Aciclovir (
INNAn International Nonproprietary Name is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
) or
acyclovir (
USANUnited States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
, former
BANA British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...
), chemical name
acycloguanosine, abbreviated as
ACV,
is a
guanosineGuanosine is a nucleoside comprising guanine attached to a ribose ring via a β-N
9-glycosidic bond.Guanosine can be phosphorylated to become GMP , cGMP , GDP and GTP .When guanine is attached to a deoxyribose ring, it is known as a...
analogueNucleic acid analogues are compounds structurally similar to naturally occurring RNA and DNA, used in medicine and in molecular biology research....
antiviral drugAntiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
, marketed under trade names such as
Cyclovir,
Herpex,
Acivir,
Acivirax,
Zovirax,
Aciclovir (
Sanofi-AventisSanofi-Aventis , headquartered in Paris, France, is a multinational pharmaceutical company, the world's fourth-largest by prescription sales. Sanofi-Aventis engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription...
) and
Zovir (
GSK GlaxoSmithKline plc is a United Kingdom-based pharmaceutical, biological, and healthcare company. GSK is the world's second largest pharmaceutical company and a research-based company with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory,...
). One of the most commonly-used antiviral drugs, it is primarily used for the treatment of
herpes simplex virusHerpes simplex virus 1 and 2 are two species of the herpes virus family, Herpesviridae, which cause infections in humans...
infections, as well as in the treatment of
herpes zoster (shingles)Herpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...
.
Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in
cytotoxicityCytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
.
PharmacologistPharmacology is the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals...
Gertrude B. ElionGertrude Belle Elion was an American biochemist and pharmacologist, and a 1988 recipient of the Nobel Prize in Physiology or Medicine. Working alone as well as with George H...
was awarded the 1988
Nobel Prize in MedicineThe Nobel Prize in Physiology or Medicine is awarded once a year by the Swedish Karolinska Institute. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in Physics, Chemistry, Literature, Peace, and Physiology or Medicine...
, partly for the development of aciclovir.
Mechanism of action
Aciclovir differs from previous
nucleoside analoguesNucleoside analogues are a range of antiviral products used to prevent viral replication in infected cells.The most commonly used is Aciclovir, although its inclusion in this category is uncertain, as it contains only a partial nucleoside structure, as the sugar ring is replaced by an open-chain...
in that it contains only a partial
nucleosideNucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine....
structure: the
sugar ringA pentose is a monosaccharide with five carbon atoms.They either have an aldehyde functional group in position 1 , or a ketone functional group in position 2 ....
is replaced by an open-chain structure. It is selectively converted into acyclo-
guanosine monophosphateGuanosine monophosphate, also known as 5'-guanidylic acid or guanylic acid and abbreviated GMP, is a nucleotide that is found in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the phosphate group, the pentose sugar ribose, and the nucleobase guanine...
(acyclo-GMP) by viral
thymidine kinaseThymidine kinase TK, is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2...
, which is far more effective (3000 times) in
phosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many protein enzymes on and off, causing or preventing the mechanisms of diseases such as cancer and diabetes....
than cellular thymidine kinase. Subsequently, the
monophosphate form is further phosphorylated into the active
triphosphate form, acyclo-
guanosine triphosphateGuanosine-5'-triphosphate is a purine nucleotide. It can act as a substrate for the synthesis of RNA during transcription process...
(acyclo-GTP), by cellular
kinaseIn chemistry and biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The process is referred to as phosphorylation...
s. Acyclo-GTP is a very potent
inhibitorEnzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of viral
DNA polymeraseA DNA polymerase is an enzyme that catalyzes the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best-known for their role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand...
; it has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in chain termination. It has also been shown that viral
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
s cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly
metabolisedMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
within the cell, possibly by cellular
phosphataseA phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
s.
In sum, aciclovir can be considered a
prodrugA prodrug is a pharmacological substance that is administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion optimization...
: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.
Microbiology
Aciclovir is active against most species in the herpesvirus family. In descending order of activity:
- Herpes simplex virus
Herpes simplex virus 1 and 2 are two species of the herpes virus family, Herpesviridae, which cause infections in humans...
type I (HSV-1)
- Herpes simplex virus type II (HSV-2)
- Varicella zoster virus
Varicella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and both shingles and postherpetic neuralgia in adults.-Nomenclature:...
(VZV)
- Epstein-Barr virus
The Epstein-Barr Virus , also called Human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans...
(EBV)
- Cytomegalovirus
Cytomegalovirus is a herpes viral genus of the Herpesviruses group: in humans it is commonly known as HCMV or Human Herpesvirus 5 . CMV belongs to the Betaherpesvirinae subfamily of Herpesviridae, which also includes Roseolovirus...
(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 gangliaIn anatomy, a ganglion is a biological tissue mass. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
.
To date, resistance to aciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.
Pharmacokinetics
Aciclovir is poorly water soluble and has poor oral
bioavailabilityIn pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%...
(10–20%), 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, only 30% is protein-bound in plasma. 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
ValaciclovirValaciclovir or valacyclovir is an antiviral drug used in the management of herpes simplex and herpes zoster . It is a prodrug, being converted in vivo to aciclovir...
, which has an oral bioavailability of about 55%. Valaciclovir is then converted to Aciclovir by esterases via hepatic first-pass metabolism.
Indications
Aciclovir is indicated for the treatment of HSV and VZV infections, including:
- Genital herpes simplex
Herpes simplex is a viral disease caused by both herpes simplex virus 1 and herpes simplex virus 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores,...
(treatment and prophylaxis)
- Herpes simplex labialis (cold sores)
- Herpes zoster
Herpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...
(shingles)
- Acute chickenpox
Chickenpox or chicken pox, also known as varicella, is a highly contagious illness caused by primary infection with varicella zoster virus...
in immunocompromised patients
- Herpes simplex encephalitis
- Acute mucocutaneous HSV infections in immunocompromised patients
- Herpes simplex keratitis
Keratitis is a condition in which the eye's cornea, the front part of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves impaired eyesight. -Types:...
(ocular herpes)
- Herpes simplex blepharitis
Blepharitis is an ocular disease characterized by inflammation of the eyelid margins. Blepharitis may cause redness of the eyes, itching and irritation of the eyelids in one or both eyes. Its appearance is often confused with conjunctivitis and due to its recurring nature it is the most common...
(not to be mistaken with ocular herpes)
- Bell's Palsy
Bell's palsy is a paralysis of cranial nerve VII resulting in inability to control facial muscles on the affected side. Several conditions can cause a facial paralysis, e.g., brain tumor, stroke, and Lyme disease. However, if no specific cause can be identified, the condition is known as Bell's...
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 that there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak.
However, it was concluded that oral therapy for episodes is inappropriate for most non-immunocompromised patients based on costs and benefits, presumably in countries where aciclovir is only available on prescription. It was concluded that there is evidence for an oral prophylactic role in preventing recurrences.
Dosage forms
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
labialLips are a visible body part at the mouth of humans and many animals. Lips are soft, movable, and serve as the opening for food intake, as an erogenous organ used in kissing and other acts of intimacy, as a tactile sensory organ, and in the articulation of speech.-Anatomical basics of the human...
herpes simplex. The intravenous injection is used when high concentrations of aciclovir are required. The ophthalmic ointment preparation is only used for herpes simplex keratitis. In Singapore, it is available as a 400 mg preparation known as
Avorax.
Systemic therapy
Common
adverse drug reactionAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial...
s (≥1% of patients) associated with systemic acyclovir therapy (oral or IV) include: nausea, vomiting, diarrhea and/or headache. In high doses,
hallucinationA hallucination, in the broadest sense, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and...
s have been reported. Infrequent adverse effects (0.1–1% of patients) include: agitation,
vertigoVertigo is a specific type of dizziness, a major symptom of a balance disorder. It is the sensation of spinning or swaying while the body is actually stationary with respect to the surroundings.The effects of vertigo may be slight...
, confusion, dizziness, oedema,
arthralgiaArthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, sore throat, constipation, abdominal pain, rash and/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures,
neutropeniaNeutropenia , from Latin prefix neutro- and Greek suffix -πενία is a hematological disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell, in the blood...
,
leukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
,
crystalluriaCrystalluria refers to crystals found in the urine when performing a urine test.-Clinical significance:It can be an indication of urolithiasis.It can be associated with cysteinuria.-External links:* *...
,
anorexiaAnorexia is the decreased sensation of appetite...
, fatigue,
hepatitisHepatitis implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
,
Stevens-Johnson syndromeStevens–Johnson syndrome is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes...
,
toxic epidermal necrolysisToxic epidermal necrolysis , also known as Lyell's syndrome, is a life-threatening dermatological condition that is frequently induced by a reaction to medications...
and/or
anaphylaxisAnaphylaxis is an acute systemic and severe type I hypersensitivity allergic reaction in humans and other mammals. The term comes from the Greek words ανα ana and φύλαξις phylaxis . Minute amounts of allergens may cause a life-threatening anaphylactic reaction...
.
Additional common adverse effects, when acyclovir is administered IV, include
encephalopathyEncephalopathy /ɛnˌsɛfəˈlɒpəθi/ literally means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:In some contexts it...
(1% of patients) and injection site reactions. The injection formulation is alkaline (
pHpH is a measure of the acidity or basicity of a solution. It is defined as the cologarithm of the activity of dissolved hydrogen ions . Hydrogen ion activity coefficients cannot be measured experimentally, so they are based on theoretical calculations...
11), and
extravasationExtravasation is the accidental administration of intravenously infused medicinal drugs into the surrounding tissue, either by leakage , or direct exposure...
may cause local tissue pain and irritation. Renal impairment has been reported when acyclovir is given in large, fast doses intravenously, due to the crystallisation of acyclovir in the kidneys.
Topical therapy
Acyclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin or transient stinging/burning sensations. Infrequent adverse effects include
erythemaErythema is redness of the skin, which can be caused by several things, including capillary congestion.-Causes:It can be caused by infection, massage, electrical treatment, acne medication, allergies, exercise, solar radiation , cutaneous radiation syndrome, or waxing and plucking of the hairs...
or itch.
When applied to the eye, acyclovir 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.
Toxicity
Since acyclovir can also be incorporated into cellular
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
, it is a
chromosomeA chromosome is an organized structure of DNA and protein that is found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions...
mutagenIn biology, a mutagen is a physical or chemical agent that changes the genetic material of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are typically also carcinogens...
, therefore, its use should be avoided during pregnancy. However it has not been shown to cause any teratogenic or
carcinogenA carcinogen is any substance, radionuclide or radiation that is an agent directly involved in the promotion of cancer or in the increase of its propagation. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic effects. The acute toxicity (
LD50In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxic substance or radiation is the dose required to kill half the members of a tested population...
) of acyclovir when given orally is greater than 1 g/kg, due to its low oral bioavailability.
Further reading
- Harvey Stewart C. in Remington’s Pharmaceutical Sciences 18th edition: (ed. Gennard, Alfonso R.) Mack Publishing Company, 1990. ISBN 0-912734-04-3.
- Huovinen P., Valtonen V. in Kliininen Farmakologia (ed. Neuvonen et al.). Kandidaattikustannus Oy, 1994. ISBN 951-8951-09-8.
- Périgaud C., Gosselin G., Imbach J. -L.: Nucleoside analogues as chemotherapeutic agents: a review. Nucleosides and nucleotides 1992; 11(2-4)
- Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995. 2003 (5th) edition ISBN 0-443-07145-4; 2001 (4th) edition ISBN 0-443-06574-8; 1990 edition ISBN 0-443-03407-9.
External links