Antihepatitis drugs

MBBS/BDS/ALLIED SCIENCES
MCI/DCI UG/PG CURRICULUM

1. Anti-hepatitis Drugs
Dr. DivyaKrishnan MBBS, MD
Associate Professor
Department of Pharmacology
KMCT Medical College
Dr Divya Krishnan

2. What we covered in the Pre-class session
•Overview of Hepatitis B&C infection
•HBV, HCV replication process
Dr Divya Krishnan

3. Learning Objectives
List drugs for HBV, HCV infections.
Describe PHARMACOLOGY (MOA, Pharmacokinetics,
Adverse effects, Contraindications & Indications for use
)of anti-hepatitis drugs.
Explain basis of important drug interactions.
Dr Divya Krishnan

4. •They are not curative
•They suppress Viral replication, put patient in remission,
prevent complications.
•Have to be taken for long duration
•Disease can flare up when drugs stopped
------------------------------------
•Most drugs are nucleoside/nucleotide analogues
•Most are prodrugs
•Most are converted to phosphate form
•Most inhibit DNA polymerase/RNA polymerase
REMEMBER THE FOLLOWING ABOUT
ANTIHEPATITIS DRUGS
Dr Divya Krishnan

5. Drugs for HBV
Lamivudine (3TC)
Telbivudine(LDT)
Entecavir-ETV(first line)
Adefovirdipivoxil(ADV)
Tenofovirdisoproxil
fumarate(TDF) (first line)
Drugs for HCV
Ribavirin
Interferon alpha
Newer Drugs (Directly
acting antiviral drugs)
NS5B polymerase
inhibitor : Sofosbuvir
NS3/4A protease inhibitor
: Simeprevir
NS5A inhibitor :
Daclatasvir, Ledipasvir,
Velpatavir
Dr Divya Krishnan

6. DRUGS FOR HEPATITIS B
Dr Divya Krishnan

7. Lamivudine
CytidineNucleoside analogue
MOA
Phosphorylated intracellularly.
Inhibits HBV DNA polymerase. Causes viral DNA chain
termination by getting incorporated into viral DNA.
(remember –pre-class session!! )
Development of Resistance to it
Due to point mutation in HBV DNA polymerase
Dr Divya Krishnan

8. Pharmacokinetics
-Good oral bioavailability
-Plasma T1/2 = 6to 8hrs (t1/2 =12hrsin HBV infected
cells)
-Excreted unchanged in urine
ADR
(Well tolerated)
-Headache, fatigue
-Nausea, anorexia, abdominal pain
-Rashes
-Pancreatitis, neuropathy (rarely)
Dr Divya Krishnan

9. Use
1. Chronic HBV infection –100mg OD
Brings about clinical, biochemical , histological
improvements but effects not sustained over the
years.
Development of resistance within 1-5yrsNOT THE
FIRST LINE DRUG
2. HIV -150-300mg OD(in combination with other anti
HIV drugs)
Q: Why is dose used in HIV higher than for HBV?
Ans: Long intracellular t1/2 in HBV infected cells
Dr Divya Krishnan

10. Telbivudine
Thymidine nucleoside analogue similar to Lamivudine
Differences from Lamivudine:-
•T1/2 = 15hrs
•Faster & more complete suppression of viral titre
than lamivudine
•Cough & Rise in serum amylase are additional ADR
Dr Divya Krishnan

11. Entecavir
Guanosinenucleosideanalogue with same MOA as
Lamivudine
Differences from Lamivudine
•Food decreases oral absorption(administered in empty
stomach)
•T1/2 : 128-148hrs
•Sleep disturbances & lactic acidosis can be additional
ADRs
•1
st
line drug for HBV
-Rapid clinical, biochemical, histological improvement
than Lamivudine
-Effect sustained
-Development of resistance rare
Dr Divya Krishnan

12. Adefovirdipivoxil
AMP nucleotide analogue.
Prodrug. Gets activated to Adefovir(by esterasesin
intestine & liver). MOA same as Lamivudine.
Pharmacokinetics
•Moderate oral bioavailability
•Excreted unchanged by kidney
•T1/2 in cells : 18hrs
ADR
•Well tolerated
•Sore throat, headache,weakness, flu syndrome
•Abdominal pain
•Nephrotoxicity (higher doses)
Dr Divya Krishnan

13. Uses
1. Chronic hepatitis B
-Not a 1
st
line drug as virologicalresponse is slow.
-Used mainly in lamivudine resistant cases
TenofovirDisoproxilfumarate
Nucleotide analogue. Prodrugconverted to Tenofovir.
Similar to Adefovirbut it is first line drug for HBV due to its
High efficacy, good tolerability & low risk of development of
resistance,
Has activity against HIV also (reverse transcriptase inhibitor)
Dr Divya Krishnan

14. DRUGS FOR HEPATITIS C
Dr Divya Krishnan

15. Ribavirin
•Guanosinenucleoside analogue
•Broad spectrum antiviral drug
HCV
Influenza A & B
Respiratory Syncytial virus (RSV)
MOA
Phosphorylated inside cells
Inhibits RNA polymerase & stops viral RNA replication.
Dr Divya Krishnan

16. Pharmacokinetics
-Oral bioavailability = 50%
-Partly metabolisedin liver
-Excreted by kidney in a multiexponentialmanner.
-Accumulates in the body (remains for months)
-T1/2 = 10days
Dose: 200mg QID/400mg TDS for body weight >75kg.
Available as aerosol also
Dr Divya Krishnan

17. Uses
1.Chronic HepatisC(in combination with interferonsor
other drugs) (6-12 months)
2. RSVBronchiolitis in children (nebulisation)
ADR
•Hemolytic anemia (dose dependent)
•Bone marrow suppression
•CNS/GIT effects
•Teratogenic(Females to practice contraception during &
till 3months after Ribavirin treatment)
Dr Divya Krishnan

18. Interferon (IFN)α
WHAT ARE INTERFERONS ?
Low molecular weight glycoprotein cytokines produced by
host cells in response to viral infections, IL-1 & other
inducers.
They have antiviral effects & effects on immunity & cell
proliferation
3 types of IFN produced by humans –IFNα(Clinically used)
IFNβ
IFN γ
Dr Divya Krishnan

19. MOA
Exert action through JAK-STAT tyrosine kinase receptor
resulting in the production of ANTIVIRAL PROTEINS)
(REVISE HOW JAK STAT KINASE RECEPTORS ACT –GENERAL
PHARMACOLOGY!!)
The antiviral proteins effect viral multiplication at the steps :-
X Viral penetration
X Synthesis of viral messenger RNA
XViralprotein synthesis (translation)
XAssemblyof viral particles&release
Dr Divya Krishnan

20. Dr Divya Krishnan
x Interferon

21. Pharmacokinetics
-Parenteral administration (IM/SC)
-Distributed to tissues
-Degraded in kidney (partly in liver)
-Detectable in plasma <24hrs (cellular effects last long
because interferon induced proteins persist)
Dr Divya Krishnan

22. Preparations
-Standard IFNα2A, IFN α2B (rDNAtechnology)
-PEGYLATED IFN α(Polyethylene glycol complexed)
IFN α pegIFNα
IM/SC SC
Slowerabsorption
Sustained effects
Thrice weekly administrationWeekly administration
Better clinical effects
Longerlasting remissions
More used
costly
Dr Divya Krishnan

23. Uses
1. Chronic hepatitis B
5-10MU 3 times/wkfor 4-6mths (StdIFN)
180µg sc/week for 24-48wks (peg IFN)
2. Chronic hepatitis C
3MU 3times/wkfor 6-12months (stdIFN)
180µg sc/week for 24-48wks (peg IFN)
3. AIDS related Kaposi sarcoma
4. Condylomaacuminata
5. H.Simplex, H. Zoster, CMV
6. CANCERS : CML, follicular lymphoma, cutaneous T cell
lymphoma, multiple myeloma
Dr Divya Krishnan

24. ADR (Distressing)
•Flu like syndrome (fatigue, fever, pains, dizziness, nausea,
taste & visual disturbances) –DEVELOP WITHIN HOURS
AFTER INJECTION
•Neurotoxicity
•Bone marrow suppression
•Thyroid dysfunction (hypo/hyper)
•Cardiotoxicity: hypotension, arrhythmias
•Alopecia
•Reversible liver dysfunction
-NON RESPONDERS TO TREATMENT POSSIBLE -
CI: pregnancy, decompensated cirrhotics, autoimmune
diseases, thyroid disease, pregnancy, CAD, Infants <1 year.
Dr Divya Krishnan

25. Direct acting anti-HCV drugs (DAA)
•Target specific nonstructural (NS) viral proteins that play
role in replication of HCV inside hepatocytes.
•Less efficacy & development of resistance on using as
monotherapy
•Used in combination therapy against HCV
-Shortens duration of therapy
-Improves clinical response.
•Minimal ADRs
•Significant drug interactions
Dr Divya Krishnan

26. Drugs
NS5B polymerase inhibitor (Buvirs) : Sofosbuvir
NS3/4A protease inhibitor(Previrs) : Simeprevir
NS5A inhibitor(Asvirs) : Daclatasvir, Ledipasvir, Velpatavir
Dr Divya Krishnan

27. SOFOSBUVIR SIMEPREVIR DACLATASVIR LEDIPASVIR VELPATASVIR
NS5B INHIBITORNS3/4A
INHIBITOR
NS5A
INHIBITOR
NS5A INHIBITORNS5A INHIBITOR
Inhibits HCV
RNA
Polymerase.
(Inhibits viral
RNA replication)
Inhibits
proteases.
(inhibits
cleavage of viral
polyprotein
complex)
Inhibits HCV
RNA replication
& viral assembly
Inhibits HCV
RNA replication
& viral assembly
Inhibits HCV
RNA replication
& viral assembly
Active againstall
6 genotypes
1-4 genotypesAll 6 genotypes1,4, 5, 6
genotypes
All 6 genotypes
Oral Oral oral oral oral
Liver
metabolism
Urine excretion
Liver
metabolism
Urine excretion
Liver
metabolism
Urine excretion
Liver
metabolism
Urine excretion
Liver
metabolism
Urine excretion
T1/2 = 27hrs13hrs 12-15hrs 48hrs 15hrs
Dr Divya Krishnan

28. SOFOSBUVIR SIMEPREVIR DACLATASVIRLEDIPASVIR VELPATASVIR
NS5B
INHIBITOR
NS3/4A
INHIBITOR
NS5A
INHIBITOR
NS5A
INHIBITOR
NS5A
INHIBITOR
ADR
Abdpain
Fatigue
Jtpain
Anemia
bradycardia
ADR
Nausea
fatigue
Headache
Rash/photosens
itivity
dyspnoea
ADR
Abdpain
Fatigue
Headache
Anemia
alopecia
ADR
Nausea
Headache
Fatigue
ADR
Nausea
Headache
fatigue
Dr Divya Krishnan

29. Dr Divya Krishnan

30. Drug interactions of DAA drugs
•All are metabolisedby CYP3A
•All are substrates of P-gpefflux transporter
CYP3A inducers/ inhibitors decrease their effect/increase
their toxicity
Inducers of P-gp(Phenytoin/rifampicin) decrease their
blood levels
Ledipasvir, Velpatasvirneed gastric acid for absorption.
Their efficacy decreased by H2 blockers
Dr Divya Krishnan

31. Summary
•Entecavir(oral) Tenofovir(oral) , IFN (parenteral) used as
first line drugs for chronic Hepatitis B
•Ribavirin with Interferon is standard regimens followed
for c/c Hepatitis C. Non interferon regimens using
Ribavirin with DAA drugs also are popular.
•All drugs only put patient in remission.
Dr Divya Krishnan

32. IMPORTANT QUESTIONS
•List drugs for Hepatitis B, Hepatitis C
•List examples of NS4A/NS5B/NS5A inhibitors
•Describe the pharmacology of Lamivudine/
Entecavir/Tenofovir.
•Describe Pharmacology of Ribavirin
•Describe the Pharmacology of Interferon alpha
•Describe the Pharmacology of direct acting anti HCV
drugs
•Explain the drug interaction between Sofosbuvirand
Rifampicin
•Explain the interaction between Ranitidine & Velpatasvir
Dr Divya Krishnan

33. THANK YOU
Short assignment shall follow
Dr Divya Krishnan