Pharmacology of Acyclovir

Introduction/Overview

Acyclovir, a synthetic purine nucleoside analogue, represents a cornerstone in the chemotherapeutic management of infections caused by herpesviruses. Its development in the late 1970s marked a pivotal advancement in antiviral therapy, providing the first agent with selective toxicity against viral replication while sparing host cells. The clinical introduction of acyclovir fundamentally altered the management and prognosis of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections, reducing morbidity, mortality, and the risk of transmission. Its enduring relevance is underscored by its inclusion on the World Health Organization’s List of Essential Medicines.

The clinical importance of acyclovir extends across multiple medical disciplines, including dermatology, infectious diseases, neurology, ophthalmology, and transplant medicine. It is employed for the treatment of acute episodes, the suppression of recurrent disease, and the prophylaxis of infection in immunocompromised hosts. Understanding its pharmacology is therefore essential for rational therapeutic decision-making, optimizing efficacy, and minimizing toxicity.

Learning Objectives

• Describe the molecular mechanism of action of acyclovir, including its selective activation by viral enzymes and its inhibition of viral DNA synthesis.
• Analyze the pharmacokinetic profile of acyclovir, including its absorption, distribution, metabolism, and excretion, and the implications for dosing in various patient populations.
• Identify the approved clinical indications for acyclovir and evaluate its role in the management of HSV and VZV infections.
• Recognize the spectrum of adverse effects associated with acyclovir therapy and formulate monitoring strategies to mitigate risks, particularly nephrotoxicity and neurotoxicity.
• Apply knowledge of acyclovir’s pharmacology to develop appropriate dosing regimens for patients with renal impairment, pediatric and geriatric patients, and pregnant individuals.

Classification

Acyclovir is systematically classified within the broader category of antiviral chemotherapeutic agents. Its specific classifications are based on chemical structure, mechanism, and target virus.

Chemical and Pharmacotherapeutic Classification

Chemically, acyclovir is designated as 9-[(2-hydroxyethoxy)methyl]guanine. It is an acyclic analogue of the natural nucleoside deoxyguanosine, differing by the replacement of the ribose sugar moiety with an acyclic side chain. This structural modification is central to its mechanism of action.

Pharmacotherapeutically, acyclovir is a member of the nucleoside analogue class of antiviral drugs. More specifically, it is classified as an anti-herpesvirus agent. Its prodrug, valacyclovir, which is the L-valyl ester of acyclovir, belongs to the same therapeutic class but offers superior oral bioavailability.

Spectrum of Activity

Acyclovir demonstrates selective activity against viruses of the Herpesviridae family. Its antiviral potency is highest against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), followed by varicella-zoster virus (VZV). Activity against Epstein-Barr virus (EBV) is variable and clinical utility is limited. Cytomegalovirus (CMV) is generally resistant to acyclovir at conventional doses due to poor phosphorylation by the CMV-encoded protein kinase UL97, though high doses may have some inhibitory effect. Human herpesvirus 6 (HHV-6) and HHV-8 (Kaposi’s sarcoma-associated herpesvirus) exhibit limited susceptibility.

Mechanism of Action

The antiviral activity of acyclovir is predicated on a multi-step process that exploits biochemical differences between virally infected and uninfected host cells. This process confers a high degree of selective toxicity.

Selective Activation and Phosphorylation

The initial and most critical step for acyclovir’s selectivity is its activation by phosphorylation. In cells infected with HSV or VZV, the viral enzyme thymidine kinase (TK) phosphorylates acyclovir to acyclovir monophosphate. This reaction occurs with an efficiency approximately 200 times greater than the phosphorylation catalyzed by cellular thymidine kinases. The viral TK has a much higher affinity for acyclovir than its natural substrate, thymidine. Subsequent phosphorylation steps are carried out by cellular kinases. Cellular guanylate kinase converts acyclovir monophosphate to acyclovir diphosphate, which is then further phosphorylated by various cellular kinases to the active form, acyclovir triphosphate (ACV-TP).

Inhibition of Viral DNA Synthesis

ACV-TP exerts its antiviral effect through two primary mechanisms directed at viral DNA polymerase.

1. Competitive Inhibition: ACV-TP competes with the natural substrate, deoxyguanosine triphosphate (dGTP), for incorporation into the growing viral DNA chain by viral DNA polymerase. The affinity of ACV-TP for viral DNA polymerase is significantly greater than for cellular DNA polymerases (α, β, γ), contributing further to its selective action.
2. Chain Termination: Following its incorporation into the DNA chain by viral DNA polymerase, the absence of a 3′-hydroxyl group on the acyclic sugar moiety of acyclovir prevents the formation of the 5′ to 3′ phosphodiester linkage with the next incoming nucleotide. This results in premature termination of the elongating DNA strand. The terminated DNA chain containing acyclovir also binds tightly to the viral DNA polymerase, leading to its irreversible inactivation.

Cellular and Molecular Consequences

The net result of these actions is the potent and selective inhibition of viral DNA synthesis in infected cells. Uninfected host cells minimally phosphorylate acyclovir and possess DNA polymerases with low affinity for ACV-TP, thus they are largely spared from the drug’s effects. This mechanism explains the drug’s excellent therapeutic index for HSV and VZV infections. Resistance to acyclovir arises primarily through mutations in the viral genes encoding thymidine kinase (TK-deficient or TK-altered mutants) or, less commonly, DNA polymerase (pol mutants). TK-deficient mutants are the most prevalent and result in complete cross-resistance to other TK-dependent drugs like penciclovir.

Pharmacokinetics

The pharmacokinetic profile of acyclovir is characterized by variable oral bioavailability, wide distribution, minimal metabolism, and predominant renal elimination. These properties have direct implications for its dosing and administration routes.

Absorption

The oral bioavailability of acyclovir is low and variable, ranging from approximately 10% to 30%. This is attributed to its poor lipid solubility and inefficient transport across the gastrointestinal epithelium. Absorption is not significantly affected by food. Peak plasma concentrations (C_max) after a standard 200 mg oral dose are typically around 0.5 to 0.7 µg/mL, achieved in 1.5 to 2.5 hours (t_max). Higher doses yield proportionally higher plasma levels, though not in a strictly linear fashion due to saturable absorption mechanisms. The development of the prodrug valacyclovir, which is converted to acyclovir by first-pass intestinal and hepatic hydrolysis, was a direct response to this limitation, providing a three- to fivefold increase in bioavailability.

Intravenous administration bypasses the absorption phase, achieving immediate and substantially higher plasma concentrations. Following a 1-hour infusion of 5 mg/kg, peak plasma levels of approximately 10 µg/mL are attained. Topical application results in minimal systemic absorption, with drug concentrations detectable only in the epidermis and dermis.

Distribution

Acyclovir distributes widely into most tissues and body fluids. The volume of distribution is approximately 0.7 L/kg, indicating distribution into total body water. It achieves therapeutic concentrations in cerebrospinal fluid (CSF), with CSF levels being about 50% of concurrent plasma concentrations in patients with normal meninges; this ratio may increase to 100% in the presence of meningeal inflammation. The drug crosses the placenta and is distributed into breast milk. Protein binding is relatively low, ranging from 9% to 33%, which implies that the majority of the drug in plasma is in the free, pharmacologically active form.

Metabolism

Acyclovir undergoes minimal hepatic metabolism. A small fraction (less than 10-15%) is metabolized to inactive compounds, primarily 9-carboxymethoxymethylguanine (CMMG). The enzyme responsible for this conversion is not a major cytochrome P450 isoform. The limited metabolism means that drug interactions mediated by hepatic enzyme induction or inhibition are not a major clinical concern for acyclovir itself.

Excretion

Renal excretion of unchanged acyclovir is the principal route of elimination, accounting for 60% to 90% of an administered dose. Excretion occurs via a combination of glomerular filtration and active tubular secretion. The renal clearance of acyclovir exceeds creatinine clearance, confirming the role of tubular secretion. Consequently, plasma half-life (t_1/2) is dependent on renal function. In adults with normal renal function, the terminal elimination half-life is approximately 2 to 3 hours. In anuric patients, this half-life can be prolonged to 20 hours or more.

Pharmacokinetic Parameters and Dosing Considerations

The relationship between dose, plasma concentration, and renal function is critical for dosing. The area under the concentration-time curve (AUC) is proportional to the dose administered intravenously. For oral dosing, AUC = (F × Dose) ÷ Clearance, where F is bioavailability. Because clearance is predominantly renal, the dosing interval must be extended in patients with impaired renal function to prevent accumulation and toxicity. Nomograms and formulas based on creatinine clearance (CrCl) are used to adjust both dose and frequency. For example, a common adjustment is to administer the standard dose every 12 hours for CrCl >50 mL/min, every 24 hours for CrCl 25-50 mL/min, and every 48 hours for CrCl 10-25 mL/min.

Therapeutic Uses/Clinical Applications

Acyclovir is indicated for the management of infections caused by HSV-1, HSV-2, and VZV. The choice of route (topical, oral, intravenous) and dose is dictated by the site and severity of infection, the immune status of the host, and whether the goal is treatment or suppression.

Approved Indications

Herpes Simplex Virus (HSV) Infections:

• Mucocutaneous HSV in Immunocompromised Hosts: Intravenous acyclovir is the treatment of choice for severe or disseminated mucocutaneous HSV infections in immunocompromised patients (e.g., those with HIV/AIDS, undergoing chemotherapy, or transplant recipients). Oral therapy is used for less severe cases.
• Genital Herpes:
  • First Clinical Episode: Oral acyclovir reduces the duration of viral shedding, time to healing, and severity of symptoms.
  • Recurrent Episodes: Oral therapy, if initiated promptly at prodrome onset, can shorten the duration of lesions.
  • Suppressive Therapy: Chronic daily suppressive therapy significantly reduces the frequency of recurrences and the risk of sexual transmission to susceptible partners.
• Herpes Labialis (Cold Sores): Topical acyclovir cream has modest efficacy if applied very early. Oral therapy is more effective for severe or frequent recurrences.
• Herpetic Whitlow: Oral acyclovir is effective in treating this HSV infection of the finger.
• HSV Encephalitis: High-dose intravenous acyclovir is the standard of care and has dramatically reduced mortality from this serious infection.
• Neonatal HSV Infection: High-dose intravenous acyclovir is the definitive treatment for disseminated, CNS, or skin-eye-mouth disease caused by HSV in neonates.
• HSV Keratitis: Topical ophthalmic ointment is used for dendritic ulcers of the cornea.

Varicella-Zoster Virus (VZV) Infections:

• Varicella (Chickenpox): Oral acyclovir is recommended for otherwise healthy individuals at increased risk of moderate to severe disease (e.g., adolescents, adults, secondary household cases) and is standard for immunocompromised patients, who require intravenous therapy.
• Herpes Zoster (Shingles):
  • Immunocompetent Adults: High-dose oral acyclovir accelerates cutaneous healing and reduces acute pain. It may reduce the risk of postherpetic neuralgia, though evidence is stronger for newer agents like valacyclovir and famciclovir.
  • Immunocompromised Patients or Disseminated Disease: Intravenous acyclovir is indicated.
  • Ophthalmic Zoster: Systemic acyclovir is used to prevent ocular complications.

Off-Label and Prophylactic Uses

Several off-label applications are well-supported by clinical evidence and are considered standard practice.

• Prophylaxis in Immunocompromised Patients: Acyclovir is widely used to prevent HSV and VZV reactivation in patients undergoing hematopoietic stem cell transplantation or solid organ transplantation, and in those with acute leukemia receiving induction chemotherapy.
• Prophylaxis in Neonates: It may be used in neonates born to mothers with active genital herpes lesions at delivery.
• Bell’s Palsy: In combination with corticosteroids, it is often prescribed for idiopathic facial nerve palsy (Bell’s palsy), based on a postulated viral etiology, though evidence of benefit is debated.
• Prophylaxis for Recurrent Herpetic Eye Disease: Long-term oral suppressive therapy can be used to prevent recurrences of herpetic keratitis.

Adverse Effects

Acyclovir is generally well-tolerated, particularly with oral and topical administration. Adverse effects are more frequent and severe with intravenous use, often related to high plasma concentrations or rapid infusion.

Common Side Effects

These are typically mild and reversible upon discontinuation.

• Gastrointestinal: Nausea, vomiting, diarrhea, and abdominal pain are the most frequent complaints with oral therapy.
• Central Nervous System: Headache, dizziness, and fatigue may occur.
• Dermatological: Rash (including photosensitivity), pruritus, and urticaria. Topical application can cause transient burning or stinging.

Serious and Rare Adverse Reactions

Nephrotoxicity: This is the most significant adverse effect associated with intravenous acyclovir. It is caused by the precipitation of acyclovir crystals in renal tubules, leading to obstructive nephropathy and acute kidney injury. Risk factors include high doses, rapid intravenous bolus administration, dehydration, pre-existing renal impairment, and concurrent use of other nephrotoxic drugs. Prevention strategies include adequate hydration, slow infusion over at least 1 hour, and dose adjustment for renal function.

Neurotoxicity: CNS effects, though rare, can be severe and are also associated with high plasma levels, typically in patients with renal failure. Symptoms may include agitation, confusion, hallucinations, tremors, myoclonus, seizures, and coma. These symptoms are usually reversible upon drug discontinuation and hemodialysis, which effectively removes acyclovir.

Hematological: Leukopenia and thrombocytopenia have been reported, particularly with high-dose intravenous therapy.

Hepatotoxicity: Reversible elevations in liver transaminases and bilirubin may occur.

Local Reactions: Phlebitis or inflammation at the site of intravenous infusion is common. Extravasation can cause severe local tissue injury and necrosis.

Black Box Warnings and Contraindications

Acyclovir does not carry a formal black box warning from the U.S. Food and Drug Administration. However, the prescribing information contains strong warnings regarding the risks of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which have been reported in immunocompromised patients receiving high-dose intravenous therapy, and the potential for severe local inflammatory reactions with extravasation. The only absolute contraindication is known hypersensitivity to acyclovir or valacyclovir.

Drug Interactions

Given its minimal metabolism, acyclovir has a low potential for pharmacokinetic drug interactions. The most significant interactions are pharmacodynamic or related to its renal excretion pathway.

Major Drug-Drug Interactions

• Nephrotoxic Agents: Concurrent use of drugs such as aminoglycosides, amphotericin B, ciclosporin, cisplatin, foscarnet, and intravenous pentamidine may potentiate the risk of renal dysfunction. Close monitoring of renal function is mandatory.
• Probenecid: Probenecid competitively inhibits the renal tubular secretion of acyclovir, decreasing its renal clearance and increasing its plasma half-life and AUC. This interaction can be used therapeutically to prolong acyclovir exposure but also increases the risk of toxicity. Dose reduction of acyclovir may be necessary.
• Zidovudine: Coadministration may potentiate neurotoxicity, manifesting as profound drowsiness and lethargy. The mechanism is not fully elucidated but may be pharmacodynamic.
• Mycophenolate Mofetil: When coadministered with valacyclovir (the prodrug of acyclovir) in transplant patients, there have been reports of increased concentrations of the mycophenolic acid glucuronide metabolite, though the clinical significance is unclear.

Contraindications

As noted, hypersensitivity to acyclovir or valacyclovir is a contraindication. Caution is advised in patients with pre-existing neurological disorders or renal impairment, where the risk of neurotoxicity and nephrotoxicity, respectively, is heightened.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy: Acyclovir is classified as Pregnancy Category B by the older FDA classification system. Extensive data from pregnancy registries and cohort studies have not demonstrated an increased risk of major birth defects above the baseline population risk. It is considered the antiviral of choice for the treatment of initial or recurrent genital herpes during pregnancy and for suppressive therapy from 36 weeks gestation to delivery to prevent neonatal herpes. The benefit of treating serious maternal HSV or VZV disease generally outweighs any theoretical risk.

Lactation: Acyclovir is excreted into breast milk, achieving milk-to-plasma ratios of approximately 0.6 to 4.1. However, the estimated daily dose ingested by a nursing infant is far below therapeutic pediatric doses. Acyclovir is considered compatible with breastfeeding.

Pediatric Considerations

Acyclovir is approved for use in children for specific indications, including neonatal HSV, chickenpox in immunocompromised children, and HSV encephalitis. Dosing is based on body surface area or weight. Neonates and young infants have immature renal function, necessitating careful dose calculation and interval extension based on gestational and postnatal age. Intravenous hydration must be managed meticulously to avoid fluid overload while preventing crystalluria.

Geriatric Considerations

Age-related decline in renal function is common in elderly patients. Creatinine clearance should be estimated, and acyclovir doses must be adjusted accordingly to prevent accumulation and toxicity. Concomitant medications and comorbidities that affect renal function or neurologic status should be carefully reviewed.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is essential for patients with creatinine clearance below 50 mL/min. Both the dose and the dosing interval require modification, as detailed in pharmacokinetic guidelines. Hemodialysis removes approximately 60% of acyclovir from plasma, so a supplemental dose is typically administered after each dialysis session. Peritoneal dialysis is less effective at clearance.

Hepatic Impairment: Dose adjustment is not routinely required for hepatic impairment alone, as metabolism is minimal. However, patients with advanced liver disease may have associated conditions (e.g., ascites, hepatorenal syndrome) that affect volume of distribution and renal function, which may indirectly necessitate dose review.

Summary/Key Points

• Acyclovir is a nucleoside analogue antiviral drug with selective activity against herpes simplex virus and varicella-zoster virus.
• Its mechanism of action involves selective phosphorylation by viral thymidine kinase in infected cells, followed by inhibition of viral DNA synthesis via competitive inhibition and chain termination by acyclovir triphosphate.
• Oral bioavailability is low (10-30%); the prodrug valacyclovir was developed to overcome this limitation. Acyclovir distributes widely, including into the CSF, is minimally metabolized, and is primarily excreted unchanged by the kidneys.
• Major clinical indications include treatment and suppression of genital herpes, treatment of HSV encephalitis, neonatal HSV, herpes zoster, and varicella in at-risk populations, and prophylaxis in immunocompromised hosts.
• The most significant adverse effects are nephrotoxicity (from intravenous crystalline nephropathy) and neurotoxicity, both of which are dose-dependent and associated with high plasma levels, particularly in renal impairment.
• Significant drug interactions are few but include potentiation of nephrotoxicity with other renal toxicants and decreased renal clearance when coadministered with probenecid.
• Dose adjustment for renal function is critical. Acyclovir is considered safe for use in pregnancy and lactation when indicated. Special attention to dosing is required in pediatric and geriatric populations due to differences in renal function.

Clinical Pearls

• Always estimate creatinine clearance and adjust the dose and interval of acyclovir before initiating therapy, especially with intravenous administration.
• Ensure adequate hydration during intravenous acyclovir infusion to minimize the risk of crystalline nephropathy.
• For severe or disseminated HSV/VZV infections in immunocompromised patients, intravenous therapy is required; oral therapy is insufficient.
• Be aware of the neurotoxic symptoms (agitation, confusion, tremor) which can mimic other CNS pathologies; check drug levels and renal function if this occurs.
• Consider valacyclovir for oral outpatient therapy when higher and more reliable bioavailability is desired, as it simplifies dosing (less frequent administration) and may improve adherence.

References

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