Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA
Department of Anesthesiology, Louisiana State University, New Orleans, LA, USA
Discovery of certain chemicals to counteract the effects of histamine occurred in the early twentieth century. The development of a drug that would alleviate allergic reactions such as itchy, watery eyes, and a runny nose from a cold or hay fever had an astronomical effect on the medical community. By the 1950s, antihistamines were being mass-produced in the USA and prescribed extensively as the drug of choice for those suffering from allergies. The public perceived antihistamines as the “wonder drug” and with the misconception that it was a “cure all” to the common cold. Eventually, scientist began to discover additional indications for the use of antihistamines. These compounds continue to be one of the most universal drugs lining the shelves of local pharmacies. However, the plethora of roles that antihistamines play in the treatment of the human condition is much more extensive, including suppression of allergy symptoms, sedative agents, and antiemetic actions to name a few.
Drug Class and Mechanism of Action
Histamine is involved in local immune responses as well as regulation of physiologic functions in the gut. It can also act as a neurotransmitter. Histamine is made and released by different cells, i.e., basophils, mast cells, platelets, histaminergic neurons, lymphocytes, and enterochromaffin cells. It is stored in vesicles or granules awaiting release upon stimulation . As part of an immune response to foreign pathogens, histamine increases the permeability of capillaries to white blood cells and other proteins in order to allow them to engage foreign invaders in the infected tissues. Clinical effects of histamine result in increased vascular permeability and leakage of plasma proteins, causing fluid to escape from capillaries into the tissues . This leads to the classic symptoms of an allergic reaction such as a localized rash, itching, puffy and watery eyes, nasal congestion, and rhinorrhea.
There are four known human histamine receptors that have been identified (Table 22.1). These receptors belong to the G-protein-coupled receptors family. They are signified as H1, H2, H3, and H4. Stimulation of the H1 receptor can activate intracellular signaling pathways leading to the development of classic allergic symptoms .
Histamine receptors classification
Airway and vascular smooth muscles, endothelial, central nervous system (nerve cells), neutrophils, eosinophils, monocytes
Cause bronchial smooth muscle contraction, separation of endothelial cells causing hives, pain, and itching. Allergic reaction symptoms, motion sickness, and regulation of sleep
Nerve cells, vascular smooth muscles and parietal cells, hepatocytes, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes
Vasodilation and stimulation of gastric acid secretion
Histaminergic neurons, eosinophils. Found primarily in the central nervous system, low expression in peripheral tissues
Inhibits histamine release and synthesis. Decreases release of serotonin, acetylcholine, and norepinephrine
High expression in bone marrow and peripheral hematopoietic cells. Low expression in nerve cells, hepatocytes, spleen, thymus, small intestine, colon, heart
Stimulates chemotaxis of eosinophils and mast cells
Historically, antihistamines were noted to cause a parallel displacement in the histamine concentration/response. This behavior was consistent with a competitive inhibition for histamine receptors, lending to the classification as the H1 receptor antagonists. With further research, it was found that the antihistamines are in the class that are now called inverse agonists
As an inverse agonist, the compound preferably binds to the inactive state of the histamine receptor, stabilizing the receptor in the inactive conformation, and moves the equilibrium shift in the direction of the inactive state. Since H1 antihistamines have been discovered as inverse agonist, the adoption of the term “H1 antihistamines” has been contemplated [1, 3]. The chemical structure of antihistamines can be varied (Table 22.2).
Chemical classifications of antihistamines
Brompheniramine, chlorpheniramine, dexchlorpheniramine, pheniramine, triprolidine
Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, orphenadrine
Methdilazine, promethazine, trimeprazine
Cyproheptadine, fexofenadine, desloratadine, loratadine
Terfenadine and astemizole recalled by FDA
Cetirizine, cyclizine, hydroxyzine, levocetirizine, meclizine
Indications and Clinical Pearls
H1 antihistamines are used to relieve or prevent allergy symptoms. Suppression of allergic inflammation in the mucous membranes and reduction of the size of wheal (swelling) and flare (vasodilation) response will help alleviate symptoms such as itching, rhinorrhea, sneezing, urticaria, and congestion . The effect on airway smooth muscle is that of bronchodilation. H1 antihistamines can be grouped into two classifications: First-generation (sedative) antihistamines and second-generation (nonsedating) antihistamines. First-generation H1 antihistamines include chlorpheniramine (Chlor-Trimeton), clemastine (Tavist), dexchlorpheniramine (Polaramine), dimenhydrinate (Dramamine), dimetindene (Fenistil), doxylamine (Unisom – used as the sedative in NyQuil), diphenhydramine (Benadryl), hydroxyzine (Vistaril), meclizine (Antivert), orphenadrine (Norflex), pheniramine (Avil), and promethazine (Phenergan).
First-generation H1 antihistamines cross the blood-brain barrier due to their lipophilic molecular structure leading to the possible unwarranted effect of sedation. Adverse reactions may be due to their inhibition on muscarinic, serotonergic, and adrenergic receptors (Table 22.3). Reports of toxicity with overdose, whether intentional or accidental, have been reported.
H1 antihistamine adverse effects on various receptors
Adverse effect of first-generation H1 antihistamines
CNS neurotransmission reduction, sedation, cognitive and neuropsychomotor performance reduction, appetite↑
Tachycardia, urinary retention
Hypotension, dizziness, reflex tachycardia
Prolongation of the QT interval, ventricular arrhythmia
Antiemetic effects may be elicited due to blockade of the histaminergic signal from the vestibular nucleus to the vomiting center in the medulla . Clinical uses can extend beyond the treatment of allergic symptoms to the treatment of vestibular disorders, sedatives, sleeping aids, and antiemetics. These agents are usually administered in three to four daily doses (Table 22.4).
First-generation H1 antihistamines
Diphenhydramine Benadryl ©
25–50 mg PO q4–6 h; 10–50 mgIV/IM
(total of 400 mg/day)
(Tabs, capsules, liquid, rapidly dissolving tab or strip, IV)
Over the counter
Dystonia in early Parkinson’s disease
Increase in chest congestion
25 mg po TID–QID
25–100 mg IM q 4–6 h
(Capsules, oral suspension, IM)
Dry mouth drowsiness
Pain (muscle spasms), headache
60–100 mg PO q 8 h, 60 mg PO, IM, IV for Parkinson’s disease
(Tabs, oral solution, IM/IV)
Increase in chest congestion
6.25–12.5 mg PO qd, 12.5–25 mg IV q 4–6 h (tabs, rectal supp, IV)
Precaution in the elderly and children
Not to be given to children under 2 years of age
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