Medications for Allergy

• describe the symptoms of hay fever;

• outline the stimuli that can cause release of histamine;

• describe the histamine receptor subtypes and their locations in the body;

• comment on the uses of antihistamines.

It has been nearly five months since 53-year-old Mrs Smythe moved from Florida to England at the end of February, following her husband’s career change. Before the move she considered herself to be a very healthy middle-aged woman who enjoyed walking in the countryside. However, since coming to England she has been complaining about the persistent symptoms of a cold, with a runny nose and watery eyes for the last three months. Whilst she is still very excited about the move, she can now no longer go for her daily stroll since her symptoms are even more severe during walking. After visiting her family doctor she was prescribed fexofenadine (Allegra).

Is Mrs Smythe’s problem likely to be a cold or can you suggest an alternative diagnosis?

An ordinary cold is not likely to account for Mrs Smythe’s symptoms. Colds are very unlikely to persist for several months and the eyes are not usually much affected. Colds are normally self-limiting and last for approximately five to seven days. An alternative diagnosis, which accounts for Mrs Smythe’s symptoms and their duration, is hay fever.

What is hay fever? What are its associated symptoms?

Hay fever (a common term for seasonal allergic rhinitis) is an allergic reaction induced by an immunoglobulin-mediated inflammatory response of the nasal mucosa to allergens, particularly pollen. There is inflammation of the upper respiratory tract, eyes and often the paranasal sinuses and throat. The major symptoms are sneezing, itchiness and increased secretion from the nose (rhinorrhoea, or runny nose) together with itchy, red, watery eyes. Other symptoms can include headache and changes in the patient’s ability to smell. The symptoms can be very troublesome, interrupting daily activities and disrupting leisure and sporting pastimes.

To which category of drugs does fexofenadine belong?

Fexofenadine (Allegra-d) is an antihistamine. This agent is also of use in urticaria.

Explain why fexofenadine was prescribed for this patient.

Antihistamines are effective in managing many of the troublesome symptoms of allergic rhinitis. Histamine is a neurotransmitter and a mediator of type 1 hypersensitivity reactions, such as urticaria and hay fever. There are several types of histamine receptors and these allergic conditions can be treated with Hi receptor antagonists, such as promethazine (Phenergan), chlorphenamine and fexofenadine (Allegra-d). First-generation antihistamines, such as promethazine (Phenergan), cause sedation and possess side effects associated with actions on muscarinic receptors. Fexofenadine (Allegra-d) is a newer drug with a longer duration of action, which does not sedate the patient.

Which other stimuli can release histamine in the body?

Histamine is released in:

(1) inflammation

(2) allergic reactions

(3) tissue damage, for example in response to venoms (bee stings).

List the histamine receptor types. Where are these receptors located?

• H1 receptors-located in the gastrointestinal (GI) tract, mediate GI contraction.

• H2 receptors-located in the GI tract and cardiovascular system, mediate gastric secretion and cardiac stimulation

• H₃ receptors-located in the central nervous system (CNS) (pre-terminal and autoreceptors) maybe involved in movement control.

What is the daily dose of fexofenadine and are there any potential side effects when using this agent?

Fexofenadine is a metabolite of another antihistamine, terfenadine, but has little or no cardiac toxicity. The development of sedation and antimuscarinic effects are limited since fexofenadine cannot easily cross the blood-brain barrier (only a very small amount can cross this barrier). The recommended adult dosage is 120 mg once daily. It is also recommended for children above 12 years of age.

By giving an example of an H₂-receptor antagonist, explain the pathophysiological conditions for which these drugs are used in the clinic.

Examples include: famotidine, ranitidine, nizatidine and cimetidine. They prevent food, histamine and acetylcholine-induced gastric-acid secretion. They are used to heal gastric and duodenal ulcers and in gastro-oesophageal reflux disease.

Key Points

• Hay fever, or allergic rhinitis, is an allergic reaction induced by an immunoglobulin-mediated inflammatory response of the nasal mucosa to allergens, particularly pollen.

• This condition causes an inflammation of the upper respiratory tract, eyes and often the paranasal sinuses and throat.

• Major symptoms are sneezing, itchiness and increased secretion from the nose (rhinorrhoea, or runny nose) together with itchy, red, watery eyes. Other symptoms can include headache and changes in the patient’s ability to smell.

• H1 receptor antagonists, including promethazine (Phenergan), chlorphenamine and fexofenadine (Allegra-d), are effective in managing many of the troublesome symptoms.

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Fexofenadine Hydrochloride). A white or almost white powder. Slightly soluble in water freely soluble in methyl alcohol very slightly soluble in acetone. It exhibits polymorphism.

The United States Pharmacopeia 31, 2008 (Fexofenadine Hydrochloride). Store at a temperature of 20° to 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects and Precautions

As for the non-sedating antihistamines in general.

Arrhythmias. A 67-year-old man suffered syncope after taking fexofenadine 180 mg daily for 2 months. His ECG showed an abnormally prolonged QT interval which shortened once fexofenadine was stopped, although the interval tended to be long even without drug therapy. Nonetheless rechallenge was positive. The manufacturers of fexofenadine have commented that the patient was at risk of developing arrhythmias before taking the drug.

The ECG effects of fexofenadine have been studied in normal subjects and doses of up to 480 mg daily [4 times the recommended dose for seasonal allergic rhinitis] did not prolong the QT interval.

Breast feeding. No adverse effects have been seen in breastfed infants whose mothers were receiving fexofenadine, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding.

See also under Adverse Effects and Precautions, in Terfenadine.

Psoriasis. Exacerbation of psoriasis has been reported in association with the use of fexofenadine.

Interactions

As for the non-sedating antihistamines in general.

Plasma concentrations of fexofenadine have been increased when given with erythromycin or ketocona-zole, but, unlike terfenadine, licensed product information states that this was not associated with adverse effects on the QT interval.

Antacids containing aluminium and magnesium hydroxide have reduced the absorption of fexofenadine. Fruit juices including grapefruit may reduce the bioa-vailability of fexofenadine and use together should be avoided.

Pharmacokinetics

Fexofenadine is rapidly absorbed after oral doses with peak plasma concentrations being reached in 2 to 3 hours. It is about 60 to 70% bound to plasma proteins. About 5% of the total dose is metabolised, mostly by the intestinal mucosa, with only 0.5 to 1.5% of the dose undergoing hepatic biotransformation by the cyto-chrome P450 system. Elimination half-life of about 14 hours has been reported although this may be prolonged in patients with renal impairment. Excretion is mainly in the faeces with only 10% being present in the urine. Fexofenadine does not appear to cross the blood-brain barrier.

Fexofenadine is a metabolite of terfenadine and as such has been detected in breast milk after the administration of terfenadine.

Uses and Administration

Fexofenadine, an active metabolite of terfenadine, is a non-sedating antihistamine. It does not possess significant sedative or antimuscarinic actions. Fexofenadine is used as the hydrochloride in the symptomatic relief of allergic conditions including seasonal allergic rhinitis and chronic urticaria.

In the UK a dose of fexofenadine hydrochloride 120 mg once daily is given orally in the treatment of seasonal allergic rhinitis the recommended dose in chronic idiopathic urticaria is 180 mg once daily. US licensed product information suggests a dose of 60 mg twice daily or 180 mg once daily for both indications.

Fexofenadine is also used with a decongestant such as pseudoephedrine hydrochloride.

For doses in children or in patients with renal impairment, see below.

Administration in children. Fexofenadine hydrochloride is used in children for the treatment of seasonal allergic rhinitis in an oral dose of 30 mg twice daily in the UK it is licensed for use in children aged 6 to 11 years whereas in the USA it may be used in children as young as 2 years.

In the USA, fexofenadine is also licensed for use in paediatric chronic idiopathic urticaria. The dose in children aged 6 months to less than 2 years is 15 mg twice daily older children may be given 30 mg twice daily.

For suggested doses in children with renal impairment see below.

Administration in renal impairment. US licensed product information recommends that initial oral doses of fexofenadine hydrochloride in adults with renal impairment should be reduced to 60 mg once daily. In children with renal impairment, the initial dose should be reduced to 30 mg once daily in patients aged 2 to 11 years, and to 15 mg once daily in children aged 6 months to less than 2 years.

UK product information advises that fexofenadine should be given with caution to patients with renal impairment however, it also states that dose adjustment is not considered to be necessary in such patients.

Preparations

The United States Pharmacopeia 31, 2008: Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets Fexofenadine Hydrochloride Capsules Fexofenadine Hydrochloride Tablets.

Proprietary Preparations

Argentina: Alerfedine Allegra Fexofen †

Australia: Fexotabs Telfast Xergic

Austria: Telfast

Belgium: Telfast

Brazil: Allegra Altiva

Canada: Allegra

Chile: Aerodan Alexia Allegra Fenax

Czech Republic: Afexil Ewofex Telfast

Denmark: Telfast

Finland: Telfast

France: Telfast

Germany: Telfast

Hong Kong: Telfast

Hungary: Altiva Telfast

India: Alernexf Allegra Fexigra Fexofen Fexova Odifex

Indonesia: Telfast

Ireland: Telfast

Israel: Telfast

Italy: Kalicet † Telfast

Malaysia: Telfast

Mexico: Allegra

The Netherlands: Telfast

Norway: Telfast

New Zealand: Telfast Xergic

Philippines: Telfast

Poland: Telfast

Portugal: Telfast

Russia: Fexadin Telfast

South Africa: Telfast

Singapore: Telfast

Spain: Telfast

Sweden: Telfast

Switzerland: Telfast

Thailand: Fenafex Telfast

Turkey: Fexadyne Fexofen Telfast

UK: Telfast

USA: Allegra

Venezuela: Allegra Fexidine Fexoril Rinolast

Multi-ingredient

Argentina: Alerfedine D Allegra-D

Australia:: Telfast Decongestant

Brazil: Allegra-D

Canada: Allegra-D

Chile: Alexia D Allegra-D

Hong Kong: Telfast-D

Indonesia: Telfast Plus

Malaysia: Altiva-D Telfast-D

Mexico: Allegra-D

New Zealand: Telfast Decongestant †

Singapore: Telfast-D

USA: Allegra-D

Venezuela: Allegra-D Rinolast D

Histamine, β-aminoethylimidazole, is formed in many tissues by decarboxy-lation of the amino acid L-histidine by the enzyme histidine decarboxylase. Mast cells and basophils are the principal histamine-containing cells in most tissues. Histamine is stored in vesicles in a complex with heparin and released by either an immunologic trigger or following a mechanical or chemical stimulus. Once released, histamine produces a number of responses including local vasodilation, transudation of fluid through endothelial cells, and stimulation of nerve ending, producing pain and itching. In the lung, histamine is a bronchoconstrictor, and this action is magnified in patients with asthma. Histamine has actions in the GI tract and causes contraction of smooth muscle; it is also a potent secretagogue for gastric acid secretion, pepsin, and intrinsic factor. In the brain, histamine acts as a neurotransmitter.

The actions of histamine are mediated by four distinct membrane receptors that are coupled to G-proteins. The H_: receptor, located in smooth muscle cells, endothelium, and brain, is coupled to increased diacylglycerol and Ca²⁺ release. The H₂ receptor is located in gastric mucosa mast cells, immune cells, and brain, and is coupled to increased cAMP. There is no clinical pharmacology yet for H₃ (located in the brain and peripheral neurons) or H₄ (found on eosinophils and neutrophils) receptors, but both of these receptors are targets for therapeutic agents and are under intense investigation. Histamine itself has a variety of untoward effects and is useful only diagnostically to assess bronchial hyperreactivity.

Antihistamines

Compounds that block the active state of histamine H_: receptors have been used for years and are widely marketed both as prescription and over-the-counter medications. The current group of available drugs can be divided into first-generation and second-generation agents. In general, first-generation agents can cross the blood-brain barrier, and they have a number of effects in the brain, including sedation and reduction in nausea. Table Currently available antihistamines lists some currently used H_: antagonists.

Table: Currently available antihistamines

I = available in an injection preparation; ANTI-CHOL = Anticholinergic

All of these drugs block the action of H₁ receptors, and they do not possess significant affinity for the H₂ receptor. However, many of the first-generation agents have significant anticholinergic activity, and this is responsible for a significant degree of their central effects. Second-generation agents are less lipid-soluble and do not penetrate the blood-brain barrier and hence have much fewer central adverse effects.

The major use of H₁-receptor blockers is in the treatment of allergic reactions. Histamine is released by IgE-sensitized cells, especially mast cells and antihistamines can reduce the rhinitis, conjunctivitis, sneezing, and urticaria associated with this reaction. They are most effective in acute allergic reactions with a relatively low antigen burden, and effectiveness diminishes in chronic disorders. Antihistamines are not effective as monotherapy for bronchial asthma. Antihistamines are marketed for treatment of the common cold, but they have very limited effectiveness in this application and their adverse effects (e.g., sedation) outweigh their benefit. Some of the first-generation agents, especially dimenhydrinate, meclizine, cyclizine, and promethazine, are useful for the prophylaxis of motion sickness and vertigo. Promethazine is the most potent in this regard but has pronounced sedative activity that limits its usefulness. The sedating action of some antihistamines has been exploited in their use as sleeping aids.

Diphenhydramine is the most commonly used antihistamine in sleeping preparations. The major adverse effect of the first-generation agents is sedation. The anticholinergic activity produces atropine-like effects including dry mouth, urinary retention, and cough. Second-generation agents avoid these effects but do have adverse effects such as headache, back pain, and in the GI tract cause nausea, loss of appetite, and constipation or diarrhea. Of the presently available second-generation antihistamines, cetirizine causes the highest incidence of fatigue and somnolence (approximately 10%); loratadine appears to have the lowest incidence of this effect (approximately 1-2%). These agents may produce cardiovascular adverse effects such as hypotension, bradycardia or tachycardia, and electrocardiograph (ECG) changes.

Administration

All of the agents listed in Table Currently available antihistamines are available for oral use, and some of the first-generation agents are available for parenteral use. Topical application of diphenhydramine is useful in the treatment of minor allergic dermatologic reactions. Azelastine is administered by nasal spray.

Pharmacokinetics

Following oral administration, the Hj antagonists reach peak levels in about 2-3 hours and last 6-24 hours depending on the agent.

H₂-Receptor Antagonists

Histamine is a potent gastric acid secretagogue and this action is mediated by histamine H₂ receptors. Cimetidine, ranitidine, nizatidine, and famotidine are H₂-specific antagonists and are used to treat gastroesophageal reflux disease and peptic ulcers.

Case: Antihistamines. Questions – Answers

An 8-year-old girl is brought in by her mother for evaluation of allergies. Each year in the spring the child develops a runny nose; itchy, watery eyes; and sneezing. She has been treated in the past with diphenhydramine, but the child‘s teacher says that she is very drowsy during school. She has no other medical problems and is on no chronic medications. Her examination is unremarkable today. You diagnose her with seasonal allergic rhinitis and prescribe fexofenadine.

What is the mechanism of action of antihistamine medications?

What are the common side effects of antihistamine medications?

What is the pharmacologic basis of switching to fexofenadine?

Answers to case: Antihistamines

Summary: An 8-year-old girl with seasonal allergic rhinitis is switched to fex-ofenadine because of the sedation caused by diphenhydramine.

Mechanism of action of antihistamines: Competitive antagonist of histamine receptors.

Common side effects: Sedation, dizziness, nausea, constipation, diarrhea, loss of appetite, anticholinergic effects — dry mouth, dry eyes, blurred vision, urinary retention.

Rationale for switching to fexofenadine: Less central nervous system (CNS) penetration and less sedating than earlier antihistamines.

Clinical correlation

Histamine is found in many tissues throughout the body. Most histamine is stored in mast cells and basophils. Histamine is released primarily from mast cells via the process of degranulation. Degranulation occurs when immunoglobulin E (IgE) fixates to mast cells, and there is a subsequent exposure to a specific antigen. Complement activation may also induce degranulation. When released, histamine becomes bound to specific membrane-bound histamine receptors. The therapeutic uses of antihistamine medications primarily involve the H₁ and H₂-receptor subtypes. H₁ receptors are located in the brain, heart, bronchi, gastrointestinal (GI) tract, and vascular smooth muscle. Their activation increases phospholipase C activity, causing increases in diacylglycerol and intracellular calcium. Activation of H_: receptors in the brain increases wakefulness. In blood vessels, activation causes vasodilation and increased permeability. H₁-receptor antagonists are competitive inhibitors at this receptor site. H₁-receptor antagonists are frequently used for the treatment of allergic rhinitis, urticaria, and hives. Some are used as prophylaxis for motion sickness and as sleep aids. Older, first-generation, antihistamines cross the blood-brain barrier, contributing to their potentially use-limiting side effect of sedation and can also have significant anticholinergic effects (dry mouth, dry eyes, blurred vision, urinary retention). They must be used with caution in the elderly and in combination with other sedating medications, because the effects can be additive. Newer, second-generation antihistamines have significantly less penetration into the CNS and reduced anticholinergic activity. This results in a lower incidence of sedation and fewer anticholinergic side effects. H₂-receptor activity is coupled to cyclic adenosine monophosphate (cAMP). Activation of H₂ receptors in gastric parietal cells causes an increase in gastric acid production. Medications that are competitive antagonists of H₂ receptors are used to reduce gastric acid secretion. These are used clinically in the management of peptic ulcer disease, gastroesophageal reflux disease, heartburn, and acid hypersecretory syndromes.

Approach to pharmacology of histamine and antihistamines

Objectives

1. Know the synthesis and mechanism of action of histamine.

2. Know the mechanism of action, uses, and adverse effects of antihistamine medications.

Definitions

Allergic rhinitis: An antigen-mediated allergic reaction that causes nasal congestion, sneezing, itchy eyes, and bronchoconstriction; also called hay fever.

Continuation: Case: Antihistamines. Class

Second-generation antihistamines

The newer antihistamines are devoid of anticholinergic and sedative effects with the exception of cetirizine, which may be mildly sedating in some patients. The low incidence of side effects is attributed to their high selectivity for peripheral H1-receptors and low propensity to cross the blood-brain barrier. Three 2nd-generation antihista-mines for oral administration are currently available in the United States: cetirizine, fexofenadine, and loratadine. All appear effective in mitigating the symptoms of allergic rhinitis. Table 2 lists available agents and dosages.

Table 2 Second-generation antihistamines

Cardiotoxicity associated with astemizole and terfenadine is the most serious side effect associated with the 2nd-generation antihistamines. Serum accumulation of these agents may deleteriously prolong the QT interval. Serious ventricular arrhythmias (including Torsades de pointes), cardiac arrest, and death have ensued as a result of overdoses and concomitant use of medications that impair the metabolism of terfenadine and astemizole (potent inhibitors of cytochrome P450 3A4 isoenzymes, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, fluoxamine). These reactions and interactions have not been associated with the currently available agents. (Both terfenadine and astemizole have since been voluntarily withdrawn from the US market; terfenadine has been replaced with its nonarrhythmogenic metabolite, fexofenadine.)

Azelastine is a new topically administered 2nd-generation antihistamine that has demonstrated efficacy in improving both early- and late-phase symptoms of allergic rhinitis. Symptomatic response may be seen as early as 30 minutes after dose. In comparative trials, intranasal azelastine appears equally as efficacious as oral antihistamines but generally less effective than corticosteroids in relieving nasal symptoms. The most commonly reported adverse effects are bitter taste, application site irritation, and somnolence. Azelastine is administered 2 sprays per nostril twice daily.

What is Allegra?

Allegra is a nonsedating antihistamine that relieves seasonal nasal allergy symptoms like sneezing, runny nose, and itchy, watery eyes in patients 12 and older.

How does Allegra work?

Allegra is an antihistamine. Histamine is a chemical in your body that causes allergy symptoms. Allegra blocks the histamines and relieves allergy symptoms such as sneezing, runny nose, and itchy, watery eyes.

How long does it take Allegra to work?

Relief of allergy symptoms may occur at 1 hour after taking a dose of Allegra.

How do I take Allegra?

Allegra is available as a 60-mg capsule. The recommended dose for patients 12 years of age or older is one capsule (60 mg) twice daily. It may be taken as one capsule in the morning and one capsule in the evening.

Can I take Allegra with food?

Allegra can be taken with or without food.

What are the side effects of Allegra?

In tests conducted by allergists, the incidence of drowsiness in people who took Allegra was similar to placebo (sugar pill), 1.3% vs 0.9%. The most commonly reported adverse experiences for Allegra and placebo are cold or flu (2.5% vs 1.5%), nausea (1.6% vs 1.5%), menstrual pain (1.5% vs 0.3%).

Will Allegra interact with other medications?

Make sure to let your doctor or pharmacist know of any other prescription or non-prescription medications you are taking. Your doctor or pharmacist can advise you about appropriate combinations of drugs.

Do I need to see my doctor to get Allegra?

Allegra is only available with a prescription from your doctor or other authorized health care provider.

How much does Allegra cost?

Retail prices may vary. However, the wholesale price of Allegra is below that of other available nonsedating antihistamines to provide nondrowsy allergy symptom relief at an economical price.