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 midbackaround 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.
Case 47
On examination he has a low-grade feverand 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).
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
Pathogenesis Primary replication site is
the respiratory tract
Spreads hematogenouslyand 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)
Presentation
3-5 days of pain and paresthesiaprior to rash
Unilateral vesiculopustulareruption
Pre-herpetic or post-herpetic neuralgia
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
Four Classes
1. DNA Polymerase Inhibitors
Acyclovir
2. Reverse Transcriptase Inhibitors
Abacavir
3. Protease Inhibitors
Ritonavir
4. Fusion Inhibitors
Enfuvirtide
All used to treat HIV
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!
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
Adverse Effects
Monophosphorylated by HZV/VZV’s thymidinekinase
NOT monophosphorylatedby uninfected cells low risk of adverse effects
Mild side effects include nausea and headache
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
Prophylaxis
Can be used to prevent subsequent herpes infection in immunocompromisedand/or elderly individuals
Toxicity
PO well-tolerated
Intravenous
Crystalline neuropathy (1%) or nephropathy
Acute renal failure (caused from dehydration)
Toxicity
This occurs because unmetabolized acyclovir is excreted through the kidneys by glomerularand tubular filtration
Why the kidneys?
Mechanisms of Resistance
1. A mutated viral thymidine kinasewill be able to resist phosphorylation
1. Mutations arising in viral DNA polymerase may also affect drug action
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
Answers
B. Acyclovir has little to no effect on
cytomegalovirus. It is primarily utilized to treat HSV1, HSV2, and VZV.
B. Acyclovir is a purine analog, specifically
guanosine.
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 kinaseb) Phosphodiesterasec) DNA polymerased) Glycogen synthasee) Both A & C
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.
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
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.
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