Antiviral Agents Flashcards
Viral Infection Properties/effects
(1) Self-limiting disease
(2) significant sequelae
(3) death
(4) latency
How do you activate anti-herpes agents (prodrugs)
Phosphorylate thrice
Enzymes used for anti-herpes agent activation
Viral thymidine kinase (TK)
G protein kinase (PKG UL97)
Drug activated by Viral thymidine kinase (TK)
Valcyclovir (HSV)
Famcyclovir (VZV)
Drug activated by PKG UL97
Valgancyclovir (for CMV)
Examples of Anti-herpes agents discussed in class
Acyclovir
Valacyclovir
Gancyclovir
Valgancyclovir
mechanism of action: Acyclovir
DNA chain terminator:
becomes activated once phosphorylated by the virus and targets polymerase
Acyclovir routes of administration
IV
Topical
Indications of IV acyclovir
severe/life threatening diseases caused by HSV/VZV
- Encephalitis
- Hepatitis
- Neonatal
- Acute retinal necrosis syndrome
- Mucocutaneous disease
- Zoster (with or without visceral disease)
critically ill patients for the therapeutic dose to be reached right away to avoid sequelae
Indication of Topical acyclovir
HSV immunocompromised hosts
Acyclovir + L-valylester
Valacyclovir
effect of addition of L-valylester
higher bioavailbility, more effects at same dose
Oral Acyclovir vs. Valacyclovir
advantage of valacyclovir:
- reduced viral shedding
- reduced fever by 1 day
- dec skin lesion
- dec time of total crusting by 2 days
- less side effects
- higher biovailability (3x higher)
synthetic guanosine analogue
Gancyclovir
Gancyclovir mechanism of action
suppresses viral DNA polymerase; competes for dGTP for incorporation into viral DNA
Gancyclovir advantage over Acyclovir
100X greater activity for CMV
Gancyclovir disadvantage
only for life threatening conditions
- myelosuppresion
- hepatotoxic
- carcinogenic
Gancyclovir routes of administration
IV
Oral
Gancyclovir IV indications
congenital CMV, CMV retinitis, only for emergency
L-valyl ester of ganciclovir
Valgancyclovir
What happens after oral ingestion of Valgancyclovir?
both diastereomers are hydroyzed by intestinal and hepatic esterases
compare Gancyclovir and Valgancyclovir
Valgancyclovir has a higher bioavailability (60%) due to addition of L-valyl ester, longer half life, both are excreted via renal pathway
Factors considered for Varicella treatment
(1) host factors
(2) extent of infection
(3) initial response to therapy
Varicella duration of replication in immunocompetent hosts
72 hours
routine use of acyclovir is not recommended in
healthy children < 12 years
Oral acyclovir is given to
- more than 12 years
- chronic cutaneous/pulmonary skin disorders
- long-term salicylate therapy
- short, intermittent, aerosolized course of corticosteroids
- pregnant women (2nd/3rd trimesters)
IV acyclovir is given to
for immunocompromised patients
- treated with chronic corticosteriods
- pregnant women with serious complications
Treatment of neonatal HSV
IV - 14 days - skin, eye and mouth disease
IV - 21 days for HSV encephalitis
Treatment of genital HSV
primary: oral acyclovir or valacyclovir
severe: IV
recurrent: same as primary + suppression therapy for 1 year (if more than 6 recurrences)
Treatment of mucocutaneous HSV
Oral always for immunocompetent
IV for immunocompromised
Treatment of Varicella zoster infections (chickenpox, shingles)
Oral always for immunocompetent
IV for immunocompromised
Anti-HSV drugs are given to those treated with immunosuppressant drugs or radiotherapy because
due to risk of HSV infection via reactivation of the latent virus
Steps involved in cell entry of HIV
attachment
co-receptor binding
fusion
converts viral RNA to DNA
reverse transcriptase
incorporates viral DNA into chromosome
integrase
Protease importance
cleaves viral proteins to several smaller units to activate them (maturation)
Target Steps of Drugs
(1) entry
(2) reverse transcriptase
(3) integrase
(5) protease
process wherein new viruses/virions are formed and released
viral budding
Classes of Antiretrovirals
(1) Nucleoside reverse transcriptase inhibitors
(2) Non-nucleoside RTI
(3) protease inhibitors
(4) entry inhibitors
(5) integrase inhibitors
nucleoside reverse transcriptase inhibitors mechanism of action
inhibits RT by being incorporated to newly synthesized viral DNA, preventing further elongation
nucleoside reverse transcriptase inhibitors adverse effects
lactic acidosis
hepatic steatosis
dyslipidemia
NRTI pro-drug
Zidovudine/Azidothymidine (AZT)
AZT adverse effects:
macrocytic anemia
NRTI examples
Zidovudine
Lamivudine
Tenofovir
Non-NRTI MOA
attaches to a site distant from the RT’s active site to inhibit it
NNRTI adverse effects
Stevens Johnson Syndrome
nausea
hypersensitivity
Drug interactions *CYP3A3
most recommended NNRTI
Niverapine
Niverapine properties
excellent BA (>90%)
not affected by food
effective in preventing maternal-fetal transmission
rash in 20%, mild and selflimiting, 7% severe
liver HT 4%
Protease inhibitors MOA
inhibits protease preventing maturation (cleavage) of viral peptides
Protease inhibitors disadvantage
limited CNS penetration
multiple drug-drug interactions as CYP450 metabolizes it
multiple side effeccts
Protease inhibitors side effects
serum lipid abnormalities, vascular system effects, body fat redistribution (lipodystrophy), glucose intolerance
Protease inhibitor in the PH
Lopinavir + Ritonavir (combination or not)
Ritonavir is a potent inhibitor of
CYP3A4
Used as a booster of other protease inhibitors
Ritonavir. fewer dose but higher effects - synergistic
T/F all adults must be given ART regardless of WHO clinical stage and at any CD4 cell count
T
ART priority given to
WHO Stage 3 or 4
CD4 count <= 350 cells/mm3
First line ART
two NRTIs + one NNRTI
NEVER MONOTHERAPY
Monotherapy for ART results to
resistance
Drugs for HepaB therapy in adults, + children above 12
Tenofovir (high barrier to drug resistance)
Entecavir
Drugs for HepaB therapy for children 2-11 years of age
Entecavir
Influenza virus infection symptoms
acute high fever dry cough myalgia arthralgia severe malaise sore throat runny nose sever and lasts for more than 2 weeks
Influenza Virus latest strain
H7N9
why is influenza vaccine administered yearly
reassortment of H and N variants produces new strains
H variant
hemagglutinin
N variant
Neuraminidase
Neuraminidase function
needed by virus to penetrate and/or escape from the cell, elicits mucus secretion from the host
Neuraminidases inhibitors function
inhibits release of progeny and/or prevents penetration of virus to the protective mucus of respiratory epithelium
Examples of Neuraminidase inhibitors
Zanamivir
Oseltamivir
Adamantanes
not effective against influenza B
Adamantanes - no longer used due to resistance
Adamantanes examples
Amantadine
Rimantadine
Zanamivir vs. Osetalmivir form/route
z: inhaled dry powder
o: capsule
Zanamivir vs. Osetalmivir effective on which age group
z: not for children <7
o: old people (O for Old)
Zanamivir vs. Osetalmivir bioavailability
z: 4-17%
o: 75%
Zanamivir vs. Osetalmivir metab/excretion
z: renal
o: liver -> active carboxylate form
Zanamivir vs. Osetalmivir halflife
z: 2.5-5.1h
o: 6-10h
effects of Zanamivir and Osetalmivir
relief of symptoms by 1-5 days, decrease viral shedding
greatest benefit when antiviral is given within
48 hours of influenza illness onset
persons with higher risk for influenza complication
<2 >65 person with immunosuppression with chronic pulmo, CV, renal, hepatic, hema, metab, neuro <19 receiving long term aspirin therapy pregnant women obese
recommended anti-influenza treatment duration
5 days
Zanamivir adverse effects
bronchospasm (not recom for ppl with pulmo disease) oropharyngeal and facial edema nausea diarrhea ENT infections
Oseltamivir
transient neuropsych events (reports only for Japanese)
Nausea/vomit (most common)
