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Pharmacology > Antivirals/ Antiretrovirals > Flashcards

Antivirals/ Antiretrovirals Flashcards

1
Q

Why is host toxicity higher for antivirals than antibiotics?

A

difficult to interfere with viral protein synthesis w/o affecting host cell pathways

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2
Q

Antivirals are predominantly do what with viruses?

A

virustatic; do not eliminate non-replicating or latent virus

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3
Q

Influenza Viruses are classified how?

A

RNA; types A (96%) and B, Highly variable and undergo frequent mutations; subtypes of hemagglutinin and neuraminidase

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4
Q

What is the most effective approach to prevent flu?

A

vaccination; certain high-risk populations may require additional prophylaxis with drug therapy

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5
Q

What is used in cases where vaccination is contraindicated?

A

chemoprophylaxis

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6
Q

Patients with suspected influenza and high risk of developing complications may benefit from chemotherapy if started ?

A

within 48 hr after onset of symptoms

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7
Q

Amantadine MOA and resistance?

A

Blocks influenza A M2 ion channel protein and reduces influx of protons that ultimately interferes with viral uncoating
Does not bind to the influenza B M2 channel (different amino acid sequence)

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8
Q

Pharmacokinetic properties of Amantadine?

A

Orally available and well absorbed from the GI tract; Eliminated by renal excretion so dose must be reduced in renal insufficiency

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9
Q

Therapeutic uses for amantadine?

A

not recommended for routine use due to resistance
Prevention and treatment of influenza A; supplanted by neuraminidase inhibitors
Parkinson’s disease

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10
Q

Adverse effects of amantadines?

A

generally well-tolerated
CNS effects (tremors, nervousness, confusion, dizziness, ataxia) are common
Teratogenic in animals – contraindicated in pregnancy (category C)
Drug interactions – anticholinergic drugs

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11
Q

What is the category and MOA of oseltamivir?

A

competitive inhibitor of neuraminidase; interferes with replication and spread by preventing release from infected cells

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12
Q

What are the pharmacokinetics of oseltamivir?

A

orally available prodrug that is metabolized in the liver to the active carboxylate form; carboxylate is excreted by the kidneys

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13
Q

What are the therapeutic uses of oseltamivir?

A

Prevention and treatment of influenza A and B; Must be given within 48 hr of onset of symptoms to be effective; reduces duration and severity of symptoms (no clinical benefit after this time); For flu prevention in nursing home residents

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14
Q

What is the resistance and adverse reactions of oseltamivir?

A

variable in seasonal flu; some in isolates of H5N1 (avian flu); generally well-tolerated; some nausea/vomiting and headache

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15
Q

What are the PK of zanamivir?

A

Low oral bioavailability – administered as a dry powder for oral inhalation

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16
Q

What are the adverse effects of zanamivir?

A

Bronchospasm and deterioration of lung function (fatalities have occurred) in patients with asthma or COPD

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17
Q

What is the MOA of acyclovir?

A

Selectively converted to acyclo-GMP by viral thymidine kinase in the cytosol of infected cells (affinity is 200-fold greater than for mammalian TK); Host cell kinases convert acyclo-GMP to acyclo-GTP; Inserted into viral DNA by viral DNA polymerase and causes chain termination

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18
Q

What is the mechanism of resistance to acyclovir?

A

viral TK deficiency; important concern in immunocompromised patients who receive prolonged therapy

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19
Q

Acyclovir PK properties?

A

Orally effective but low bioavailability; widely distributed in the body and eliminated unchanged by the kidneys

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20
Q

How is valacyclovir different from acyclovir?

A

L-valyl ester prodrug that has 5-fold greater oral bioavailability; rapidly converted to acyclovir by hepatic first-pass metabolism

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21
Q

What are the therapeutic uses for acyclovir?

A

HSV – initial or recurrent infection;
Genital (oral, topical, IV)
Prim. herpetic gingivostomatitis
Prophylaxis/treatment in immnsupp, HSV encephalitis; ZVZ- infections in children and adults (oral, IV); Elderly with localized herpes zoster (oral)
Immunocompromised patients with herpes zoster

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22
Q

What are the adverse effects of acyclovir?

A

generally well-tolerated (top/orally); dose-limiting toxicities after IV use:
Reversible renal dysfunction from crystalline nephropathy
Neurotoxicity – alt. sensorium, tremor, myoclonus, seizures, extrapyramidal signs

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23
Q

What is the MOA of ganciclovir?

A

Selectively converted to the mono-PO4 by CMV UL97 kinase; further metabolized by host cell kinases to di- and tri-phosphates which inhibits viral DNA polymerase; DNA chain is not immediately terminated because of the 3’-like OH group

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24
Q

What are the PK properties of ganciclovir?

A

analogous to acyclovir/valacyclovir; valganciclovir (Valcyte) has a much higher oral bioavailability than ganciclovir

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25
Q

How is the selectivity of ganciclovir compared to acyclovir?

A

lower to CMV than A is to HSV; ther. index is much lower

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26
Q

What are the therapeutic uses of ganciclovir?

A

restricted due to toxicity; Treatment of CMV retinitis in immunocompromised patients (oral, IV, ocular insert); Prevention of CMV infection in transplant patients

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27
Q

What are the adverse effects of gancyclovir?

A

Myelosuppression is the major dose-limiting toxicity; need to perform CBC and can be treated with G-CSF (filgrastim); CNS effects – fever, headache, convulsions, behavioral changes

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28
Q

What is the MOA of cidofovir?

A

Not dependent on viral TK phosphorylation; converted to the active diphosphate by host cell kinases; Diphosphate competitively inhibits viral DNA polymerase (displaces dCTP)

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29
Q

What are the PK prop. of cidofovir?

A

Poor oral bioavailability; usually given IV: Prolonged intracellular t1/2 permits infrequent dosing regimens; Cleared by renal glomerular filtration and tubular secretion (90%); usually given with probenecid to block OAT1-mediated efflux

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30
Q

What are the therapeutic uses of cidofovir?

A

CMV retinitis in AIDS patients; alternative to ganciclovir, foscarnet

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31
Q

What are the adverse effects of cidofovir?

A

Nephrotoxicity – major dose-limiting toxicity; PCT dysfunction (proteinuria, azotemia, glycosuria); probenecid and saline pre-hydration reduce the risk; Neutropenia (monitor CBC); Possible human carcinogen and teratogen

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32
Q

What is the MOA of foscarnet?

A

Inhibits herpesvirus DNA polymerase; 100-fold higher inhibitory activity of viral vs. mammalian polymerase; Inhibits HIV reverse transcriptase; Not phosphorylated by viral or host cell kinases

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33
Q

What are the PK prop. of foscarnet?

A

Oral bioavailability is poor; usually give IV; Taken up slowly by cells and not metabolized; 80% eliminated unchanged in the urine

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34
Q

What are the therapeutic uses of foscarnet?

A

not as active as primary agents; used mostly for drug-resistant infections; Treatment of CMV retinitis (including ganciclovir-resistant) in AIDS patients; Acyclovir-resistant HSV and VZV infections

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35
Q

What are the adverse effects of foscarnet?

A

Nephrotoxicity; Pronounced electrolyte disturbances – symptomatic hypocalcemia (paresthesias, arrhythmias, tetany, seizures)

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36
Q

What are the properties of HCV infection?

A

RNA; does not integrate into human genome; curable; >70% of patients acute to chronic; significant morbidity and mortality

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37
Q

What are the general features of HCV treatment?

A

no vaccine; Left untreated it can result in progressive liver injury with fibrosis and eventual cirrhosis; major risk factor for HCC

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38
Q

What is the MOA of ribavirin?

A

multiple; Converted to mono-, di-, and tri-phosphates by host cell kinases
Inhibits IMP dehydrogenase, depletes GTP
Causes lethal mutations in RNA viruses

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39
Q

What are the PK prop. of ribavirin?

A

Given orally, IV and by aerosol inhalation; Avidly taken up by cells (high Vd); long plasma half-life (200-300 hr);
Eliminated by hepatic metabolism and renal excretion

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40
Q

What are the uses of ribavirin?

A

Oral ribavirin in combination with peg-interferons is the standard of care
Pediatric RSV bronchiolitis and pneumonia – given by inhalation to hospitalized children

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41
Q

What are the adverse reactions of ribavirin?

A 
Hemolytic anemia (after oral or IV use)
Contraindicated during pregnancy – category X
42
Q

What are the Classification of human endogenous IFNs?

A

3 major classes – IFN-a, IFN-b, IFN-g; only IFN-a is used clinically

43
Q

What are IFNs?

A

Host-derived polypeptide cytokines expressed in response to viral infection; Possess antiviral, immunomodulatory and antiproliferative activities

44
Q

What is the MOA of IFN-a2a?

A 
Binds to receptors on host cell membrane and activates JAK-STAT pathway (inhibits protein synthesis, maturation and release)
Stimulates host immune system – up-regulates MHC class I and II
45
Q

What are the formulations of IFN?

A

Conventional (IFN-a2a) – short-acting

Long-acting – pegylated IFN-a2a (Pegasys) – IFN attached to large inert PEG

46
Q

What are the PK prop. of IFN?

A

Not absorbed orally; well absorbed after SC or IM

Pegylation provides superior efficacy and once-per-week dosing

47
Q

What are the uses of IFN?

A

Chronic HCV and HCB in combo with other drugs
Condylomata acuminata from HPV; administered directly into the lesions
Some cancers

48
Q

What are the adverse effects of IFN?

A

Flu-like syndrome in >50% of patients; occurs early on and diminishes with continued therapy
Neuropsychiatric – depression
Myelosuppression – granulocytopenia and thrombocytopenia

49
Q

What are the properties of HBV?

A

DNA virus that integrates into host genome; HBV polymerase is functionally related to retroviral RT

50
Q

What are the general features of treatment of HBV?

A

Vaccination is the most effective approach to prevent HBV infection; given to high risk adult groups and universally for infants

51
Q

Why is prolonged therapy necessary for HBV?

A

required to produce a sustained response; Development of resistance
Relapse after therapy is discontinued

52
Q

What are risks to carriers of HBV?

A

increased risk of hepatitis that can lead to fibrosis/cirrhosis and HCC; drug therapy is recommended for patients with persistently elevated ALT and HBV DNA

53
Q

How is pegIFN-a2a dosed?

A

given SC 1/wk X 48 wks

54
Q

What is the MOA of entecavir?

A

converted by host cell kinases to the triphosphate; inhibits HBV DNA polymerase and acts as a chain terminator; guanosine analog

55
Q

What are the PK prop. of entecavir?

A

orally available and excreted in urine

56
Q

What are the uses of entecavir?

A

1st line chronic HBV (evid. of viral rep and liver inflammation for 1 yr), Lower incidence of resistance with long-term therapy, Not as active against HIV

57
Q

What are the adverse effects of entecavir?

A

Risk of lactic acidosis and severe hepato-megaly with steatosis; Acute exacerbations of HBV after discontinuation; monitor liver function

58
Q

What are the treatment goals of antiretrovirals?

A

Maximal and durable suppression of plasma HIV RNA; Restoration and/or preservation of immune function; Limitation of drug adverse effects; Reduction in HIV-associated morbidity and mortality

59
Q

What are the treatment guidelines of antiretrovirals?

A

recommend drug therapy: 1) in symptomatic patients; 2) when CD4 counts are ≤350 cells/µL; 2) in pregnancy; and 3) in HIV nephropathy or HBV regardless of CD4 count

60
Q

What is the drug regimen for antiretroviral therapy?

A

A 3-drug regimen of HAART is the minimum standard of care; expected clinical outcome is undetectable viral load by 24 weeks

61
Q

What is considered therapeutic failure of antiretroviral therapy?

A

an increase in viral load in a patient with previously undetectable virus despite continued treatment; usually requires initiation of a completely new regimen

62
Q

Why does HIV mutate rapidly?

A

replicates constantly and because RT is error-prone;

63
Q

Why is strict adherence to antiretroviral therapy?

A

crucial to maintain viral load below levels that are associated with development of drug resistance and disease progression; Probability of drug resistance is directly proportional to the viral load

64
Q

What are the therapeutic consequences of Antiretroviral therapy?

A

lifelong and complex; non-adherence-> emergence of permanent drug resistance and disease progression; long term met. effects of therapy (10-40% HIV lipodystrophy syndrome, most associated with increased risk of MI

65
Q

The complex PK drug interactions that apply to all protease inhibitors and NNRTIs results from?

A

inhibition/induction of CYPs

66
Q

What is Immune reconstitution inflammatory syndrome?

A

reversal of immunodeficiency in patients with low CD4 counts; usually occurs during initial phase of treatment; due to accelerated inflammatory rxn to overt or subclinical opportunistic infection

67
Q

What is the MOA of zidovudine (AZT)?

A

(NRTI), converted to active triphosphate by host cell kinases; insertion of ZTP into viral DNA by RT causes chain termination (no 3’-OH group);inhibits RT activity; competes with endogenous TTP for the nucleotide binding site

68
Q

What is the selectivity of zidovudine (AZT)?

A

low affinity for mammalian DNA polymerase but is capable of inhibiting mitochondrial DNA polymerase

69
Q

What is the method and properties of resistance of zidovudine (AZT)?

A

Accumulates gradually in RT when used as the sole agent; prolonged monotherapy promotes cross-resistance to other NRTIs

70
Q

How is zidovudine usually given to reduce likelihood of resistance?

A

Usually combined with lamivudine (Combivir) to maintain low viral load

71
Q

What are the PK prop. of zidovudine?

A

Orally available and widely distributed into tissues (CNS); short half-life
Eliminated by hepatic glucuronidation

72
Q

What are the ther. uses of zidovudine?

A

combination with other antiretrovirals for HIV infection; usually combined with lamivudine
Prevention of HIV infected mother-to-child transmission as monotherapy
Post-exposure prophylaxis in healthcare workers

73
Q

What are the adverse effects of zidovudine?

A

Myelosuppression – severe anemia and granulocytopenia; monitor CBC
Rare lactic acidosis with hepatic steatosis; risk factors include female sex, obesity and prolonged exposure to the drug

74
Q

What are the unique characteristics of lamivudine?

A

much lower toxicity than AZT; also treats HBV

75
Q

What are the unique characteristics of emtricitabine?

A

3TC analog that can be administered once per day

76
Q

What are the unique characteristics of Tenofovir?

A

only nucleotide; also treats HBV

77
Q

What are the MOA of efavirenz?

A

Non-competitive (allosteric) inhibition of HIV-1 RT
Does not require phosphorylation and is not inserted into the DNA strand
Does not inhibit host cell DNA polymerases

78
Q

What is the mechanism of resistance of efavirenz?

A

Highly susceptible due to single amino acid changes in RT NNRTI-binding pocket; resistance emerges in only a few days if given as monotherapy
HIV-2 is intrinsically resistant

79
Q

What are the PK prop. of efavirenz?

A

Orally effective and cleared by hepatic CYPs (2B6, 3A4)

Can be given in once-daily dosing

80
Q

What are the uses of efavirenz?

A

HIV-1 infection; commonly used in a 1X per day fixed-dose combination with tenofovir and emtricitabine (Atripla)
Effective in patients who have failed previous antiretroviral therapy not containing an NNRTI

81
Q

What are the adverse effects of efavirenz?

A

CNS symptoms (50% of patients) – dizziness, insomnia, drowsiness, vivid dreams; resolve with continued use
Rash – can be severe and life-threatening but usually resolves
Teratogen (pregnancy category D)

82
Q

What are the unique features of Nevirapine from other NNRTIs?

A

boxed-warning for liver toxicity

83
Q

What category of antiretroviral are lopinavir and ritonavir?

A

protease inhibitor

84
Q

What is the MOA of lopinavir and ritonavir?

A

Competitive inhibition of HIV protease
Prevents cleavage of gag and pol precursor polyproteins; virus fails to mature and remains non-infective
Human aspartyl proteases are not inhibited by these drugs

85
Q

What are the PK prop of lopinavir?

A

orally available and well-absorbed, active antiretroviral component; Extensively metabolized by hepatic CYP3A4; also a substrate for P-glycoprotein efflux transporter

86
Q

What are the PK prop of ritonavir?

A

orally available and well absorbed; presence only “boosts” the activity of lopinavir by inhibiting its CYP-mediated clearance; Extensively metabolized by hepatic CYP3A4; also a substrate for P-glycoprotein efflux transporter

87
Q

What are the adverse effects of ritonavir and lopinavir?

A

GI intolerance is the most common effect

Lipodystrophy syndrome with long-term use

88
Q

What are the drug interactions of ritonavir and lopinavir?

A

Ritonavir is a potent inhibitor of CYP3A4; also induces 3A4; Other CYP inhibitors (antifungal agents, grapefruit juice, clarithromycin); reduce the dose; Other CYP inducers (rifampin, anticonvulsants, St. John’s wort); loss of efficacy; Prolongs effects of PDE5 inhibitors for ED

89
Q

What are the unique features of atazanavir from other protease inhibitors?

A

less likely to cause lipodystrophy; FDA warning – do not use with proton pump inhibitors (PPIs - omeprazole) because they reduce efficacy

90
Q

What is the MOA of enfuvirtide?

A

binds to HIV gp41 protein and prevents the HIV envelope from fusing with the CD4 T cell membrane

91
Q

What are the PK prop. of enfuvirtide?

A

administered SC 2X/day; only antiretroviral that must be given parenterally

92
Q

What are the uses of enfuvirtide?

A

added to existing regimens when there is evidence of HIV replication despite continued therapy

93
Q

What are the adverse effects of enfuvirtide?

A

Injection-site reactions – common and persistent pain, erythema and cysts; Elevated risk of bacterial pneumonia

94
Q

What is the MOA of maraviroc? Use?

A

blocks chemokine CCR5 co-receptor; prevents binding of viral gp120; only antiretroviral that targets a host protein
Used only in CCR5-tropic HIV infections (no activity against CXCR4 trope)

95
Q

What is the MOA and selectivity of raltegravir?

A

Inhibits HIV integrase; prevents insertion of viral DNA into host genome
Selectivity – human DNA does not undergo excision and re-integration

96
Q

What are the PK prop, uses and adverse effects of raltegravir?

A

orally avail, cleared by glucuronidartion; HIV infections in HAART; gen well tolerated

97
Q

Direct acting antivirals for HCV that target specific nonstructural proteins of HCV?

A

NS3/4A – serine protease that cleaves viral polyproteins into mature forms (analogous to HIV protease); NS5B – RNA polymerase responsible for replicating viral RNA; NS5A – protein critical in viral replication and assembly

98
Q

What is MOA of simeprevir? resistance?

A

inhibits viral NS3/4A protease; high if used alone

99
Q

What are the PK prop of simeprevir?

A

orally 1X per day always in combination with ribavirin/IFN or sofosbuvir

100
Q

What are the adverse reactions to simeprevir?

A

photosensitivity and rash; contraindicated during pregnancy (X); CYP3A4-related drug interactions

101
Q

What is the MOA of sofosbuvir (Sovaldi)?

A

nucleotide prodrug metabolized to the active triphosphate; inhibits NS5B polymerase and acts as a chain terminator

102
Q

What are the PK prop. of sofosbuvir (Sovaldi)?

A

efficacy across all HCV genotypes and a high barrier to resistance, orally 1X per day in combination with ribavirin/IFN

Pharmacology (8 decks)

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