da III exam 1 (daniels's material)

what are the 3 types of immunologic types of influenza viruses?

A, B, and C

what are viral surface glycoproteins in influenza?

hemagglutinin

neuraminidase

how does replication happen in influenza virus?

it binds to cell surface of host via hemagglutinin and sialic acid groups

how is influenza virus release?

neuraminidase removes sialic acid from surface glycoproteins

what is the chemical structure of amantadine?

symmetric tricyclic primary amine

how does amantadine/rimantadine inhibit viral uncoating?

inhibits penetration of RNA virus particles into host cell

blocks uncoating of viral genome and transferring of nucleic acid into host cell - inhibits early stages of replication

how do neuraminidase inhibitors work to prevent viral release?

no neuraminidase → sialic acid not hydrolyzed from hemagglutinin → viron cannot be released

which neuraminidase inhibitor is a prodrug

tamiflu → must be hydrolyzed for activity

which neuraminidase inhibitor is the only orally active drug?

tamiflu

when does maximum binding to neuraminidase occur?

R is 3-pentyloxy side chain at C6

NAI SAR

carboxyl at C2

basic group at C4

N-acetyl at C5

R at C6

how is oseltamivir hydrolyzed?

esterase

how is zanamivir administered?

oral inhalation

how is peramivir administered?

IV

how is baloxavir marboxil activated?

prodrug → hydrolyzed to baloxavir acid

xofluza MOA

blocks PA endonuclease → no cap snatching → no viral mRNA

baloxavir marboxil SAR

binds Mn2+ in PA active site (this same group binds dietary cations)

how are all nucleoside/nucleotide analogues activated?

phosphorylation

nucleoside/nucleotide analogue MOA

inhibitors of viral DNA polymerase

because acyclovir has poor absorption/water solubility, what does that mean for counseling point?

drink plenty of water to avoid crystal nephropathy

valacyclovir is the ___ ____ of acyclovir

ester prodrug

which drug is a guanosine analogue?

ribavirin

what does ribavirin cover?

broad spectrum antiviral activity

how is ribavirin activated?

phosphorylation by adenosine kinase

foscarnet MOA

directly binds/inhibits viral DNA polymerase → blocks pyrophosphate binding site

NS5A inhibitors characteristics

dimeric

critical proline-valine-carbamate cap

NS5A inhibitors MOA

bind to NS5A protein and inhibit development of HCV

which is potent inhibitor of HCV NS5B?

sofosbuvir

sofosbuvir MOA

act on viral RNA-dependent RNA polymerase → non-obligate chain termination

gp41

transmembrane subunit of HIV-1 glycoprotein subunit complex

enfuvirtide MOA

binds gp41 and blocks fusion

maraviroc MOA

CCR5 antagonist and blocks co-receptor binding

what mediates fusion of HIV-1 viral envelope with host plasma membrane?

gp41

which entry inhibitor is a linear 36 amino acid synthetic peptide?

enfuvirtide

where are NRTIs phosphorylated?

5’ position (green OH)

what kind of derivatives are NRTIs?

pyrimidine or purine

which NRTI must be hydrolyzed then phosphorylated?

TDF

what is the part that competes with natural substrates for incorporation into proviral DNA?

triphosphate form (active form)

what do NRTIs lack → inhibition propagation of DNA and termination of elongation?

3’ hydroxyl (yellow)

which NRTI is the exception to good bioavailability?

tenofovir

which portion of tenofovir allows for better absorption/bioavailability?

disoproxil

what is the tenofovir prodrug?

phosphonamidate

T/F: TAF is unmasked inside cells

true

NNRTIs MOA

do not require bioactivation by kinases

aren’t incorporated into growing DNA chain

binds directly to RT at allosteric site

what does NNRTI specifically cover?

HIV-1

when does NNRTI resistance develop?

when used as monotherapy

second gen NNRTIs alternative name

diarylprimidine derivatives

what the advantage of 2nd gen over 1st gen NNRTIs?

increased conformational flexibility → binds both native and drug-resistant mutant HIV-1

what is vital for retroviral replication?

HIV integrase (inserts the viral genome into DNA of host cell)

integrase inhibitors MOA

bind to integrase-viral DNA complex in the catalytic core domain

used in combination due to INSTIs inhibiting specific step

what is the crucial characteristic trait in INSTIs?

coplanarity between ketone and beta-carbonyl → improves chelation of metal (do not take with divalent/polyvalent cations)

what starts maturation process of HIV?

HIV protease

which part of protease inhibitor mimics tetrahedral transition state?

hydroxyl-bearing sp3 carbon

highly active anti-retroviral therapy (HAART)

3 or 4 antiretroviral drugs taken in combo for treatment of HIV

advantages of HAART

therapeutic antiviral effect

decreased toxicity

low incidence of drug-resistance

amphotericin B brand

amphocin

fungizone

ambisome

fluconazole brand

diflucan

voriconazole brand

vfend

capsofungin brand

cancidas

micafungin brand

mycamine

ketoconazole brand

nizoral

nystatin brand

nystop

terbinafine brand

lamisil

clotrimazole/betamethasone brand

lotrisone

bacteria are (prokaryotes/eukaryotes)

prokaryotes

fungi/mammals are (prokaryotes/eukaryotes)

eukaryotes

what kind of sterol is in fungal cell membrane?

ergosterol

what kind of sterol is in mammalian cell membrane?

cholesterol

polyene structure

macrocyclic lactones with four to seven conjugated alkenes

polyenes have conjugated double bonds which correlates with what?

directly with antifungal activity

inversely with degree of toxicity of mammalian cells

T/F: polyenes are amphipathic

true

polyenes lipophilic region

polyenes hydrophilic region

polyene MOA

bind to ergosterol in the fungal cell membrane through the lipophilic portion of the polyene

which kind of sterol do polyenes have higher afffinity for?

ergosterol

polyenes mechanism of resistance

reduced of ergosterol concentration

synthesis of alternative sterols

how is nystatin administered?

topically

how is amphotericin administered?

IV

T/F: polyenes are highly protein bound

true

can polyenes get into the CNS?

no poor penetration

is amphotericin B broad or narrow spectrum?

broad

how are broad-spectrum drugs used?

initial treatment for many invasive fungal infections

how does liposomal amphotericin B compare to the conventional formulation?

fewer toxicities

amphotericin B BBW

primarily for progressive potential life-threatening fungal infections

medication errors confusing the lipid-based forms of amphotericin and conventional amp B → cardiopulmonary arrest and death

what DW solution is amp B compatible with?

D5W

what are the meds that should be given to reduce infusion-related reactions before amp B?

tylenol or NSAID

diphenhydramine or hydrocortisone

NS boluses (decreases nephrotoxicity)

meperidine (duration of severe rigors)

what should be monitored with amp B?

renal function

LFTs

electrolytes

CBC

another name for allylamines

squalene epoxidase inhibitors

what do allylamine antifungals target?

dermatophytes

dermatophytes

fungi that require keratin for growth

allylamine MOA

blocks epoxidation of squalene

decrease in ergosterol content of fungal cell membrane leading to cell membrane leakage

buildup of squalene which is toxic in high amounts

terbinafine is lipophilic or hydrophilic?

lipophilic

what is oral terbinafine CI in?

chronic or active liver disease

azole structure

5 membered aromatic ring containing 2-4 nitrogen

at least one aromatic ring

azole MOA

basic N3/N4 atom of azole forms a bond with heme iron of CYP450 group in the position occupied by activated oxygen

what is essential for azole binding?

N3/N4

what is the first tetrazole?

oteseconazole

azole mechanism of resistance

decreased binding affinity to demethylase

increased activity of efflux pumps

increased production of demethylase

azole PK/PD

IV voriconazole and posaconazole require cyclodextrin for solubility

cyclodextrin associated with nephrotoxicity

require low stomach pH → DDI with antacids

azole ADR

skin reactions (SJS/TEN)