ANTI VIRAL DRUGS

Question 1

Name 5 drugs used to treat herpes

Answer 1

acyclovir, famciclovir, ganciclovir, cidofovir, foscarnet

Question 2

acyclovir: MOA and type

Answer 2

type: guanine nucleoside analog
MOA: 3 sequential phosphorylation events for activation
1. converted to the monophosphate by a viral thymidine kinase
TK encoded by herpes simplex and varicella zoster viruses
then converted to active drug (acyclovir triphosphate, by host cell kinases.
2. inhibits utilization of dGTP by HSV and VZV DNA pol.
3. acyclovir incorportated into viral DNA and acts as a chain terminator bc of lack of 3/ hydroxyl group.v Selectivity because higher affinity for viral DNA pol.

Question 3

acyclovir: MOR. administration

Answer 3

mutations in viral thymidine kinase that dec. viral TK activity or that alter the affinity of TK ofr acyclovir
or, muts in viral DNA pol
oral and IV forms- but oral absorption is poor.

Question 4

Use, administration, and sides of acyclovir. related prodrugs?

Answer 4

use:
Oral: oral/genaital HSV, VZV/shingles in adults
IV: HSV encephalitis, VZV in immunocompromised, VZV pneumonia
few sides, though can cause kidney damage if patient is not hydrated. may be neurotoxic at high doses.
valacyclovir is an oral prodrug

Question 5

famiciclovir and penciclovir. use? prodrug?

Answer 5

famiciclovir is an oral prodrug of penciclovir
related to acyclovir in structure, MOA, MOR.
penicilovir used topically for recurrent mucocutaneous HSV infections (cold sores)

Question 6

ganciclovir MOA and MOR

Answer 6

MOA: quanosine derivative similar to acyclovir
activation via initial phosphorylation step by a viral enzyme followed by 2 additional phosphorylation events by host kinases.
efficiently converted to monophosphate by CMV (acytomegalovirus) phosphotransferase. Could also work for HSV, VZV, epstein-barr, but we usually just give for CMV because we have good drugs with fewer side effects for HSV and VZV.

competitively inhibits viral DNA pol and is incorportated into growing DNA chain –> formation of an unstable complex. NOT a chain terminator.

it is a nucleoside analog
MOR as with aciclovir (TK or DNA pol mutations
Availabe IV and PO

Question 7

Ganiciclovir sides and use

Answer 7

sides: frequent and severe- myelosuppression (neurtopenia and thrombocytopenia), CNS toxicity
use for CMV infections in immune-compromised pts like CMV retinitis and CMV pneumonia, and transplant prophylaxisis

Question 8

What does foscarnet do? MOA, MOR, uses.

Answer 8

phosphate analog that reversibly blocks deoxynucleotidyl triphosphates (ie. prevents DNA pol from working). Doesn’t require phosphorylation steps.
MOR: rare, but can happen with DNA pol mutations
good for CMV, HSV, VZV, EBV, HHV-8.
may be used for CMV and HSV that is resistant to acyclovir.
Toxicity: renal, some rare hypokalemia.
only IV. good tissue penetration.

Question 9

amantadine and rimantadine MOA and MOR

Answer 9

anti-influenza virus agents
tricyclic amines that inhibit uncoating of the viral RNA of influenza A within infected cells. interfere with ion channel function of the viral M2 protein (only present in influenza A). durgs accumulate in the endsomes where they prevent acid mediated dissociation of the viral ribonucleoprotein complex
MOR: point mutations in the TM domain of the M2 protein. prevalent.iuo

Question 10

amantadine and rimantadine: side effects and clinical use

Answer 10

sides: GI disturbances and CNS complaints (fewer with rimantadine)
use as prophylaxis against influenza A virus infection in high risk ppl or within first 48 hrs of symptoms.

Question 11

Zanamivir MOA

Answer 11

sialic acid analog that inhibits flu virus neuraminidase activity, which is needed for viral release of flu A and flu B

Question 12

Zanamavir: uses and sides/contraindications

how is it administered?

Answer 12

uncomplicated influenza virus infections caused by influenza A or B, given within 48 hrs of symptoms onset. can shorten the duration of the flu. serious risks for people with asthma (causes bronchospasm)
administered in an inhaled form.
less resistance to zanamavir than to oseltamivir because zanamavir is smaller and can fit in NA pocket even after steric changes. only for ppl over 7

Question 13

oseltamivir/Tamiflu: MOA, uses, and administration

Answer 13

oral drug that prevents release of influenza A and influenza B virus particles from infected cells, much like zanamivir. can cause GI upset. given within 48 hrs of symptoms. LOTS of resistance. Only for ppl over 1 yo.

Question 14

AZT (zidovudine): MOA and MOR

Answer 14

thymidine nucleoside analog
phosphorylated by host cell thymidine kinase after diffuses into cells.
triphosphate form inhibits reverse transcriptase by competing with dTTP; incorporation causes DNA chain termination.
also may partially inhibit dTTP and dCTP levels- contributes to side effects.
resistance due to mutations in reverse transcriptase that reduce affinity for AZT

Question 15

AZT/zidovudine side effects

Answer 15

bone marrow suppression –> neutropenia and anemia. Macrocytosis is the hallmark of adherence. inhibit some mitochondrial DNA pol, leading to fat redistribution and lactic acidosis (esp. the thymidine analogs) nausea, insomnia, headache, drug interactions

Question 16

5 drugs that act a little like AZT (reverse transcriptase inhibitors). (not important for DPT)

Answer 16

1. didanosine/ ddI
2. zalcitabine (ddC)
3. lamivudine (3TC)
4. stavudine (d4T)
5. abacavir (ABC)

Question 17

didanosine- MOA and type. side effects?

Answer 17

analog of deoxyadenosine (purine) that is activated by phosphorylation. used to treat HIV. acts as a chain terminator. Sides of all NRTIs, but also pancreatitis.

Question 18

zalcitabine, lamivudine, stavudine

Answer 18

pyrimidine nucleoside analogs. reverse transcriptase inhibitor. activated by phosphorylation. used to treat HIV. chain terminator.

Question 19

abacavir: MOA and type. Side effects?

Answer 19

dGTP analog. acts as a chain terminator. activated by phosphorylation. reverse transcriptase inhibitor (HIV infection). Can cause fatal hypersensitivity in some people- check HLA type before prescribing this drug.

Question 20

What are the side effects of zalcitabine, stavudine, and didanosine, lamivudine, and abacavir

Answer 20

all are less myelosuppressive than AZT.zalcitabine and stavudine can cause peripheral neuropathy
didanosine can cuase pancreatitis

Question 21

nevirapine, delavirdine, efavirenz, etravirine

MOA, uses, sides

Answer 21

non-nucleoside analog inhibitor of HIV reverse transcriptase.
don’t need to be phosphorylated: they are non-competitive inhibitors that block RT action.
can be used to treat HIV in combo with other drugs or as a monotherapy in prevention of perinatal HIV (these uses less important for this class)
nevirapine can cause a life-threatening rash (not for this class)
Efavirenz is NOT for pregnant women- causes birth defects.
drug-drug interactions

Question 22

HIV protease inhibitors (5)

Answer 22

ritonavir, indinavir, saquinavir, nelfinavir, amprenavir

Question 23

How doe protease inhibitors work? MOR?

Answer 23

mimc peptide substrates of HIV protease and act as transition state analogs to compettively inhibit the protease. they bind more tightly than the native substrates.
resistance via mutations in the protease

Question 24

side effects of indinavir and ritonavir? Of PIs in general?

Answer 24

inhibitors of cytochrome P450- beware of drug interactions! In fact, ritonavir is such a potent P450 analog that we use it in very small doses to prevent breakdown of other HIV drugs. this decreases frequency of dosing and necessary does and keeps other drug levels more consant.
PIs can cause GI probs, dyslipidemias, insulin resistance and fat redistribution.

Question 25

Raltegravir- MOA, MOR, uses, sides

Answer 25

targets HIV integrase to prevent insertion of linear HIV DNA into host cell genome. that way, the provirus can’t form. This is a well tolerated drug, though there is occasionally nausea and vomiting. orally available.
resistance possible but rare- requires several mutations. no cross-resistance. should be part of initial therapy cocktail.

Question 26

Maraviroc: use, sides, MOA, etc.

Answer 26

blocks CCR5 receptor and prevents HIV entry into macrophages and T cells. orally available and well tolerated. doesn’t work well once the virus switches to using CXCR receptors for entry.

Question 27

Enfuvirtide: MOA, uses, sides, etc.

Answer 27

binds gp41 transmembrane glycoprotein of HIV and prevents fusion of viral envelope with host cell membrane. given as a subcutaneous injection. cuases a rxn at the injection site. may also cause allergy, CNS effects, and GI upset. respsitance seen from gp41 mutations. No cross-resistance with other anti-retrovirals.

Question 28

Ribavirin uses (NOT FOR DPT)

Answer 28

resp viral infections in kids due to RSV
hemorrhagic fever due to Hanta virus
in combo with interferon alpha to treat hep C`

Question 29

Interferon Alpha (NOT FOR DPT)

Answer 29

endogenous proteins
virus non-specific activites
altering cellular metabolic processes important for DNA and protein synthesis
cytokines
interferons induce cellular proteins that inhibit protein synthesis and lead to RNA cleavage.

Question 30

inteferon-alpha uses and side effects (NOT FOR DPT)

Answer 30

hep B and hep C infections, esp. when combined with ribavirin. effects hard to predict because they cause such long-lasting changes
sides: flu-like symptoms and GI disturbances. bone marrow suppression and CNS toxicity, drug interactions (P450)

Question 31

ribavirin MOA (NOT FOR DPT)

Answer 31

purine nucleoside analog
underoges phosphyrlation by host cell kinases
competitively inhibits GTP syntehsis, caping of viral mRNAs, and viral RNA0dependent RNA pol of some viruses
wide spectrum of activy, esp. against RSV, hemorrhagic fever, and hep C