Antivirals and Antifungals Flashcards
what are the oral nucleoside analogs
acyclovir, valacyclovir, famciclovir
acyclovir requires what steps
3 phosphorylation steps: becomes acyclovir monophosphate via viral thymidine kinase. then converts to diphosphate and triphosphate by host cell kinases like guanylate kinase. the drug requires viral kinase for initial phosphorylation, so acyclovir is selectively activated only in infected cells
acyclovir mechanism
inhibits viral DNA synthesis by competition with deoxyGTP for viral DNA polymerase, resulting in binding to DNA template as an irreversible complex. chain termination following incorporation into the viral DNA
valacyclovir structure
L-valyl ester of acyclovir
famciclovir structure
diacetyl ester prodrug of 6-deoxy penciclovir, an acyclic guanosine analog
what is different about penciclovir from acyclovir
does not cause chain termination
docosanol structure
saturated 22 carbon aliphatic alcohol
docosanol mechanism
inhibits fusion between the host cell membrane and the HSV envelope, thereby preventing entry into cells and subsequent viral replication
baloxavir marboxil mechanism
prodrug converted by hydrolysis to baloxavir, a cap-dependent endonuclease inhibitor that interferes with viral RNA transcription and blocks virus replication
neuraminidase inhibitors
oseltamivir, zanamivir
neuraminidase inhibitors mechanism
interfere with the release of progeny influenza A and B virus from infected host cells, thus halting spread. competitively and reversibly interact with the enzyme active site to inhibit viral neuraminidase activity
adamantanes
amantadine, rimantadine
adamantanes mechanism
block the M2 protein ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication
griseofulvin mechanism
fungistatic: interferes with fungal mitosis and nuclear acid synthesis.
nystatin structure
polyene macrolide
nystatin mechanism
binds to sterols in fungal cell membrane, changing the cell wall permeability allowing for leakage of cellular contents
terbinafine structure
synthetic allylamine
terbinafine mechanism
inhibits squalene epoxidase, a key enzyme in sterol biosynthesis in fungi. results in a deficiency in ergosterol within the fungal cell membrane and results in fungal cell death. leads to the accumulation of sterol squalene, which is toxic to the organism
what are the imidazoles
clotrimazole, miconazole, ketoconazole
structure of imidazoles
2-nitrogen azole ring
imidazoles mechanism
inhibits the CYP51 enzyme lanosterol 14-alpha-demethylase which converts lanosterol to ergosterol in fungi cellular membranes. inability to produce ergosterol increases membrane permeability, which results in cell lysis and death
what is ergosterol
the most abundant sterol in fungal cell membranes, aids in the regulation of permeability and fluidity
what are the triazoles
voriconazole, itraconazole, fluconazole, posaconazole
triazoles structure
3-nitrogen ring
acyclovir activity against?
HSV1, HSV2, VSV. FAR MORE POTENT AGAINST HSV COMPARED TO VSV
bioavailability of acyclovir
very low, 15-20% and unaffected by food
elimination considerations for acyclovir
eliminated via the kidney, so reduction in dose may be necessary in reduced kidney function
counseling for acyclovir
take the dose with plenty of water to reduce the likelihood of acute kidney injury secondary to crystal-induced nephropathy
what happens to valacyclovir upon PO administration
it is rapidly converted to acyclovir via first pass enzymatic hydrolysis in the liver and intestine. results in serum levels that are 3-5x greater
valacyclovir bioavailability
54-70%
what happens to famciclovir after PO administration
it is rapidly deacetylated and oxidized by first pass metabolism to penciclovir
famciclovir bioavailability
70%
what are the instructions for docosanol
specific time: apply within 12 hours of the onset of prodromal symptoms, 5x daily
what does baloxavir have activity against
influenza A and B
half life of baloxavir
LONG, 80 hours. given as a single dose treatment initiated within 48 hours of the onset of symptoms
how is baloxavir metabolized
UGT1A3, minor contributions from CYP3A4
what is an advantage with baloxavir
it binds to a different active site than the neuraminidase inhibitors, so you can enhance activity by combining these agents. it is well tolerated.
counseling point for baloxavir
do not take with cation-containing products (antacids) or dairy products
what do the neuraminidase inhibitors have activity against
influenza A and B
neuraminidase inhibitors bioavailability
80%
elimination considerations for neuraminidase inhibitors
eliminated via the kidney, dose adjustment is necessary in patients with impaired kidney function
when to give neuraminidase inhibitors
early administration is crucial: influenza illness peaks at 24-72 hours after the onset of illness
how long is neuraminidase inhibitor course of therapy
5-days within 48h after onset of symptoms
how is zanamivir given
it is given via inhalation and administered directly to the respiratory tract: 10-20% reaches the lungs. Not recommended in patients with underlying airway disease
what do the adamantanes have activity against
influenza A only
dose reductions for amantadine
elderly and reduced kidney function
dose reductions for rimantadine
elderly, reduced kidney function, severe reduced hepatic function
griseofulvin absorption
Ultra-microsize almost complete absorption. Microsize 27-72%
counseling point for griseofulvin
take with a fatty meal: absorption is enhanced by fatty meal
griseofulvin adverse effects
rash: can be phototoxic/photoallergic or not. transient headaches that occur early in therapy and cease spontaneously. dizziness, mental confusion, GI upset
microsize dose
500 mg/day
ultra-microsize dose
375 mg/day
griseofulvin duration for ringworm
2-4wks
griseofulvin duration for jock itch
6 wks
griseofulvin duration for scalp ringworm
4-6wks
griseofulvin duration for athlete’s foot
4-8wks
griseofulvin duration for onychomycosis
4-6 months
nystatin major PK consideration
absorption is minimal, used topically only
nystatin adverse effects
diarrhea, nausea, stomach pain, vomiting
terbinafine adverse effects
rash, d/v, dyspepsia, abdom pain, vision color confusion, decreased visual acuity, depression, taste disturbance, reversible severe neutropenia, hepatic failure, hypersensitivity, changes in ocular lens and retina, smell disturbance
terbinafine drug interactions
CYP2D6
difference in safety profile between imidazoles and triazoles?
imidazoles exhibit less selectivity for target enzyme, so greater frequency of ADRs. triazoles exhibit greater selectivity for target enzyme, thus have a better safety profile.
uncomplicated vaginal candidiasis
mild/moderate symptoms, sporadic, candida albicans, normal host
complicated vaginal candidiasis
ANY of the following: severe symptoms, recurrent, nonalbicans, abnormal host (DM, pregnant, immunosuppressed, recurrent)
duration for topical, vaginal candidiasis
uncomplicated: 1-3 days, complicated: 7-14 days
duration for systemic, vaginal candidiasis
uncomplicated: fluconazole 150 mg x 1. complicated: q72h x 2
vaginal candidiasis in pregnancy
use topicals
what defines recurrent vaginal candidiasis
4+ infections/year
treatment for recurrent vaginal candidiasis
fluconazole q72h x 3, then weekly x 6 months
options for oral candidiasis, mild
nystatin suspension 400,000-600,000 u 4x/day swish, retain, swallow. or clotrimazole troches 10 mg dissolved BID. x 7-14 days
options for oral candidiasis, severe
systemic: fluconazole 100 mg Day 1. 100-200 mg/day x 7-14 days (choice for immunocompromised)
who typically gets oral candidiasis
denture-wearers, dry mouth, antibiotics, inhaled steroids
topical options for onychomycosis
ciclopirox 8% or efinaconazole 10% daily x 48 weeks
1st line systemic option for onychomycosis
terbinafine daily x 6 weeks if fingernail or 12 weeks if toenail
other systemic options for onychomycosis
itraconazole, fluconazole, griseofulvin (4-6 months)
BCS class of griseofulvin
class II: very insoluble, high permeability
griseofulvin is fungi____
static
in addition to inhibiting fungal cell mitosis, griseofulvin binds to _____
alpha and beta tubulin to interfere with the function of spindle and cytoplasmic microtubules
name for body surface ringworm
tinea corporis
name for jock itch
tinea cruris
name for scalp ringworm
tinea capitis
name for athlete’s foot
tinea pedis
name for onychomycosis
tinea unguium
besides taking griseofulvin with a high fat meal, what else should you counsel the patient
use suncreen
nystatin works similarly to _____
amphotericin b
terbinafine is largely associated with treatment of _____
onychomycosis
terbinafine is fungi____ and ____philic
fungicidal and keratophilic
what is the difference in mechanism between terbinafine and the imidazoles if they both cause ergosterol deficiency?
imidazoles interfere with the CYP51 enzyme
what labs to check with terbinafine
LFTs baseline and at 6 weeks
pros and cons of pulsed dosing with terbinafine
less effective, but reduces ADE, cost, and improves patient compliance
drug options when the fungal infection reaches follicles, dermis, or nails
terbinafine, itraconazole, fluconazole, griseofulvin
what to avoid with diaper dermatitis
topical corticosteroids with antifungal creams
ketoconazole drug interactions
CYP3A4 inhibitor
characteristics of viruses
obligate intracellular parasites, cannot replicate independent of host, must be infectious to endure, most use host cellular machinery to produce necessary components, must self-assemble, cannot make energy/proteins outside of host cell
components of viruses
contain RNA or DNA (not both), have a naked capsid or envelope morphology. viral components are ASSEMBLED (not replicated by cell division)
surface structures of the capsid or envelope are critical for interaction with the target host cell through _____
viral attachment proteins (VAPs)
viruses contain ______ that are crucial for entry into host cell and replication
enzymes that catalyze reactions
nucleocapsid characteristics
viral nucleic acid genome, protein coat serves as rigid structure, serves to package/protect/deliver during viral transmission, surrounded by lipid layer with insertions, may be contained in an envelope made of lipids/proteins/glycoproteins in aqueous conditions
envelope characteristics
environmentally labile, must stay in aqueous medium and cannot survive GI tract, spreads via large droplets/secretions/transfusions, does not need to kill host cell in order to spread, antibody and cell-mediated immune response often secondary to envelope, elicits hypersensitivity and inflammatory responses
naked capsid characteristics
environmentally stable (temp, acidic, detergents, drying), spread via fomites/hand to hand/dust/small droplets, may dry out but still infectious, ability to survive harsh acidic pH of the stomach, resistant to detergents, antibodies must be generated for immune protection
viruses penetrate a host cell membrane via a ______
receptor-mediated interaction
once the virus attaches to the host cell membrane, the viral genetic material enters the host cell and what happens
the cellular machinery of the host transcribes the viral genome, followed by translation of viral proteins
if RNA virus
host cell ribosomes translate RNA into protein
if retrovirus
RNA transcribed into DNA (reverse transcriptase) before entering viral genome
if DNA virus
transcription into mRNA, then translation into viral proteins
viral enzymes assemble material into ____ which are then released
VIRIONS
_____ is the complete infective form of a virus outside of a host cell
virion
steps of viral pathogenesis
acquisition, primary site of infection, activation of innate, incubation period, replication in target tissue, adaptive immune response, contagion, resolution or persistent/chronic infection
common cold/flu follows what patten of infection
acute
HSV follows what pattern of infection
latent
varicella-zoster follows that pattern of infection
chronic
susceptibility to viral infection and severity: the virus
viral load, genetics of virus, stability of virion in environment, replication and secretion into aerosols
susceptibility to viral infection and severity: the host
genetics of the host, immune status, age, overall general health, asymptomatic transmission, risk factors (travel, environment like daycare, sexual activity)
how is valacyclovir prodrug converted to acyclovir
first pass enzymatic hydrolysis in liver and intestine
in pregnant women with recurrent HSV, when is suppressive therapy recommended
36 weeks gestation
how is famciclovir prodrug converted to penciclovir
deacetylated and oxidized by first pass metabolism
influenza b viruses infect
only people
influenza a viruses infect
people and animals
neuraminidase inhibitors are analogs of ___
sialic acid
