Pharmacology of antiviral drugs used for treatment of herpes simplex, influenza, hepatitis, retroviruses

1. Antiviral Drugs
Dr. Sameh Ahmad Muhamad abdelghany
Lecturer Of Clinical Pharmacology
Mansura Faculty of medicine

2. INTRODUCTION

3. Life cycle Of DNA virus
3

4. Life cycle Of RNA virus
4

5. A n t i v i r a l d r u g s
5
1 ANTI-HERPES VIRUS
AGENTS
3 ANTI-RETROVIRAL
DRUGS
2 ANTI-INFLUENZA
AGENTS
4 ANTI-HEPATITIS
VIRUS DRUGS

6. 6

7. ANTI-HERPES
VIRUS AGENTS

8. 1. Acyclovir
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 is a purine analog
Mechanism of action
 inhibits the activity of viral DNA polymerase.(HOW?)

9. 1. Acyclovir
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Mechanism of action
 Acyclovir molecules entering the cell are converted to
acyclovir monophosphate by virus-induced thymidine kinase.
Host-cell enzymes add 2 more phosphates to form acyclovir
triphosphate, which is transported into the nucleus.
 After the herpes DNA polymerase cleaves pyrophosphate from
acyclovir triphosphate (indicated by the blue arrow in the
inset), viral DNA polymerase inserts acyclovir monophosphate
rather than 2’-deoxyguanosine monophosphate into the viral
DNA (indicated by black arrows in the inset).

10. 1. Acyclovir
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Mechanism of action
 Further elongation of the chain is impossible because
acyclovir monophosphate lacks the 3’ hydroxyl group
necessary for the insertion of an additional nucleotide, and the
exonuclease associated with the viral DNA polymerase cannot
remove the acyclovir moiety. In contrast, ganciclovir and
penciclovir have a 3’ hydroxyl group; therefore, further
synthesis of viral DNA is possible in the presence of these
drugs.

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12. 1. Acyclovir
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 Spectrum
 Herpes simplex virus (HSV) types I and II
 Epstein–Barr virus
 Varicella-zoster virus
 cytomegalo virus (CMV).
 Adverse effects
 Nephrotoxicity (reversible)
 Neurotoxicity(reversible)

13. 2. Gancyclovir
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 Similar to acyclovir but highly active against CMV.
Adverse effects
 Neutropenia (reversible)
 Thrombocytopenia

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15. ANTI-INFLUENZA
AGENTS

16. 1. Amantadine and rimantadine
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Mechanism of action
 inhibit the uncoating and replication of the viral
RNA in infected cells.

17. 1. Amantadine and rimantadine
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Mechanism of action
 The primary target of action is the influenza A virus M2 protein, an
essential protein of the membrane which functions as an ion channel. Due
to interruption of this function of the M2 protein, the drugs inhibit the acid
(H+)-mediated dissociation of the ribonucleoprotein (RNP) complex early
in the process of replication.
 In certain strains of influenza A virus, the pH changes that result from M2
inhibition alter the conformation of hemagglutinin during its intracellular
transport later in replication and thus block the viral assembly also.

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19. 1. Amantadine and rimantadine
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 Uses
 Treat influenza A infections when administered within the first 48
hours of symptoms
 For Prophylaxis during flu season.
 Adverse effects
 CNS effects : insomnia, nervousness
 GI dysfunction.
N.B. Patients with a history of seizures require close monitoring.

20. 2. Ribavirin
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 Is a guanosine analog
Mechanism of action
 inhibit viral RNA polymerases.

21. 2. Ribavirin
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Mechanism of action
 It is a guanosine (ribonucleic) analog used to stop viral RNA
synthesis and viral mRNA capping, thus, it is a nucleoside
inhibitor.
 Ribavirin is a prodrug, which when metabolized resembles
purine RNA nucleotides. In this form, it interferes with RNA
metabolism required for viral replication..

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23. 2. Ribavirin
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 Uses
 Treat respiratory syncytial virus (RSV)
 Treat influenza A and B.
 HCV , HBV in combination with Interferon alpha
Adverse effects
 Hemolytic anemia
 Teratogenic in pregnancy

24. 3. Zanamivir and Oseltamivir (Tamiflu)
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 Oseltamivir, (administered orally-Prodrug)
 Zanamivir, (administered by inhalation)
 Mechanism of action
 inhibit neuraminidase enzyme.

25. 3. Zanamivir and Oseltamivir (Tamiflu)
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 Mechanism of action
 Inhibition of influenza neuraminidase resulting in inhibition of virus
particle release from host cells
 bind to the active site of the neuraminidase enzyme. This blocks the
release of progeny virions from infected host cells, which stops the
spread of infection.
 because the viral replication rate is reduced, the immune system can
more effectively destroy any remaining viruses.

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27. 3. Zanamivir and Oseltamivir (Tamiflu)
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 Uses
 Treatment and prophylaxis of acute uncomplicated
influenza infection. (effective against both influenza A
and B)
Adverse effects
 Oseltamivir :Abdominal pain and GI dysfunction.
 Zanamivir: may cause bronchospasm.

28. ANTI-RETROVIRAL
DRUGS

29. 29
Life cycle Of HIV

30. 1. Reverse Transcriptase Inhibitors (RTIs)
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Nucleoside analogs (NRTI):
 zidovudine, lamivudine, tenofovir
Non-Nucleoside analogs (NNRTI):
 efavirenz, nevirapine

31. 1. Reverse Transcriptase Inhibitors (RTIs)
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Nucleoside analogs (NRTI):
 NRTI’s compete with the normal physiological nucleosides used for DNA
synthesis.
 They differ from the normal substrates only by a minor modification in the
sugar (ribose) molecule.
 Acting as "false building blocks“, nucleoside analogs incorporate
themselves, preventing DNA synthesis, because normal bridges can no
longer be built to build the double strand.
 Thus they prevent the development of functional viral DNA

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33. 1. Reverse Transcriptase Inhibitors (RTIs)
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Non-nucleoside analogs (NNRTI):
 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
NNRTIs attach directly to the reverse transcriptase enzyme.
Enzyme with NNRTI attached cannot function normally
Production of viral DNA from RNA is blocked Virus is unable
to convert RNA into DNA, therefore unable to infect the cell
and produce new virus

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35. 1. Reverse Transcriptase Inhibitors (RTIs)
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Adverse effects
 All agents:
o peripheral neuropathy(-- of mitochondrial DNA polymerase)
o interaction with CYP450.
 Zidoviodine: Myopathy and Anemia.

36. 2. Protease inhibitors
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 Ritonavir, Lopinavir, Atazanavir
Mechanism of action
 Infected cell produces large viral proteins (polyproteins)
 Protease enzyme cleaves polyproteins into enzymes and
structural proteins required to make new virus
 Protease inhibitors attach to and block protease enzyme The
virus particles produced are defective and inactive and are
unable to infect new cells

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38. 2. Protease inhibitors
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 Ritonavir, Lopinavir, Atazanavir
Adverse effects
 All agents(Metabolic):
o Diabetes
o Hypertriglyceridaemia and Hypercholesterolaemia
 Ritonavir: is the most potent inhibitor of CYP450 known.

39. 3. Fusion receptor protein inhibitors
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 Enfuvirtide.
 Mechanism of action
 competes with the gp41 subunit of the HIV-1 viral envelope
and prevents fusion to the cell membrane CD4 receptors.
 Adverse effects
 Injection site:Pain erythema etc..

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41. 4. Integrase inhibitors
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 Raltegravir.
 Mechanism of action
 inhibit the viral enzyme integrase to prevent HIV replication
and viral integration into the host cell.
 Adverse effects
 GIT: nausea , diarrhea

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43. ANTI-HEPATITIS
VIRUS DRUGS

44. 1. Interferon-alpha and peginterferon-alpha (Pegasys)
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 Interferons are group of natural cytokines released by
host cells in response to infection.
 Genetically engineered interferon-α is used, in
combination with ribavirin, for both HBV and HCV.
 Peginterferon has long duration (injected once-weekly
s.c.).

45. 1. Interferon-alpha and peginterferon-alpha (Pegasys)
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Antiviral mechanism
 Interferon binds to cell membrane receptors to initiate a series
of reactions leading to inhibition of viral replication.
 It causes induction of host cell enzymes that inhibit viral RNA
translation.
 Promote apoptosis of viral-infected cells.

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47. 1. Interferon-alpha and peginterferon-alpha (Pegasys)
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Adverse effects
 Flu-like symptoms: muscle pain, fever, and fatigue.
 Bone marrow depression: neutropenia.
 Neuropsychiatric effects: depression, convulsions.

48. 2. Lamivudine
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 It is a nucleoside reverse transcriptase inhibitor
(NRTI)
 Used for HBV infections
 effective and rapid response in most patients
 slow progression of liver fibrosis.

49. 3. Sofosbuvir (Sovaldi®)
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 is a nucleotide analog
 Mechanism of action
 Works by inhibition of viral RNA polymerase(NS5B
polymerase inhibitor).
 Used for treatment of HCV in combination with
ribavirin and interferon.

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51. 4. Grazoprevir/Elbasvir (Zepatier®)
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 It is a recently approved combination for treatment of
HCV (genotypes 1, 3, 4).
 Mechanism of action
 Grazoprevir is a NS3/4A protease inhibitor. This
protease enzyme enables the C virus to survive and
replicate in host cells.
 Elbasvir is a NS5A inhibitor. NS5A is a protein needed
by the virus for various stages of infection.

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55. Management of
chronic HCV
infection

56. Management of chronic HCV infection
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 Treatment with interferon-α alone gives 10-15% success
rate in achieving long term clearing of plasma hepatitis
C RNA.
 A combination of interferon and ribavirin gives 50%
success rate.
 About 50% of successfully treated patients will relapse
despite treatment.

57. Management of chronic HCV infection
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 HCV genotype will give guidance to the length of
treatment and response rate:
 Those with genotype 2 and 3 can achieve SVR after 24
weeks as they have better response to treatment.
 In genotype 1 and 4, therapy is continued for 48 weeks
due to lower response rate.

58. Management of chronic HCV infection
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 The following also predict a good long term response to
interferon:
• Younger age.
• Female gender.
• Absence of cirrhosis on liver biopsy.
• Non-black racial origin.
• Low hepatic iron.
 No HCV vaccine is currently available.

59. T H A N K Y O U !
A N Y Q U E S T I O N S ?