Case Files: Pharmacology. Acyclovir's mechanism of action and its efficiency in treating herpes zoster virus (shingles).

1. ACYCLOVIR
Case Files: Pharmacology
Camille Renee
February 16, 2015
Dr. FM
PHRM1 3101

2. Case 47
 A 58-year-old man presents for the evaluation of a
painful rash. He says that for 3 or 4 days he had a
sharp, burning pain radiating from his midback
around to his left side. He thought that he was
having a kidney stone.Yesterday he noticed a rash
which spread in a distribution “like a line” in the
same area in which he had the pain. He is on
glyburide for type II diabetes, simvastatin for high
cholesterol, and lisinopril for hypertension, all of
which he has been on for several years. He does have
a history of having chickenpox as a child.

3. Case 47
 On examination he has a low-grade fever
and otherwise normal vital signs. His skin
examination is remarkable for a rash in a
belt-like distribution from his spine around
his left flank to the midline of the
abdomen.The rash consists of
erythematous patches with clusters of
vesicles.The remainder of his examination
is normal.You make the diagnosis of
herpes zoster and prescribe a course of
acyclovir (ACV).

5. Case Summary
 58-year-old man
 Rash with ‘line-like distribution’
 History of chickenpox as a child
 Erythematous patches with vesicles
in a belt-like distribution
 Diagnosed with herpes zoster virus
(HZV) and prescribed acyclovir

6. HERPES ZOSTER VIRUS (SHINGLES)

7. Pathogenesis
 Primary replication site is
the respiratory tract
 Spreads hematogenously
and lymphatically
 Replicates in
 Monocytes
 Capillary endothelial cells
 Epithelial cells
 Cytotoxic lymphocytes
allow virus to enter
sensory nerves and travel
to DRG
Reactivation of
varicella zoster
(VZV)

8. Presentation
 3-5 days of pain
and paresthesia
prior to rash
 Unilateral
vesiculopustular
eruption
 Pre-herpetic or
post-herpetic
neuralgia

9. Management
 Compress rash with
normal saline solution
 Administer analgesics
i.e. NSAIDs
 Administer antiviral
drugs i.e. acyclovir
 Gabapentin may be
prescribed for post-
herpetic neuralgia

10. ANTIVIRAL AGENTS

11. Four Classes
1. DNA Polymerase Inhibitors
 Acyclovir
2. ReverseTranscriptase Inhibitors
 Abacavir
3. Protease Inhibitors
 Ritonavir
4. Fusion Inhibitors
 Enfuvirtide
All used to
treat HIV

12. Herpesviridae Agents
 Acyclovir
 Valacyclovir
 Penciclovir
 Famciclovir
 Ganciclovir
 Foscarnet
 Trifluridine
VALACYCLOVIR
(VCV) is an analog of
acyclovir that is
rapidly converted to
acyclovir in the
body. Its advantage
is better oral
BIOAVAILABILITY!

13. HZV Therapy

15. ACYCLOVIR (ZOVIRAX)

16. Structure
Purine Analog

17. Mechanism of Action
• Guanosine analog
• Converted to nucleoside
triphosphate by cellular
enzymes (phosphorylation)
• Affects only viral DNA
polymerase activity using
competitive inhibition,
terminating its growing
chain

18. Mechanism of Action
1 2
3

19. Mechanism of Action
Acyclovir
HZV

21. Adverse Effects
 Monophosphorylated by
HZV/VZV’s thymidine
kinase
 NOT monophosphorylated
by uninfected cells  low
risk of adverse effects
 Mild side effects include
nausea and headache

22. Adverse Effects

23. CLINICAL INDICATIONS

24. Herpesviridae
• HSV (Herpes simplex
virus)
• VZV (varicella zoster virus)
• Weak activity against EBV
(Epstein-Barr virus)
• HSV-induced
• Mucocutaneous lesions
• Dendritic keratitis
• Genital lesions
• Encephalitis

25. Ineffective
 No activity against CMV
(cytomegalovirus)!!
 No effect on latent forms
of HSV andVZV

26. Prophylaxis
 Can be used to
prevent subsequent
herpes infection in
immunocompromised
and/or elderly
individuals

27. TOXICITY

28. Toxicity
 PO  well-tolerated
 Intravenous
 Crystalline
neuropathy (1%)
or nephropathy
 Acute renal failure
(caused from
dehydration)

29. Toxicity
 This occurs because unmetabolized acyclovir
is excreted through the kidneys by glomerular
and tubular filtration
Why the
kidneys?

30. RESISTANCE

31. Mechanisms of Resistance
1. A mutated viral
thymidine kinase
will be able to resist
phosphorylation
1. Mutations arising in
viral DNA
polymerase may
also affect drug
action

32. Mechanisms of Resistance

33. QuizTime!!
MULTIPLE CHOICE QUESTIONS

34. Questions 1 & 2
 True or False: Acyclovir can be used to
treat cytomegalovirus (CMV) in children.
a) True
b) False
 Acyclovir is an analogue of which
nucleoside?
a) Adenosine
b) Guanosine
c) Cytosine
d) Thymidine

35. Answers
B.Acyclovir has little to no effect on
cytomegalovirus. It is primarily utilized to
treat HSV1, HSV2, andVZV.
B.Acyclovir is a purine analog, specifically
guanosine.

36. Question 3
 Acyclovir is a purine analog that works by
inhibiting viral DNA polymerase. Drug resistance
is a mechanism that allows a microbe to evade
drug action. Mutations in which of the following
enzymes will allow herpes zoster to evade the
drug action of acyclovir?
a) Thymidine kinase
b) Phosphodiesterase
c) DNA polymerase
d) Glycogen synthase
e) Both A & C

37. Answer
E.Acyclovir, a DNA polymerase inhibitor,
works by acting as a guanosine analog to
cease viral replication.Viruses may be able to
evade the action of acyclovir if they possess
mutations in either thymidine kinase or DNA
polymerase.

38. Question 4
 A disadvantage of acyclovir is the fact that it
has a low oral bioavailability. Which of the
following agents may be substituted for
treatment of herpes zoster because of its high
bioavailability?
a) Famciclovir
b) Foscarnet
c) Valacyclovir
d) Penciclovir

39. Answer
C.Valacyclovir (VCV) is an analog of
acyclovir that acts as a prodrug. It is rapidly
converted to acyclovir in the body, resulting
in higher concentrations of acyclovir. Its
advantage is better oral bioavailability.

40. References
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42. Questions?