Introduction
Acyclovir is a synthetic nucleoside analogue and antiviral medication that has revolutionized the treatment of herpesvirus infections since its FDA approval in 1982. As one of the most widely prescribed antiviral agents worldwide, acyclovir represents a cornerstone therapy for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections across various clinical presentations and patient populations.
Mechanism of Action
Acyclovir exerts its antiviral activity through selective inhibition of viral DNA synthesis. The drug undergoes a three-step activation process: first, viral thymidine kinase phosphorylates acyclovir to acyclovir monophosphate; then, cellular enzymes convert it to acyclovir diphosphate and finally to acyclovir triphosphate. Acyclovir triphosphate competitively inhibits viral DNA polymerase and incorporates into growing DNA chains, causing chain termination. This selective activation in infected cells results in minimal effects on uninfected host cells, contributing to its favorable safety profile.
Indications
FDA-approved indications:- Herpes simplex virus (HSV) infections:
- Genital herpes (initial and recurrent episodes) - Mucocutaneous herpes in immunocompromised patients - Herpes labialis (cold sores) - Herpetic keratitis (ophthalmic formulation)
- Varicella-zoster virus (VZV) infections:
- Chickenpox (varicella) - Herpes zoster (shingles)
Off-label uses:- HSV encephalitis
- Neonatal herpes infections
- Herpes whitlow
- Prevention of HSV reactivation in immunocompromised patients
Dosage and Administration
Oral administration:- Genital herpes (initial): 200 mg every 4 hours (5× daily) for 10 days
- Genital herpes (recurrent): 200 mg every 4 hours (5× daily) for 5 days
- Chronic suppression: 400 mg twice daily
- Herpes zoster: 800 mg every 4 hours (5× daily) for 7-10 days
- Chickenpox (children >2 years): 20 mg/kg/dose (max 800 mg) QID for 5 days
- HSV in immunocompromised: 5 mg/kg every 8 hours
- HSV encephalitis: 10 mg/kg every 8 hours for 14-21 days
- Neonatal HSV: 20 mg/kg every 8 hours for 21 days
- Renal impairment: Dose adjustment required for CrCl <50 mL/min
- Elderly: Consider reduced dosing due to age-related renal function decline
- Hemodialysis: Administer after dialysis sessions
Pharmacokinetics
- Absorption: Oral bioavailability 10-20%; significantly affected by food
- Distribution: Widely distributed to tissues and body fluids, including CSF (50% of plasma concentration)
- Metabolism: Minimal hepatic metabolism; converted to inactive metabolites
- Elimination: Primarily renal excretion (62-90% unchanged); half-life 2.5-3.3 hours in adults with normal renal function
- Protein binding: 9-33%
Contraindications
- Hypersensitivity to acyclovir or valacyclovir
- Patients with known serious hypersensitivity reactions to the drug
Warnings and Precautions
Black Box Warning:- May cause nephrotoxicity, especially with rapid IV administration or in dehydrated patients
- Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) reported in immunocompromised patients
- Neurological symptoms including agitation, confusion, hallucinations, and seizures
- Maintain adequate hydration during IV administration
- Use with caution in patients with pre-existing renal impairment or neurological disorders
- Monitor for thrombocytopenia in immunocompromised patients
Drug Interactions
- Probenecid: Decreases acyclovir clearance, increasing AUC and half-life
- Nephrotoxic drugs (aminoglycosides, amphotericin B, cyclosporine): Increased risk of renal toxicity
- Zidovudine: May cause increased drowsiness and lethargy
- Mycophenolate mofetil: Potential additive effects on immunosuppression
Adverse Effects
Common (≥1%):- Nausea/vomiting (oral: 2-5%; IV: 5-9%)
- Diarrhea (2-3%)
- Headache (1-2%)
- Rash (1-2%)
- Acute renal failure (especially with IV administration)
- Neurotoxicity (agitation, confusion, hallucinations, seizures)
- Hepatotoxicity (elevated transaminases)
- Hematologic abnormalities (anemia, thrombocytopenia, leukopenia)
- Anaphylaxis
Monitoring Parameters
- Renal function: Serum creatinine at baseline and during therapy
- Hydration status: Especially during IV administration
- Neurological status: Monitor for changes in mental status
- Hepatic function: Periodic LFTs with prolonged therapy
- CBC: In immunocompromised patients or with prolonged treatment
- IV site: Monitor for phlebitis or extravasation
Patient Education
- Complete the full course of therapy even if symptoms improve
- Maintain adequate hydration, especially during treatment
- Oral formulation may be taken with food to reduce GI upset
- Not a cure for herpes infections; reduces severity and duration
- Still contagious during treatment; take appropriate precautions
- Report any neurological symptoms, decreased urine output, or unusual bleeding/bruising
- Use sun protection as herpes outbreaks may be triggered by sun exposure
- For genital herpes, continue safer sex practices
References
1. American Society of Health-System Pharmacists. Acyclovir monograph. AHFS Drug Information. 2023. 2. Kimberlin DW, et al. Red Book: 2021 Report of the Committee on Infectious Diseases. 32nd ed. American Academy of Pediatrics; 2021. 3. Gnann JW Jr, Whitley RJ. Clinical practice: Herpes zoster. N Engl J Med. 2002;347(5):340-346. 4. FDA Prescribing Information: Zovirax (acyclovir). 2022. 5. Wagstaff AJ, et al. Acyclovir: A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1994;47(1):153-205. 6. Tyring SK, et al. Famciclovir for acyclovir-resistant mucocutaneous herpes simplex virus infection in HIV-infected persons. Ann Intern Med. 1995;122(5):350-352.