Astemizole

Astemizole (marketed under the brand name Hismanal) 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 It has been withdrawn from the market in most countries because of rare but potentially fatal side effects.

Metabolism
It is metabolized by CYP3A4.

It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4 enzyme inhibitors (e.g. erythromycin, grapefruit juice).

Pharmacology
Astemizole is an histamine H1-receptor antagonist. It is structurally similar to terfenadine 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.

Toxicity
Astemizole has an oral LD50 of approximately 2052 mg/kg (in mice).

Research
It has been reported that this drug might prevent much of the muscle wasting (atrophy) 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.