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PDA Block 3 > Antiviral > Flashcards

Antiviral Flashcards

1
Q

challenges with antiviral therapy

A

for man infections viral replication peaks near the time slinical symptoms first appear

  • drugs most effective if administered before onset of symptoms
  • not true for herpesvirus, HIV, or hepatitis: replication continues over long periods
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2
Q

Antiviral infections laten infections

A

therapy does not eliminate latent (dormant forms)

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3
Q

are these drugs virustatic or virucidal

A

most are virustatic. so viral eradication requires competent host immune system

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4
Q

Immunization

A

Active-vaccination
Passive-injection of immune globin (antibodies)
*Palivizumab: monoclonal Ab to prevent severe resspiratory synctial virus in high risk pediatric patients

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5
Q

Palivizumab

  • use
  • mechanism
A
  • humanized monoclonal Ab to prevent severe RSV in high risk pediatric patients
  • binds to fusion protein of RSV to prevent fusion to host cells
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6
Q

Infleunza A prophylaxis

A

-Amantadine

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7
Q

Influenza A and B treatment/prophylaxis

A

Oseltamivir

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8
Q

Amantadine

A
  • prophylaxis against influenza A not influenza B (Best for prevention)
  • therapy for infleunza A: reduces fever in 50% of patients and illness duration by 1-2 days if given within first 2 days
  • resistance is now a common problem
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9
Q

Amantadine

A

-blocks viral uncoating by interfering with influenza A M2 protein (an ion channel)

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10
Q

Amantadine sie effects

A
  • CNS effects
  • slurred speech
  • confusion, depression
  • headaches, hallucinations
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11
Q

Oseltamivir

A
  • prodrug, given orally
  • competitively inhibits influenza neuraminidases
  • interferes with viral release and viral penetration
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12
Q

approved uses for Oseltamivir

A
  • treatment of uncomplicated influenza A and B in patients over one year old
  • greatest benefit when given within 48 hours of symptom onset
  • cinically it is less effective against influenza B than A
  • influenza prophylaxis for people over 1 year old
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13
Q

side effects for oseltamivir

A
  • nausea, vomiting, diarrhea

- bronchitis

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14
Q

Trifluridine

A

thymic analog

interferes with DNA synthesis

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15
Q

Trifluridine

A
  • ophthalmic use only

- treatment of HSV 1 and 2

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16
Q

Acyclovir

A
  • phosphorylated form is produced 40-100x faster in infected cells by herpes thymidine kinase
  • inhibits herpes DNA polymerase 10-30x more effectively than host cell DNA polymerase
  • competes with deoxy-GTP for DNa polymerase
  • terminates DNA chain elongation
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17
Q

Acyclovir IV use

A
  • serious systemic herpes simplex virus
  • HSV encephalitis
  • disseminated neonatal HSV
  • severe!! initial genital herpes
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18
Q

Acyclovir oral use

A
  • primary genital herpes

- primary herpetic gingivostomatitis

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19
Q

Acyclovir topical uses

A

-primary genital herpes

may shorten healling time and pain when applied early

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20
Q

Acyclovir side effects

A
  • generally well-tolerated
  • rash, itching
  • nausea, vomiting, heaadache, fatugue
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21
Q

Famciclovir

A
  • prodrug activation

* active component is penciclovir-triP

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22
Q

Famciclovir mechanism

A

-Penciclovir-triP inhibits viral DNA polymerase (similar mechanism to acyclovir)

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23
Q

uses of famciclovir

A
  • acute herpes zoster
  • shingles latent chicken pox virus. localized and less than 3 days duration
  • treatment and suppression of recurrent gential herpes
  • oral administration and better absorbed than acyclovir
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24
Q

what is the effect of Famciclovir daily

A

its a suppressive therapy that markedly reduces recurrent episodes of genital herpes

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25
Q

Side effects of famciclovir

A

similar to acyclovir

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26
Q

Penciclovir
MOA
Use

A
  • mechanism similar to acyclovir
  • recurrent herpes of the lips and face
  • topical administration
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27
Q

Drug for CMV prophylaxis

A

-Acyclic nucleoside analogs
*Ganciclovir
Pyrophosphate analogs
*Foscarnet

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28
Q

Ganciclovir MOA

A

similar to acyclovir, except monophos by CMV protein kinase

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29
Q

why do we ever care about CMV virus if most of the population has it?

A

-in immunocompromised people like HIV positive or solid organ transplant

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30
Q

Uses of Ganciclovir

A
  • CMV retinitis
  • in aids patients. doesn’t stop the retinitis completely
  • CMV prophylaxis for transplant recipietns
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31
Q

side effects for Gangciclovir

A
  • bone marrow suppression

* leukopenia (less than 40%) thrombocytopenia, anemia

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32
Q

Foscarnet

A
  • selectively inhibits CMV DNA polymerase by binding to its pyrophosphate-binding site
  • does not require conversion to triphosphate form to be active
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33
Q

Foscarnet uses

A
  • CMV retinitis
  • acyclovir resistant herpes simplex
  • eg those with thymidine kinase mutations
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34
Q

Foscarnet side effects

A
  • renal damage
  • electrolyte imbalances
  • seizures
  • compared to gancivlovir, higher percent of patients on foscarnet must be take off due to the side effects
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35
Q

so what is the real effect of an anti-CMV drug on retinitis

A

Anti-CMV drugs will slow the progression of CMV retinitis but not cure it

the best retinitis strategy is prevention, for HIV patients, effective anti-HIV drug regimens to keep CD4 counts elevated

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36
Q

Drugs for Hepatitis B

A
  • Lamivudine
  • Tenofovir
  • Interferon-alpha
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37
Q

Hepatitis C drugs

A
  • Ribavirin
  • Interferon-alpha
  • Simeprevir
  • Sofosbuvir
  • Ledipasvir
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38
Q

RSV-Repiratory syncytial virus

A

Ribavirin

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39
Q

Why is Hepatitis B difficult to cure

A

persistent HBV cccDNA in the nucleus

typically requires prolonged or lifelong therapy

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40
Q

Lamivudine

A
  • nucleoside analog converted by cell enzymes to triphosphate form
  • competitively inhibits the reverse transcriptase domain of the HBV polymerase
  • causes DNA chain termination
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41
Q

Use of lamivudine

A

hepatitis B

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42
Q

side effect Lamivudine

A

nausea diarrhea

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43
Q

Tenofovir

A
  • adenosine monophosphate prodrug that is phophorylated by cell enzymes to the triphosphate form
  • competitively inhibits the reverse transcriptase domain of the HBV polymerase
  • casues DNA chain termination
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44
Q

use of Tenofovir

A

approved fr hepatitis B

45
Q

side effects for Tenofovir

A

GI upset

46
Q

alpha interferons approved use

A
  • condyloma acuminata (venereal warts)
  • Hepatitis B and C given with other drugs Pegylation decreases IFN clearance
  • better clearance and less frequent dosing
47
Q

Side effects of interferon alpha

A
  • flu-like syndrome
  • leukopenia, bone marrow suppression
  • neurotoxicity, myalgia
  • side effects are the greatest limitation to long-term use of interferon alpha
48
Q

Ribavirin MOA

A
  • interferes with viral mRNA synthesis by
  • mono-P form inhibits inosine-5’-P-dehydorgenase and thus GMP (and GTP) synthesis
  • Tri-P form inhibits GTP-dependent capping of viral mRNA
49
Q

Uses of RIbavirin

A
  • aerosol use: subset of infants and young children with documented severe RSV infections. it is no longer commonly used
  • oral capsules
  • hepatitis C in combination with PEG interferon alpha and other drugs
50
Q

Ribavirin side effects

A
  • aerosol use:
  • drugs may precipitate in and clog respiratory equipment
  • pulmonary function deterioration; rash
  • IV or oral use:
  • anemia bone marrow suppression
51
Q

Hepatitis C

A

RNA virus (ssRNA, + strand)

Does not integrate into host DNA
-theoretically curable

52
Q

are there vaccines available for hepatitis

A

yes for hepatitis B no for hepatitis C

53
Q

Drugs for Hepatitis C

A
  • *Multidrug therapy**
  • PEG-interferon alpha
  • ribavirin
  • *Ns3/Ns4 A protease inhibitors
  • simeprevir
  • *NS5B RNa polymerase inhibitors
  • sofosbuvir
  • *NS5A protein inhibitors
  • ledipasvir
54
Q

Simeprevir MOA

A
  • reversible inhibitor of hepatitis C NS3/NS4A protease

- blocks cleavage of polyprotein and thus formation of infectious virus

55
Q

Approved use of simprevir

A
  • hepatitis C genotype 1

- In combo with other drugs for HCV

56
Q

Adding simprevir does what to the outcomes for HCV genotype 1

A

Simprevir greatly improves the outcomes for HCV genotype 1

57
Q

simprevir side effects

A
  • rash (with r without photosensitivity)
  • nausea, itching
  • CYP3A interactions: SImprevir is metabolized by CYP3A
  • avoid use with moderate or strong inducers or inhibitors of CYP3A they significantly alter simprevir levels
58
Q

Sofosbuvir

A
  • Nucleoside (uridine) analog prodrug
  • active for is the triphosphate
  • inhibits HCV NS5B RNA polymerase
  • its incorporation causes chain termination
59
Q

Sofobuvir uses

A

all hepatitis C drugs

-give with other HCV drugs

60
Q

Sofosbuvir adverse effects

A

avoid potent inducers of P-glycoprotein (Pgp)

ex: rifampin, ST johns wart

61
Q

Ledipasvir
MOA
use
adverse efects

A
  • inhibits NS5A phosphoprotein
  • given with sofosbuvir
  • HCV genotypes 1,4,5,6
  • SE: avoid potent inducers of P-glycoprotein
62
Q

important properties of HCV drug combinations

A
  • given 2 or more drugs with different mechanism
  • avoid IFN-alpha when possible
  • genotype appropriate therapy
  • side effect tolerance (lengthy therapy, potential drug interactions, IFN alpha is the most difficult to tolerate overall)
63
Q

HIV therapy

A
  • multidrug
  • Reverse transcriptase (RT) inhibitors
  • Nucleoside analog (NRTIs)
  • Non-nucleoside inhibitors (NNRTIs)
  • protease inhibitors (PIs)
  • Fusion inhibitors
  • CCR5 antagonists
  • integrase inhibitors
64
Q

NRTIs

A
  • Zidovudine (AZT)
  • Lamivudine (3TC)
  • Abacavir
  • Tenofovir
  • Emtricitabine (FTC)
65
Q

NNRTIs

A

-Efavirenz

66
Q

Protease Inhibitors

A

(navir)

  • Lopinavir
  • Ritonavir (booster)
67
Q

Fusion Inhibitors

A

-Enfuvirtide

68
Q

Zidovudine or AZT

A

-thymidine nucleoside analog phosphorylated by cell enzymes to AZT-triphosphate, which competitively inhibits RT and acts as a chain terminator

69
Q

Zidovudine (AZT) side effects

A
  • bone marrow suppression
  • neutropenia, anemia
  • avoid drugs which inhibit glucuronyltransferases
  • myopathy
70
Q

Why shouldn’t you use a Glucuronyl Transferase with an AZT

A

-drugs that inhibit glucuronidation of AZT increase the hemolytic toxicity of AZT

so basically AZT can be metabolized in two ways, one is via glucuronyl transferases and the other is reduction by cytochrome P450s. The cytochrome pathway leads to a toxic amine production that causes bone marrow toxicity

so if you block glurcuronyl trasferase it all goes throught the path that causes bone amrorow toxicity

71
Q

Mechanism fo NRTIs

A
  • nucleoside analogs that must be phosphorylated to tri-phos form to be active
  • competitive inhibitors of RT
  • cause DNA chain termination when incorporated into DNA
72
Q

Tenofovir

A

-adenosine monophosphate drug that is hydrolyzed to tenovir phosphonate, which is further phosphorylated by cellular enzymes to triphosphate form

73
Q

similarities of Tenofovir and AZT

A

triphosphate form competitively inhibis RT causing DNA chain termination

74
Q

Tenofovir uses

A

-combination therapy HIV

75
Q

Side effects Tenofovir

A

overall well tolerated

76
Q

Lamivudine

A
  • nucleoside analog inhibitor of RT
  • phosphorylated by cell enzymes to triphosphate form that competitively inhibits RT, causes DNA chain termination
  • AZT resistant strains are 3C sensitive and
  • 3TC resistant strains are AZT sensitive

-synergistic with AZT against HIV

77
Q

side effects of Lamivudine

A

nausea, diarrhea, rash

78
Q

Emtricitabine

A
  • FLuortinated analog of lamivudine

- same mechanism and resisitance as 3TC

79
Q

Abacavir

A
  • nucleoside analog

* triphosphorylated form inhibits RT and causes DNA chain termination

80
Q

adverse effects of abacavir

A
  • HYPERSENSITIVITY
  • associated with HLA-B*5701 allele

-If hypersensitivity occurs STOP drug immediately and never start again

81
Q

other side effects associated with NRTIs as a group

A
  • Lactic acidosis

- Hepatic steatosis

82
Q

Non-nucleoside inhibitors RT (NNRTIs)

A

efavirenz

**this is active as given it does not need to be phosphorylated to be active

83
Q

Efavirenz

A
  • non-nucleoside inhibitor RT
  • binds at different site than NRTIs
  • disrupts active site of RT
  • active as given
  • as part of a multi-drug therapy for HIV
  • once per day dsingL 2005 #1 anti HIV drug in USA
84
Q

side effects of Efavirenz

A
  • rash
  • CNS/psychiatric symptoms (various) nightmares, vivid dreams
  • occurs in 50% of patients especially early in the treatment (first month, sometimes goes away after the first month)

these side effects are why it isn’t being prescribed as much

85
Q

Protease Inhibitors for HIV

A
  • Lopinavir
  • Ritonavir (used as a PI booster not as a PI)
  • Ataznavir: less incidence of lipid abnormalities
  • Darunavir: effective against many strains resisitant to other PIs
86
Q

Use of protease inhibitors

A
  • in combination with inhibitors of RT: for HIV-1 and HIV-2

- significantly decrease viral blood level-often below detectable levels

87
Q

Mechanism of Protease Inhibitors

A
  • prevents viral aspartic protease from cleaving Gag-pol polypeptide into separate functional proteins
  • competitive inhibitor of protease active site
  • results in non-infectious viral particles
88
Q

Toxicities common to a number of protease inhibitors including Lopinavir

A
  • diabetes
  • alterations in lipid metabolism: increase in triglycerides and cholesterol
  • fat redistribution
  • alters metabolism of many other drugs
  • potent CYP3A inhibitors
89
Q

Liponavir

A

protease inhibitor

90
Q

Ritonavir

A
  • used to boost levels of other protease inhibitors because it blocks their metabolism by CYP3A
  • avoid other drugs metabolized by CYP3A
91
Q

Retonavir as a PI booster

A

-Ritonavir boosts lopinavir levels by blocking the metabolism of lopinavir by CYP3A

92
Q

Enfuvirtide

A
  • used only for HIV-1 not HIv-2

- HIV treatment experienced patients who have failed multiple regimens

93
Q

MOA Enfuvirtide

A
  • binds to gp41 subunit of HIV glycoprotein

- block conformational changes required for membrane fusion to CD4 cells

94
Q

side effects for Enfuvirtide

A

-local injection site reactions in 98% of people (pruritis, pain,, erythema, cysts, nodule formation can be very serious)

  • diarrhea, nausea, fatigue
  • used as a later option when other regimens have failed
95
Q

Maraviroc-use

A
  • treatments of CCR5-tropic HIV 1
  • effective for strains resistant to other drugs
  • CCR5 tropic strains tend to predominate early in infection
96
Q

Maraviroc mechanism

A
  • small molecule antagonist chemokine co-receptor CCR5 preventing interaction with HIV gp120
  • the only anti HIV drug that targets a human protein
  • blocks entry of HIV into cells
97
Q

what is the only anti-HIV drug that targets a human protein

A

Maraviroc is targeting OUR CCR5 receptor, not HIV

98
Q

Maraviroc side effects

A

possible hepatotoxicity

-cardiovascular events

99
Q

Inhibitors of HIV Integrase

A

raltegravir

100
Q

Raltegravir- use

A
  • treatment HIV-1 in new and treatment-experienced patients
  • works on virus that is resisitant to other drugs
  • as a part of multi drug therapy, common 1st like use

(teg in the name comes come inTEGrase)

101
Q

Raltegravir

A

inhibits HIV-1 integrase activity

-preventing integration of HIV-1 DNA into the genome

102
Q

raltegrase

A

potential for severe/fatal skin and hypersensitivity reactions

103
Q

Current reasons for HIV therapeutic failure

A
  • failure to maintain adherence to rug regimens
  • resistant stains emerge (replication not stopeed)
  • test initially and when changing regimens
  • the available drugs are very effective at suppressing viral replication when selected and used properly
  • the best way to prevent opportunistic infection is anti-HIV therapy to stop HIV replication, keeping CD4 counts higher
104
Q

Selection of drug combinations

A
  • viral resistance profiles
  • compliance
  • ease of administration
  • tolerance of side effects
  • co-morbid conditions
105
Q

Drug combination for treating HIV

A

3 or more drugs per patient ( more than two drug classes)
-YOU WANT TO KEEP REPLICATION AT ZERO TO PREVENT RESISTANCE

  • HAART: Highly active anti-retroviral therapy
  • combination of drugs of 2 or more classes
106
Q

what is the current guideline to monitor therpy effectiveness

A

-current guidelines use viral load to monitor therapy effectiveness

107
Q

indications for starting HAART DHHS Guidelines

A
  • initiate treatment in all HIV infected individuals as soon as possible in order to:
  • reduce risk of disease production
  • reduce risk of HIV transmission
108
Q

How soon after infection should you initiate anti-HIV drugs

A

ASAP!!!! even 24 hours-36 hours may be too late

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