Pharmacology of antiviral drugs

1. Prepared by
Shishir Maharjan

2.  They are obligate intracellular parasites.
 They contain either double- or single-stranded DNA
or RNA enclosed in a protein coat called a capsid.
Some may contain lipid envelope or antigenic
glycoproteins.
 They lack both cell wall and cell membrane, and also
do not carry out metabolic processes
 Their replication depends primarily on synthetic
processes of the host cell

3. Antiviral drugs
 Antiviral drugs are one class of antimicrobials used
specifically for treating viral infections.
 Unlike most antibiotics, antiviral drugs do not destroy
their target pathogens; instead they inhibit their
development.
 Progress in antiviral chemotherapy began in the early
1950s, when the search for anticancer drugs generated
new compounds capable of inhibiting DNA synthesis

5. Classification of Antiviral Drugs

6. 4. Anti- Retrovirus
(a) Nucleoside reverse transcriptase inhibitors (NRTIs):
Zidovudine (AZT), Didanosine, Stavudine,
Lamivudine, Abacavir, Emtricitabine, Tenofovir (Nt RTI)
(b) Nonnucleoside reverse transcriptase inhibitors
(NNRTIs): Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors:
Ritonavir,Atazanavir, Indinavir, Nelfinavir,Saquinavir,
Amprenavir, Lopinavir
(d) Entry (Fusion) inhibitor: Enfuvirtide
(e) CCR5 receptor inhibitor: Maraviroc
(f) Integrase inhibitor: Raltegravir

7. Anti-Herpes virus Drugs
 They are active against Herpes group of DNA viruses
which includes
 Herpes simplex virus-1(HSV-1)
 Herpes simplex virus-2(HSV-2)
 Varicella-Zoster virus(VZV)
 Epstein-Barr virus(EBV)
 Cytomegalovirus(CMV)

8. Acyclovir
 It is deoxiguanosine analogue antiviral drug.
 It requires a virus specific enzyme for conversion to
active metabolite .
 It is active against…
HSV-1>HSV-2>VZV=EBV

9. Mechanism of Action

10. Pharmacokinetics
 Only about 20% of an oral dose is absorbed
 It is widely distributed attaining CSF conc. That is 5o%
of plasma conc.
 It is primarily excreted unchanged in urine
 Its t1/2 is 2-3 hrs..

11. Uses
1. Genital Herpes simplex
2. Mucocutaneous H. simplex
3. H. simplex encephalitis(type -1 virus)
4. H. simplex (type 1) keratitis
5. Herpes zoster
6. Chickenpox

12. Adverse effects
 Topical- Stinging and burning sensation
 Oral – headache, nausea, and some CNS effects
 IV – rashes, sweating, emesis , fall of BP
 Reversible neurological manifestations like
Tremors, lethargy, disorientation, hallucinations,
convulsions, etc.

13. Anti – Influenza virus Drugs
Amantadine, Rimantidine, Oseltamivir, Zanamivir
Amantadine
 It is a tricyclic amine which is active against only Influenza A.
Mechanism of action
 Inhibits an early step in viral replication, probably viral
uncoating;
 For some strains, it also have an effect on a late step in viral
assembly probably mediated through altering hemagglutinin
processing.
 The primary locus of action is the influenza A virus M2
protein, an integral membrane protein that functions as an ion
channel..

14. PK of Anti-influenza drugs

15.  Adverse effects
Nausea, anorexia, insomnia , dizziness,
nightmares, lack of mental concentration,
rarely hallucinations.
 Uses
1. Prophylaxis of influenza
2. Treatment of influenza illness
3. Parkinsonism

16. Anti-Hepatitis virus drugs
 Hepatitis B virus(HBV) - DNA virus, which can
integrate into chromosomal DNA to establish
permanent infection.
 Hepatitis C virus(HCV) - RNA virus, which does not
integrate into chromosomal DNA but frequently causes
chronic hepatitis.
Drugs used…
 Primarily for Hepatitis B: Lamivudine, Adefovir
dipivoxil, Tenofovir
 Primarily for Hepatitis C: Ribavirin, Interferon a

17. Adefovir dipivoxil
 It is a monophosphate analogue of AMP
 Adefovir dipivoxil enters cells and is deesterified to
adefovir.
 Cellular enzymes convert adefovir to the diphosphate,
which competitively inhibits viral DNA polymerases
and reverse transcriptases
 Finally results in termination of viral DNA synthesis.

18. PK
 It is primarily excreted by kidney.
 Plasma half life is 7 hrs, intracellular half life of
diphosphate is upto 18 hrs
 Oral bioavailability is approx. 60%
Dose- 10mg/day
Side effects
o Sore throat, headache, weakness, abdominal pain, flu
syndrome
o Nephrotoxicity at high dose

19. Interferon α
 Interferons (IFNs) are low mol. Wt glycoprotein cytokines
produced by host cells in response to viral infections
 Three types of human IFNs- α, β, and γ.
 Their receptors are JAK-STAT tyrosine protein kinase
receptors which on activation phosphorylate cellular
protein, which migrate to nucleus and induce transcription
of interferon-induced-proteins which exerts antiviral
effects.
 They bind to specific cell surface receptors and affect viral
replication at multiple steps
Viral penetration, synthesis of viral mRNA, assembly of viral
particles and their release, viral protein synthesis(most
widespread effect)

20. Pk
 It is degraded mainly in liver and kidney
 Oral bioavailability: < 1%
 Administered Intralesionally, S.C, and I.V
 Distribution in all body tissues, except CNS and eye.
 Half lives: 1-4 hours
ADR
 Flu like syndrome
 Neurotoxicity
 Myelosuppresion
 Thyroid dysfunction
 Hypotension, alopecia and liver dysfunction

21. Anti-retro virus drugs
 HIV is a single stranded RNA retrovirus which carries
out reverse transcription of proviral DNA form viral
RNA with the help of viral RNA-dependent DNA
polymerase
 It attacks primarily CD4 helper T-lymphocyte,
macrophages
 When CD4 cells declines , cell mediated immunity is
lost and opportunistic infections abound.
 Aim of anti-HIV therapy is to cause maximal
suppression of viral replication for the maximal period
of time that is possible.

22. Nucleoside reverse transcriptase
inhibitors(NRTIs)
Zidovudine(AZT), Didanosine, Stavudine,
Lamivudine, Abacavir, Emtricitabine, Tenofovir
 Zidovudine is a thymidine analogue
 It is first phosphorylated in the host cells-zidovudine
triphosphate selectively inhibits viral reverse
transcriptase.

23. Pk
 Oral absorption is rapid and its bioavailability is ~65%
 It is cleared by hepatic glucuronidation and 15-16% is
excreted unchanged in urine.
 Plasma protein binding is 30%
 It crosses placenta and is found in milk
ADR
Anaemia and neutropenia
Nausea, anorexia, abdominal pain, headache,
myopathy, lactic acidosis,etc

24. Non-nucleoside reverse
transcriptase inhibitors(NNRTIs)
Nevirapine, Efavirenz, Delavirdine
 These drugs are noncompetitive inhibitors that bind to
a peripheral site on HIV-1 reverse transcriptase.
 induces a conformational change that greatly reduces
the enzyme’s activity
 NNRTIs do not require intracellular phosphorylation
for activity

26. Protease Inhibitors
Ritonavir, Atazanavir, Indinavir, Nelfinavir, Saquinavir,
Amprenavir, Lopinavir
 HIV protease inhibitors are peptide-like chemicals that
competitively inhibit the action of the virus aspartyl
protease.
 These drugs bind reversibly to the active site of the protease
and prevent proteolytic cleavage of HIV gag and pol proteins
into essential structural and enzymatic components of the
virus. This prevents the metamorphosis of HIV virus
particles into their mature infectious form.
 Since, they act at a late step of viral cycle, they are effective
in both newly as well as chronically viral progeny- hence
prevent further round of infection

27. PK
 Oral bioavailability of PIs
 IDV and RTV~65%
 NFV>20%
 SQV 15%
- Their plasma half life ranges from 2-8hrs
- All are extensively metabolized mainly by CYP3A4,except
NFV- CYP2C19
ADR
Gastrointestinal intolerance, asthenia, headache,
dizziness, limb and facial tingling, numbness and rashes

28. Entry(fusion) Inhibitor
Enfuvirtide
 It is a 36-amino-acid synthetic peptide.
 binding to HIV-1 envelope transmembrane
glycoprotein (gp41) which is involved in fusion of viral
and cellular membranes. Fusion of the two
membranes is thus prevented and entry of the virus
into the cell is blocked
 It is not active against HIV-2

29. PK
 Enfuvirtide must be given parentally.
 Peak concentration after subcutaneous administration
occurs on average 4 hours after dosing
 The mean elimination t1/2 is 4 hours
 The drug is highly bound by proteins, mainly albumin.
ADR
including pain, erythema, induration, and nodules or
cysts.
increased lymphadenopathy and pneumonia

30. CCR5 receptor inhibitor
Maraviroc
 It binds specifically and selectively to the host
proteinCCR5, one of two chemokine receptors necessary
for entrance of HIV into CD4+ cells.
 Attachment of the virus and subsequent entry of viral
genome into the cell is thus interfered.
 Most of the drug (≥ 75%) is excreted in the feces, whereas
approximately 20% is excreted in urine.
 Potential adverse effects include cough, upper respiratory
tract infections, postural hypotension, muscle and joint
pain, abdominal pain, diarrhea, and sleep disturbance

31. Integrase inhibitor
Raltegravir
 It is a pyrimidinone analog.
 binds integrase, a viral enzyme essential to the replication of
both HIV-1 and HIV-2. By doing so, it inhibits strand
transfer, the third and final step of provirus integration, thus
interfering with the integration of reverse-transcribed HIV
DNA into the chromosomes of host cells
 The drug is metabolized by glucuronidation and does not
interact with the cytochrome P450 system
 Potential adverse effects of raltegravir include myopathy,
insomnia, headache, diarrhea, nausea, dizziness, and fatigue