Mechanisms of action and effects

The antihistamines are selective antagonists at histamine H₁ receptors; antagonists at other histamine receptors are traditionally not called antihistamines. Antihistamines are competitive inverse agonists (see Ch. 1) that reduce the basal level of spontaneous activity at histamine H₁ receptors as well as blocking the agonist effects of histamine. Useful actions of antihistamines include:

 suppression of many of the vascular effects of histamine,

 inhibition of inflammatory cell accumulation in tissues by second-generation antihistamines; this may result from downregulation of the activation of NF-κB in tissues at the site of an allergic response.

First-generation antihistamines have other actions that can be used therapeutically. They are lipophilic and cross the blood–brain barrier, producing sedation. They also have central antimuscarinic effects that may be clinically useful in suppressing nausea in motion sickness (e.g. cyclizine [no longer used as an antihistamine], promethazine; Ch. 32).

Second-generation (non-sedating) antihistamines such as cetirizine, fexofenadine, loratadine and mizolastine are either more hydrophilic or more ionised at physiological pH; they do not penetrate the blood–brain barrier well, and have little sedative effect. They also have little antimuscarinic action.

So-called ‘third-generation’ antihistamines, such as desloratadine, are active metabolites or optical isomers of second-generation drugs. They have similar efficacy to second-generation drugs but may have a different profile of unwanted effects.

Pharmacokinetics

Chlorphenamine is more slowly absorbed from the gut than promethazine; both undergo considerable first-pass hepatic metabolism to inactive compounds and have half-lives of 10–20 h. Formulations of chlorphenamine and promethazine are available for administration by intravenous or intramuscular injection in medical emergencies.

Most second-generation antihistamines are rapidly absorbed from the gut and metabolised in the liver to active compounds with half-lives ranging from 2 to 20 h. Cetirizine and fexofenadine undergo little metabolism and are mainly eliminated unchanged by the kidneys.

There are several topical formulations of antihistamines, including nasal sprays for allergic rhinitis, eye drops for allergic conjunctivitis and topical skin preparations for insect stings (although the latter are relatively ineffective).

Unwanted effects

 Drowsiness or psychomotor impairment, especially with first-generation compounds, although paradoxical stimulation can occur in children and the elderly.

 Headache.

 Dry mouth, blurred vision, urinary retention and gastrointestinal upset from the antimuscarinic effects of first-generation compounds.

 Topical antihistamines for use on the skin can cause hypersensitivity reactions.

Anaphylaxis

Anaphylaxis is a medical emergency and requires rapidly acting treatments. It most commonly arises as an allergic response to stings, nuts, penicillins, cephalosporins and muscle-relaxant drugs. The person should be laid flat with their feet raised if there is hypotension, and the airway secured. Adrenaline (epinephrine; Ch. 4) should be given intramuscularly and doses repeated every 10 min until the clinical state is stable. Adrenaline produces vasoconstriction by its action at α₁-adrenoceptors, reducing oedema, and bronchodilates via β₂-adrenoceptors. It also attenuates the release of mediators from mast cells by binding to cell surface β₂-adrenoceptors. People known to have allergies that cause anaphylaxis can carry a preloaded adrenaline syringe for emergencies, accompanied by detailed instructions on its appropriate use. Intravenous adrenaline should only be given if there is profound shock, and then in a very dilute solution with close cardiac monitoring. Intravenous use carries a risk of arrhythmias and intense vasoconstriction with myocardial ischaemic damage.

Once adrenaline has been given, late relapse can be prevented by intramuscular injection or slow intravenous injection of chlorphenamine and hydrocortisone (Ch. 44). Oxygen should be given in high concentration, and an inhaled β₂-adrenoceptor agonist such as salbutamol (Ch. 12) administered if there is marked bronchospasm. This can be particularly useful if a β-adrenoceptor antagonist has previously been taken, when adrenaline may be less effective on the airways. If there is persistent hypotension, intravenous fluid should be given rapidly, preferably a crystalloid such as isotonic saline.

Seasonal and perennial rhinitis

Allergic inflammation of the lining of the nose produces symptoms of rhinitis including nasal obstruction, sneezing and itching. These result from increased glandular secretions producing nasal obstruction and mucous rhinorrhoea, as well as afferent nerve stimulation, which is responsible for itching and sneezing. Allergies can cause both perennial rhinitis (usually house dust mite) and seasonal rhinitis (pollens and moulds). The allergic response makes individuals more susceptible to the nasal irritant effects of other, non-allergenic stimuli, such as tobacco smoke and changes in temperature. Rhinitis also has several non-allergic causes, including acute infection and chronic sinus infection for which antibacterial treatment is indicated. Aspirin and other non-steroidal anti-inflammatory drugs can produce rhinitis (as well as asthma, see Ch. 12) in sensitive subjects, probably by enhancing cysteinyl-leukotriene generation. Less frequent causes include β-adrenoceptor antagonists (Ch. 5) and angiotensin-converting enzyme (ACE) inhibitors (Ch. 6).

Oral antihistamines are useful for reducing itching, sneezing and rhinorrhoea, but they are less effective for nasal obstruction. They can also suppress associated allergic conjunctivitis. Azelastine is an antihistamine used as a topical nasal spray. For more severe allergic rhinitis, a topical intranasal corticosteroid spray (Ch. 44) is the treatment of choice, providing relief from most symptoms. Topical sodium cromoglicate or nedocromil (Ch. 12) can be useful in atopic individuals, but they are less effective than antihistamines or topical corticosteroids and are no longer preferred treatments. An oral leukotriene receptor antagonist (montelukast) may be beneficial in allergic rhinitis with concomitant asthma. The antimuscarinic drug ipratropium bromide (Ch. 12) can be used topically for relief of non-allergic rhinorrhoea.

Topical nasal decongestants have a short-term role in treatment. These contain α₁-adrenoceptor agonists such as ephedrine or xylometazoline and produce local vasoconstriction. Prolonged use impairs ciliary activity in the nasal mucosa and can be associated with rebound nasal congestion during long-term use. Oral corticosteroids are reserved for the most severe symptoms.

If drugs fail the possibility of structural abnormalities such as nasal polyposis, hypertrophied inferior turbinates or a deviated nasal septum should be considered, since surgery may be helpful.