Blood And Lymph- Antiviral Drugs By Boy Bridges

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Blood and Lymph- Antiviral Drugs by Boy Bridges

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Blood and Lymph- Antiviral Drugs by Boy Bridges

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Herpes viruses are...

Most drugs are...

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Herpes viruses are DNA viruses
Herpes simplex (HSV)
Varicella zoster (VZV)
Cytomegalovirus (CMV)

Most drugs used are nucleoside analogs (antimetabolites)
Triphosphate (TP) is active metabolite
TP competitively inhibits viral DNA polymerase
TP may cause chain termination

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how these things work

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antiviral drug is a nucleoside analog. the key step is the first step. the nucleoside is phosphorylated. what's important is that it's a VIRAL ENZYME that does this. a viral kinase. that gives you the selectivity. uninfected cell. drug goes in, no viral protein. there is some, but not as much phosphorylation. these drugs work in the infected cells because of the viral kinase. then you need two more steps. you create the di and triphosphate. now the triphosphate. this can inhibit the viral polymerase to prevent it from replicating its DNA genome and/or incorporate into the dna chain and terminate it.

*turns into a triphosphate and inhibits the viral polymerase

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acyclovir works against...

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Clinical activity against:
HSV-1
HSV-2
VZV

it's a guanosine analog*

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Acyclovir DOC

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DOC: HSV encephalitis, neonatal HSV infection and serious HSV or VZV infection

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MoA of acyclovir... it's phosphorylated by what?

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viral thymidine kinase.

Mechanism of Action
Phosphorylated by viral thymidine kinase
-Has 200x affinity for acyclovir compared to host enzyme (selectivity)
-ACV-TP levels are 40 to 100x higher than in infected than uninfected cells
Di-and tri-phosphosphate added by host cellular enzymes

Triphosphate inhibits viral DNA synthesis
1) competes with dGTP for viral DNA polymerase
2) chain termination

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Resistance

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Resistance
Decreased viral thymidine kinase

viral thymidine kinase mutation
decreased drug affinity


Cross-resistance with valacyclovir, famciclovir, and ganciclovir

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Adverse effects

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Adverse Effects

No significant drug-drug interactions
This holds for nucleoside analogs in general
Well tolerated po

IV acyclovir:
**Acute renal failure (crystalline nephropathy)
**Neurologic toxicity (eg, tremors, delirium, seizures)
Nephrotoxicity and CNS symptoms uncommon with adequate hydration and slower infusion rates

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Antiherpesvirus Drugs
HSV, VZV, CMV
ganciclovir

use

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CMV infection (has more activity compared to acyclovir)

but it's more toxic.
also a guanosine analog.

MoA:
similar to acyclovir
-**CMV phosphotransferase (viral enzyme) responsible for initial phosphorylation of GCV
-selectivity: GCV levels 10x higher in CMV infected cells

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GCV toxicity.

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-**bone marrow depression
--additive effect can occur with AZT or azathioprine
-**CNS

both are dose limiting

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Antiherpesvirus Drugs
HSV, VZV, CMV
Foscarnet

when do you use this?

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**Serious HSV and CMV infections such as
-ganciclovir-resistant CMV
--AIDS and transplant patients (principle use)
-CMV retinitis in AIDS patients
-acyclovir-resistant HSV and VZV

pharmacokinetics: IV only.

**NOT a nucleoside analog; does not require activation by kinases!

-inhibits viral DNA polymerase (chain elongation)

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Foscarnet adverse

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**renal insufficiency
**hypocalcemia

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Antiviral Drugs – Respiratory Virus Infections
Neuraminidase Inhibitors:
Zanamivir
Oseltamivir

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Effective against both **influenza A & B

Both are competitive inhibitors of influenza A & B neuraminidase

zanamivir- Inhalation only
Oseltamivir- Oral only

*Oseltamivir is effective prophylactically & in treatment

**Potentially effective against:
avian flu (influenza A H5N1)
swine flu (influenza A H1N1)

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Zanamivir & Oseltamivir

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-NV
-neuropsychiatric events

zanamivir: bronchospasm

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Antiviral Drugs – Respiratory Virus Infections
Viral Uncoating Inhibitors:
Amantadine
rimantadine

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treatment of Influenza A!!! (not B)

MoA: prevents uncoating of viral RNA
Pharm:**Amantadine enters CNS (rimantadine does not)
Adverse: GI, CNS, rimantadine used more than amantadine b/c less CNS effects

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Antiviral Drugs – Respiratory Virus Infections
Respiratory Syncytial Virus (RSV):
Ribavirin

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kills anything, but it's toxic.
2 approved FDA uses:
-**severe RSV
-**Hepatitis C

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key drugs for Hep C

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Interferon-alfa + Ribavirin

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Hepatitis B

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Interferon-alfa

Nucleoside analogs:
Lamivudine

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Ribavirin adverse effects

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oral: dose-dependent reversible **anemia (hemolytic and bone marrow-level)

Pregnancy category X

and know it's hep C

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Interferon alfa

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for hep B and C, chronic

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Anti-HIV agents...what is the backbone of therapy?

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Nucleoside analogs (nukes): mainstay (or backbone) of therapy
Used in combination with either a NNRTI(non-nuke) or PI

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Nucleoside analogs

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Lamivudine
Zidovudine
Stavudine
Didanosine
Zalcitabine

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Protease inhibitors (PIs)

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Ritonavir (RTV)
Indinavir
Amprenavir
Nelfinavir
Saquinavir

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Nonnucleosides

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Efavirenz*
Nevirapine

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Fusion inhibitors

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Enfuvirtide

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Entry Inhibitors – CCR5 co-receptor antagonists

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Maraviroc

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Integrase inhibitor

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Raltegravir

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Class effect: nucleoside analogs have a black box warning of...

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lactic acidosis with hepatic steatosis

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non-nukes...

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bind directly to HIV-RT and inhibit the polymerase and bind on separate site on HIV-RT

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NNRTIs MoA

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Mechanism of Action
Bind directly to HIV-reverse transcriptase (HIV-RT)

Bind at a different site than nucleoside analog triphosphates

Binding to HIV-RT causes a conformational change in the nucleotide binding site

Binding stops HIV-RT from adding new nucleotides to the growing viral DNA chain

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efavirenz is preferred to nevirapine, BUT it's

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teratogenic, so if the pt is pregnant, you switch it to nevirapine

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NNRTI’s: Drug Interactions

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Eliminated by hepatic metabolism (CYP3A4)

Efavirenz and nevirapine are CYP3A4 inducers
-Concs of concomitant drugs can inc. or dec.

Potential for MAJOR interactions with numerous HIV (PI’s) & non-HIV drugs
-Do not prescribe without first checking for potential drug interactions
-May be contraindications or need for dose adjustment(s)


can induce or inhibit

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Protease Inhibitors

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inhibits protease, prevents maturation of the virus

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Ritonavir

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used with EVERY PI. revolutionized therapy. inhibits p450s. you only need to treat once a day because it's not metabolized as fast in the liver. increases bioavailabilty, preventing clearance of the PI.CORNERSTONE OF HIV THERAPY!

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all protease inhibitors give you ___ problems

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GI. NVD.
liver and metabolic problems
-body fat redistribution
need lipid lowering drugs
need insulin drugs