Antihistamines

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

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:

• Nasal allergies especially seasonal allergic rhinitis (hayfever)
• Urticaria
• Anaphylaxis
• Angio-oedema

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)

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).¹
• 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.²

Antihistamines and sedation

• A prescription-event monitoring study in general practice found that the overall risk of reported sedation was low for fexofenadine, acrivastine, cetirizine and loratadine, with no evident increased risk of accident or injury.³ However, there were patients who felt sedated on these drugs and it was noted that fexofenadine and loratadine carried the lowest risk of subjective sedating effects. It was recommended that these drugs were most suitable for individuals with jobs where safety was critical.
• An objective study of sedation (measuring EEG response potentials) in children treated with cetirizine showed evidence of sedation/slowing that was not symptomatically noted.⁴
• A study assessing reaction times in driving tasks found significant impairment of function with the 1st-generation antihistamine hydroxyzine, but not with fexofenadine (as compared to placebo).⁵
• A comparison of fexofenadine and cetirizine using objective and subjective criteria showed that fexofenadine was no more likely than placebo to cause sedation, whereas cetirizine was.⁶

• First-generation antihistamines possess anti-muscarinic activity and therefore must be used with caution in:
  • Benign prostatic hyperplasia and urinary retention
  • Acute glaucoma
• Pyloric outflow obstruction.
• Hepatic and/or renal impairment - dose reduction should be considered.
• Epilepsy - use with caution.
• Hepatic and renal impairment.
• Acute porphyria - such patients should not be prescribed antihistamines, although it is thought that chlorphenamine and cetirizine are safe.
• Pregnancy and lactation - antihistamines should be prescribed only where absolutely necessary in pregnant patients; avoid in first trimester. Long-term clinical experience suggests that the older agent chlorphenamine is suitable for use in pregnancy. Use of antihistamines, particularly the newer 2nd-generation agents, is not recommended in breastfeeding.

• Sedation - This is a problem with many 1st-generation antihistamines but may also affect some patients taking 2nd-generation products. Patients should be made aware of this. 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 - 2nd-generation antihistamines mizolastine and terfenadine are particularly prone to cause ventricular arrhythmias (predominantly ventricular tachycardia and torsades de pointes).⁷This 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 1st-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 increase the risk of this complication, as does pre-existing QT prolongation.

Other side effects include

• Headache
• Psychomotor impairment
• Urinary retention
• Blurred vision
• Dry mouth
• Gastrointestinal disturbance
• Hypotension
• Hypersensitivity reactions (eg bronchospasm, anaphylaxis, rashes, photosensitivity)
• Extrapyramidal side effects and tremor
• Confusion (especially in the elderly)
• Sleep disturbance
• Depression
• Decreased epileptic threshold
• Haematological disorders
• Hepatic dysfunction

• Tricyclic antidepressants - antimuscarinic and sedative effects are potentially enhanced by co-administration of antihistamines. Similarly with other antimuscarinic or sedative drugs e.g. hypnotics, anxiolytics, monoamine oxidase inhibitors.
• Co-administration of anti-fungal 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 2nd-generation antihistamines.
• Consumption of grapefruit juice increases the plasma concentration of terfenadine and patients should be advised to avoid its consumption whilst taking this drug.⁸

Allergic rhinitis

Antihistamines reduce rhinorrhoea and sneezing but not nasal congestion.There is little clinical trial data on the effectiveness of the 1st-generation antihistamines for this indication. The 2nd-generation drugs have been subjected to many RCT and comparative trials and are considered first line in the treatment of allergic rhinitis.⁹ Treatment may then be stepped up with addition of steroids along with these measures (allergen avoidance must be prevailed upon). All the licensed drugs have been shown to reduce the symptoms of hayfever and are more effective when used constantly rather than intermittently. There is no convincing data from the various trials to suggest selecting one agent above the other, though the once-daily preparations desloratadine and fexofenadine appear to be more beneficial in reducing the symptom of blocked nose, a symptom not classically controlled by the use of antihistamines in hayfever. A recent comparative study suggests greater efficacy for levocetirizine compared to desloratadine. Cetirizine and levocetirizine have been shown to be beneficial in children.¹⁰ Long-term use of cetirizine by children with atopic dermatitis appears to have no impact on their behavioural, cognitive and psychomotor development.⁴ A recent study comparing the topical antihistamine azelastine with oral cetirizine in children appears to show greater efficacy for the nasal spray compared to the oral drug.¹¹

Chronic idiopathic urticaria

There is little evidence that antihistamines used symptomatically to treat non-specific itching have any effect greater than placebo.
Most of the 2nd-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.¹²

Choice of agent to treat allergic rhinitis and urticaria appears to be largely arbitrary amongst the 2nd-generation agents and will be based on the individual preference of the prescriber and patient, cost considerations and the individual nature of the problem in a given patient.