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Antihistamines

Second-generation antihistamines are generally recommended as first-line treatment for allergic rhinitis.

They are safe and effective at reducing nasal symptoms such as itching, sneezing, and watery rhinorrhoea in most patients, but they have less affect on nasal blockage.

Mode of Action

Histamine is a major mediator of the immune response in allergic rhinitis.

When an allergen is presented to a sensitised person, histamine is released from mast cells and basophils in the nasal mucosa. It activates H1 receptors that are found on nerve endings, smooth muscles, and glandular cells, causing vasodilation, increased capillary permeability, smooth muscle constriction, itching, and increased glandular secretion. This results in nasal itching, sneezing, and rhinorrhoea.

Antihistamines are H1 receptor antagonists; they attach to H1 receptors, blocking the attachment of histamine. They thus inhibit the histamine-induced symptoms of allergic rhinitis. They are less effective at controlling nasal obstruction as this is probably caused by other inflammatory mediators, eg kinins, prostaglandins, leukotrienes, and cellular mediators. The action of antihistamines is competitive and reversible, and both early-phase and late-phase allergic responses are inhibited.

Second-generation antihistamines have a greater affinity with H1 receptors than first-generation antihistamines, and a slower dissociation rate. They may also prevent histamine release from mast cells and basophils. Some second-generation antihistamines also inhibit other inflammatory mediators such as leukotrienes, prostaglandins, and kinins, although it is not known whether this contributes to their clinical efficacy.

Efficacy

In adults with seasonal allergic rhinitis, 36–80% of patients on antihistamines experience good to excellent symptom relief after 2 weeks of treatment compared with 16–47% of patients on placebo (50–83% versus 32% for perennial allergic rhinitis). Furthermore, in a randomised, double-blind study with patients with seasonal allergic rhinitis, antihistamine was reported to significantly improve patient-reported quality of life, and to reduce performance impairment in work and daily activities compared with placebo. Oral antihistamines may also reduce non-nasal symptoms such as conjunctivitis and urticaria.

First-generation antihistamines have relatively short half-lives and it is recommended that they are taken 3–4 times daily. Second-generation antihistamines have a longer duration of action and only need to be taken once or twice a daily.

Most antihistamines are available orally, but eye-drops (for treating allergic rhinoconjunctivitis) and nasal sprays and are also available. These have a faster onset of action (15–30 min) than oral antihistamines, are effective at low doses, and may help to relieve nasal congestion. However, their action is limited to the area applied, and they must be taken twice daily.

Safety of First-Generation Antihistamines

First-generation antihistamines typically cause sedation and performance impairment, and this has been associated with fatal car and occupational accidents. The risk is increased when patients are unaware that they are performing suboptimally, and by co-administration of drugs that act on the central nervous system such as alcohol, sedatives, hypnotics, and anti-depressants. Even when given in the evening only, there may still be significant daytime sedation. In children, the sedative effects of first-generation antihistamines may cause reduced learning ability and academic performance.

Sedation is probably caused when the lipophilic molecules cross the blood–brain barrier and interact with central H1 receptors. They may also inhibit histamine N-methytransferease, and the increased levels of histamine may also act on central receptors to cause sedation.

In addition to these central nervous system effects, anticholinergic effects (eg irritability, nervousness, and insomnia) and peripheral effects (eg blurred vision, dilated pupils, dry mouth, and urinary hesitancy) may occur.

Safety of Second-Generation Antihistamines

Second-generation antihistamines do not cross the blood–brain barrier to the same extent as first-generation antihistamines as they are more lipophobic, possess different ionic charges, and have a larger molecular size. As a result, second-generation oral antihistamines are not associated with the sedative and other central nervous system side effects that occur with first-generation antihistamines. However, it must be cautioned that sedation may still occur at high doses. No significant sedative effects have been reported with nasal sprays and eye drops, but patients may complain of them having a bitter taste.

Terfenadine and astemizole have been found to prolong QTC intervals when co-administered with drugs that affect the hepatic cytochrome P-450 system, and because of the resulting risk of cardiac arrhythmias they have been withdrawn in several countries. These drugs are contraindicated in patients with heart or liver disease. Patients at risk should be advised to use antihistamines which are not metabolised and do not have quinidine-like actions. Loratadine, cetirizine, azelastine, and fexofenadine do not cause QTC prolongation.

Increased appetite and weight gain may be a problem with astemizole, azelastine, and ketotifen. Astemizole and azelastine have shown teratogenicity in animals and so are contradicted for use in pregnant women. Antihistamines have not been well studied in elderly patients or children.

Current Treatment Practice

Because of the sedative effects of first-generation antihistamines, non-sedating second-generation antihistamines are generally recommended, and are even mandated in some segments of the transport industry. Certainly patients whose occupations require vigilance and concentration should not be given first-generation antihistamines. Not all antihistamines are suitable for use in children, but it is generally recommended that children are given non-sedating ones to avoid adverse effects on learning capability. However, first-generation antihistamines may be useful in those patients whose symptoms cause disrupted sleep.

Individual response to any antihistamine can vary, and caution is advocated with both first- and second-generation formulations until the patient has gained experience with the drug. There is no evidence that pharmacological tolerance develops to antihistamines, thus rotating from one to another is not beneficial.

First-generation antihistamines are generally cheaper than second-generation antihistamines, and more over-the-counter preparations are available, so patients often choose these despite the potential for side effects.

Drug Information (First Generation)

The following table gives some of the first-generation antihistamines available in the UK, US, and Canada. The majority are available over-the-counter. Only brand name drugs are given, but generic alternatives may be available.

Drug Information (Second Generation)

The following table gives some of the major second-generation antihistamines available in the UK, US, and Canada.For many formulations, over-the-counter preparations are available for certain doses. Only brand name drugs are given, but generic alternatives may be available.

* is a metabolite of loratadine ** is a metabolite of terfenadine

Combination Treatments

Antihistamines and decongestants

Antihistamines are effective at reducing rhinorrhoea, sneezing and nasal itching, but have limited effects on nasal obstruction. In combination with oral decongestants, which do effectively reduce nasal congestion, combination treatment can counteract all the symptoms of allergic rhinitis. There are various proprietary combined formulations; these tend to be more effective than individual components alone.

Click here for a table listing some of the many antihistamine and decongestant formulations available in the UK, US, and Canada, most of which are available over the counter.

Antihistamines and topical corticosteroids

Topical corticosteroids and antihistamines given together do not out-perform corticosteroids given alone. Despite this, in patients not fully controlled by corticosteroids, the addition of antihistamines may be useful, particularly when they suffer from eye symptoms.

References

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Day J. Pros and cons of the use of antihistamines in managing allergic rhinitis. J Allergy Clin Immunol 1999;103:S395–S399.

Meltzer EO, Casale TB, Nathan RA, Thompson AK. Once-daily fexofenadine HCl improves quality of life and reduces work and activity impairment in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1999;83:311–317.

Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81:478–518.

Kay CG. The effects of antihistamines on cognition and performance. J Allergy Clin Immunol 2000;105:S622–S627.

Hansen GR. Loratadine in the high performance aerospace environment. Aviat Space Environ Med 1999;70:919–924.

Virant FS. Allergic rhinitis. Immunol Allergy Clin North Am 2000;20:265–282.

Mattila MJ, Paakkari I. Variations among non-sedating antihistamines: are there real differences? Eur J Clin Pharmacol 1999;55:85–93.