Astemizole
Encyclopedia
Astemizole was a second generation antihistamine
drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica
in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias).
.
It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4
enzyme inhibitors (e.g. erythromycin
, grapefruit juice
).
and haloperidol
(a butyrophenone
antipsychotic
). It has anticholinergic
and antipruritic
effects.
Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema
and pruritus (caused by histamine).
Astemizole does not cross the blood-brain barrier
, and H1 receptor binding is mostly in the peripheral
rather than central nervous system
(CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.
Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96%.
Astemizole may cause life threatening arrhythmia.
) that occurs in immobile, bedridden patients.
An experiment on a small number of mice showed that astemizole blocked the activity of a protein present in muscle that is involved in muscle atrophy. However the concerns for the drug's long-term effects on the heart preclude its routine use in humans for this indication.
Astemizole has recently been found to be a potent treatment for malaria
. It has a mechanism of action similar to chloroquine
but has activity even in chloroquine-resistant parasites.
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias).
Metabolism
It is metabolized by CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
.
It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
enzyme inhibitors (e.g. erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
).
Pharmacology
Astemizole is an histamine H1-receptor antagonist. It is structurally similar to terfenadineTerfenadine
Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia...
and haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
(a butyrophenone
Butyrophenone
Butyrophenone is a chemical compound ; some of its derivatives are used to treat various psychiatric disorders such as schizophrenia, as well as acting as antiemetics....
antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
). It has anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
and antipruritic
Antipruritic
Antipruritics, also known as anti-itch drugs, are medications that inhibit the itching that is often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and...
effects.
Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and pruritus (caused by histamine).
Astemizole does not cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, and H1 receptor binding is mostly in the peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
rather than central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.
Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96%.
Astemizole may cause life threatening arrhythmia.
Research
It has been reported that this drug might prevent much of the muscle wasting (atrophyAtrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
) that occurs in immobile, bedridden patients.
An experiment on a small number of mice showed that astemizole blocked the activity of a protein present in muscle that is involved in muscle atrophy. However the concerns for the drug's long-term effects on the heart preclude its routine use in humans for this indication.
Astemizole has recently been found to be a potent treatment for malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. It has a mechanism of action similar to chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
but has activity even in chloroquine-resistant parasites.