CASE 38

A 32-year-old woman comes to your office during the height of the spring pollen season complaining of sneezing and congestion. She gets these symptoms every year. Her nose runs constantly, her eyes water and itch, and she sneezes. She is only getting partial relief from oral antihistamines. She asks if there is anything else that she can do for her allergies. On examination she has red, irritated conjunctiva with clear eye drainage and periorbital discoloration (“allergic shiners”). Her nasal mucosa is boggy and appears congested. You agree with her diagnosis of seasonal allergic rhinitis and prescribe a corticosteroid nasal spray to be used along with her oral antihistamine.

How long does it take to see the full effect of nasal steroids?

What are the common side effects of nasal steroids?

ANSWERS TO CASE 38:

Rhinitis and Cough Medications

Summary: A 32-year-old woman with seasonal allergic rhinitis is prescribed nasal steroid medication to take together with her antihistamine.

Length of time until maximal effect of nasal steroids: 1–2 weeks.

Common side effects: Nasal burning, throat irritation, nose bleeds.

CLINICAL CORRELATION

The mechanism of action of nasal steroids for allergic rhinitis is not entirely Known; however, it does reduce allergic inflammation by downregulating the transcription and activity of cytokines. Corticosteroids have a wide range of activity on many inflammatory mediators, including histamine, cytokines and leukotrienes, and cell types such as mast cells, eosinophils, and macrophages, which are involved in allergic symptoms. Nasal steroids are effective at reducing the congestion, rhinitis, and sneezing associated with seasonal and environmental allergies. They require treatment for up to 2 weeks before maximal benefit is seen. For that reason it is recommended that they be used on a daily, not an as needed, basis. The adverse effects of nasal steroids are primarily a result of local effects, because they are not largely systemically absorbed. These include nasal burning and bleeding and throat irritation.

Histamine (H₁-receptor) antagonists are also widely used for allergic rhinitis and may be used in combination with nasal steroid medications. Antihistamines alone are less effective than nasal steroids. H₁-receptors are membrane bound and coupled to G-proteins. Their activation leads to increased phospholipase C activity, with increases in diacylglycerol and intracellular Ca²⁺. The net effect of this in blood vessels is vasodilation and increased permeability, which clinically contributes to the mucosal swelling and congestion seen in allergic rhinitis. The H₁-receptor antagonists, therefore, cause vasoconstriction and decreased permeability, thereby decreasing these symptoms.

APPROACH TO:

Pharmacology of Drugs Used to Treat Rhinitis and Cough

OBJECTIVES

1. Understand the characteristics of rhinitis and cough.

2. List the drugs used for rhinitis, their mechanisms of action, and adverse effects.

3. Know the agents used to treat cough, their mechanisms of action, and adverse effects.

DEFINITIONS

Rhinitis: Inflammation of the mucus membranes of the nose.

Allergic conjunctivitis: An inflammatory condition of the conjunctiva secondary to an allergic stimulus. Common symptoms include itchy, red, and tearing eyes.

DISCUSSION

Class

Rhinitis is caused by increased mucus production, vasodilation, and increased fluid accumulation in mucosal spaces. Inflammatory mediators including histamine, leukotrienes, interleukins, prostaglandins, and kinins are responsible for these effects. Increased production of these mediators can be provoked by an allergic response, or a bacterial or viral infection.

Allergic rhinitis affects 20 percent of the adult population and up to 40 percent of children. The hallmark of allergic rhinitis is an IgE-mediated inflammatory response. Antihistamines, anticholinergics, intranasal corticosteroids, and chromones have proven to be useful in treating allergic rhinitis.

Both first- and second-generation histamine H₁-receptor blockers (see Case 24) are useful in treating acute allergic rhinitis, but their long-term benefits are questionable. First-generation agents, including diphenhydramine, cyclizine, and chlorpheniramine, have been shown to reduce sneezing, nasal congestion, and nasal itching. Second-generation agents, including fexofenadine, cetirizine, and loratadine, have comparable efficacy and significantly fewer adverse effects such as sedation and dry mouth. Second-generation antihistamines effectively reduce all seasonal allergic rhinitis symptoms in children, but dosages must be appropriately reduced. Following oral administration, effects are seen with antihistamines in 1–2 hours. The most common adverse effects seen with the second-generation agents are headache, back pain, and cough.

Inhaled nasal corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone acetonide are useful for long-term management of allergic rhinitis. This route of administration reduces the frequent adverse effects associated with systemic administration of corticosteroids. Corticosteroids are potent anti-inflammatory agents and reduce both the production of inflammatory mediators (cytokines, leukotrienes, and prostaglandins) and cellular components (mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils). The major adverse effects seen with inhaled corticosteroids are pharyngitis and an increased risk of upper respiratory tract infections.

The chromones, cromolyn and nedocromil, have also been used to treat allergic rhinitis. These agents are administered by inhalation and are poorly absorbed into the systemic circulation. Their major action is to reduce the activity of a number of chloride channels that are important in the release of mediators such as histamine. The major adverse effects of these agents are bronchospasm, cough, and nasal congestion (which can be severe); less frequent adverse effects include anaphylaxis, dizziness, and anemia.

Nasal decongestants are α-adrenoreceptor agonists that reduce the discomfort of allergic rhinitis, and to a lesser extent congestion associated with the common cold or flu, by decreasing the volume of nasal mucosa and causing vasoconstriction of capacitance vessels in the nasal passages. The most common α-adrenergic agent used as a decongestant is pseudoephedrine (a stereoisomer of ephedrine), which acts directly on α₁-adrenoreceptors. Because of the potential for psuedoephedrine to be converted into methamphetamine, it is being replaced by the slightly less effect phenylephrine. Ephedrine has largely been discontinued as a decongestant because it has significant central nervous system (CNS) effects. A major limitation in the use of these agents is rebound hyperemia and worsening of symptoms that often occurs with chronic use or after discontinuation. Oxymetazoline is an inhaled adrenergic agonist that can be used for no more than 3 days to alleviate nasal congestion. Nasal decongestants should be used with caution in patients with hypertension.

The leukotriene receptor antagonist, montelukast, is an oral agent that also is effective in the treatment of allergic rhinitis.

Cough and Antitussives Cough is produced by the cough reflex, which is integrated in the cough center in the medulla. The initial stimulus for cough arises in the bronchi where irritation causes bronchoconstriction. Stretch receptors in the trachea and bronchial tree monitor the state of this bronchoconstriction and send vagal afferents to the cough center that trigger the cough reflex. Agents that have antitussive activity act either to relieve the bronchoconstriction or reduce the activity of the cough center.

Codeine and hydrocodone are opioid congeners that are used as antitussives. Cough suppression occurs at lower doses than required for analgesia. The exact mechanism of the antitussive activity of the opioids is unclear because isomers devoid of binding to classic receptors still display antitussive activity. Both codeine and hydrocodone are available as syrups for oral administration.

Dextromethorphan is the d-isomer of the codeine analog methorphan. It is the most common antitussive agent prescribed. It has no analgesic or addictive properties and does not act through the classic opioid receptors. Binding sites for dextromethorphan have been identified in membrane preparations from various parts of the brain, but it is still unclear whether they mediate the antitussive actions of the drug.

β-Adrenergic agonists have been shown to reduce cough without having any significant central effects. This action is likely mediated within the bronchi and reduces vagal afferent signals to the cough center.

Benzonoate is a tertracaine congener that acts peripherally as an anesthetic on respiratory stretch receptors to achieve its antitussive effects. Guaifenesin is an expectorant that stimulates respiratory tract secretions, thereby decreasing mucus viscosity.

COMPREHENSION QUESTIONS

38.1 Pseudoephedrine is used to treat nasal congestion because of which of the following?

A. It is an α₁-adrenergic agonist.

B. It is an α₂-adrenergic agonist.

C. It inhibits leukotrienes.

D. It inhibits the production of IgE.

38.2 A 34-year-old man complains of nasal congestion and a “runny nose.” Which of the following would be the best for long-term management of a patient with allergic rhinitis?

A. Diphenhydramine

B. Inhaled glucocorticoids

C. Oral glucocorticoids

D. Oral pseudoephedrine

38.3 A 24-year-old man is taking two medications to help with the symptoms of allergic rhinitis. He is noted to have a blood pressure of 150/70 mm Hg. The clinician notes that one of the medications may be responsible for the new-onset hypertension. The most likely etiology is which of the following?

A. Inhaled chromone

B. Inhaled glucocorticoids

C. Oral diphenhydramine

D. Oral pseudoephedrine

ANSWERS

38.1 A. Pseudoephedrine is the most common agent used today as a decongestant. It is a directly acting α₁-sympathomimetic agent.

38.2 B. Systemic glucocorticoids cause too many adverse effects; pseudoephedrine acts primarily only on nasal congestion; diphenhydramine is not useful for long-term management.

38.3 D. Pseudoephedrine has activity on the α₁-adrenergic receptor, causing vasoconstriction to the nasal mucosa. Hypertension may also be seen at times.

PHARMACOLOGY PEARLS

The hallmark of allergic rhinitis is an IgE-mediated inflammatory response.

Antihistamines are useful for treating symptoms of acute rhinitis, but their long-term benefit is questionable.

Pseudoephedrine has activity on the α,₁-adrenergic receptor, causing vasoconstriction to the nasal mucosa.

REFERENCES

Gentile DA, Friday GA. Management of allergic rhinitis: Antihistamines and decongestants. Immunol Allergy Clin North Am. 2000;20:355.

Morice AH, Fontana GA, Sovijarvi AR, et al. The diagnosis and management of chronic cough. Eur Respir J. 2004;24:481.

Nayak A, Langdon RB. Montelukast in the treatment of allergic rhinitis: an evidence-based review. Drugs. 2007;67:887.

Ressel GW, Agency for Healthcare Research and Quality. AHRQ (agency for healthcare research and quality) releases review of treatments for allergic and nonallergic rhinitis. Am Fam Physician. 2002;66:2164, 2167.

Seth D, Secord E, Kamat D. Allergic rhinitis. Clin Pediatr (Phila) 2007;46:401–7.

Simmons FE. Advances in H₁-antihistamines. N Engl J Med. 2004;351:2203.

Storms WW. Pharmacological approaches to daytime and nighttime symptoms of allergic rhinitis. J Allergy Clin Immunol. 2004;114:S146.