Antihistamines

Article Author:
Khashayar Farzam
Article Editor:
Maria O'Rourke
Updated:
6/29/2019 2:21:37 PM
PubMed Link:
Antihistamines

Indications

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

H-1 antihistamines are further classified by the 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

Mechanism of Action

Histamine induces an increased level of vascular permeability. This 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. 

Administration

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.  

Adverse Effects

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 has been known to 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.

Contraindications

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. 

Monitoring

Dosages of the antihistamines require monitoring. The cardiotoxic effects of antihistamines may be monitored on an electrocardiogram (ECG) to assess prolongation of the QT interval. 

Toxicity

There is no specific antidote used for the treatment of antihistamine overdose. However, physostigmine may be an option if a patient is experiencing delirium due to the anticholinergic effects of the antihistamine. 

Enhancing Healthcare Team Outcomes

Antihistamines are a class of medications which subdivide into H-1 and H-2 categories. H-1 antihistamines, which further subdivide into first and second generations, are primarily used to treat allergic symptoms and illnesses mediated through similar mechanisms. H-2 antihistamines are used to lower excessive stomach acid and thereby treat acid reflux, gastritis, and gastrointestinal ulcers. 

Given the availability of antihistamines at pharmacies for off-the-shelf purchase, pharmacists serve as dispensers and educators of these medications. They serve a crucial role in advising the patient to utilize the correct dosage and to be cautious of any contraindications and adverse effects. 

Providers that recommend antihistimines such as nurse practitioners, physician assistants, and physicians should use caution and make sure the healthcare team is aware of the recommendation. [Level V]


References

[1] Current Knowledge and Perspectives on Histamine H1 and H2 Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands., Monczor F,Fernandez N,, Molecular pharmacology, 2016 Nov     [PubMed PMID: 27625037]
[2] Schaefer TS,Zito PM, Antiemetic, Histamine H1 Receptor Blockers 2018 Jan;     [PubMed PMID: 30422595]
[3] Curto-Barredo L,Giménez-Arnau AM, Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamine. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2019 Feb 4;     [PubMed PMID: 30717573]
[4] Kuna L,Jakab J,Smolic R,Raguz-Lucic N,Vcev A,Smolic M, Peptic Ulcer Disease: A Brief Review of Conventional Therapy and Herbal Treatment Options. Journal of clinical medicine. 2019 Feb 3;     [PubMed PMID: 30717467]
[5] Pirahanchi Y,Sharma S, Physiology, Bradykinin 2018 Jan;     [PubMed PMID: 30725872]
[6] Heda R,Tombazzi CR, Physiology, Pepsin 2018 Jan;     [PubMed PMID: 30725690]
[7] Boley SP,Olives TD,Bangh SA,Fahrner S,Cole JB, Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clinical toxicology (Philadelphia, Pa.). 2018 Jun 29;     [PubMed PMID: 29956570]
[8] Farzam K,Tivakaran VS, QT Prolonging Drugs 2018 Jan;     [PubMed PMID: 30521285]
[9] Bowman JD,Kim H,Bustamante JJ, Drug-induced gynecomastia. Pharmacotherapy. 2012 Dec;     [PubMed PMID: 23165798]