|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) ? (US)|
|Legal status||POM (UK) ℞-only (US)|
|Routes||Intravenous, oral, topical|
|Metabolism||Viral thymidine kinase|
|ATC code||J05 D06 S01|
|Mol. mass||225.21 g/mol|
|Melt. point||256.5 °C (494 °F)|
| (what is this?)
Aciclovir (INN) // or acyclovir (USAN, former BAN), chemical name acycloguanosine, abbreviated as ACV, is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, Xovir and Imavir  . One of the most commonly used antiviral drugs, it is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of varicella zoster (chickenpox) and herpes zoster (shingles).
- 1 History
- 2 Pharmacology
- 3 Pharmacokinetics
- 4 Clinical use
- 5 Adverse effects
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of aciclovir. It was codiscovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity. Later, Schaffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion. Vince later went on to invent abacavir, an nRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir. Dr. Richard Whitley, a University of Alabama at Birmingham researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.
Mechanism of action
Aciclovir differs from previous nucleoside analogues in containing only a partial nucleoside structure: the sugar ring is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral Thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular guanosine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases. Acyclo-GTP has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. Although aciclovir resembles a nucleotide, it has no 3' end. Therefore, after its incorporation into a growing DNA strand, no further nucleotides can be added to this strand. It has also been shown that viral enzymes cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.
In sum, aciclovir can be considered a prodrug: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.
- Herpes simplex virus type I (HSV-1)
- Herpes simplex virus type II (HSV-2)
- Varicella zoster virus (VZV)
- Epstein-Barr virus (EBV)
- Cytomegalovirus (CMV) – least activity
Activity is predominantly against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.
Resistance to aciclovir is rare, but is more common in patients on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity. Aciclovir has also shown cross-resistance with valaciclovir and famciclovir.
Aciclovir is poorly water soluble and has poor oral bioavailability (15–30%), hence intravenous administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%. The elimination half-life of aciclovir is approximately 3 hours. It is renally excreted, partly by glomerular filtration and partly by tubular secretion.
The poor oral bioavailability may also be improved by administering valaciclovir, which has an oral bioavailability of about 55%. Valaciclovir is then converted to aciclovir by esterases via hepatic first-pass metabolism.
Aciclovir is indicated for the treatment of HSV and VZV infections, including:
- Genital herpes simplex (treatment and prophylaxis)
- Herpes simplex labialis (cold sores)
- Herpes zoster (shingles)
- Acute chickenpox in immunocompromised patients
- Herpes simplex encephalitis
- Acute mucocutaneous HSV infections in immunocompromised patients
- Herpes simplex keratitis (ocular herpes)
- Herpes simplex blepharitis (not to be mistaken with ocular herpes)
- Prophylaxis against herpesviruses in immunocompromised patients (such as patients undergoing cancer chemotherapy)
It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak. An earlier review of scientific literature showed there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak. However, oral therapy for episodes was found to be inappropriate for most nonimmunocompromised patients based on costs and benefits, presumably in countries where aciclovir is only available on prescription. There is evidence for an oral prophylactic role in preventing recurrences.
Aciclovir trials show that this agent has no role in preventing HIV transmission, but it can help slow HIV disease progression in people not taking anti-retroviral therapy (ART). This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir and cotrimoxazole, in people with HIV.
Dosage and route
Aciclovir is commonly marketed as tablets (200 mg, 400 mg, 800 mg and 1 gram), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%).
- Cream preparations are used primarily for labial herpes simplex.
- The ophthalmic ointment preparation is only used for herpes simplex keratitis.
- The intravenous injection is used when high concentrations of aciclovir are required such as in HSV encephalitis, Acute retinal necrosis, and disseminated zoster disease.
Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhea and/or headache. In high doses, hallucinations have been reported. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat, constipation, abdominal pain, hair loss, rash and/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, thrombotic thrombocytopenic purpura and/or anaphylaxis.
Additional common adverse effects, when aciclovir is administered IV, include encephalopathy (1% of patients) and injection site reactions. The injection formulation is alkaline (pH 11), and extravasation may cause local tissue pain and irritation.
Intravenous acyclovir may cause reversible nephrotoxicity in 5% to 10% of patients because of precipitation of acyclovir crystals in kidney. Acyclovir crystalline nephropathy is more common when acyclovir is given as a rapid infusion and in patients with dehydration and preexisting renal impairment. Adequate hydration, a slower rate of infusion, and dosing based on renal function may reduce this risk.
Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin or transient stinging/burning sensations. Infrequent adverse effects include erythema or itch. When applied to the eye, aciclovir is commonly associated (≥1% of patients) with transient mild stinging. Infrequently (0.1–1% of patients), ophthalmic aciclovir is associated with superficial punctate keratitis or allergic reactions.
Since cellular DNA can incorporate aciclovir into itself, the drug acts as a chromosome mutagen; therefore it "...should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus..." However, it has not been shown to have any teratogenic or carcinogenic effects and is frequently prescribed for pregnant women, to prevent transmission of HSV to the neonate. The acute toxicity (LD50) of aciclovir when given orally is greater than 1 g/kg, due to its low oral bioavailability. Patients with renal impairment often exhibit elimination half-lives for the drug that are five to six times longer than in those with normal renal function, leading to accumulation of aciclovir in the plasma and the likelihood of development of toxic reactions, such as lethargy, confusion and myoclonus.
Occurrences of the Cotard delusion have been reported as an adverse drug reaction to aciclovir, and about 1% of people who take the drug orally experience some psychiatric side-effects. The symptoms of Cotard's were associated with high serum concentrations of 9-Carboxymethoxymethylguanine (CMMG), the principal metabolite of aciclovir.
Detection in biological fluids
Aciclovir may be quantitated in plasma or serum to monitor for drug accumulation in patients with renal dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.
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