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Mandie Pharm IV > antivirals > Flashcards

antivirals Flashcards

1
Q

general steps of viral replication

A

1) attachment of the virus to receptors on the host cell surface (virus can be cell specific, not just species specific)
2) entery of the virus through the host cell membrane
3) uncoating of viral nucleic acid
4) synthesis of early regulatory PRO
5) synthesis of new viral RNA or DNA
6) integration into the nuclear genome (if retrovirus)
7) synthesis of late/structural PRO
8) assembly of viral partiless
9) viral release from the cell

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2
Q

herpesvirus family members

A 
latent, recurring infections
-HSV -1 (oral) and HSV 2 (genital)
Varicella zoster virus
-EBV (mono, burkitt lymphoma)
-CMV
-all herpesviruses mimic guanasine
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3
Q

guanosine analogs gen info and MOA

A

acyclovir and valacyclovir

  • all prodrugs (converted to triphosphates)
  • acyclic guanosine nucleoside analogs
  • *triphosphate forms inhibit viral DNA synthesis by
  • competitions with dGTP in binding to viral DNA polymerase and polymerase inhibitions or
  • viral DNA chain termination following incorporation
  • *metabolic activation req viral enzyme (HSV thymidine kinase)
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4
Q

valcyclovir metabolism

A

is a prodrug of acyclovir (prodrug)

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5
Q

acyclovir info, use, resistance

A
  • *prodrug guanosine alanol selectively activated only in infected cells
  • relative activity: HSV1/2&raquo_space; VZV&raquo_space; EBV, CMV
  • *resistance in HSV or VZV occurs through alterations in viral thymidine kinase or DNA polymerase, mainly in immunocompromised patients
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6
Q

acyclovir MOA

A

compared to guanosine, acyclovir is missing hydroxyl group. chain terminates after incorporation into the DNA

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7
Q

acyclovir applications

A
  • *effective against VZV (higher doses than HSV)
  • if used 24h after onset of chx pox, reduces number of lesions, duration of symptoms, and viral shedding
  • similar effects against shingles if begun within 72h
  • *LT supression of genital herpes (HSV2)
  • *not effective against oral herpes (HSV1)
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8
Q

valacyclovir PK and use

A
  • *prodrug of acyclovir
  • rapidly activated with first pass metabolism in intestine and liver
  • *improved bioavailability
  • similar uses and action to acyclovir, shorter duration of zoster associated pain than with acyclovir, effective in prevention of CMV in organ transplantation
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9
Q

docosanal info and use

A
  • long chain saturated alcohol
  • *blocks fusion of viral and cellular membranes
  • *topical only
  • *orolabial herpes only: application of 10% OTC cream within 12h of symptoms shortens duration of healing ~1 day
  • *advertising claim “cuts healing time in half” ruled false
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10
Q

cidofovir use outside of CMV

A

**acyclovir resistant HSV and VZV & immunocompromised pt

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11
Q

foscarnet use outside CMV

A

**acyclovir resistance HSV and VZV infections

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12
Q

ganciclovir -MOA, effective against, resistance

A
  • *guanasine analog, similar mechanism to acyclovir and prodrug
  • metabolic conversion to nucleoside monophosphate requires kinase UL97 (and also substrate of DNA polymerase)
  • activity against CMV, HSV, VZV, and EBV
  • activity against CMV 100x that of acyclovir
  • *resistance via mutation of CMV kinase gene UL 97 or viral DNA polymerase (UL54)
  • UL54 mutation high level resistance and possible cross ressitance with cidofovir and foscarnet
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13
Q

ganciclovir use & SE

A
  • oral, IV and **intraocular implant formulations
  • oral bioavail low
  • *used for CMV infections in the setting of advanced immunosuppression (AIDS or organ transplant)
  • disseminated CMV infection resulting in end-organ disease: retinitis, colitis, esophagitis, CNS disease, pneumonitis
  • *IV or intraoccular implant for CMV retinitis
  • *most common adverse effect of IV admin: myelosuppression
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14
Q

valganciclovir

A
  • ester **prodrug of ganciclovir
  • *enhanced oral bioavailability relative to ganciclovir, other pharm similar
  • *replacing IV and oral ganciclovir
  • CMV retinitis in pt with AIDS and for prevention of CMV disease in high risk organ transplants
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15
Q

cidofovir MOA & active against & adverse effect

A
  • *cytosine nucleotide analog
  • inhibitor/alternative substrate for DNA polymerase
  • *metabolic activation does not require viral kinase
  • in vitro activity against **CMV, **HSV 1/2, VZV, EBV, adenovirus, poxviruses, polyomaviruses, and HPV
  • *adverse effect: dose-dependent proximal tubular nephrotoxicity
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16
Q

cidofovir use & adjunct therapy

A
  • CMV retinitis
  • *thymidine kinase deficient or altered strains of CMV or HSV
  • *renal toxicity mandates concomitant admin of high dose probenecid (inhibits tubular secretion of metabolites)
17
Q

foscarnet MOA

A
  • inorganic pyrophosphate analog
  • *inhibits DNA polymerases of herpesviruses, RNA polymerases and HIV reverse transcriptase
  • blocks pyrophosphate binding site of polymerases, inhibits cleavage of pyrophosphate from of deoxynucleotide triphosphates
  • activity against HSV, VZV, CMV, EBV, HIV 1/2
  • *significant adverse effects including renal impairment
18
Q

forscarnet applications

A
  • poor bio availability
  • renal clearance, dose adjusted to Cr clearance
  • CMV retinitis, colitis, and esophagitis
  • *ganciclovir and cidofovir resistant CMV
  • *acyclovir resistant HSV
  • *acyclovir resistant VZV
19
Q

standard HIV therapy drug treatments

A
  • *combination therapy with at least 3 maximally potent agents
  • *reduce viral replication to the lowest possible level and decrease the emergence of resistance
  • *tailored to individual patient and drug sensitivities of the specific viral variant (genotype)
  • *modified in response to alterations in drug sensitivity (genetive evolution of resistance)
  • *maximize tolerability, convenience, adherance
20
Q

Nucleoside/tide reverse transcriptase inhibitors MOA

A
  • *include first effective agent, zidovudine (AZT)
  • *inhibit viral reverse transcriptase, a RNA/DNA dependent DNA polymerase that converts viral ssRNA genome to proviral dsDNA
  • *compete with deoxynucleotide substrates in binding to the polymerase
  • lack of 3’hydroxyl group on **incorporated analog causes chain termination
  • *prodrugs activated by conversion to nucleotide triphosphate form by cellular enzymes
  • *genetic resistance via RT mutations
21
Q

abacavir MOA, resistance, adverse effect

A
  • guanosine analog, often used in combo with lamuvidine
  • *high level resistance req multiple RT mutations
  • *combination formulations: abacavir-lamivudine** and abacavir-lamivudine-zidovudine
  • possible increased risk of myocardial events
22
Q

lamivudine MOA, resistance

A
  • cytosine analog
  • synergizes with many antiretroviral NRTI
  • anti-HVB activity (d/c can flare hepatitis)
  • *therapy rapidly selects for M184V RT mutations in regimens not fully suppressive
23
Q

emtricitabine

A
  • fluorinated analog of **lamivudine: common properties
  • long intracellular half life (>24h) allows once daily dosing
  • *fixed dose combinations: emtricitabine tenofovir or **emtricitabine-tenofovir-efavirenz
24
Q

tenofovir

A
  • adenosine **nucleotide analog
  • synergizes with many antiretroviral NRTI
  • possible enhanced risk of bone toxicity
  • risk of renal function reduction/failure
  • *1% gel effective in decreasing incidence of heterosexual HIV acquisition
25
Q

non-nucleoside reverse transcriptase inhibitors MOA, resistance, SE

A
  • inhibit retroviral RT activity
  • *binding site of NNRTI distinct from that of NRTI
  • *allosteric inhibitors: do not compete with nucleoside triphosphates nor req phosphorylation
  • primary resistance significant (2-8%) requires HIV prior genotyping
  • some mutations cause resistance across class
  • *not cross resistance with NRTI
  • *All metabolized by CYP3A4, drug interactions
  • *SE: GI disturbances, rash including stevens johnson syndrome
26
Q

efavirenz t1/2, SE

A

NNRTI

  • long half life (50h) once daily dosing
  • *numerous CNS symptoms varying from mild to psycho
  • may cuase fetal abnormalities
27
Q

nevirapine SE

A

NNRTI
occasional severe rash mandating cessation and s-j syndrome
-inducer of CYP3A4, **lowers methadone levels
**effective in the prevention of transmission of HIV from mother to newborn when admin at onset of labor with a 2nd oral dose to the neonate within 3 days after delivery

28
Q

antiretroviral protease inhibitors MOA

A
  • *retroviral gene products are synthesized as polyprotein precursors that are cleaved by viral protease during maturation of viral particle
  • *inhibitors of the viral protease leads to the production of immature, noninfectious viral particles
29
Q

antiretroviral PI PK

A
  • *do not require phosphorylation by viral kinases

- are not useful as monotherapy due to the common occurance of phenotypic resistance

30
Q

genetic resistance of antiretroviral PI

A
  • *results from several distinct mutations in the viral protease gene that are cumulative in their impact
  • individual mutations can confer resistance to all PIs
  • some mutations confer resistance to a subset of PIs while increasing sensitivity to others
  • *wide spectrum of PIs with different patters of mutational sensitivity all find application
31
Q

antiretroviral PI SE

A
  • metabolic effects: hyperglycemia and insulin resistance, redistribution of body fat
  • possible bone loss and osteoporosis with LT use
  • some PI associated with bleeding risk
32
Q

antiretroviral PI drug interactions

A
  • all PI metabolized by CYP3A4
  • some PI are inducers of some CYP isoforms
  • extensive and significant drug interactions with PI
  • *inhibition of CYP3A4 by a PI can enhance the concentration of another retroviral drug in combination thus resulting in synergy
33
Q

ritonavir

A
  • metabolized to active metabolite by CYP enzymes
  • diverse potential adverse effects: GI, alt serum enzyme levels
  • initiated with dose escalation over 1-2 weeks
  • *potent CYP3A4 inhibitor with numerous drug ineractions but can be beneficial in combo
  • *used as a PK enhancer of saquinavir (booster)
34
Q

saquinavir

A
  • various PK issues: short t1/2, low oral bioavail
  • *once daily fixed dose saquinavir-ritonavir combo (“booster”)
  • combination has reduced GI upset and dyslipidemia of other boosted PI regimens
  • concurrent use of saquinavir and ritonavir has recognized risk of cardiac toxicity: prolonged QT and PR intervals
35
Q

antiretroviral entry inhibitors MOA

A
  • HIV entry to host cells occur in multiple steps
  • binding of the viral envelop glycoPRO complex to host cellular receptor CD4
  • gp120 conformational change allows interaction with coreceptors CCR5 and CXCR4 (cellular chemokine receptors)
  • viral envelope with host cell membrane
  • entry of viral core into cytoplasm

-each step in viral entry is a potential target for drug intervention

36
Q

enfurvirtide MOA, resistance, SE

A
  • antiretroviral entry inhibitor
  • *peptide inhibitor that binds to the gp41 subunit of the viral envelope glycoPRO
  • prevents conformational change necessary for fusion
  • *admin subQ (only parenteral antiretroviral agent)
  • *genetic resistance: mutations in gp41
  • *no cross resistance with other antiretrovirals
  • limited SE: injection site reax
37
Q

maraviroc MOA, resistance, SE

A
  • CCR5 receptor antagonist
  • *binds to host PRO ccr5
  • *used for ccr5 tropic HIV1 infection after virologic failure due to resistance to other therapies
  • *genetic resistance: mutations in gp120
  • *no cross resistance with other antiretrovirals including enfurvirtide
  • contraindicated with stron CYP3A4 inhibitors
  • diverse potential SE
38
Q

antiretroviral integrase inhibitors

A
  • block integration of proviral DNA into host genome
  • *bind/inhibit viral inegrase enzyme
  • resistance by integrase gene mutations
39
Q

dolutegravir MOA, SE, PK

A

-integrase inhibitor
-newly approved for treatment naive, treatment experienced HIV infected and combo therapies
SE: allergy, abnormal liver function in pt with HVB/C
-PK impacted by drugs altering drug metabolizing enzymes (CYPS)

Mandie Pharm IV (12 decks)

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