This is a presentation on the pharmacology of the antiviral agents.

1. ANTIVIRAL AGENTS
1

2. INTRODUCTION
 Viruses are obligate intracellular parasites.
 Replication depends on the synthetic
processes of the host cell.
 :. Antiviral agents must either block entry into
the cell or be active inside the cell to be
effective.
2

3. Contd….
 Viral replication peaks at or before the
manifestation of clinical symptoms.
 Optimal efficacy depends on early initiation
therapy or prevention of infection.
3

4. Contd…
 Viral replication:
1. Adsorption and penetration into susceptible
host cells
2. Uncoating of viral nucleic acid
3. Synthesis of early, regulatory proteins eg.
Nucleic acid polymerases
4. Synthesis of RNA or DNA
5. Synthesis of late, structural proteins
4

5. Contd…
6. Assembly (maturation) of viral particles
7. Release from the cell
5

6. Classification
1. Agents used to treat HSV and VZV
 Acyclovir
 Valacyclovir
 Famciclovir
 Forscanet
 Penciclovir - topical
 Docosanol - “
 Trifluridine - “
6

7. Contd…
2. Agents used in the treatment of CMV
 Valganciclovir
 Ganciclovir
 Cidofovir
 Forscanet
7

8. Contd…
8
3. Anti-influenza agents
 Amantadine
 Rimantadine
 Zanamivir
 Ostelamivir

9. Antiherpes agents
1. Acyclovir
 An acyclic guanosine derivative with clinical
activity against HSV 1 and 2 and against VZV.
 Weaker against EBV, CMV HSV 6.
9

10. Mechanism of action
 Requires 3 phosphorylation steps for
activation.
 1st to be converted to the monophosphate
derivative by the virus specified thymidine
kinase and then to the di- and tri-phosphate
compound by the cell’s enzymes.
 The viral kinase is required for the first
phosphorylation, acyclovir is selectively
activated and the triphosphate accumulates
only in infected cells.
10

11. Contd…
 Acyclovir triphosphate inhibits viral DNA
synthesis by two mechanisms:
1. Competitive inhibition of dGTP for the viral
DNA polymerase, with binding to the DNA
template as an irreversible complex and
chain termination following incorporation into
the viral DNA.
11

12. Resistance
 Resistance to acyclovir can develop in HSV or
VZV through alteration in either the viral
thymidine kinase or viral polymerase.
12

13. Pharmacokinetics
 Acyclovir is available in oral, IV and topical
formulations.
 Bioavalibility of the oral formulation is 15-20%.
 Topical formulations produce local
concentrations that may exceed 10μg/ml in
herpetic lesions, but systemic concentrations
are undetectable.
13

14. Contd…
 Cleared primarily by glomerular filtration and
tubular secretion.
 T ½ is 3-4 hours in patients with normal renal
function.
 20 hours in patients with anuria.
 IV administration, a loading dose of 5-10mg/kg
and maintenance dosage eg. 15mg/kg/d is
reduced by 1/3 for creatinine clearance of 25-
50mL/min and by 2/3 for clearance of 10-
25mL/min.
14

15. Contd…
 Anuric patients give 1/6 of the dosage.
 Readily cleared by haemodialysis but not
peritoneal dialysis.
 Diffuses into most tissues and body fluids to
produce concentrations that are 50-100% that
of serum.
 CSF concentrations: 50% of serum values.
15

16. Clinical uses
1. Primary infections
2. Recurrent infections of genital and labial
herpes
 200mg *5/day shortens duration of
symptoms, time of viral shedding and time to
resolution of lesions in 10 HSV infections.
3. HSV proctitis: 400mg *5/day.
4. Herpes encephalitis and neonatal HSV
infection: IV 10mg/kg every 8 hours.
16

17. Contd…
 Topical is much less effective than oral therapy
for 10 HSV infection.
 It is not beneficial in treating recurrences.
 VZV is less susceptible to acyclovir than HSV.
 Dosage of 800mg*5/d or 20mg/kg every 6
hours in children shortens the duration of
varicella or zoster in immunocompetent
patients by 1-2 days.
17

18. Contd…
 In immunocompromised patients with zoster,
IV acyclovir 10mg/kg every 8 hours.
 It reduces the incidences of cutaneous and
visceral dissemination.
 Treatment does not reduce the frequency of
post herpetic neuralgia.
 PO 400mg *12 hours or 200mg *8 hours is
effective for chronic suppression of recurrent
genital and labial herpes.
18

19. Adverse effects
 Nausea, diarrhoea, headache
 IV- renal insufficiency or neurologic toxicity
with tremors and delirium.
 Uncommon with adequate hydration and
avoidance of rapid infusion rates.
19

20. Valacyclovir
 Is the L-valyl ester of acyclovir.
 Rapidly converted to acyclovir after oral
ingestion.
 In vitro activity, mechanism of action,
emergence of resistance and
pharmacokinetics are identical to those of
acyclovir.
20

21. Contd…
 Used for treatment of patients with recurrent
genital herpes 500mg*12 hours.
 Herpes zoster infections 1g* 8 hours
 Well tolerated: nausea, diarrhoea and
headache have been reported.
 HIV/AIDS patients receiving high doses-8g/d
had an increased incidence of GI intolerance
and thrombotic microangiopaties-TTP and
HUS.
21

22. Famciclovir
 It is the diacetyl ester prodrug of 6-deoxy
penciclovir, an acyclic analogue of guanosine.
 Rapidly converted to penciclovir through 1st
pass metabolism.
 Penciclovir is the active form.
 Activation by phosphorylation is catalysed by
the virus-specified thymidine kinase in infected
cells followed by competitive inhibition of the
viral DNA polymerase to inhibit DNA synthesis.
22

23. Pharmacokinetics
 Available orally
 Bioavalability of penciclovir is 70%
 Clearance of penciclovir and dosage
adjustments is similar as to those for acyclovir
23

24. Clinical uses
 Recurrent genital herpes 125mg*12 hours
 Herpes zoster infections: 500mg *8 hours
 Comparison with acyclovir in
immunocompetent patients with zoster
showed no differences in time until healing but
more rapid resolution of zoster associated pain
in patients treated with famciclovir.
24

25. Adverse reactions
 Headache, diarrhoea and nausea though the
drug is well tolerated.
25

26. Penciclovir
26
 Guanosine analog
 Active metabolite of famciclovir
 For active use
 1% cream is effective for treatment of
recurrent herpes labialis in immunocompetent
adults.
 Shortens healing time
 Side effects-uncommon

27. Docosanol
27
 Saturated 22-carbon aliphatic alcohol that
inhibits fusion between the plasma membrane
and the HSV envelope.
 :. Prevents viral entry into cells and
subsequent viral replication.
 Available as topical docosanol 10% cream.
 Apply *5/day: reduces healing time.

28. Trifluridine
28
 Trifluorothymidine
 Fluorinated pyrimidine nucleoside that inhibits
viral DNA synthesis in HSV1, HSV 2, vaccinia
and some adenoviruses.
 Phosphosrylated intracellularly to its active
form by host cell enzymes and then competes
with thymidine triphosphate for incorporation
by the viral DNA polymerase.
 Incorporation of trifluridine triphosphate into
both viral and host DNA prevents its systemic
use.

29. Contd…
29
 1% solution is effective in treating
keratoconjuctivitis and recurrent epithelial
keratitis due to HSV1 and HSV 2.
 Topical application of trifluridine solution alone
od in combination with IFN α ; treatment of
acyclovir resistant HSV infections.

30. Ganciclovir
 Guanosine analogue
 Requires triphosphorylation for activation prior
to inhibiting the viral DNA polymerase.
 Has activity against CMV, HSV, VZV, and EBV
 100* more active than acyclovir in treatment of
CMV.
30

31. Pharmacokinetics
 Available in IV and oral formulations
 Oral bioavailabilty is poor: 6-9%.
 CSF concentrations are ~ 50% of those in
serum.
 T ½ is 2-4 hours with normal renal function.
 Dosage adjustment is recommended for
creatinine clearances less than 80mL/min.
 Readily cleared by dialysis.
31

32. Clinical uses
 Loading dose IV is 5mg/kg *8 12 hours then
5mg/kg/d for maintenance.
 This is indicated for treatment of CMV retinitis
in patients with HIV/AIDS.
 Also reduces the incidence of symptomatic
CMV disease if administered before organ
transplantation Ig.
 CMV colitis and eosphagitis.
32

33. Contd…
 Administered intraocularly to treat CMV retinitis,
either by direct intravitreal administration or via an
intraocular implant.
 The implant achieves high and prolonged
intraocular levels of ganciclovir, delays progression
of retinitis to a greater degree than systemic
therapy with ganciclovir.
 Surgical replacement is required at intervals of 5–8
months. Concurrent therapy with a systemic anti-
CMV agent is recommended.
33

34. Adverse reactions
 Myelosuppression may be additive in patients
receiving both ganciclovir, mycophenolate
mofetil and zidovudine.
 CNS toxicity headache, changes in mental
status, seizures has been rarely reported.
 Is mitogenic in mammalian cells and
carcinogenic and embryotoxic in animals.
34

35. Cidofovir
 Cytosine nucleotide analog.
 Has in vitro activity aagainst CMV, HSV 1,2,
VZV, EBV, Adenovirus and HPV.
 Phosphorylation to the active diphosphate is
independent of virus infection and the
compound has a prolonged intracellular t 1/2.
 CMV retinitis: IV 5mg/kg weekly for 2 weeks
then once every other week.
35

36. Contd…
 Can also be given intravitreally.
 the terminal T 1/2 2.6 hours but of the active
metabolite, cidofovir diphosphate, has a prolonged
intracellular half-life of 17–65 hours, thus allowing
widely spaced administration.
 A separate metabolite, cidofovir phosphocholine,
has a half-life of at least 87 hours and may serve as
an intracellular reservoir of active drug.
36

37.  Cerebrospinal fluid penetration is poor. Elimination
involves active renal tubular secretion.
 High-flux hemodialysis has been shown to reduce
the serum levels of cidofovir by approximately
75%.
37

38.  Intravenous cidofovir is effective for the treatment
of CMV retinitis.
 Has been used experimentally to treat
adenovirus infections. Intravenous cidofovir must
be administered with probenecid (2 g at 3 hours
before the infusion and 1 g at 2 and 8 hours after),
which blocks active tubular secretion and
decreases nephrotoxicity.
38

39. Contd…
 Nephrotoxicity is the major dose limiting
toxicity.
 Concurrent administration with other
nephrotoxic agents eg. Amphotericin B,
aminoglycosides, NSAIDs should be avoided.
39

40. Valganciclovir
 L-valyl ester prodrug of ganciclovir that exists as a
mixture of two diastereomers . After oral
administration, both diastereomers are rapidly
hydrolyzed to ganciclovir by intestinal and hepatic
esterases.
 Well absorbed and rapidly metabolized in the
intestinal wall and liver to ganciclovir; no other
metabolites have been detected.
40

41. Contd…
41
 bioavailability of oral valganciclovir is 60%; it
is recommended that the drug be taken with
food.
 Plasma protein binding is less than 2%. The
major route of elimination is renal—through
glomerular filtration and active tubular
secretion.

42. Contd…
 Plasma concentrations are reduced ~ 50% by
hemodialysis.
 Indicated for the treatment of CMV retinitis in
patients with AIDS.
 prevention of CMV disease in high-risk kidney,
heart, and kidney-pancreas transplant patients.
 Adverse effects, drug interactions, and resistance
patterns are the same as those associated with
ganciclovir.
42

43. Foscarnet
 An organic pyrophosphate compound that
inhibits viral DNA polymerase, RNA
polymerase, HIV reverse transcriptase.
43

44. Pharmacokinetics
 IV formulation only.
 Poor oral bioavailability, and GI intolerance
have precluded the production of oral
formulation.
 CSF concentrations are approximately 2/3 of
steady state serum concentrations.
 Clearance is directly proportionate to
creatinine clearance.
44

45. Contd…
 Initial elimination t1/2 is 4-8 hours then
prolonged to 3-4 days in a patient with normal
renal function.
 Serial dose adjustments is according to the
calculated creatinine clearance throughout the
administration of the drug.
45

46. Clinical uses
 CMV retinitis- 60mg/kg *8 hours or 90mg/kg
*12 hours- induction dose.
 Maintenance dose is 90-120mg/kg/d
 CMV colitis and CMV esophagitis.
 Acyclovir resistant VZV infection
46

47. Adverse effects
 Renal insufficiency
 Hypo/hyper calcaemia, hyper/hypo
phosphatemia.
 Genital ulcerations due to high levels of
ionised drug in the urine
 CNS- headache, hallucinations, seizures.
 Use of an infusion pump to control the rate is
preferred.
 Saline preloading and avoidance of other
nephrotoxic drugs!!!
47

48. Anti influenza Agents
48
 Influenza virus strains are classified by their
core proteins ie. A, B, C ; species of origin-
avian, swine ; Geographical site of isolation.
 Influenza A is the only strain that causes
pandemics.

49. Amantadine and Rimantadine
49
 Amantadine (1-aminoadamantane HCl) and its
methyl derivative inhibit the uncoating of the
viral RNA within the infected host cells thus
preventing its replication.
 Active against influenza A only.
 Amantadine is excreted unchanged in the
urine.
 Rimantadine undergoes extensive metabolism
by hydroxylation conjugation and
glucoronidation before urinary excretion.

50. Contd….
50
 Dose reductions are required for both in the
elderly in patients with renal insufficiency and
for rimantadine in patients with marked hepatic
insufficiency.
 Without resistance, both given at 100mg BD or
200mg OD, are 70-90% protective in the
prevention of clinical illness when initiated
before exposure.

51. AEs
51
 Nausea, anorexia
 CNS- nervousness, difficulty in concentrating,
insomnia, light headedness with Rimantadine
 Birth defects have been reported after
exposure during pregnancy.

52. Zanamivir and Oseltamivir
52
 Neuraminidase inhibitors; analogs of sialic
acid: They interfere with release of progeny
influenza virus from infected to new host cells,
halting the spread of infection within the
respiratory tract.
 Both are active against both Influenza A and B
viruses.
 Zanamivir is delivered directly to the
respiratory tract via inhalation.
 10-20% of the active compound reaches the
lungs and the rest is deposited in the
oropharynx.

53. Contd…
53
 Oseltamivir is administered orally as a
prodrug.
 It is activated by hepatic esterases and widely
distributed throughout the body.
 Dose reduction in patients with renal
insufficiency is necessary.
 T ½ is 6-10 hours, excretion is primarily in the
urine.
 Aes: Nausea, vomiting and abdominal pain
 Headache, fatigue and diarrhoea have been
reported commonly with prophylactic use.

54. AOB
54