Antihistamines are medications that counteract the action of histamine. Histamine is most notoriously known as a mediator of allergic reactions, but it’s also involved in important physiological processes such as immune response, gastric acid secretion, sleep and wake cycle, cognitive ability and food intake. Histamine is synthesized from the amino acid histidine.
It is present in all tissues but most abundant in the skin, lungs and gastrointestinal tract. Most of histamine in tissues is stored as granules inside mast cells. In the brain, histamine also functions as a neurotransmitter.
It is found in histaminergic neurons of the hypothalamus, whose axons project throughout the brain. Histamine exerts its action by binding to histamine receptors, H-receptors, all of which are G-protein- coupled. There are four H-receptors, with different tissue expression patterns and functions.
Both H1 and H4 are involved in allergic inflammation, but only H1-antihistamines are currently available for allergy treatment. The major function of H2-receptor is to stimulate gastric acid secretion, so H2-antihistamines are used to treat gastric acid disorders such as gastric reflux and peptic ulcers. The term “antihistamine” generally refers to allergy-treating H1-antihistamines.
Most allergies occur upon a repeated exposure to an allergen. Mast cells that were previously sensitized to the allergen are activated, releasing histamine and other inflammatory chemicals. Histamine causes dilation and increased permeability of blood vessels, stimulation of sensory nerves, contraction of smooth muscle; and is responsible for most allergic symptoms, ranging from watery eyes, runny nose, sneezing, itching; to swelling, hives, and difficulty breathing due to bronchospasm.
When released systemically, histamine can cause extensive vasodilation and bronchoconstriction which may lead to life-threatening anaphylaxis. Most H1-antihistamines are not similar to histamine in structure and do not compete with it for binding to H1-receptor. Instead, they bind to a different site on the receptor and stabilize it in its inactive state.
The first-generation H1-antihistamines derive from the same chemical class as muscarinic, adrenergic and serotonin antagonists, so they also have anti-cholinergic, anti-adrenergic, and anti-serotonin effects. More importantly, they can cross the blood-brain barrier and interfere with histamine functions in the brain, causing drowsiness, cognitive impairment and increased appetite. Some of these drugs are actually used for their sedative side effect, as sleeping aid medications.
Second-generation antihistamines are less able to cross the blood-brain barrier, and are therefore minimally or non-sedating. They are also highly selective for H1-receptor and have no anti-cholinergic effects.
