This term is used to describe drugs that antagonise histamine H1 receptors.

Indications

They are used primarily to treat disorders where abnormal or excessive histamine release by inflammatory cells is thought to underly illness. This includes conditions such as:

• Rhinitis - especially seasonal allergic rhinitis (hay fever).
• Urticaria.
• Anaphylaxis.
• Angio-oedema.
• Asthma - antihistamines may be of benefit in the treatment of asthma, particularly where the patient has rhinitis and, currently, ARIA (= Allergic Rhinitis and its Impact on Asthma) guidelines support their use (although the British Thoracic Society (BTS) does not at present).¹

Other conditions such as hyper-reactive (vasomotor) rhinitis and pruritus of any cause are commonly treated with antihistamines, although there is little evidence that histamine plays a contributory role.

Other uses

• Topically on the eye to treat allergic conjunctivitis, allergic rhinitis and on the skin for pruritus (e.g. bites where they have limited efficacy and may cause sensitisation).
• Nausea and vertigo, e.g. cinnarizine, cyclizine.
• Cough suppressants.
• Terminal care for their sedating and anti-emetic effects.
• Sometimes prescribed as sedatives for children (unlicensed, and not recommended).

Classification

First-generation 'sedating' antihistamines

• These are highly lipid-soluble, crossing the blood-brain barrier with ease and antagonise H1 receptors in both the CNS and periphery.
• They cause sedation, cognitive impairment, motor retardation and, in certain individuals, agitation/stimulation.
• These properties are sometimes useful for treating conditions where sleep is disturbed due to symptoms of urticaria or atopic dermatitis.
• Alimemazine and promethazine are considered to be the most sedating, whilst chlorphenamine and cyclizine are considered to be the least so (of the 'sedating' group).²
• They may also antagonise muscarinic acetylcholine receptors, causing symptoms such as dry mouth, urinary retention and confusion in the elderly.

Second-generation 'non-sedating' antihistamines

• These are newer drugs.
• Larger molecules and less lipophilic, and thus less likely to cross the blood-brain barrier.
• However, all antihistamines can cross the blood-brain barrier to some degree and cause psychomotor impairment in susceptible individuals.³

• Sedation - although some drugs are more sedating than others, the sedative tendency varies from patient to patient and so all patients must be warned of this and the potential danger. Alcohol increases any sedative effect and should be avoided. Drowsiness tends to diminish over time.
• Paradoxical stimulation may also occur and this is a particular problem for some children. Use of a test dose prior to using the drug in a given situation is advisable to avoid this idiosyncratic reaction.
• Arrhythmias - second-generation antihistamines mizolastine and terfenadine are particularly prone to cause ventricular arrhythmias (predominantly ventricular tachycardia and torsades de pointes).⁴ This is more likely to occur where a relatively high dose is being taken or where there is hepatic cytochrome P450 impairment, both of which raise the plasma concentration of the drug. Of the first-generation drugs, alimemazine, hydroxyzine and promethazine have been implicated as causing this complication. For this reason, terfenadine and astemizole have been withdrawn. Hypokalaemia or hypomagnesaemia increases the risk of this complication, as does pre-existing QT prolongation.

Important interactions

• Tricyclic antidepressants - antimuscarinic and sedative effects are potentially enhanced by co-administration of antihistamines.
• Co-administration of antifungal imidazoles (e.g. ketoconazole, itraconazole) and macrolide antibiotics (e.g. erythromycin, clarithromycin) is to be avoided, as these drugs interact and raise the plasma concentration of second-generation antihistamines.

Choice of agents and evidence of effectiveness

Allergic rhinitis

A comparative study suggests greater efficacy for levocetirizine compared to desloratadine. Cetirizine and levocetirizine have been shown to be beneficial in children.⁵ Long-term use of cetirizine by children with atopic dermatitis appears to have no impact on their behavioural, cognitive and psychomotor development.⁶

Chronic idiopathic urticaria

There is little evidence that antihistamines used symptomatically to treat nonspecific itching have any effect greater than placebo.
Most of the second-generation antihistamines have been shown to benefit chronic idiopathic urticaria. Once-daily fexofenadine appears to offer effective and well-tolerated relief from the symptoms of this illness.⁷

Document references

1. Management of allergic rhinitis and its impact on asthma - pocket guide, ARIA, 2008
2. Ng KH, Chong D, Wong CK, et al; Central nervous system side effects of first- and second-generation antihistamines in school children with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled comparative study. Pediatrics. 2004 Feb;113(2):e116-21. [abstract]
3. Ramaekers JG, Vermeeren A; All antihistamines cross blood-brain barrier. BMJ. 2000 Sep 2;321(7260):572.
4. Recanatini M, Poluzzi E, Masetti M, et al; QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2005 Mar;25(2):133-66. [abstract]
5. de Blic J, Wahn U, Billard E, et al; Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal allergic rhinitis trial. Pediatr Allergy Immunol. 2005 May;16(3):267-75. [abstract]
6. Stevenson J, Cornah D, Evrard P, et al; Long-term evaluation of the impact of the h1-receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis. Pediatr Res. 2002 Aug;52(2):251-7. [abstract]
7. Kaplan AP, Spector SL, Meeves S, et al; Once-daily fexofenadine treatment for chronic idiopathic urticaria: a multicenter, randomized, double-blind, placebo-controlled study. Ann Allergy Asthma Immunol. 2005 Jun;94(6):662-9. [abstract]

Internet and further reading

• Blaiss MS; Antihistamines: treatment selection criteria for pediatric seasonal allergic rhinitis. Allergy Asthma Proc. 2005 Mar-Apr;26(2):95-102. [abstract]