DSA05 - Pharmacology of the Liver

> 95% conjugated by glucuronidation and sulfation, then excreted

> 5% converted in Phase I to toxic intermediates ==> At LOW LEVELS, liver can conjugate metabolite with GSH (to make it NON-TOXIC)

How is Acetaminophen normally metabolized by the liver?

Acetaminophen Toxicity

Define Condition:

Glucoronidation pathway is SATURATED --> More of Acetaminophen metabolized by Phase 1 to TOXIC N-acetyl benzoiminoquinone ==> GSH DEPLETION

-Sx/PE:

> N/V/D

> Abd Pain

> SHOCK (after 4-12 hrs after ingestion)

> Myocardial Injury

> Renal Failure

-Dx:

> Aminotransferase levels ~ 10,000 IU

-Tx:

> Gastric Lavage

> Oral N-acetylcysteine (GSH precursor) to replace depletion

> IV + Emetics (if there's too much vomiting

REDUCE MORBIDITY & MORTALITY via suppression of HBV replication:

> Reduce Hepatic Aminotransfersase levels

> Histo improvement in liver

> Loss of Hb e/s/c Ag

> Suppression of HBV DNA to undetectable levels

What is the goal of HBV Treatment?

Adenosine Non-Structural Analog that competes with deoxyadenosine 5'-triphosphate for incorporation into viral DNA --> inhibits HBV polymerase

Tenofovir MoA

1st line for HBV (lowest rate of resistance + higher SVR & histo improvement); effective against Lami & Ente resist strains BUT less activity against Adefovir resist strains

Tenofovir Tx

Nausea, Abd Pain, Diarrhea, Dizziness, Fatigue, Rash --> Black Box = Lactic Acidosis & Hepatomegaly

Tenofovir S/E

Guanosine Non-Structural Analog that inhibits ALL functions of HBV DNA Polymerase (base priming, reverse transcription of negative strands, synthesis of positive strands)

Entecavir MoA

1st line for HBV (lowest rate of resistance) - should be taken on an empty stomach (+/-2 h from meals) for 100% bioavailability

Entecavir Tx

Few --> Black Box = Acute exacerbation of HBV upon D/C in HIV/HBV co-infex + Resistance to HIV nucleoside RT inhibitos in HIV/HBV co-infex + Lactic Acidosis & Hepatomegaly

Entecavir S/E

Adenine Nucleotide Analog that inhibits HBV replication (competes with deoxyadenosine 5'-triphosphate for incorporation into viral DNA --> inhibits HBV polymerase ==> terminates chain)

Adefovir MoA

2nd line for HBV

Adefovir Tx

Well tolerated; Nephrotoxicity (high dose) --> Black Box = Acute exacerbation of HBV upon D/C, + Lactic Acidosis & Hepatomegaly

Adefovir S/E

should NOT; avoid resistance (must use MOST POTENT NAs in that case)

Patients with minimal HBV disease OR those unlikely to achieve SVR (should/should NOT) be treated with NAs to do what?

Thymidine Non-Structural Analog that competes with natural thymidine triphosphate --> DNA Chain termination & HBV replication inhibition

Telbivudine MoA

HBV (superior to Lamivudine)

Telbivudine Tx

MILD Sx = fatigue, HA, cough, nausea, diarrhea, rash, fever, myalgia --> Black Box = Acute exacerbation of HBV upon D/C + Lactic Acidosis & Hepatomegaly

Telbivudine S/E

Cytosine Non-Structural Analog that competes w/ natural deoxycytidine triphosphate --> DNA chain termination & HBV replication inhibition

Lamivudine MoA

HBV (highest rate of resistance d/t resistant strains of HBV) - last line

Lamivudine Tx

Few --> Black Box = Acute exacerbation of HBV upon D/C in HIV/HBV co-infex + Lactic Acidosis & Hepatomegaly

Lamivudine S/E

Genotype 1

What is the most common HCV Genotype in the U.S.?

Viral Eradication:

Sustained Viral Response (Absence of HCV RNA 12-24 wks after therapy) --> Improve liver histology, less risk of Cirrhosis or Hepatocellular Carcinoma

What is the goal of HCV Treatment?

Dac (DAA) = inhibits HCV RNA replication & Virion assembly by binding NS5A --> prevents interaction with host cell proteins needed for replication + Sofo (DAA) = defective substrate for HCV NS5B protein (inhibits viral RNA replication); low probability for resistance

Daclatasvir + Sofosbuvir MoA

HCV genotype 1, 3, 4

Daclatasvir + Sofosbuvir Tx

Nausea, HA, Fatigue; Black Box = HBV reactivation in HCV/HBV co-infex

Daclatasvir + Sofosbuvir S/E

NS5B Nucleoside Inhibitors --> Sofosbuvir

Which family of drugs for HCV lowest possible resistance? Which of these drugs specifically has the LOWEST resistance?

Ombit = NS5A inhibitor w/ pan-genotypic activity; Parita = NS3/4A serine protease inhibitor; Rito = inhibits CYP3A4 (increases Parita level); Dasa = Non-nucleoside NS5B polymerase inhibitor ==> Target multiple steps of HCV lifecycle

Ombitasvir + Paritaprevir + Ritonavir (Fixed Dose Tablet) +/- Dasabuvir (Separate Dose Tablet) MoA

HCV genotype 1

Ombitasvir + Paritaprevir + Ritonavir (Fixed Dose Tablet) +/- Dasabuvir (Separate Dose Tablet)

Tx

MILD Sx = Skin irritation, Nausea, Asthenia, Insomina, Fatigue --> Black Box = HBV reactivation in HCV/HBV co-infex

Ombitasvir + Paritaprevir + Ritonavir (Fixed Dose Tablet) +/- Dasabuvir (Separate Dose Tablet)

S/E

Sofo (DAA) = defective substrate for HCV NS5B protein (inhibits viral RNA replication); low probability for resistance + Ledi (DAA) = Inihibits HCV NS5A & active against Sofosbuvir resistance (SVR > 93% after 12 wks)

Sofosbuvir + Ledipasvir MoA

HCV genotypes = 1, 4, 5, 6

Sofosbuvir + Ledipasvir Tx

Asthenia, HA, Fatigue, Insomnia --> Black Box = HBV reactivaiton in HCV/HBV co-infex

Sofosbuvir + Ledipasvir S/E

Sofo (DAA) = defective substrate for HCV NS5B protein (inhibits viral RNA replication); low probability for resistance + Velpa (DAA) = inhibits HCV NS5A (SVR > 95% after 12 wks)

Sofosbuvir + Velpatasvir MoA

HCV genotypes 1-6

Sofosbuvir + Velpatasvir Tx

C/I wtih Rifampin (potent CYP inducer) + NAUSEA, HA, Fatigue --> Black Box = HBV reactivation in HCV/HBV co-infex

Sofosbuvir + Velpatasvir S/E

Sofo (DAA) = defective substrate for HCV NS5B protein (inhibits viral RNA replication); low probability for resistance + Velpa (DAA) = inhibits HCV NS5A (SVR > 95% after 12 wks) + Voxil = pan-genotypic HCV NS3/4A protease inhibitor (SVR > 96%)

Sofosbuvir + Velpatasvir +/- Voxilaprevir MoA

HCV genotypes 1-6

Sofosbuvir + Velpatasvir +/- Voxilaprevir Tx

C/I wtih Rifampin (potent CYP inducer) + DIARRHEA, HA, Fatigue --> Black Box = HBV reactivation in HCV/HBV co-infex

Sofosbuvir + Velpatasvir +/- Voxilaprevir S/E