Aciclovir
Encyclopedia
United States Adopted Name
United 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 BAN
British Approved Name
A 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 guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
analogue
Nucleic acid analogues
Nucleic acid analogues are compounds structurally similar to naturally occurring RNA and DNA, used in medicine and in molecular biology research....
antiviral drug
Antiviral drug
Antiviral 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, and Zovir. One of the most commonly used antiviral drugs, it is primarily used for the treatment of herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
infections, as well as in the treatment of varicella zoster (chickenpox)
Varicella zoster virus
Varicella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:...
and herpes zoster (shingles)
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...
.
History
Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicityCytotoxicity
Cytotoxicity 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:...
. It was co-discovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising anti-viral activity. Later, Schaffer joined Burroghs-Wellcome and continued the development of aciclovir with Pharmacologist
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
Gertrude B. Elion. Vince later went on to invent abacavir
Abacavir
Abacavir is a nucleoside analog reverse transcriptase inhibitor used to treat HIV and AIDS. It is available under the trade name Ziagen and in the combination formulations Trizivir and Kivexa/Epzicom...
, the NNRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
, partly for the development of aciclovir. Dr. Richard Whitley, a University of Alabama at Birmingham
University of Alabama at Birmingham
The University of Alabama at Birmingham is a public university in Birmingham in the U.S. state of Alabama. Developing from an extension center established in 1936, the institution became an autonomous institution in 1969 and is today one of three institutions in the University of Alabama System...
researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.
Mechanism of action
Aciclovir differs from previous nucleoside analoguesNucleoside analogues
Nucleoside analogues are a range of antiviral products used to prevent viral replication in infected cells. The most commonly used is Acyclovir, 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 containing only a partial nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
structure: the sugar ring
Pentose
A pentose is a monosaccharide with five carbon atoms. Pentoses are organized into two groups. Aldopentoses have an aldehyde functional group at position 1...
is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate
Guanosine monophosphate
Guanosine monophosphate, also known as 5'-guanidylic acid or guanylic acid and abbreviated GMP, is a nucleotide that is used as a monomer 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...
(acyclo-GMP) by viral thymidine kinase
Thymidine kinase
Thymidine kinase 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 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(acyclo-GTP), by cellular kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s. Acyclo-GTP is a very potent inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases 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 polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback 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. Although acyclovir 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 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
within the cell, possibly by cellular phosphatase
Phosphatase
A 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 prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
: 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 known species in the herpesvirus family. In descending order of activity:- Herpes simplex virusHerpes simplex virusHerpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
type I (HSV-1) - Herpes simplex virusHerpes simplex virusHerpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
type II (HSV-2) - Varicella zoster virusVaricella zoster virusVaricella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:...
(VZV) - Epstein-Barr virusEpstein-Barr virusThe 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. It is best known as the cause of infectious mononucleosis...
(EBV) - CytomegalovirusCytomegalovirusCytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
(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
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
.
Resistance
Resistance to aciclovir is rare, but is more common in patients on chronic antiviral prophylaxis (transplant recipients, people with Acquired Immunodeficiency SyndromeAIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
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.
Acyclovir has also shown cross-resistance with Valacyclovir and Famcyclovir.
Pharmacokinetics
Aciclovir is poorly water soluble and has poor oral bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and 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...
(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 9-33%. 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.
Indications
Aciclovir is indicated for the treatment of HSV and VZV infections, including:- Genital herpes simplexHerpes simplexHerpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 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 or fever...
(treatment and prophylaxis) - Herpes simplex labialis (cold sores)
- Herpes zosterHerpes zosterHerpes 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 chickenpoxChickenpoxChickenpox or chicken pox is a highly contagious illness caused by primary infection with varicella zoster virus . It usually starts with vesicular skin rash mainly on the body and head rather than at the periphery and becomes itchy, raw pockmarks, which mostly heal without scarring...
in immunocompromisedImmunodeficiencyImmunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
patientPatientA patient is any recipient of healthcare services. The patient is most often ill or injured and in need of treatment by a physician, advanced practice registered nurse, veterinarian, or other health care provider....
s - Herpes simplex encephalitis
- Acute mucocutaneous HSV infections in immunocompromised patients
- Herpes simplex keratitisKeratitisKeratitis 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 blepharitisBlepharitisBlepharitis is an ocular condition characterized by chronic inflammation of the eyelid, the severity and time course of which can vary. Onset can be acute, resolving without treatment within 2–4 weeks , but more generally is a long standing inflammation varying in severity...
(not to be mistaken with ocular herpes) - Prophylaxis against herpesvirus' in immunocompromised patients (such as patients undergoing cancer chemotherapy)
HIV-1 progression can be delayed by using Aciclovir, according to study led by Dr Jairam Lingappa. Effective in 16% of cases, can delay the HAART treatment by 1–2 years. University of Washington, Seattle.
During a 2 year trial, 284 people progressed with the HIV-1, versus 324 who had not been treated with Aciclovir.
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 labialLip
Lips 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 and in the articulation of sound and speech...
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 and a 800 mg preparation known as Herperax.available as injection form also.
Systemic therapy
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with systemic acyclovir therapy (oral or IV) include: nausea, vomiting, diarrhea and/or headache. In high doses, hallucination
Hallucination
A hallucination, in the broadest sense of the word, 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,...
s have been reported. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, confusion, dizziness, oedema, arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, sore throat, constipation, abdominal pain, hair loss, rash and/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, crystalluria
Crystalluria
Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered as one of the side effects of sulphonamides.-Clinical significance:It can be an indication of urolithiasis.It can be associated with cysteinuria....
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, fatigue, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, Stevens–Johnson syndrome, toxic epidermal necrolysis
Toxic epidermal necrolysis
Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
and/or anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
.
Additional common adverse effects, when acyclovir is administered IV, include encephalopathy
Encephalopathy
Encephalopathy 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:...
(1% of patients) and injection site reactions. The injection formulation is alkaline (pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
11), and extravasation
Extravasation
Extravasation 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
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
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 cellular DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
can incorporate acyclovir into itself, the drug acts as a chromosome
Chromosome
A chromosome is an organized structure of DNA and protein 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.Chromosomes...
mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
; 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 cause any teratogenic or carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic effects and is frequently prescribed for pregnant women, to prevent transmission of HSV to the neonate. The acute toxicity of acyclovir 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 5 to 6 times longer than in those with normal renal function, leading to accumulation of acyclovir in the plasma and the likelihood of development of toxic reactions such as lethargy, confusion and myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
.
Detection in biological fluids
Acyclovir may be quantitated in plasma or serum in order to monitor for drug accumulation in patients with renal dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.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.