Id 3T1: Antiviral Agents

Front 1

ANTIVIRAL THERAPY

• Inhibition of steps unique to viral replication -- (5)

• Preferential inhibition of steps shared with host -- (2)

Resistance?

Virustatic/Virucidal?
Availability?

Back 1

• Inhibition of steps unique to viral replication -- adsorption, penetration, uncoating, assembly, release

• Preferential inhibition of steps shared with host -- transcription, translation

• Susceptibility testing less predictive

• Resistance may develop

• Virustatic - immune response needed for cure; there are no virucidal antivirals available

• Limited availability -- therapy available only for herpes, influenza, RSV, hepatitis, papilloma, HIV

Front 2

DRUGS EFFECTIVE AGAINST
HERPESVIRUSES

Nucleoside analogs

Non-nucleoside analogs

Back 2

Nucleoside analogs
Acyclovir
Ganciclovir
Trifluorothymidine

Non-nucleoside analogs
Foscarnet

Front 3

TOPICAL DRUGS

(4)

Back 3

• Trifluorothymidine
• Cidofovir
• Docosanol
• Penciclovir

Front 4

What is the drug of choice HSV keratoconjunctivitis?
(put in the eye)

Back 4

TRIFLUOROTHYMIDINE

Front 5

TRIFLUOROTHYMIDINE

How does it act?

Drug of choice for?

Okay for pregnancy?

Side effect?

Back 5

• Fluorinated thymidine analog
• Incorporated into viral, cellular DNA,
produces faulty DNA structure
• Mutagenic, teratogenic
• Drug of choice HSV keratoconjunctivitis
• Edema, burning, allergic reactions

Front 6

CIDOFOVIR

Mechanism of action?

Active against? (6)

Toxicity?

Use limited to what organisms due to toxicity?

Used topically for?

Back 6

• Cytosine analog, inhibits DNA synthesis
• Active against CMV, HSV, EBV, papilloma, adenovirus, poxviruses
• Very toxic – use limited to CMV, HSVresistant
strains
• Used topically for orolabial HSV in
immunocompromised hosts

Front 7

DOCOSANOL

• Inhibits fusion between _______ and _______

• Used for?

• Clinical effect?

Back 7

• Inhibits fusion between plasma membrane , HSV envelope

• Recurrent orofacial HSV

• Shortens healing time, duration of
symptoms

• Over the counter

Front 8

DRUGS PHOSPHORYLATED BY
VIRAL THYMIDINE KINASE

Back 8

• Acyclovir (drug), Valacyclovir (prodrug)
• Penciclovir (drug), Famciclovir (prodrug)
• Ganciclovir (drug), Valganciclovir (prodrug)

Front 9

ACYCLOVIR ACTION

Explain

Back 9

• Selective concentration in virus-infected cells by viral thymidine kinase

• Phosphorylated to mono, di and triphosphate

• Acyclovir triphosphate has higher affinity for HSV than cellular DNA polymerase, less toxic to host cells

• Competitive inhibition; irreversible inactivation of DNA polymerase after complex with incorporated triphosphate

• Triphosphate incorporated into elongating DNA chain,
causes chain termination

Front 10

ACYCLOVIR RESISTANCE

• How? (2)

• Seen in what patients?

Back 10

• Altered DNA polymerase

• Thymidine kinase deficient strains, or strains with altered substrate affinity

• Seen in immunocompromised patients on prolonged therapy e.g. AIDS patients

Front 11

Which two organisms can you NOT use acyclovir for?

Which organism do you need higher doses of acyclovir for due to decrease susceptibility?

Back 11

EBV, CMV

VZV

Front 12

ACYCLOVIR ADVERSE EFFECTS

Common? Reversible?

Renal effects?

Neuro?

Back 12

• Uncommon, reversible

• Precipitation in renal tubules - hydrate patient

• CNS symptoms - confusion, lethargy, tremors, seizures- especially in the elderly and with renal failure

Front 13

VALACYCLOVIR

Relationship to acyclovir?

Oral bioavailability vs. acyclovir?
Dosage as compared to acyclovir for treatment for ____ and ____

Oral treatment for?

Side effects?

Back 13

• Prodrug, converted to acyclovir in intestine, liver

• Increased oral bioavailability 4-fold

• Twice instead of 5 times daily for oral therapy of VZV, HSV

• Oral treatment of HSV, VZV infection

• Hallucinations, confusion, TTP

Front 14

PENCICLOVIR, FAMCICLOVIR

Action?

Active in vitro against?

Used in?

Side effects?

Adjust dose for?

Cost?

Back 14

• Guanosine derivative, action same as acyclovir

• Famciclovir (oral use) is the prodrug, converted to penciclovir (topical use) in liver

• Active in vitro HSV, VZV, EBV, hepatitis B

• Used in HSV (initial, recurrent), VZV (shingles)

• Headache, nausea, diarrhea

• Adjust dose renal failure.
Expensive!

Front 15

KEY POINTS ACYCLOVIR,
VALACYCLOVIR, FAMCICLOVIR

• Require phosphorylation by viral ______ _________

• Bind to DNA, cause______ _______; inhibit ________ __________

• Resistance by decreased ______ __________

• Toxicity?

• Valacyclovir converted to acyclovir, effect on oral levels?

• Acyclovir: excellent activity for ? (2) . ____needs higher dose

• IV for ____, ____ _______, serious infection in immunocompromised patients

Back 15

• Require phosphorylation by viral thymidine kinase

• Bind to DNA, cause chain termination; inhibit DNA polymerase

• Resistance by decreased thymidine kinase

• Minimal toxicity; CNS symptoms

• Valacyclovir converted to acyclovir, higher oral levels

• Acyclovir: excellent activity HSV-1, HSV-2. VZV needs higher dose

• IV for HSV, VZV encephalitis, serious infection in immunocompromised patients

Front 16

GANCICLOVIR ACTION

• Deoxyguanosine analog, 10– 50 fold ↑ potency against ____ (virus); ___, ____ (2 viruses) activity same as acyclovir

• Converted to triphosphate by viral kinases - HSV _____ _______ , CMV ___ _______

• Inhibits CMV ___ __________

• Competitive inhibitor of viral ___ ____________

• Following incorporation, _____ viral DNA _____ _________

• Resistance?

Back 16

• Deoxyguanosine analog, 10– 50 fold ↑ potency against CMV; HSV, VZV activity same as acyclovir

• Converted to triphosphate by viral kinases - HSV thymidine kinase , CMV protein kinase

• Inhibits CMV DNA replication

• Competitive inhibitor of viral DNA polymerase

• Following incorporation, slows viral DNA chain elongation

• Resistance - altered kinase, DNA polymerase with ↓ affinity

Front 17

GANCICLOVIR USES

• Treatment of choice for serious ____ infection (retinitis, colitis, pneumonia), and prophylaxis in
________ patients

• Maintenance therapy needed to prevent _______ in ___ infected patients

• Eliminated via ______, dose reduction needed in ______ ______

• Oral ganciclovir _____ bioavailability, replaced by
__________

• ______ release, intravitreal implant for suppression of ____ ________

Back 17

• Treatment of choice for serious CMV infection (retinitis, colitis, pneumonia), and prophylaxis in
transplant patients

• Maintenance therapy needed to prevent relapse
in HIV infected patients
• Eliminated via kidney, dose reduction needed in
renal failure
• Oral ganciclovir poor bioavailability, replaced by
valganciclovir
• Slow release, intravitreal implant for
suppression of CMV retinitis

Front 18

GANCICLOVIR ADVERSE
EFFECTS

• ____ ________ cells extremely susceptible

• _____ , ______most important adverse effect

• Neuro?

• General SEs?

Back 18

• Bone marrow cells extremely susceptible

• Neutropenia, anemia most important adverse effect

• Reverse with discontinuation, GMCSF

• CNS effects - confusion, seizures, psychosis

• Rash, fever

Front 19

VALGANCICLOVIR

• Oral? Converted to what in body?

• Treatment and maintenance therapy of?

Back 19

• Oral prodrug, converted to ganciclovir in body

• Serum levels equal to IV

• Similar side effects; also causes nausea

• Treatment and maintenance therapy of CMV retinitis in HIV

• Other CMV infection ( colitis, pneumonia) in immunosuppressed hosts

Front 20

KEY POINTS GANCICLOVIR,
VALGANCICLOVIR

• Phosphorylated by ?

• Inhibits ?

• Increased potency against ?

• Used for ?

• Prophylaxis in ?

• Bone marrow suppression?

• __________ is prodrug; oral levels high, useful in maintenance therapy

Back 20

• Phosphorylated by HSV thymidine kinase, CMV protein kinase

• Inhibits DNA polymerase, slows DNA chain elongation

• Increased potency against CMV

• Used for CMV retinitis, colitis, pneumonia

• Prophylaxis in transplant recipients

• Bone marrow suppression frequent

• Valganciclovir is prodrug; oral levels high, useful in maintenance therapy

Front 21

FOSCARNET

• Class of herpes virus inhibitor?

• Inhibits ?

• Not affected by ?

• 100-fold higher affinity for?

Toxicity?

• Oral?

Back 21

• Non-nucleoside inhibitor

• Inhibits herpesvirus DNA polymerase, HIV reverse transcriptase directly (no
intracellular metabolism)

• Not affected by thymidine kinase or other mutations

• 100-fold higher affinity for viral than
cellular polymerase;

Significant toxicity

• Poor oral bioavailability, requires IV route

Front 22

Drug of choice for resistant herpesvirus?

Back 22

FOSCARNET USES

Front 23

FOSCARNET USES

(3)

Back 23

• Inhibits HSV, VZV, EBV, CMV, HIV-1
• Acyclovir resistant HSV, VZV
• Ganciclovir resistant CMV

Front 24

FOSCARNET TOXICITY

Back 24

• Eliminated via kidney, decrease dose in renal
failure
• Nephrotoxicity due to renal tubular injury
• Hypo, hypercalcemia, hyperphosphatemia
• Hematologic toxicity -- reversible
• Nausea, vomiting, diarrhea
• Rare CNS effects -- confusion, ataxia, seizures
• Painful penile ulcers (irritation drug in urine)

Front 25

KEY POINTS FOSCARNET
• Inhibits viral ? directly

• Not affected by _________, other ____ _________ mutations

• Drug of choice for resistant ? (3)

• Administration route?

• Toxicity (2)?

Back 25

• Inhibits viral DNA polymerase directly

• Not affected by thymidine, other viral kinase mutations

• Drug of choice for resistant HSV, VZV, CMV

• Intravenous route only

• Very toxic – nephrotoxicity, electrolyte imbalance

Front 26

INFLUENZA VIRUS

• Prevention using _______ _________ most important?

• _________ if vaccine unavailable, or contra indicated

Back 26

• Prevention using inactivated VACCINE most important

• Chemoprophylaxis if vaccine unavailable, or contra indicated

• Therapy in selected patients

Front 27

AMANTADINE, RIMANTIDINE
• Prevent ________ of influenza __ only

• Resistance occurs in __ - ___% within days

• Current resistance ____% in 120 influenza A isolates ( was 14.5% ) - DO NOT USE FOR TREATMENT OF _______________

• CDC Health Alert January 14, 2006

• May need to use if __________ resistance

Back 27

• Prevent uncoating of influenza A only

• Resistance occurs in 25-50% within days

• Current resistance 91% in 120 influenza A isolates ( was 14.5% ) - DO NOT USE FOR TREATMENT OF INFLUENZA

• CDC Health Alert January 14, 2006

• May need to use if oseltamivir resistance

Front 28

NEURAMINIDASE INHIBITORS

(2)

Back 28

zanamivir
oseltamivir

Front 29

ZANAMIVIR, OSELTAMIVIR

• Inhibit ____________ of influenza A, B, prevent release of new virus particles

• New host cells (are/are not) infected?

• Resistance?

• ________ (drug) by inhalation, ______ (drug) oral

• Side effects?

• Cost?

Back 29

• Inhibit neuraminidases of influenza type(s) __, prevent release of new virus particles

• New host cells not infected, infection halted

• Resistance due to neuraminidase mutation, increasing

• Zanamivir by inhalation, oseltamivir oral

• Few side effects (nausea, vomiting; delirium reported in Japan; bronchospasm - zanamivir)

• Very expensive

Front 30

Oseltamavir, Zanamavir

• Illness reduced __-__ days?

• Start treatment within ___ hours of fever

• ↓ ________, ↓ ________ in elderly

• ↓ _____ _______ 44%, ↓ _______ 36 h in children

• Stockpiles for _____ _______ preparedness

Back 30

• Illness reduced 1-2 days

• Start treatment within 12 hours of fever

• ↓ pneumonia, ↓ hospitalization in elderly

• ↓ otitis media 44%, ↓ illness 36 h in children

• Prophylaxis 80 – 90 % effective

• 2004 H5N1, 1918 pandemic, avian flu 97-99 strains susceptible

• Stockpiles for avian influenza preparedness

Front 31

OSELTAMIVIR RESISTANCE

• H_N_ resistance reported in Europe 6/08 ( 25%) , Canada (26%), USA( 11%)

• Mutation H274Y , no ______(drug) resistance

• Use zanamivir if H_N_ virus, resistance seen

• If zanamiivr contraindication, use combination of _______ plus ________

Back 31

• H1N1 resistance reported in Europe 6/08 ( 25%) , Canada (26%), USA( 11%)

• By Dec 08, 49 of 50 US isolates resistant

• Mutation H274Y , no zanamivir resistance

• Use either if no resistance on surveillance

• Use zanamivir if H1N1 virus, resistance seen

• If zanamiivr contraindication, use combination of rimantidine plus oseltamivir

Front 32

KEY POINTS NEURAMINIDASE INHIBITORS

• Inhibit ____________ of influenza _ and _

• Resistance to _______ increasing, use _________ if suspected

• If contraindicated, use _______ plus ________

• Administration: Zanamivir by ______, oseltamivir ____

• Reduce illness ______, decrease
________ ; useful in prophylaxis

• Side effects?

Back 32

• Inhibit neuraminidase of influenza A and B

• Resistance to oseltamivir increasing, use zanamivir if suspected

• If contraindicated, use oseltamivir plus rimantidine

• Zanamivir by inhalation, oseltamivir oral

• Reduce illness duration, decrease
complications ; useful in prophylaxis

• Nausea, vomiting; bronchospasm

Front 33

RIBAVIRIN

• Broad spectrum, inhibits ___ and ____ viruses

• Inhibits viral ____ _____ _________, processing ______; resistance?

• Aerosol for ___ ________, ________; not used due to questionable ______, _______

• Oral ________ + _______ for hepatitis C

Also used for what 2 viruses?

• Side Effect: (blood related?)

• Contraindicated in?

Back 33

• Broad spectrum, inhibits RNA and DNA viruses

• Inhibits viral nucleic acid synthesis, processing mRNA; resistance infrequent

• Aerosol for RSV brochiolitis, pneumonia; not used due to questionable efficacy, high cost

• Oral ribavirin + interferon for hepatitis C

• Hemorrhagic fevers - Lassa fever , hantavirus

• Hemolytic anemia as concentrated in RBC’s; nausea, CNS effects

• Contraindicated in pregnancy

Front 34

KEY POINTS RIBAVIRIN
• Interferes with viral ____ formation

• _____ spectrum antiviral

• Aerosol for _____ _________, rarely used

• Oral _____ + _____ for hepatitis C

• Concentrated in RBC’s – _______ _________

Back 34

• Interferes with viral mRNA formation

• Broad spectrum antiviral

• Aerosol for RSV bronchiolitis, rarely used

• Oral ribavirin + interferon for hepatitis C

• Concentrated in RBC’s – hemolytic anemia

Front 35

INTERFERON

• Natural cytokines that inhibit viral
_______?

• Interfere with? (5)

• Major effect - inhibit ?

• Effect is ______ spectrum, variable?

Back 35

• Natural cytokines that inhibit viral
replication

• Interfere with penetration, uncoating, mRNA synthesis, assembly, release

• Major effect - inhibit translation of viral protein

• Effect is broad spectrum, variable

Front 36

INTERFERON ADVERSE EFFECTS

(5)

Back 36

• Fever, chills, myalgias, acute ‘influenza’

• Myelosuppression

• Hepatitis

• Neurotoxicity -- depression, ataxia, seizures

• Chronic fatigue

Front 37

KEY POINTS INTERFERON

Natural ________?

• Inhibit _________ of viral proteins?

• Used for chronic hepatitis __ and __, ___ , ____

• _________ form has longer half life, more effective

• Side effects - (3)

Back 37

• Natural cytokines

• Inhibit translation of viral proteins

• Used for chronic hepatitis B and C, HPV, HHV-8

• Pegylated form has longer half life, more effective

• Side effects - influenza like syndrome; myelosuppression, fatigue