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.

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

Allergy refers to a broad state of altered reactivity to a foreign substance, resulting from prior experience with the same substance. Used today, the term allergy generally refers to the unfavorable clinical consequences of an antigen-antibody interaction. Although the term allergic disorder implies an immune mechanism, in many allergic disorders, most notably bronchial asthma and atopic dermatitis, non-immune mechanisms may be of great importance. Many of the clinical conditions being treated by an allergist may be aggravated by non-immune factors such as pollution, psychic stress, cold air, and exertion -for example, exercise-induced asthma. We must always remember that there are three main principles in the therapy of allergic diseases:

1. Most important: avoidance of allergens and irritants known or suspected to be causing or aggravating the disorder.

2. The use of pharmacologic agents, restricted to as few as possible.

3. The use of specific immunotherapy or hyposensitization.

We must use a drug appropriate to the patient’s symptoms; antihistamines, for example, are useful for ear and nose complaints as well as pruritis of the skin (i.e. urticaria, eczema).

Drugs Used in the Treatment of Allergic Disorders

Antihistamines have been used in the treatment of allergic conditions for the past 30 years. They compete with the histamine released through either an antigen-antibody reaction, by physical trauma or by a histamine-liberating agent (eg. morphine, codeine). This histamine is released from the mast cells. The antihistamines compete for the cellular receptor sites, but they do not combine with the histamines in vivo or in vitro.

There are many commercially available antihistamines, which can be classified into five major groups. Physicians should be familiar with one member of each group. If the initial drug chosen does not give a good therapeutic response, use an antihistamine in another group. At times, it is necessary to try an antihistamine of one group after another, often in various combinations with sympathomimetic agents, to obtain reasonable results.

The classes of antihistamines are as follows:

1. Ethanolamines, e.g. diphenhydramine (Benadryl), dosage five mg/kg/day in three or four divided doses. A side effect is marked sedation.

2. Ethylenediamine; e.g. tripelennamine (Pyribenzamine), dosage five mg/kg/day in three or four divided doses. Side effects include moderate sedation.

3. Alkylamine; e.g. chlorpheniramine (Chlor-Tripolon), dosage 0.3 mg/kg/day in three or four divided doses. There is minimal sedation.

4. Piperazines; e.g. hydroxyzine (Atarax).

5.Phenothiazine, e.g. promethazine (Phenergan), dosage 0.5 mg/kg before retiring or 0.3 mg/kg/day. This has side effects of marked sedation.

Remember that antihistamines compete with the histamine already released in the body of the cell receptors, thus blocking the effect of the released histamine on the effector organs. Antihistamines do not combine chemically with the histamine, and they do not interfere with the antigen antibody reaction.

The sympathomimetic amine drugs or beta adrenergic agonists and theophylline are useful bronchodilators for bronchospasm.

The antibiotics used for infection in an allergic individual are tetracycline after age seven (five to ten mg/kg every six hours) and erythromycin, an unusually safe drug, orally, 10 mg/kg every six hours.

Steroids are used for more severe and acute symptoms.