Medications for Allergy

• describe the pathophysiology of allergic rhinitis;

• outline the causes of allergic rhinitis;

• explain why antihistamines may be contraindicated in asthmatic patients;

• describe alternatives to antihistamines in treating allergic rhinitis.

Part 1

It’s that time of year when 14-year-old Dean’s symptoms trouble him most. He suffers from excessive sneezing, rhinorrhoea and nasal congestion. These symptoms make him very irritable, he cannot sleep properly, feels very fatigued and as a result is less focused on his school work. Since some important school exams are due to begin soon, his mother insists that Dean sees a doctor. His doctor prescribes azelastine hydrochloride. Before writing the prescription, the doctor checked Dean’s medical notes and questioned him to make sure that he did not suffer from asthma.

What is the likely diagnosis of Dean’s symptoms?

Allergic rhinitis.

What is allergic rhinitis and what are the causative factors?

Perennial and seasonal allergic rhinitis affects many individuals and can cause serious complications, such as otitis media and chronic sinusitis. The symptoms of allergic rhinitis can be caused by house dust mites, pollens, moulds and other allergens.

Comment on the pathophysiology of this condition.

A type 1 hypersensitivity reaction is responsible for the development of the allergy. The symptoms are due to the effects of mast cell degranulation with the release of histamine. Mast cells are located in the nasal passages and the nasal mucosa is sensitive to the effects of histamine released from these cells, leading to inflammation of the mucous membranes of the nose. The inflammation is associated with oedema and swelling, vasodilation and an increase in the secretion of mucus. The mucous membrane of other sections of the respiratory tract (accessory sinuses, nasopharynx, and upper and lower respiratory tract) will also be affected by the allergic reaction.

What category of drugs can be used for perennial allergic rhinitis?

Perennial allergic rhinitis can be treated with antihistamines and corticosteroids.

To which category of drugs does azelastine hydrochloride belong?

Azelastine hydrochloride is an antihistamine, an H1 receptor antagonist which is available as a nasal spray.

Why is it important that Dean’s doctor checks whether he suffers from asthma?

Antihistamines should be used with caution in patients with asthma. This is due to a reduction in expectoration following the drying effect of the drugs, which may thicken the bronchial and bronchiolar secretions.

Part 2

After a couple of weeks Dean returned to his doctor, complaining that his symptoms were persistent.

Is there an alternative medication for Dean’s persistent symptoms?

An alternative medication could be the use of topical nasal corticosteroids, such as beclometasone or budesonide, administered as a nasal spray: cromoglicate may also be used. The mechanism of cromoglicate is poorly understood; it may stabilize the mast cells to reduce degranulation and histamine release. It is useful in the prophylaxis of both asthma and allergic rhinitis. The topical antihistamines are less effective than topical corticosteroids, but more effective than cromoglicate. Cromoglicate, however, is the first choice in children < 12 years of age.

Key Points

• Perennial and seasonal allergic rhinitis are type 1 hypersensitivity reactions to an allergen.

• The symptoms are due to the effects of mast cell degranulation. The effects can cause serious complications, such as otitis media and chronic sinusitis.

• Allergens which cause these symptoms include house dust mites, pollens and moulds.

• Treatment of allergic rhinitis includes antihistamines, H1 receptor antagonists, such as axelastine, and corticosteroids, such as beclometasone or budesonide. However, cromoglicate is the first choice for children.

• 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.

Questions

[1] The major use of second-generation histamine Hj-receptor blockers is the treatment of which of the following complaints?

A. Cough associated with influenza

B. Hay fever

C. Motion sickness

D. Sleeplessness

[2] You see a long-distance truck driver in the clinic who complains of serious allergic rhinitis. Which of the following would be the best anti-histamine to prescribe?

A. Diphenhydramine

B. Fexofenadine

C. Meclizine

D. Promethazine

[3] Which of the following statements is correct?

A. Antihistamine agents used for allergic rhinitis have antagonistic activity against both H₁ and H₂ receptors.

B. Antihistamine agents are generally useful in the treatment of asthma.

C. Antihistamines are the preferred agent in the treatment of acute anaphylaxis.

D. Second-generation antihistamines have fewer anticholinergic effects than first-generation antihistamines.

Answers

[1] B. First-generation agents that cause sedation have been used as sleeping aids, and some have antiemetic effects.

[2] B. The other agents are sedating.

[3] D. Second-generation antihistamines have less sedating and anticholinergic side effects than first-generation agents.

Pharmacology pearls

Second-generation antihistamines do not penetrate the blood-brain barrier and have little sedative effect.

Antihistamines are of little or no benefit in treating the common cold.

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

A woman in her early thirties wants some advice. She tells you that she has hay fever and a blocked nose and is finding it difficult to breathe. You find out that she has had the symptoms for a few days; they have gradually got worse. She gets hay fever every summer and it is usually controlled by chlorphenamine tablets, which she buys every year and which she is taking at the moment. As a child, she suffered quite badly from eczema and is still troubled by it occasionally. She tells you that she has been a little wheezy for the past day or so, but she does not have a cough, and has not coughed up any sputum. She is not taking any other medicines.

The pharmacist’s view

This woman has a previous history of hay fever, which has, until now, been dealt adequately with chlorphenamine tablets. Her symptoms have worsened over a period of a few days and she is now wheezing. It seems unlikely that she has a chest infection, which could have been a possible cause of the symptoms. She should be referred to the doctor at once since her symptoms suggest more serious implications such as asthma.

The doctor’s view

This woman should be referred to her doctor directly. She almost certainly has seasonal asthma. In addition to the hay fever treatment recommended by her pharmacist, it is likely that she would benefit from a steroid inhaler such as beclometasone. Depending on the severity of her symptoms, she would probably be prescribed a beta-agonist, such as a salbutamol inhaler, as well. This consultation is a complex one for a doctor to manage in the usual 10 min available in view of the time required for information-giving, explanation about the nature of the problem, the rationale for the treatments and the technique of using inhalers.

A young man presents in late May. He asks what you can recommend for hay fever. On questioning, he tells you that he has not had hay fever before, but some of his friends get it and he thinks he has the same thing. His eyes have been itching a little and are slightly watery, and he has been sneezing for a few days. His nose has been runny and now feels quite blocked. He will not be driving, but is a student at the local sixth-form college and has exams coming up next week. He is not taking any medicines.

The pharmacist’s view

This young man is experiencing the classic symptoms of hay fever for the first time. The nasal symptoms are causing the most discomfort; he has had rhinorrhoea and now has congestion, so it would be reasonable to recommend a corticosteroid nasal spray, provided he is aged 18 years or over. If he is under 18 years, an oral or topical antihistamine could be recommended, bearing in mind that he is sitting for exams soon and so any preparation that might cause drowsiness is best avoided. His eyes are slightly irritated, but the symptoms are not very troublesome. You know that he is not taking any other medicines, so you could recommend acrivastine, loratadine or cetirizine. If the symptoms are not better in a few days, he should see the doctor.

The doctor’s view

A corticosteroid nasal spray is likely to be more effective. If he cannot use the OTC product because he is under 18 years, acrivastine (Benadryl), loratadine (Claritin) or cetirizine (Zyrtec) would be worth a try. Even though they are generally non-sedating, they can cause drowsiness in some patients. The student should be advised not to take his first dose just before the exam. If his symptoms do not settle, then referral is appropriate. He may benefit from sodium cromoglicate eye drops if his eye symptoms are not fully controlled by the antihistamine. It is often worthwhile trying an older antihistamine as an alternative because some people are unaffected by the sedative properties.