Why older allergy pills make you drowsy and newer ones mostly don't
Histamine, the chemical behind a runny nose and watery eyes, also helps keep the brain alert. Early antihistamines slipped easily into the brain, which is why some were even used as sleep aids. Later versions were designed to stay mostly outside it, and the first of these non-sedating drugs arrived in 1973.
Histamine makes small blood vessels leaky, letting fluid seep from capillaries into tissue, which produces the swelling, sneezing and streaming eyes of an allergic reaction. It acts through four kinds of receptor, labelled H1 to H4. What most people call an antihistamine blocks H1, found on mast cells, smooth muscle, blood vessel linings and in part of the brain. A separate family blocks H2 receptors in the stomach, where histamine triggers acid release, so those drugs are used for ulcers and reflux instead.
A subtle twist emerged about how they work. H1 receptors are never fully switched off; they have a background level of activity even without histamine. Researchers long assumed antihistamines simply sat in the receptor and blocked histamine. Most actually turn out to be inverse agonists, pushing the receptor's activity below its normal resting level, the opposite of histamine's effect.
The first compound with antihistamine effects, piperoxan, was identified in 1933 but proved too toxic for people. Phenbenzamine became the first clinically useful one in 1942, diphenhydramine was made in 1943, and by 1950 at least 20 antihistamines were on sale. These first-generation drugs cross the blood-brain barrier readily, so drowsiness is common. Second-generation drugs, such as loratadine and cetirizine, reach the brain far less, although high amounts can still cause sleepiness. Not every new drug fared well: US authorities withdrew terfenadine and astemizole over evidence of heart problems.
Blocking H3 receptors in the brain has the opposite result to blocking H1, producing stimulant rather than sedating effects, because H3 normally acts as a brake on histamine release. Plenty of questions remain open. Head-to-head comparisons between antihistamines are scarce, most studies involved younger people, and long-term use of older, first-generation types has been linked with a higher risk of cognitive decline in older adults.
Source: Antihistamine
