The Development of Antihistamines

Overview

An antihistamine is a drug used to counteract the effects of histamine, the chemical released by certain cells in the body during an allergic reaction. Although antihistamines do not change the cause of the allergic reaction, they do suppress the symptoms associated with allergy. The groundwork for the development of antihistamines was made in the first half of the twentieth century by Swiss-Italian pharmacologist Daniel Bovet (1907-1992). Bovet's work led to the discovery and production of antihistamines for allergy relief and earned him the Nobel Prize for physiology or medicine in 1957.

Background

In some humans, the immune system perceives irritants such as pollen or animal dander to be foreign substances dangerous to the body. When these are inhaled into the body, antibodies seek out the irritant and combine with it. A large blood cell known as a basophil, or mast cell, then releases the compound histamine, which attaches itself to receptor cells in mucous membranes. Histamine then causes the local blood vessels to dilate. A drop in blood pressure and increased permeability of the vessel walls also occurs, allowing fluids from the blood to escape into surrounding tissues. These reactions are responsible for the itching, "runny nose," and "watery eyes" of a cold or hay fever, as histamines attempt to rid the body of the irritant.

While working in the therapeutic chemistry department of the Pasteur Institute in Paris, Bovet discovered that certain chemicals counteracted the reactions of histamine in guinea pigs. The first antihistamine identified was named compound F929 (thymo-ethyl-diethylamine), described by Bovet and his colleagues in 1937. Bovet observed that compound F929 protected the guinea pigs against histamine in doses high enough to be presumed lethal. F929 also lessened the symptoms of anaphylaxis, a severe allergic reaction often resulting in airway obstruction, shock, and death. Although compound F929 proved unsuitable for clinical use in humans due to weakness and toxicity, its discovery opened the door for the pursuit of a histamine-blocking agent suitable for clinical use.

By 1942 the first antihistamine successfully used to treat humans, Antergan, was developed in France. Antergan was revised to Neo-Antergan in 1944. Scientists in the United States introduced diphenhydramine and tripellinamine in 1946, both of which remained in use through the end of the century. A flurry of antihistamine development ensued, with virtually all derived from the original compound F929.

Impact

By 1950 antihistamines were mass-produced and prescribed extensively as the drug of choice for those suffering from allergies. Hailed as "wonder drugs," antihistamines were often mistakenly perceived by the public as a cure for thecommon cold. Although not a cure, antihistamines provided the first dependable relief for some of the cold's symptoms.

Physicians prescribed antihistamines for conditions associated in any way with allergic response, including asthma. Thus began a debate continuing long after 1950 on the benefits and risks involved with asthma and antihistamines. In 1948 medical literature showed that histamine could induce bronchial constriction in asthmatics. Antihistamines were recommended to block this effect. In 1950 asthma had proved unresponsive to the antihistamines available at that time. In 1951 scientists suggested that anti-histamines would be beneficial to asthmatics, since histamine release and bronchial constriction occurred simultaneously when tissue from the lungs of allergic asthmatics was exposed to specific antigens in vitro (i.e. in a laboratory environment). By 1955 the prevailing thought was that antihistamines may actually be harmful to asthmatics by drying their lung secretions and making the secretions more viscous (thick). After years of indecision by the medical establishment, medical students were taught after 1955 not to prescribe antihistamines to patients with asthma. The debate and research into the potential benefits of antihistamines for asthmatics continued.

As different formulations were developed, scientists eventually found additional indications for the use of antihistamines. Diphenhydramine became available as a sleeping preparation and a remedy for itching. The piperazine group of antihistamines were used to prevent motion sickness. Dimenhydrinate was used as an anti-nausea medicine. The phenothiazines have a pronounced sedative effect, and hydroxizine was used as a tranquilizer. These wide-ranging properties of available drugs led to the potential for overuse and, at times, abuse of anti-histamines.

Patients taking antihistamines experienced side effects that affected their daily activities of life. Studies indicated that one third of patients receiving antihistamines experienced drowsiness substantial enough to impair their concentration. While this was perhaps a desirable consequence at nighttime, it was a potential serious complication during waking hours. Antihistamine therapy became one of the first opportunities for physicians to educate patients and enlist their involvement in managing an ongoing drug therapy, rather than administer the therapy in a hospital or confine the patient to home. Patients were advised not to drive a vehicle or operate equipment requiring fine motor coordination while taking antihistamines. Patients were also encouraged to time doses according to their own schedules and body rhythms to minimize side effects, rather than adhering to a rigid schedule.

Despite the side effects, antihistamines have become widely used for a variety of medical problems. Their broad use in medicine at the turn of the twenty-first century is a testament to the importance of Bovet's discovery.

BRENDA WILMOTH LERNER