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Which antihistamine is the most effective?

Allergy, Asthma, Skin Conditions | December 21, 2014 | Author: The Super Pharmacist


Which antihistamine is the most effective?

The primary use of antihistamines is to control the symptoms of conditions associated with allergic reactions. They are not cures for such conditions, but do provide relief from pain, itchiness and discomfort resulting from symptoms. Conditions on which antihistamines can help include urticuria (also known as nettle rash, or hives), atopic eczema, allergic rhinitis (an inflammation of the nasal passage commonly associated with hay fever), insect bites or stings, allergic conjunctivitis (inflammation of the eyes) and mild allergic reactions caused by particular foods.

How do antihistamines work?

It is the function of antihistamines to inhibit the action of histamine by targeting histamine receptors in cells. Histamine is a chemical that forms part of the body’s immune system and helps protects the body’s cells against infection. When the immune system detects a potentially harmful bacteria or virus, histamine is released into cells, causing blood vessels to expand and skin to swell. This inflammation can often lead to skin becoming red and swollen, resulting in itchiness. It also causes fluid to escape from capillaries into tissues, often manifesting as a runny nose and watery eyes during allergic reaction.

As antagonists, the purpose of antihistamines is to prevent the binding of histamine to receptors in the endothelium (the thin layer of cells lining the interior surface of blood and lymphatic vessels), nerves, vascular smooth muscle (which composes the majority of the walls in blood vessels), glandular cells and mast cells (a key part of the body’s immune system).

How do antihistamines work?There are four separate histamine receptors in each of the body’s cells.

H1- receptor causes inflammation

H2- receptor aids in the stimulation and production of stomach acids

H3- receptor is understood to help stimulate chemical reactions that help transmit information around the brain

H4- receptor is not currently well understood but is considered to play a role in the regulation of the immune system (1).

Different types of Antihistamines

Antihistamines are classified in two distinct groups: 

  • First generation (or sedating antihistamines)
  • Second generation (or non-sedating antihistamines)

First generation drugs offer sedative which result in their use for the alleviation of discomfort and disturbed patterns of behaviour, such as being unable to sleep through excessive itching. Drugs in this group include chlorphenamine, diphenhydramine and promethazine.

Second generation drugs do not usually cause symptoms of drowsiness (although it may still occur) and include cetirizine, loratadine and fexofenadine.

The majority of antihistamines on the market are designed to block the H1- receptor, with a small number of antihistamines that are designed to treat stomach ulcers blocking the H2-receptor. Research is ongoing regarding potential pharmaceutical solutions for blocking the H3- receptor, with initial research and evidence suggesting potential benefits for the treatment of a range of mental health conditions (such as depression) and neurological disorders (including Alzheimer’s disease) (2). Further research is also ongoing regarding antagonists for the H4- receptor, believed to be beneficial for the future treatment of autoimmune conditions such as rheumatoid arthritis (3).

Antihistamine tolerance 

Antihistamine tolerance (diminishing response when using the same product). 

Studies carried out almost 65 years ago concluded that increased tolerance, or a diminished response to the continued use of the same antihistamine product, could occur (4). Yet a systematic review of more recent literature concerned with the persistent use of antihistamines shows that there is no evidence to support this initial finding. 

Many of the more recent studies undertaken have concerned themselves with the tachyphylaxis of antihistamines – a decrease in the body’s response to a drug after it has been administered.

In one observational study, a sample group were observed over a period of 56 days to monitor their response to the administration of terfenadine, a commonly used H1- receptor antagonist. At both 28 and 56 days there were no recorded signs of diminished response in any of the study participants, with the antihistamine evidenced to be as effective at the end of treatment as it was at the beginning in suppressing histamine-induced wheals, flares and rashes (5).

A range of other long term observational studies, and RCTs, have observed no tachyphylaxis, tolerance or rebound in trials designed to study the long-term impact of antihistamine use on persistent rhinitis (6) and allergic rhinitis (hay fever) (7).

Which antihistamine is the most effective?

There is very little public literature and evidence available that has set out with the specific question of which antihistamine is the most effective, either generally or for a particular condition. A recent systematic review of literature concerned with the comparison and effectiveness of antihistamines identified over 3000 studies for screening, but only 18 were found to provide direct evidence (8).

It is generally held that that the majority of antihistamines have equal levels of effectiveness in the reduction of the symptoms of both hay fever and hives. Non-sedating antihistamines (second generation) are more commonly used to avoid unnecessary drowsiness, and are generally the preferred option when prescribing for most allergic reactions. Fexofenadine and loratadine are most frequently recommended for urticaria.

Which antihistamine is the most effective?Antihistamine use and children

There is a lack of available, good quality literature on the use of second generation antihistamines on children. As such, there is little knowledge regarding both their effectiveness and safety when used on children under the age of 16.

Chronic allergies

Despite the high prescribing levels of fexofenadine for individuals with chronic allergies, there is no body of evidence to support its particular use (9).

Studies that have been undertaken comparing antihistamines for hay fever generally highlight differing levels of drowsiness, but no difference in drug effectiveness and the relief of symptoms (10,11,12).

Combining antihistamines

There is an increased interest in the prescribing of a combination of antihistamines to increase their benefit, particularly for patients with chronic allergy problems. Such combinations usually comprise both a H1 and H2 antagonist, such as Ranitidine with Fexofenadine. As with general antihistamine use, there is a very limited evidence base, with only a small number of studies comparing the use of H1 antihistamine with the combined use of H1 and H2 antihistamines as long term treatment options. A review of this literature finds no clear cut benefit of combined drug use, although there is limited evidence to suggest combined drugs can cause the faster resolution of rash symptoms (13,14). There remains an ongoing need for much more evidence to be generated before combination therapies can be more accurately scrutinised for both their safety and effectiveness.  Australia’s best online discount chemist


1. Deiteren A, De Man JG, Pelckmans DA, De Winter BY. (2014). Histamine H4 receptors in the gastrointestinal tract. Br J Pharmacol doi: 10.1111/bph.12989 [Epub ahead of journal publication.

2. Vohora D, Bhowmik M. (2012). Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci. Oct 23;6:72. doi: 10.3389/fnsys.

3. Thurmond RL, Gelfand EW, Dunford PJ. (2008). The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov. 2008 Jan;7(1):41-53

4. Dannenburg TB, Feinberg SM. (1951). The development of tolerance to antihistamines: A study of the quantitative inhibiting capacity of antihistamines on the skin and mucous membrane reaction to histamine and antigens. Journal of Allergy 22(4)330-339

5. Estelle F, Simons R. (1988). Lack of subsensitivity to terfenadine during long-term terfenadine treatment. Jour Allergy Clin Immun 82(6)1068-1075

6. Klos K, Kruszewski J. (2008). Do new antihistamines characterize tachyphylaxis phenomenon? Otolaryngol Pol. 61(5)898-901.

7. Riechelmann H. (2005). Oral second generation antihistamines in allergic rhinitis. Laryngorhinootologie 84(1):30-41

8. Allergies, Hay Fevers, & Hives: Comparing Effectiveness, Safety, and Price. Consumer Health Choices. Available online at (last accessed 13th December 2014)

9. Van Cauwenberge P, Juniper EF. Comparison of the efficacy,safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy 2000;30(6):891-899.

10. Berger W, Hampel F, Jr., Bernstein J, Shah S, Sacks H, Meltzer EO. Impact of azelastine nasal spray on symptoms and quality of life compared with cetirizine oral tablets in patients with seasonal allergic rhinitis. Ann Allerg Asthma Im. 2006;97(3):375-381.

11. Ciprandi G, Cirillo I, Vizzaccaro A, et al. Desloratadine and levocetirizine improve nasal symptoms, airflow, and allergic inflammation in patients with perennial allergic rhinitis: a pilot study. International Immunopharmacology 2005;5(13-14):1800-1808.

12. Hampel F, Ratner P, Mansfield L, Meeves S, Liao Y, Georges G. Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis. Ann Allerg Asthma Im. 2003;91(4):354-361.

13. Lin RY, Curry A, Pesola GR, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med 2000;36(5):462-68

14. Watson NT, Weiss EL, Harter PM. Famotidine in the treatment of acute urticaria. Clin Exp Dermatol 2000;25:186-9

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