Topical application

Topical sympathomimetic decongestant sprays or drops produce results faster than oral applications. However, repeated use of these agents can cause a vicious cycle of increased secretions and nasal edema as the effect of the agent fades. This condition is referred to as rebound congestion and can cause the patient to become addicted to the agent and use it repeatedly. Nasal vasoconstriction does not occur, and the nasal mucosa actually swells.

Systemic application

Systemic, as compared with topical, application has the advantage of giving more extensive decongestant effects involving deeper blood vessels. However, producing nasal vasoconstriction through systemic routes often leads to other systemic effects of sympathomimetics, such as an increase in blood pressure and increased heart rate.

Effect of histamine

Histamine is an important mediator of local inflammatory responses causing effects such as smooth muscle contraction, increased capillary permeability and dilation, itching, and pain. Scraping a tongue depressor or blunt pencil across the sensitive skin of the inner arm can illustrate a local inflammatory reaction at least partly mediated by histamine. The result is a wheal and flare reaction, also called a “triple response” (local redness, welt formation, and a reddish white border). The redness and wheal (welt) are caused by dilation and leakage of plasma proteins from skin capillaries. The exudation of plasma causes the swelling. The flare, or reddish white area surrounding the wheal, is probably due to local axon reflexes from sensory fibers causing dilation of neighboring arterioles.

Histamine receptors

Histamine produces its inflammatory effects by stimulating specific cell surface receptors. Three types of histamine (H) receptors have been discovered. Two of the receptors are distinguished in mediating local inflammatory responses. The three histamine receptors are as follows:

The typical antihistamine found in cold medications is an H₁-receptor antagonist. Examples of these are pyrilamine and chlorpheniramine. H₁-receptor antagonists block the bronchopulmonary and vascular actions of histamine, to prevent rhinitis and urticaria.⁴ H₂-receptor antagonists are used to block gastric acid secretion when treating ulcers. Examples of H₂-receptor antagonists are cimetidine (Tagamet) or ranitidine (Zantac).

Antihistamine agents

All of the antihistamines discussed in this chapter are H₁-receptor antagonists. These antihistamine agents are classified further into the major groups listed in Table 15-3. The first five groups of antihistamines listed in Table 15-3 all are first-generation agents and can be found in cold preparations. Some of the brand names given may be familiar from OTC preparations readily available in drugstores. Others are found in combination products; these are discussed and listed subsequently. Second-generation antihistamines, which are longer acting and nonsedating, are also listed in Table 15-3.

Effects of antihistamines

Antihistamines have three major classes of effects: antihistaminic, sedative, and anticholinergic activity. Second-generation agents are selective for H₁ receptors and are less sedating than first-generation agents. Antihistaminic activity blocks the increased vascular permeability, pruritus, and bronchial smooth muscle constriction caused by histamine. These actions are the reason antihistamines are used to treat allergic disorders such as rhinoconjunctivitis, allergic rhinitis, and urticaria.

The sedative effect of antihistamines is thought to be caused by penetration of the agents into the brain, where inhibition of histamine N-methyltransferase and blockage of central histaminergic receptors occurs. There is also antagonism of other CNS receptors, such as serotonin and acetylcholine.² The effect of drowsiness with first-generation (older) antihistamines can be a major hazard if alertness is required, such as in operating heavy machinery (e.g., a car) or monitoring a patient. This effect can be so pronounced that diphenhydramine HCl is added to acetaminophen in Tylenol PM, and the compound is described as a nonprescription sleep aid.

Finally, the anticholinergic effect produces considerable upper airway drying, just as would occur with an antimuscarinic agent such as atropine sulfate. In addition, effects seen with cholinergic blockade may occur, including CNS effects of stimulation, anxiety, and nervousness and peripheral effects of dilated pupils, blurred vision, urinary retention, and constipation.³ These effects are less likely in occasional use with a cold, but they may be significant with greater use (and dose) for allergic rhinitis or other conditions (e.g., urticaria).

The duration of action of older antihistamines is generally 4 to 6 hours. However, newer, second-generation agents, often termed “nonsedating,” are effective for 12 hours or more, depending on dose, and lack the sedating and anticholinergic effects. Examples of these newer agents are fexofenadine (Allegra) and cetirizine (Zyrtec) (see Table 15-3). Second-generation agents have little affinity for muscarinic cholinergic receptors and therefore do not cause dry mouth or gastrointestinal side effects. They also lack antiserotonin activity and do not cause appetite stimulation and weight gain, although astemizole and ketotifen may differ in this.³ These newer drugs may inhibit mediator release from allergic inflammatory cells, in addition to blocking the histamine receptor. Allergic symptoms of sneezing and rhinorrhea are equally well controlled with first-generation and second-generation H₁ antagonists.³

Structure-activity relationships

H₁-receptor antagonists were first discovered in 1937.⁴ The chemical structure of histamine, the general structure of H₁-receptor antagonists, and two examples of H₁-receptor antagonists are shown in Figure 15-2. Chlorpheniramine is an antihistamine found in many cold remedies; it represents one of the older, classic H₁-receptor antagonists. Fexofenadine is a newer, nonsedating H₁-receptor antagonist.

The resemblance between histamine and the general formula for the H₁-blocking agents can be seen in the structures shown. In older agents, exemplified by chlorpheniramine, R₁ and R₂ attachments are usually a ring structure connected to an ethylamine (C–C–N) group. The presence of the ring structures and other substitutions on the structure makes older antihistamines lipophilic. As a result, classic first-generation antihistamines readily penetrate into the CNS and produce the effect of sedation and drowsiness previously discussed. Newer, nonsedating agents, such as terfenadine, do not readily cross the blood-brain barrier and therefore do not block central H₁ receptors.⁴

Use with colds

A beneficial effect of antihistamine use with a cold is the drying of upper airway secretions, which lessens the rhinitis and accompanying sneezing. There is some question whether the drying of secretions is due to histamine antagonism or to the anticholinergic effect of these agents. How much histamine release occurs with colds is debated. In allergic rhinitis, there is no question that histamine causes much of the inflammatory response, and the newer long-acting agents are particularly helpful with this condition. Blockade of H₁ receptors prevents the histamine contribution to the symptoms of nasal itching, congestion, sneezing, rhinorrhea, and ocular irritation.

Regardless of the exact effect, the drying of runny nasal secretions is welcomed by individuals with a cold, and the drying of secretions coupled with drowsiness can be useful to produce needed rest and sleep at night. Secretions, however, are a defense mechanism with an upper airway viral infection. Antihistamines may cause harm as a result of suppressed secretion clearance and impacted secretions with sinus blockage.⁴ Adequate hydration with a cold is always helpful, with or without use of antihistamines.

An alternative to antihistamines for rhinorrhea in a cold is the anticholinergic nasal spray ipratropium bromide (Atrovent), which is discussed in Chapter 7. Ipratropium has been shown to be effective in reducing nasal discharge in viral infectious rhinitis (colds) and allergic and nonallergic rhinitis.⁵ There is no evidence of rebound congestion, mucosal irritation, or significant systemic effects. Ipratropium can be effective for 4 to 8 hours. An anticholinergic agent applied topically offers an attractive alternative to vasoconstricting decongestants and antihistamine H₁ antagonists.

Treatment of seasonal allergic rhinitis

Second-generation H₁-receptor antagonists are more useful in the treatment of seasonal allergic rhinitis and other disorders requiring antihistamine treatment than in the treatment of colds. They are also better tolerated in treating allergic rhinitis than the first-generation agents because side effects of drowsiness are minimal, and duration of action is longer. Agents such as astemizole, loratadine, fexofenadine, and cetirizine are indicated for use in seasonal allergic rhinitis and chronic urticaria. They are intended to relieve symptoms of sneezing; rhinorrhea; itchy nose, palate, and throat; itchy, watery eyes; and pruritus. Table 15-4 lists categories and examples of agents used in the treatment of seasonal allergic rhinitis.⁶ Other uses of antihistamines include the treatment of symptoms seen with motion sickness and control of nausea.

Efficacy and use

There is controversy over the effectiveness and use of expectorants. The issue is clouded by the following:

Use in chronic bronchitis

Petty⁷ reported the results of a national study evaluating use of the expectorant iodinated glycerol (Organidin). Patients had chronic bronchitis, which is quite different from a common cold. The study concluded that in chronic obstructive bronchitis, iodinated glycerol was safe and effective. Its use improved cough symptoms, chest discomfort, ease in bringing up sputum, and sense of well-being. The duration of acute exacerbations of chronic bronchitis was decreased. It is reasonable that in bronchitis, symptoms and airflow improve and further infection is reduced if mucus clearance can be improved. However, Rubin and associates⁸ found no change in lung function or sputum in patients with chronic bronchitis.

Irwin and colleagues⁹ published evidence-based guidelines in the diagnosis and management of cough. The guidelines cover acute and chronic cough and specific diseases such as chronic bronchitis and cystic fibrosis. The specific guidelines can be accessed at http://www.chestjournal.org/cgi/content/full/129/1_suppl/1S.

Mode of action

Stimulant expectorants are thought to work by various means, depending on the agent. The mechanisms include the following:

Guaifenesin, also known as glycerol guaiacolate, is classified as a category I agent, which is safe and effective.¹⁰ Ziment¹¹ reviewed the mechanisms of action with iodides, such as iodinated glycerol. Other agents, such as terpin hydrate, sodium citrate, ammonium chloride, and menthols, have no demonstrated efficacy.¹⁰

Because mucus incorporates water as it is produced, an adequate intake of plain water or other nondiuresing liquids (milk, fruit juices) can help preserve normal mucus viscosity and clearance, especially with a simple cold.

Expectorant agents

Table 15-5 lists available expectorant agents. Major agents or groups of agents are briefly characterized.

Agents and mode of action

Cough suppressants act by depressing the cough center in the medulla. Narcotics (see Chapter 20) exert powerful depressant effects on the medullary centers, including the carbon dioxide chemoreceptors, and are often used for this purpose. Common agents are codeine or hydrocodone. A commonly used nonnarcotic is dextromethorphan.

Benzonatate (Tessalon), a nonnarcotic, is chemically related to the local anesthetic tetracaine and anesthetizes stretch receptors in the lungs and pleura; this inhibits the cough reflex at its source. There is no inhibitory effect on the CNS. The effect begins in 15 to 20 minutes and lasts 3 to 8 hours.¹⁵ The antihistamine diphenhydramine (Benadryl), available as a syrup, in liquid form, and in combination with other products, may be an effective cough suppressant. Diphenhydramine is becoming more common in products because of increased abuse of dextromethorphan. It should be noted that individuals taking any agent with diphenhydramine should be warned of the effect of drowsiness.

Some cough suppressants, or antitussives, contain codeine. In a dose less than 15 mg, codeine does not produce analgesia in an adult. In the 10- to 20-mg range, there is an antitussive action. At doses greater than 30 mg, codeine produces analgesia. Hydrocodone produces an antitussive effect with a dose of approximately 5 mg. Box 15-1 lists common antitussive agents, many of which are used in cold compounds. Both dextromethorphan and codeine are available in OTC preparations. These two agents are considered to be preferred cough suppressants based on safety and efficacy. The need for a prescription antitussive is unusual, especially in a cold, with the availability of OTC preparations.

Use of cough suppressants

Several principles apply to the use of antitussives, as follows:

The combination of expectorant and antitussive is based on the rationale that a dry, hacking, frequent cough can be better replaced by a less frequent but productive cough. It can be questioned whether this is needed in an uncomplicated cold. Also, many cold compounds combine an antihistamine to dry secretions with an expectorant to stimulate mucus production. The rationale for this is questionable.

Treating a cold

There is no cure for the common cold, and the four classes of drugs used in cold remedies treat only symptoms. Their potentially undesirable effects should be considered:

A combination of all four classes of drugs in one compound does not allow acute or occasional use of the sympathomimetic for decongestion, nocturnal use of antihistamines, and separate use of an expectorant or antitussive, as indicated by symptoms. Single-entity cold medications, such as Sudafed for decongestion or Delsym for cough suppression, are available to treat specific symptoms based on the principles outlined. Fluids and rest remain a basic and rational approach to managing colds and preventing spread of the rhinovirus, but this approach is probably the least feasible for current lifestyles.