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GI Pharm > GI Rx of Viral Hepatitis > Flashcards

GI Rx of Viral Hepatitis Flashcards

1
Q

Which agents are used in the Rx of Chronic Hepatitis B infections? (7)

A 
Rx HBV w/ "TEETLAP, Bitch"
B=HBV
Tenofovir (prodrug form = Tenofovir disoproxil fumurate)
Entecavir
Adefovir
Telbivudine
Lamivudine
(the five above are orally active antivirals)

Emtricitabine
Peginterferon alfa-2a can be used for both chronic HBV and HCV.

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2
Q

How does the use of the two Peg-IFN alpha agents differ?

A
  1. PegIFN alpha-2a is approved for Rx of both HBV and HCV

2. PegIFN alpha-2b is approved only for HCV infection

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3
Q

What is important about Emtricitabine?

A

It is used to Rx pt’s co-infected w/ both HIV and HBV, as it has activity against both.

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4
Q

What are the first line agents used in Rx of chronic HepB? Which two are the preferred agents?

A

a. First line agents: the five orally active antivirals (1st EAT bLT: Entecavir, Adefovir, Tenofovir, Lamivudine, Telbivudine)
b. Tenofovir or Entecavir is preferred

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5
Q

Why are the 5 oral antivirals the 1st line agents? (2)

A
  1. Better tolerated than IFNs

2. Better suppression of the virus

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6
Q

When might a first line agent other than Tenofovir or Entecavir be used in the Rx of HepB? (3)

A

Alternative regimens may be preferred over Tenofovir/Entecavir due to:

  1. Comorbidities that preclude their use
  2. Resistance
  3. Co-infections (HBV + another virus)
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7
Q

T/F: Combination regimens diminish resistance and are more effective in the Rx of HepB.

A

False, combination regimens may diminish resistance but are not necessarily more effective.

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8
Q

What is important concerning antiviral resistance in the Rx of chronic HBV?

A

Antiviral resistance tends to be SUGAR-RESIDUE-SPECIFIC (structure-specific)
(meaning that when virus becomes resistant to one antiviral agent, it is usually also resistant to others w/ the same sugar residue)

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9
Q

Which antivirals used to treat HBV have cross-resistance? (2 groups of 2)

A

Agents that share the same sugar residues (structure)
1. L-nucleosides→Lamivudine + Telbivudine
2. Acyclic Phosphonates→Tenofovir + Adefovir
(Entecavir is the only D-cyclopentane so no cross-resistance with the other 4)

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10
Q

If a HepB infection has resistance to Lamivudine and Tenofovir, which agent can be substituted and still have full activity? How should it be substituted?

A

Entecavir→no cross resistance w/ Vudines or Fovirs.
When HBV develops resistance to an agent, the new agent is added on (patient still takes old drug too) rather than as sequential monotherapy.

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11
Q

How does HBV antiviral resistance arise?

A

Resistance arises from mutations in HBV Polymerase causing reduced sensitivity to the drug

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12
Q

Which antivirals are L-nucleosides?

A

the “-vudiNe’s”→N=Nucleoside

Lamivudine and Telbivudine (and Emtricitabine)

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13
Q

Which antivirals are Acyclic Phosphonates? (2)

A

the “-FOvirs’s→FO=Fosphonates
Tenofovir disoproxil and Adefovir
these are nucleo-T-ide analogs of A-denosine-5-monophosphate (AMP)

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14
Q

Which antiviral is a D-Cyclopentane?

A

Entecavir (guanosine nucleoside analog)

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15
Q

What is a general feature concerning the activity of antivirals used in the Rx of chronic HepB?

A

They have to be phosphorylated to achieve active forms, which serve as analogs for building blocks of RNA/DNA replication.
(All inhibit HBV polymerase except Adefovir)

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16
Q

Which antivirals are active as Diphosphates (2)? As Triphosphates (4)? Which cause chain termination (3)

A
  1. Diphosphates→TA-D→Tenofovir, Adefovir which are nucleoTide analogs (acyclic phosphonates, based on name they already have one so add two more)
  2. Triphosphates→all the others b/c they are nucleoSide analogs→Entecavir, Telbivudine, Lamivudine, Emtricitabine
  3. Terminator TAToo→Telbivudine, Adefovir, and Tenofovir produce chain termination
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17
Q

MoA of Entecavir?

A

EGS; E=Entecavir

Guanosine nucleoSide analog→the triphosphate form inhibits HBV polymerase

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18
Q

MoA of Tenofovir disoproxil? (2)

A

Pro-drug for Tenofovir→Nucleotide Analog of adenosine-5-monophosphate (AMP). The diphosphate form:

  1. Inhibits HBV Polymerase
  2. Produces chain termination
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19
Q

MoA of Adefovir? What is unique about Adefovir’s mechanism compared to the other oral antivirals.

A

a. Adenosine-5-monophosphate (AMP) nucleotide analog→Diphosphate form is incorporated into viral DNA producing chain termination.
b. Adefovir is the only one that is incorporated into viral DNA and the only one that does NOT inhibit HBV polymerase (Note to self: I’m not sure if this is true but if it comes up on test, this would be the drug)

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20
Q

MoA Telbivudine?

A

TeLbivudine = L-isomer of Thymidine.

Triphosphate form inhibits HBV polymerase and produces chain termination.

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21
Q

MoA of Lamivudine and Emtricitabine? How do their activities compare?

A

a. MoA: L-isomers of Cytosine. Triphosphate form inhibits HBV Polymerase.
b. They have similar activity, potency, side effects, and patterns of resistance

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22
Q

Three general patterns concerning ADME of the antivirals used in the Rx of HBV?

A

a. No CYP interactions
b. All excreted in urine (RENAL Elimination), so:
1. Competitive renal secretory mechanisms may be an opportunity for drug-drug interactions (DDI’s)
2. Dose reduction may be required in Renal Dysfunction (ie in the elderly)

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23
Q

Which antiviral has the longest half-life?

A

Entecavir

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24
Q

Which agent is excreted in urine by passive processes? Which 4 are secreted by glomerular filtration and renal tubular secretion?

A

a. Telbivudine is via passive processes (so maybe no competition???)
b. GFR+RTS→TALE→Tenofovir/Adefovir, Lamivudine/Emtricitabine

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25
Q

How do the oral bioavailability properties of antivirals used in Rx of HepB compare when taken with food? (3)

A

a. Food has no substantial effect on bioavailiability of A-LET (Adefovir+L-Nucleosides: Telbivudine, Lamivudine, Emtricitabine)
b. TenoFovir=Take w/ Fat→Tenofovir bioavailability increases when taken w/ high fat meal
c. Food delays absorption of Entecavir→coordinate meals and dosing (Entecavir is the only D-cyclopentane so its the only one w/ D-elayed abs w/ food)

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26
Q

Tenofovir is associated w/ what rare toxicity? Most often in who (2)? How does it manifest? What should be monitored? What do these pt’s on Tenofovir need to avoid?

A

a. Acute Renal Failure (ARF)
b. ARF most often in pt’s w/ systemic/renal disease or taking concurrent nephrotoxic drugs, BUT sometimes in pt’s with no identified risk factors
c. Proximal tubule damage may manifest as: BONE PAIN/FRACTURES, pain in extremities, and/or muscle pain/weakness
d. SrCr/BUN and Phosphate (bone) testing recommended
e. Pt’s should avoid concurrent nephrotoxic drugs like NSAIDs

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27
Q

Besides Tenofovir, which other antivirals need to be monitored for renal damage (SrCr/BUN)? (3)

A

In addition to tenofovir, SrCr/BUN tests also recommended for Lamivudine, Adefovir, Entecavir (ALE can hurt the kidneys)

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28
Q

Mechanism of HBV antiviral (NRTI)-mediated renal/hepatic toxicity? (Just read)

A

Background: Some of these drugs are eliminated by glomerular filtration, others by renal tubular secretion (RTS). RTS involves active, energy-dependent apical membrane pumps.

Mechanism: In a genetically predisposed pt:

  1. Drugs cross basolateral membrane into PCT cells (via pumps??)
  2. Predisposition prevents their apical secretion by pumps→NRTI accumulates in PT cells
  3. NRTI’s inhibit host mitoch DNA (mtDNA) Polymerase gamma (required for mtDNA replication)→Mitochondrial toxicity
  4. This becomes significant when organ’s energy threshold is not met due to damaged mitoch.
29
Q

Antiretoviral drugs are associated w/ what ADE? Which agent used to treat HBV is particularly associated w/ this ADE? What else should the pt take to help with this?

A
  1. Antiretrovirals are associated w/→reduced bone mineral density, increased bone turnover, and increased risk of osteoporotic fracture
  2. Tenofovir has a particular high association w/ this
  3. Calcium and Vit D supplements are recommended in the Rx of HIV
30
Q

The nucleoside/nucleotide analog antiretrovirals used in the Rx of HBV are associated w/ what other toxicity?

A

Hepatotoxicity w/ Lactic Acidosis and Steatosis (esp w/ Adefovir, Telbivudine, Entecavir→monitor w/ LFTs)

31
Q

What are risk factors associated w/ antiretroviral hepatotoxicity? (4)

A

Lactic Acidosis and Steatosis:

  1. mc in Women
  2. Obesity
  3. Alcoholism
  4. Prolonged drug exposure
32
Q

What should the doctor do if a pt being treated for HBV develops Rx-related hepatotoxicity?

A

Suspend Rx in any pt that develops clinical/lab findings suggestive of hepatotoxicity (including hepatomegaly/steatosis even in the absence of elevated transaminases)

33
Q

LFTs are recommended to monitor which agents used in Rx of HBV? (3)

A

ATE

Adefovir, Telbivudine, Entecavir

34
Q

Which anti-HBV agents can be used in Rx of HIV/HBV co-infection? How do their activities compare?

A

ETE

  1. Emtricitabine→best anti-HIV activity. Actually only approved for Rx of HIV but has some activity against HBV as well.
  2. Tenofovir→active against HIV
  3. Entecavir→weakly active against HIV
35
Q

What is the most effective regimen in Rx of HIV/HBV co-infection? Which regimen should not be used and Why?

A

a. Tenofovir + Emtricitabine combo is most effective

b. Do NOT use Lamivudine + Emtricitabine b/c they have similar structure/MoA→no advantage

36
Q

Initial Rx regimen of HBV/HCV co-infection?

A

Initially treated w/ Peginterferon + Ribavirin to target the HCV

37
Q

General and 4 specific MoAs of IFN-alpha’s?

A

a. General: Cytokines w/ ANTIVIRAL, anti-proliferative, and immunomodulatory effects

b. Specific: Binds cell-surface IFN-R→activates Tyrosine Kinases→JAK-STAT→production of several IFN-stimulated enzymes, leading to:
1. Cleavage of viral ss-RNA by endoribonucleases
2. Inhibitory effects on ds-RNA
3. Inhibition of viral penetration/uncoating/assemmbly/release
4. Enhanced lytic effects of cytotoxic T lymphocytes (CTLs)

38
Q

Administration of IFNs? Why PEGylated (2)?

A
  1. IM or SC (unlike oral antivirals). Cellular effects exceed persistence of the drug in the body
    2a. Pegylation provides sustained serum levels (longer t1/2) permitting once weekly dosing
    2b. Pegylated products are usually better tolerated→lower rates of discontinuance due to ADEs
39
Q

ADE of Peginterferons following injection? What is given to reduce this?

A

a. Acute flu-like syndrome following IM/SC injection (fever, chills, headache, my/arthralgia, n/v/d, etc)
b. Give Antipyretics to help w/ this, but patient will become tolerized to this over time

40
Q

ADEs of IFNs? (6)

A

“IfN HIT Me”
If: acute InFluenza-like syndrome following IM/SC injection (give antipyretics)
N: NEUROPSYCHIATRIC issues (major dose limiter)
a. Depression (mc in HCV than HBV)
b. Somnolence, confusion, behavioral changes, rarely seizures→possible effect on serotonin/corticotropin
Me: Myelosuppression→granulocytopenia & thrombocytopenia, less commonly anemia
H: increased Hepatic enzymes (hepatotoxicity)
I: Increased Triglycerides
T: Thyroid dysfunction→temporary thyrotoxicosis (weeks to months)

41
Q

How can IFN treatment lose its clinical effectiveness/responsiveness?

A

Infrequently, pt may develop serum neutralizing antibodies

42
Q

How does IFN Rx cause thyroid dysfunction?

A

IFN modulates immune system→immune-mediated destruction of thyroid tissue in predisposed pt’s→temporary thyrotoxicosis (lasts weeks to months)

43
Q

Do pt’s with IFN-related thyroid dysfunction need to discontinue IFN antiviral therapy?

A

No, can take additional drugs to Rx thyroid problem, allowing continuation of IFN antiviral Rx.

44
Q

What drugs are used in pt’s w/ IFN-related thyroid disorders to allow continuation of IFN antiviral therapy? (JUST READ)

A

Depends on type of thyroid problem: (IFN may have to be stopped til thyroid under control)

  1. Destructive thyrotoxicosis (increased ANS stimulation)
    a. Asymptomatic→No therapy
    b. Symptomatic→BB’s
  2. Graves Hyperthyroidism:
    a. Mild→Antithyroid drugs
    b. Severe→Radio-iodine
45
Q

Which agents are used in the treatment of chronic Hepatitis C infections? (5)

A 
"C'ing (seeing) Riblets Intimidated Bo & Telep"
C=HCV
R: Ribavirin
I: PegInterferon alfa-2a and alfa-2b
B: Boceprevir
T: Telaprevir
46
Q

Rx Regimens (2) for HCV? What determines which regimen is used?

A

Recommended regimen depends on genotype.

  1. Rx of Genotype 1:
    PegIFN-alfa + Ribavirin (24-48 wks) + Telaceprevir/Boceprevir
  2. Rx of Genotypes 2 and 3
    Peg-IFN-alfa + Ribavirin for 24-48 wks
47
Q

Ribavirin MoA? (4)

A
  1. Enhanced host T-cell immune clearance of HCV
  2. Inhibition of host IMPDH→depletion of GTP pools. GTP is an essential substrate for HCV RNA synthesis.
  3. Inhibition of RNA-dependent RNA polymerase→direct inhibition of HCV replication
  4. RNA virus mutagensis→drives HCV to error catasrophe
48
Q

Effect of Ribavirin actions on HCV RNA levels and serum alanine aminotransferase levels?

A

May only transiently reduce HCV RNA levels, BUT often normalizes serum alanine aminotransferase levels (LFTs)

49
Q

T/F: Ribavirin can be used alone in the Rx of HCV infections?

A

False, it is always used in combination w/ IFN

50
Q

Why is Ribavirin always used in combo w/ IFN? What does this result in?

A
  1. Ribavirin SYNERGIZES w/ IFN, greatly enhancing activity

2. This leads to reduced risk of viral relapse

51
Q

Ribavirin ADME?

A

A: Hight-fat meal increases oral bioavailability
D: Very large volume of distribution + long t1/2; extensive uptake by cells including erythrocytes (RBCs)
M: No CYP action
E: Renal elimination→accumulation possible w/ renal dysfunction

52
Q

Why is it difficult to assign ADEs to Ribavirin?

A

b/c it’s always used w/ IFN

53
Q

ADEs (4) of Ribavirin? Which is the primary ADE?

A

Riblets: Highly Annoying Manipulative Terrible Dick
HA: Primary ADE→HEMOLYTIC ANEMIA (w/in 1-2 wks of initiation; monitor hematocrit)
M: MI (fatal and non-fatal)
D: Difficulty breathing (inhalant form)
(2 and 3 are secondary to hemolytic anemia)
T: Teratogen→female and MALE-mediated, CI’d in pregnant women & men w/ pregnant partner

54
Q

Ribavirin Contrainidication?

A

Teratogen, including MALE-MEDIATED CI’d in:

  1. Pregnant women
  2. Men w/ pregnant partner
55
Q

What other two agents used in Rx of HCV are also labeled as teratogens? Why?

A
  1. Boceprevir, Telaprevir

2. Guilty by association→b/c they MUST be used w/ Ribavirin

56
Q

MoA of Boceprevir and Telaprevir?

A

Oral NS3/4A Serine Protease Inhibitors→prevent protease-mediated cleavage of HCV polyprotein→prevents formation of several essential enzymes needed for viral replication

57
Q

Is HCV resistance to Boceprevir/Telaprevir a problem? Why or why not?

A

Yes, b/c of the inherently high rate of HCV Variation. Sometimes to both, other times just to one, so in that case the other can be substituted.

58
Q

Why does HCV have a high rate of variation (2)? What does this mean for HCV infections?

A

High rate of HCV variation due to:
1. High replication rate in infected cells
2. Inherently unstable viral replication process
This results in a heterogeneous infection w/ multiple different variants (quasi species), some of which may be resistant to Boceprevir/Telaprevir.

59
Q

Against what genotype of HCV are Protease Inhibitors used?

A

Genotype 1 (in combo w/ IFN + Ribavirin)

60
Q

When is protease inhibitor treatment initiated in the Rx of Genotype 1 HCV?

A

It is added ~4 weeks after initiation of combination therapy (IFN + Ribavirin)

61
Q

T/F: Protease inhibitors are equally effective in all ethnicities?

A

False: somewhat less effective in African Americans

62
Q

T/F Protease inhibitors produce benefit in the treatment of both naive patients and those relapsing on combination therapy?

A

True

63
Q

Boceprevir vs. Telaprevir: Absorption? (2)

A
  1. Take BOTH w/ FOOD→increases bioavailability

2. High fat food for TELAPREVIR, no preference w/ Boceprevir

64
Q

Boceprevir vs. Telaprevir: Distribution/Activation? (2)

A
  1. Both extensively bind plasma proteins

2. Boceprevir is an equal mixture of 2 diastereomers (one active, one inactive) that rapidly interconvert in plasma.

65
Q

Boceprevir vs. Telaprevir: Metabolism/Elimination similarities (2)? Differences (2)?

A
  1. BOTH undergo hepatic metabolism w/ CYP involvement (unlike other antivirals)→both are substrates for CYP3A4/P-gp
  2. Both eliminated primarily in stool
  3. Boceprevir primarily metabolized by aldoketoreductase (but still a substrate of 3A4/Pgp)
  4. Telaprevir is potent inhibitor CYP3A4 and P-gp
66
Q

Boceprevir/Telaprevir DDIs? (2)

A

Contraindicated w/ co-administration of:

  1. Strong CYP3A4 inducers (Rifampin)
  2. Drugs reliant on CYP3A4 or P-gp→ie reduce the effectiveness of systemic hormonal contraceptives
67
Q

ADEs of Boceprevir/Telaprevir? Which agent has a unique ADE? (2 in common, 1 unique)

A

TRashed-FAN
F,N: Fatigue, nauea
A: Anemia (additive w/ that of Ribavirin)
T-Rash: Telaprevir (but NOT Boceprevir)→pruritis/rash and BBW for sometimes SERIOUS RASH (DRESS, SJS, TEN, EM)

68
Q

Summary of Issues associated w/ Boceprevir/Telaprevir? (4)

A
  1. Resistance due to high rate of HCV variation
  2. 3A4/P-gp DDIs
  3. Anemia (also fatigue and nausea)
  4. Severe Rash w/ Telaprevir

GI Pharm (7 decks)

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