Acyclovir is a nucleotide analog antiviral medication which is used for the treatment of herpes simplex, herpes zoster, herpes labialis, varicella zoster and acute herpetic keratitis. Generally, Acyclovir is used as the first line treatment for these viruses and some Acyclovir products are specified for pediatric patients as young as 6 years old.
What is Acyclovir?
Acyclovir is FDA FDA-approved antiviral drug used for treating viral infections (Eg. herpes simplex viruses). It is sold under different brand names including Zovirax and Sitavig. Acyclovir is the generic name for this drug. It is available in various forms and strengths. Since the 1970s, Acyclovir medication has been widely used as an efficient drug for treating various infections caused by herpesvirus family and varicella zoster viruses.
Indications for Acyclovir
Acyclovir is used for the treatment of infections caused by HSV (herpes simplex virus). FDA has approved Acyclovir medication for use to treat genital herpes and HSV encephalitis. Non-FDA-approved uses of Acyclovir include the treatment of mucocutaneous HSV, varicella zoster and herpes zoster. For the treatment of HSV encephalitis, Acyclovir is the first-line treatment. Presently, no other drugs are indicated for the treatment of this particular condition.
Acyclovir oral forms such as capsules, tablets and suspensions are indicated for the treatment of genital herpes, herpes zoster and chickenpox. Acyclovir topical cream is indicated for the treatment of recurrent herpes simplex labilais in immunocompetent patients (12 years and older).
Acyclovir ointment is indicated for the treatment of initial genital herpes and limited uncomplicated mucocutaneous herpes simplex in immunocompromised patients.
Acyclovir cream with hydrocortisone is an indicated product for the treatment of recurrent herpes labialis and shortening lesion healing time in patients (6 years and above). Acyclovir buccal tablets are indicated treatment for recurrent herpes labialis. Acyclovir ophthalmic ointment is indicated for the treatment of acute herpetic keratitis.
This drug is also used for the prevention of skin, nose, eyes and mouth infections. Sometimes Acyclovir is also used for treating eczema herpeticum in patients suffering from HIV (Human Immunodeficiency Virus). Eczema herpeticum is a rare disease but can be extremely progressive when left untreated.
Patients with extensive involvement, reduced oral intake or systemic symptoms must be admitted for intravenous Acyclovir therapy. Acyclovir also treats oral hairy leukoplakia.
Research and Studies Regarding The Use of Acyclovir
Herpes simplex virus keratitis responded well to oral Acyclovir in pediatric patients. Stromal keratitis with ulceration that is caused by HSV is a corneal infection and is clinically difficult to treat. Researchers examined the effectiveness of intravenous Acyclovir treatment in two patients.
This diagnosis was established by corneal scraping samples which experienced polymerase chain reaction analysis. One patient was suffering from herpes simplex virus types 1 and 2.
Patients with HSV1 corneal infection first received oral Acyclovir treatment. however, the infection and the condition deteriorated so the patient was switched to intravenous Acyclovir therapy. The corneal infection improved gradually.
On the other hand patients with HSV2 corneal infection, the treatment was started with Acyclovir intravenous injection. The infection got better however the patient also had an epithelial lesion that required additional treatment with 100% autologous serum till the lesion healed. Both of these patients got prophylactic treatment (oral Acyclovir) to prevent corneal reinfection.
Acyclovir has shown benefits for treating myelopathy secondary to varicella zoster infection. In a small case study taken from 1994 to 2014, patients with laboratory-confirmed varicella-zoster virus and MRI-confirmed myelopathy demonstrated improvement in symptoms within 2 months in most patients.
Brachial plexus neuritis secondary to Varicella Zoster Virus infection and visceral disseminated VZV infection (with symptoms like abdominal and absence of skin lesions) has also a better response to acyclovir, lessening all symptoms.
Among the recipients of hematopoietic stem cell transplantation, reactivation of varicella-zoster and herpes simplex virus may respond to Acyclovir prophylactic treatment. Prophylactic use of Acyclovir can also be considered in HSV 1 and HSV 2 seropositive organ recipients.
Diseases caused by such viruses are reduced secondary to this intervention however a breakthrough infection may occur. HSV and varicella zoster virus infections are common in patients who have obsolete Acyclovir prophylaxis.
Another advantage of prophylactic Acyclovir is juvenile-onset recurrent respiratory papillomatosis. A prospective observational study involved 21 patients and oral Acyclovir was a postoperative appurtenant. It has demonstrated reduced recurrence of papillomas and reduced the requirement of consecutive surgeries and allied operative risks.
Varicella zoster virus infections may have various complications such as cerebellitis. Treating the root infection has been demonstrated to reduce the complication burden. The case report of a study performed in 2019 describes a patient presenting with truncal ataxia. After undergoing intravenous Acyclovir treatment the patient was free from neurologic disability and cerebellitis.
In the same way, paresis secondary to dermatomal herpes zoster infections has responded well to oral Acyclovir. It is a rare complication of herpes zoster infection when the virus impacts motor nerve fibres instead of or in addition to the dorsal root ganglion.
Pregnancy and Breastfeeding
In patients treated with Acyclovir through empirical observation, it demonstrated no risks to the fetus. Acyclovir medication enters breast milk however generally it is considered compatible with breastfeeding.
Pharmacokinetics of Acyclovir
Acyclovir is a poorly water-soluble drug and it also has poor oral bioavailability therefore if high concentrations are needed, intravenous administration of the drug is obligatory. When the drug is administered orally, peak plasma concentration reaches after one to two hours.
As per the Biopharmaceutical Classical System, Acyclovir comes under the BCS Class 3 drug which means it is soluble with low intestinal permeability. The drug has a high distribution rate, and protein binding is reported to range from 9 to 33%.
The elimination half-life of Acyclovir depends on the age group neonates have an elimination half-life of 4 hours, children of 1 to 12 years of age have an elimination half-life of 2 to 3 hours and adults have an elimination half-life of 3 hours.
Acyclovir Mechanism of Action
The antiviral agent Acyclovir joins itself to the viral DNA, averting further synthesis. It constrains the synthesis of DNA and viral replication after altering to Acyclovir triphosphate via viral and cellular enzymes.
Acyclovir is a synthetic purine nucleoside analog showing in vitro and in vivo inhibitory activity against the herpes simplex virus type and type 2 as well as varicella-zoster virus.
Acyclovir-resistant HSV is not common in immunocompetent patients except in the case of corneal infections. Acyclovir-resistant HSV is more commonly seen in immunocompromised patients such as hematopoietic stem cell transplant patients.
Acyclovir becomes Acyclovir monophosphate because of the action of viral thymidine kinase. Acyclovir monophosphate is transformed into diphosphate form by guanylate kinase. Acyclovir diphosphate is transformed into Acyclovir triphosphate by nucleoside diphosphate kinase, creatine kinase, pyruvate kinase, phosphoglycerate kinase, phosphoenolpyruvate carboxykinase, succinyl-CoA synthetase and adenylosuccinate synthetase.
Acyclovir triphosphate has a greater attraction for viral DNA polymerase than the cellular DNA polymerase and combines with the DNA where the missing 2 and 3 carbons cause DNA chain termination. In other cases Acyclovir triphosphate participates so powerfully for viral DNA polymerase that other bases can not subordinate with the enzyme, disabling it.
Acyclovir Administration Process
Acyclovir can be administered orally or intravenously. For limited mucocutaneous lesions, Acyclovir is administered orally. In cases that involve CNS, visceral or disseminated Acyclovir is administered intravenously.
For oral administration, you can take Acyclovir with or without food two to five times a day for 5 to 10 days or as suggested by your doctor. Your healthcare professional may prescribe you to take this drug for up to 12 months for the prevention of genital herpes outbreaks.
Acyclovir intravenous administration should be done only via intravenous infusion over 1 hour at a constant rate to avoid renal damage. Medication should be in a diluted D5W solution or 0.9% NaCl to a final concentration equal to or less than 7 mg/mL.
Detection in Biological Fluids
Acyclovir may be assessed in serum or plasma to screen for drug buildup in patients with renal dysfunction or for the diagnosis of poisoning in acute overdose sufferers.
Resistance to Acyclovir
People with healthy immune systems are not likely to develop Acyclovir resistance however it is more common in patients with immunodeficiencies on chronic antiviral prophylaxis (transplant recipients and patients with acquired immunodeficiency syndrome due to HIV infection). In the case of HSV, the mechanisms of resistance include deficient viral thymidine kinase and mutations to viral thymidine kinase or DNA polymerase changing substrate sensitivity.
Absorption of Acyclovir
The oral bioavailability of Acyclovir medication is 10-20% and decreases with increasing doses. Acyclovir buccal tablets and Acyclovir ophthalmic ointment are absorbed minimally. The bioavailability is Acyclovir is not influenced by food.
Metabolism of Acyclovir
Acyclovir is < 15% oxidized to 9-carboxy methoxymethyl guanine by alcohol dehydrogenase and aldehyde dehydrogenase and 1% 8-hydroxylated to 8-hydroxy-acyclovir by aldehyde oxidase.
Acyclovir Route of Elimination
Acyclovir is broadly distributed into body fluids and tissues. plasma protein binding is quite low at 9 to 24%. major route of elimination of this drug is renal excretion.
The majority of Acyclovir medication is expelled via the urine as an unchanged drug. 90 to 92% of this medication can be excreted unchanged via glomerular filtration and tubular secretion. < 2% of this medication is recovered in faeces and < 0.1% expired as CO2.
Clearance of Acyclovir
The clearance of the drug varies from 2.5 to 3 hours depending on the patient’s creatinine clearance. The plasma half-life of Acyclovir during hemodialysis is approximately 5 hours. The mean half-life in patients from 7 months to 7 years old is 2.6 hours.
The renal clearance of this drug is 248mL/min/1.73m2. The complete clearance in neonates is 105-122mL/min/1.73m2
Acyclovir Toxicity
Symptoms of Acyclovir overdose include lethargy, agitation, coma and precipitation in renal tubules. These symptoms are mostly common in patients taking high doses of this drug without monitoring fluid and fluid balance or reduced kidney function. In case of Acyclovir drug overdose, treatment should be given with symptomatic and supportive care.
Acyclovir Drug Interactions
- Abacavir – Acyclovir may reduce the excretion rate of Abacavir which may cause higher serum levels.
- Abametapir – Combining Abametapir with Acyclovir can amplify the concentration of Acyclovir.
- Abatacept – The metabolism of Acyclovir can be enhanced when it is combined with Abatacept.
- Abemaciclib – Combining Abemaciclib with Acyclovir can decrease the excretion of Abemaciclib.
- Abiraterone – When you combine Acyclovir with Abiraterone, it results in an increased serum concentration of Acyclovir.
- Acamprosate – Pairing Acyclovir with Acamprosate decreases the excretion of Acamprosate.
- Aceclofenac – When Acyclovir is combined with Aceclofenac it increases the risk or severity of nephrotoxicity.
- Acemetacin – Combining Acemetacin with Acyclovir can increase the risk or severity of nephrotoxicity.
- Acenocoumarol – Taking Acyclovir with Acenocoumarol can decrease the metabolism of Acenocoumarol.
- Acetaminophen – Taking Acyclovir with Acetaminophen can decrease the metabolism of Acyclovir.
Acyclovir and Food Interactions
While taking Acyclovir drink plenty of fluids and stay hydrated. Dehydration with Acyclovir inclines patients to nephrotoxicity. Take this medicine with or without food as suggested by your doctor. The absorption of the drug is unaffected by food.
Plasma protein binding of Acyclovir is small at about 15% and can breach the blood-brain barrier. Acyclovir is mainly renally eliminated unaltered by glomerular filtration and active tubular secretion. The mean half-life of Acyclovir post intravenous administration ranges between 2.5 to 3 hours. The renal clearance of the patient correlated well with the creatine clearance.
Thus, patient variability in the safety and effectiveness of Acyclovir is prominently based on the age and renal function of the patient that needs conscious monitoring. Renal impairment can intensely enhance the half-life of Acyclovir (eg. up to 10 times). The pharmacokinetics of Acyclovir is similar in pediatric patients. Variants in the NUDT15 and ABCC4 genes may impair the effectiveness of Acyclovir.
Adverse Effects of Acyclovir
The most common adverse effect of this drug is malaise. Less common adverse effects include inflammation at the infusion site, vomiting, nausea, transaminitis and rash when the drug is administered intravenously. Inflammation or phlebitis at the site of infusion can be prevented by spinning the infusion sites and reducing the final infusion concentration to less than 10 mg/mL.
Patients may also experience headaches, nausea, vomiting and diarrhoea when the drug is taken orally. In rare cases, patients may experience abdominal pain, fatigue, dizziness, coma, anaemia, alopecia, agitation and confusion.
Acyclovir Against Herpes Simplex Virus, Genital Herpes And Varicella Zoster Virus
Acyclovir is a considerably safe and active antiviral drug that works as a specific inhibitor of herpes virus DNA polymerase. It demonstrates good in vitro activity against herpes simplex virus infections and varicella-zoster virus. This medication can be applied topically to the skin, administered orally, intravenously or topically to the eye.
Acyclovir kinetics are defined by a two-compartment open model. The medication and its metabolites are expelled by the kidney via glomerular filtration and tubular secretion. Dose adjustment is needed in patients with impaired renal function and renal failure.
Safety and tolerance studies in humans and animals have demonstrated Acyclovir to be well tolerated. The most significant adverse effect is crystalluria and elevated serum creatinine related to bolus intravenous administration. Some patients reported inflammation at the infusion site and rash.
Topical Acyclovir is effective for treating initial genital herpes and mucocutaneous herpes in the compromised patient however it has not been demonstrated to be clinically effective against recurrent genital herpes or labial herpes.
Intravenous Acyclovir works well for mucocutaneous herpes infections in compromised patients and initial genital herpes in normal patients and it is being assessed for the treatment of herpes simplex virus encephalitis and varicella zoster infections.
An investigational oral preparation can be an effective treatment for initial as well as recurrent genital herpes. Acyclovir therapy does not eliminate latent virus or prevent subsequent recurrences.
