Antihistamine was discovered more than a century ago by Anne Marie Staub and Daniel Bovet. Antihistaminic drugs were made by doing primarily modifications in cholinergic antagonists and are formed from diverse chemical entities such as piperazines, piperidines, ethanolamine’s, ethylene diamines, alkylamines, and phenothiazines.
These first-generation antihistamines have poor receptor selectivity and thus cause significant unwanted side effects. Histamine released from the mast cells during the inflammatory process including type I hypersensitivity allergic reactions is antagonized by antihistamines. Although, antihistamines do not antagonize histamine binding on all types of histamine receptors. Antihistamines are H1-receptor antagonists.
Antihistamines include some of the most commonly prescribed drugs in the primary health care system for the symptomatic relief of allergic diseases, the common cold, seasonal rhinitis, conjunctivitis, urticaria, dermatitis, and asthma and insomnia.
H1 receptor blockers are well absorbed after oral administration. Time to reach peak plasma level is 1 to 2 hours. The duration of onset of action of these drugs is often similar to the rate of its oral absorption. Onset of action is 1 to 3 hours. Duration of action is at least 24 hours after once daily dosing.
These drugs have high bioavailability and are readily distributed in body tissue as well as in CNS.
Cetirizine and levocetirizine are the drugs that are not metabolized and are excreted primarily unchanged in the urine. Desloratadine undergoes extensive metabolism in the liver.
Most antihistamines act upon the substrate of CYP3A4, grapefruit juice increases the bioavailability of the drugs by inhibiting drug metabolism in intestinal mucosa. Most of antihistamines undergo hepatic metabolism by several cytochrome p450 (CYP) isoenzymes, with exceptions such as cetirizine, levocetirizine that undergo urinary excretion, and fexofenadine that is excreted through feces.
The average half-life is 4 to 6 hours expect for meclizine which is 12 to 24 hours.
Fexofenadine is also minimally metabolized and is excreted primarily in the feces after its active secretion into the intestine under the influence of active drug–transporting molecules.
The primary mechanism of action of antihistamines in the treatment of allergic diseases is by binding to H1-receptors that are present on nerve endings, smooth muscles, and glandular cells. So they are competitive antagonists of histamine binding to cellular receptors.
Majority of research on H1-antihistamines is focused on the histamine dependent early symptoms of the allergic response. It is now clearly evident that these drugs have anti-inflammatory effects.
Histamine activates NF-B, which is transcription factor that is involved in the synthesis of a lot of pro-inflammatory cytokines and adhesion molecules involved in the initiation and maintenance of allergic inflammation process.
Diphenhydramine, dimenhydrinate, cyclizine, meclizine and promethazine are highly effective against prevention of the symptoms of motion sickness.
Many first-generation antihistamines, such as diphenhydramine and doxylamine are used as sedative agents.
Antihistamines are not metabolized and are excreted unchanged that’s why no pharmacokinetic drug-drug interactions occur. Although there are chances of pharmacodynamics drug-drug interaction but no significant interactions have been reported.
H1 receptor blocker are usually non selective, they not only bind to histamine receptor but also with other receptors. So, they have various side effects.
When acting on H1 receptors Sedation
When acting on muscarinic receptors
When acting on alpha adrenergic receptors
When acting on cardiac channels
The safety margin of H1-receptor blockers is relatively high, and chronic toxicity is rare. Acute poisoning is relatively common, especially in young children.
The side effects of acute poisoning are caused due to effect on the CNS, which includes hallucinations, excitement, ataxia, and convulsion that may leads to coma and collapse of the cardiorespiratory system, if remain untreated.
Read More: Mechanism Of Action Of First Generation (Sedating) Antihistamines