Acyclovir

ACYCLOVIRCase Files: Pharmacology

Camille ReneeFebruary 16, 2015Dr. FMPHRM1 3101

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

HERPES ZOSTER VIRUS (SHINGLES)

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

ANTIVIRAL AGENTS

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!

HZV Therapy

ACYCLOVIR (ZOVIRAX)

Structure

Purine Analog

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

Mechanism of Action

1 2

3

Mechanism of ActionAcyclovir

HZV

Adverse Effects

Monophosphorylated by HZV/VZV’s thymidinekinase

NOT monophosphorylatedby uninfected cells low risk of adverse effects

Mild side effects include nausea and headache

Adverse Effects

CLINICAL INDICATIONS

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

Ineffective

No activity against CMV (cytomegalovirus)!!

No effect on latent forms of HSV and VZV

Prophylaxis

Can be used to prevent subsequent herpes infection in immunocompromisedand/or elderly individuals

TOXICITY

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?

RESISTANCE

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

Mechanisms of Resistance

Quiz Time!!

MULTIPLE CHOICE QUESTIONS

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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Questions?