Anti Hepatitis Drugs

Hepatitis is the inflammation of liver cells, caused by drugs, toxins, organisms. A number of viruses are more prone to cause hepatitis (type A, B, C, D, E or G). among these viruses leading to hepatitis, B and C are more troublesome, being more prone to chronic illness, if immediate treatment is not initiated, and liver transplant is the only option left.

To prevent acute phase from progressing to chronic stage, anti-hepatitis therapy is initiated. Rapid multiplication of hepatitis virus occurs within liver cells.

Aims of treatment

1. To reduce viremia/viral load, inhibiting viral replication
2. Inhibit progress to chronic stage.

Chances for complications and the need for liver transplant is to be reduced and. We have to reduce the elevated hepatic aminotransferase enzymes.

In hepatitis B, drugs recommended are:

• Lamivudine (dose of 100 mg once daily orally )
•  Adefovir    (Adefovir dipivoxil once daily orally )
• Entecavir (once daily 0.5 mg)
• Tinofavir (300 mg once daily)
• Talbevedine (600 mg once daily)

Besides Interferons are used:

1. Interferon alfa 2b (SC) (dose 50 million units once)
2. Pegelated alfa 2a (180 micrograms once weekly)

Hepatitis C

Aim of treatment is to decrease viral load and to inhibit progress to chronic phase. Therapy is initiated, if after 12 weeks viremia is still present, only then anti-viral therapy is initiated.

Complications include

1. cirrhosis,
2. massive damage,
3. renal cell carcinoma

Drugs for chronic hepatitis include:

• Interferon alfa 2a (subcutaneous or I/M route)
• Interferon alfa 2b
• Peg Interferon alfa 2a
• Peg interferon alfa 2b

Ribavirin (oral) is also established drug, interferons are not effective alone, when combined therapeutic effects occur.

Immunomodulators

Interferons (IFN)

• Interferons (endogenous glycoproteins) are low molecular weight cytokines produced by host cells in response to viral infections.
• Released in response to various biochemical changes in cell.
• Having antiviral, immunomodulatory & antiproliferative activities.
• Synthesized by DNA recombinant technique.
• Used in a number of carcinoma.

Mechanism of Action

Interferons are induced by various inducers and bring about a number of biochemical changes.

1. IFN- induced in ribosomes of host’s cells cause production of enzymes (e. g. Protein kinase, 2 – 5 oligoadenylate synthase, phosphodiesterase).

These enzymes inhibit translation of viral mRNA into viral proteins, stopping the production of viruses.

2. Interferon alpha causes inhibition of:

1. viral penetration,
2. translation,
3. transcription,
4. protein processing
5. maturation and
6. release.

3. Increased expression of major histocompatibity complex antigen.

4. Anti-proliferative causing enhanced phagocytosis.

5. Enhance apoptosis

6. Augmentation of proliferation and survival of cytotoxic T cells.

7. Interferons alfa and beta type possess potent anti-viral activity.

8. Interferons act as signal transduction transmission by JAK/STAT pathway. Number of proteins and steps are involved, final step inhibition leads to inhibition of synthesis of viral proteins, growth and multiplication.

Types

Two types:
1. Interferon type I

• Alpha –synthesized by leukocytes
• Beta –synthesized by epithelial cells

Both of type I are acid stable having potent anti-viral activity. Interferon alpha has high anti-viral activity, it is divided into:

• 2a
• 2b

Both are administered I/M or by subcutaneous route.
2. Interferon type II –gamma –not potent so no role in anti-viral treatment, synthesized by lymphocytes.

Newer type are the pegelated interferons:

• 2a
• 2b

These are superior to the older ones and possess polyethylene glycol structure which makes covalent bond, hence improve pharmacokinetic profile of interferons. By virtue of polyethylene glycol component:

1. Clearance is decreased
2. More sustained plasma levels
3. Longer half life -168 hours
4. Better bioavailability
5. Less frequent doses as compared with conventional treatment

Efficacy is more towards management of chronic hepatitis C. activity is further enhanced when combined with Ribavarin.

Therapeutic uses

Beside anti-viral agents:

1. Chronic Hepatitis B & C
2.  Genital warts, caused by papilloma virus.
3. Malignant melanoma
4. Carcinoid syndrome
5.  Hairy cell Leukemia.
6. Renal cell carcinoma
7.  Kaposi’s Sarcoma.
8.  Relapsing remitting multiple sclerosis
9.  Chronic – granulomatous disease
10. HSV HZV and CMV infection in immunocompromised patients.

Adverse effects

1. Commonly occuring

Flue like syndrome,

1. Headache,
2. vomiting,
3. anorexia,
4. fatigue
5. myalgias
6. edema
7. hypotension
8. rashes,
9. alopecia

2. Dose limiting toxicity

1. Thrombocytopenia,
2. Granulocytopenia,
3. increased aminotransferase
4. proteinurea
5. azotemia

3. CVS

1. hypotension
2. tachycardia

4. CNS

1. confusion
2. seizures
3. depression
4. behavorial changes
5. pneumonia
6. hepatotoxicity
7. Induction of autoantibodies.

Contraindications

1. Autoimmune diseases,
2. cardiac arrhythmias,
3. hepatic decompansation/cirrhosis.
4. psychosis

Lamivudine

• For clinical treatment of Hepatitis B infection.
• Prolong T1/2  in HBV cells  17-19hrs
• short T1/2 in HIV cells  10-15 hrs
• Safe for decompensated liver disease.

Mechanism of Action

Lamivudine is antiretroviral agent which inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxyuridine triphosphate and leads to chain termination.

It has to be phosphorylated to triphosphate compound.

Adverse effects

Excellent safety profile for doses used against Hepatitis B infections but risk of pancreatitus in case of HIV infections.

Ribavarin (with anti-influenza agents)

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