration by binding to and inhibiting protein M2, which acts as a proton pump to acidify and activate viral RNA transcriptase
What are Amantidine and Rimantadine effective against?
Influenza A (NOT B)
Toxic effects of Amatidine/Rimantidine?
GI upset, dizziness, ataxia, slurred speech

Amantidine requires dosage adjustment in renal failure
MOA of Oseltamivir and Zanamivir?
Inhibit neuraminidases of influenza A and B, which cleave sialic acid from viral proteins and surface proteins of host cells to release virions, preventing viral spread
When are Oseltamivir and Zanamivir most effective?
if used within 24h after onset of sxs
Toxic effects of Oseltamivir and Zanamivir?
Oseltamivir: GI sxs

Zanamivir: cough, sore throat, bronchospasm in asthmatics
What agents are used to suppress viral hepatitis?
IFN-α
Adefovir dipivoxil
Lamivudine
Entecavir
Ribavirin
MOA of IFN-α?
cytokine that increases activity of JAK-STAT receptors that increase txn of antiviral proteins, esp. host ribonuclease that degrades viral mRNA

also promotes formation of NK cells
When is IFN-α useful against HBV?

When is it useful against HCV?
Used individually or in combination with Lamivudine against chronic HBV

Used in combination with Ribavirin to reduce the progression from acute to chronic HCV
What is IFN-α used against?
HBV, HCV, Kaposi sarcoma, HPV, preventing dissemination of VZV in cancer pts, reduces CMV shedding after renal txp
Toxic effects of IFN-α?
GI upset, flulike syndrome, neutropenia, profound fatigue and myalgia, alopecia, reversible hearing loss, thyroid dysfxn, mental confusion, severe depression
MOA of Adefovir dipivoxil?

Clinical use?
activated by phosphorylation, competitively inhibits HBV DNA polymerase and results in chain termination

suppresses HBV replication, improves liver histology and fibrosis, used against lamivudine-resistant strains of HBV
Toxic effects of Adefovir dipivoxil?
nephrotoxicity, lactic acidosis, severe hepatomegaly w/ steatosis
Clinical uses of Lamivudine?
nucleoside inhibitor of HIV reverse transcriptase, also active in chronic HBV; longer half-life in HBV-infected cells than in HIV-infected, is nontoxic when used as monotherapy
What increases the risk of pancreatitis in an HBV pt being treated with Lamivudine?
Co-infection with HIV
MOA of Entecavir?
guanosine nucleoside, inhibits HBV DNA polymerase (reverse transcriptase)
Toxic effects of Entecavir?
HA, dizziness, fatigue, nausea

cross-resistance with Lamivudine
MOA of Ribavirin?
Inhibits guanosine triphosphate (purine nucleotide) formation, prevents capping of viral mRNA, blocks RNA-dependent RNA polymerases
Clinical use of Ribavirin?
prevents replication of influenza A/B, parainfluenza, RSV, paramyxoviruses, HCV, HIV

Not effective as monotherapy, used with IFN-α in chronic HCV in pts with compensated liver dz
Toxic effects of Ribavirin?
Hemolytic anemia (systemic use)
Conjunctival and bronchial irritation (aerosolic use)
Teratogenic
which of the systemic antiherpes drugs do not require activation by thymidine kinase?
Cidofovir, Foscarnet
which of the antiherpes drugs inhibit DNA polymerase but do not cause chain termination?
Penciclovir, Famciclovir
which antivirals are contraindicated in pregnancy?
Emtricitabine (propylene glycol)
Amprenavir/Fosamprenavir (propylene glycol)
Vidarabine
Delavirdine
Efavirenz
Ribavirin
What side effect do Acyclovir and Indinavir have in common?
Kidney problems -
Acyclovir is very insoluble in urine and can crystallize and cause hematuria; Indinavir can cause kidney stones. Adequate hydration necessary for both