Antihistamines are a pharmaceutical class of drugs that act to treat histamine-mediated conditions. There are two main classes of histamine receptors: H-1 receptors and H-2 receptors. Antihistamine drugs that bind to H-1 receptors are generally used to treat allergies and allergic rhinitis. Drugs that bind to H-2 receptors treat upper gastrointestinal conditions that are caused by excessive stomach acid.[1]

H-1 antihistamines further classify according to first and second-generation agents. First-generation H-1 antihistamines cross the blood-brain barrier into the central nervous system (CNS), whereas second-generation H-1 antihistamines do not. The first generation drugs will bind to both central and peripheral histamine-1 receptors, whereas second-generation drugs only bind to peripheral histamine-1 receptors; this leads to different therapeutic and side effect profiles.[2] 

FDA-approved Indications[3][4]:

H-1 Antihistamines

• Allergic rhinitis
• Allergic conjunctivitis 
• Allergic dermatological reaction(s)
• Sinusitis
• Urticaria
• Angioedema
• Atopic dermatitis
• Bronchitis
• Motion sickness
• Nausea
• Vomiting

H-2 Antihistamines

• Peptic ulcer
• Acid reflux
• Gastritis

Non-FDA approved uses for H-1 antihistamines include insomnia and for H-2 antihistamines include indigestion. 

There are two other classes of histamine receptors: H-3 and H-4. While compounds exist that bind them, there is no specific clinical benefit to the usage of those compounds in humans.

Example Drugs

H-1 antihistamines

• Diphenhydramine
• Cetirizine
• Chlorpheniramine
• Cyclizine
• Dimenhydrinate
• Doxylamine
• Hydroxyzine
• Meclizine

H-2 antihistamines

• Cimetidine
• Famotidine
• Nizatidine
• Ranitidine
• Roxatidine

Histamine induces an increased level of vascular permeability, which leads to fluid moving from capillaries into the surrounding tissues. The overall outcome of this is increased swelling and dilation of vessels. Antihistamines stop this effect by acting as antagonists at the H-1 receptors. The clinical benefit is a reduction in allergy symptoms and any related symptoms.[5]

First-generation antihistamines cross the blood-brain barrier into the central nervous system and antagonize H-1 receptors, which leads to a different therapeutic and adverse effect profile in contrast to second-generation antihistamines, which only bind to peripheral histamine receptors. 

The duration of the pharmacological action of first-generation antihistamines is about 4 to 6 hours. In contrast, second-generation antihistamines work for 12 to 24 hours. They are both metabolized by the liver using the P450 cytochrome system. 

Parietal cells in the gastrointestinal tract exist to secrete hydrochloric acid. They undergo regulation by acetylcholine, gastrin, and also histamine. The histamine releases from enterochromaffin-like (ECL) cells. When histamine binds to the H-2 receptors on parietal cells, cyclic adenosine monophosphate (cAMP) increases, thereby inducing protein kinase A. This then leads to phosphorylation of the proteins that take part in the transport of hydrogen ions. Increased histamine leads to increased stomach acid secretion.[6]

The use of antihistamines that are specific to the H-2 receptor blocks the entire process and thereby reduce stomach acid secretion. 

Antihistamine medications are generally administered orally in pill form. Intravenous (IV) and intramuscular (IM) administration are also possible, reserved mostly for in-patient usage for the treatment of specific conditions.  

Antihistamine medications carry a broad range of adverse effects depending on the specific class of drugs utilized. H-1 receptor antihistamines will generally cause clinically noticeable adverse effects that are dosage-dependent. These side effects are far more commonly seen in first-generation antihistamines. Second-generation antihistamines do not cross the blood-brain barrier, and therefore their side effect profile is far more limited. In contrast to H-1 receptor antihistamines, H-2 receptor antihistamines do not commonly cause adverse effects except for cimetidine. 

H-1 receptor antihistamines have anticholinergic properties, which are adverse effect-inducing; this principally occurs from the first generation category of antihistamines only. As a whole, they are sedating but may cause insomnia in some users. Due to their anticholinergic properties, dry mouth is a relatively common adverse effect. Some users experience dizziness and tinnitus. At increasing dosages, euphoria and decreased coordination may also occur, and at even higher dose ranges, delirium is a potential adverse effect.[7] Antihistamines may also be cardiotoxic in some users as they have QT-prolonging effects.[8] 

H-2 receptor antihistamines are generally well tolerated by users but do carry the risk of uncommon side effects. Gastrointestinal changes can be seen, including both diarrhea and constipation. Reports exist of fatigue, dizziness, and confusion. One specific drug in this category that may cause a range of adverse effects is cimetidine. Its antiandrogenic effects correlate with the possible occurrence of gynecomastia in men. In women, it can cause galactorrhea. Other H-2 receptor antihistamines do not exhibit the same properties as cimetidine.[9] 

H-2 receptor antihistamines can cause inhibition of the cytochrome system, thereby leading to drug toxicity and interactions with other medications.

Patients who suffer from hemodynamic alterations increased intraocular pressure, or increased urinary retention should use antihistamines with caution as these conditions can become exacerbated.

Given the potential cardiotoxic effects of antihistamines, they are relatively contraindicated in any patient with QT prolongation. Patients using other QT-prolonging drugs require careful monitoring for further prolongation of the QT interval, due to the risk of potentially fatal cardiac arrhythmias.[8] 

Usage in pregnant women is a relative contraindication. Additionally, women who are lactating should also avoid antihistamines. 

Patients with impaired renal or hepatic function should use antihistamines with caution. 

Hypertension, cardiovascular disease, urinary retention, increased ocular pressure are relative contraindications to the usage of antihistamines.