Drugs that reduce the effects mediated by histamine, a chemical released by the body during allergic reactions. Antihistamines are often administered to reduce secretions (e.g., runny nose and sneezing), but they can cause drowsiness and impaired responses. Note: Drying of secretion, whether caused by antimuscarinic or antihistamine action, may suppress a needed defense reaction of the airways. Nocturnal use is indicated more than around-the-clock use.

Antitussives

Drugs that suppress the cough reflex. Note: Productive coughs should not be suppressed; the logic of an expectorant-antitussive combination is questionable.

Common cold

Nonbacterial respiratory tract infection, generally caused by a viral infection of the epithelial layer of the upper airway and characterized by malaise, low-grade fever, cough, sneezing, and a runny nose.

Expectorants

Drugs that increase the stimulation of mucus. Many have questionable efficacy in a cold. The best expectorant, especially with colds, is plain water and juices, avoiding caffeinated beverages such as tea or colas and beer or other alcoholic mixtures.

Flu

Nonbacterial infection with rapid onset of symptoms, including fever, headache, and fatigue.

Mucokinesis

Therapeutic movement of excessive or abnormal secretions from the respiratory tract.

Mucolytic expectorants

Agents that facilitate removal of mucus by a lysing, or mucolytic, action. Example: dornase alfa.

Stimulant expectorants

Agents that increase the production and presumably the clearance of mucus secretions in the respiratory tract. Example: guaifenesin.

Sympathomimetics

Drugs that partially or completely mimic the effects of the sympathetic nervous system. Note: Tremor, tachycardia, and increased blood pressure can occur with their use, especially when taken orally. Rebound congestion can occur if used for longer than a day.

Bewildering and in some cases irrational numbers of compounds, both prescription and over-the-counter (OTC), are available for treating symptoms of the common cold. The term “common cold” is used to describe nonbacterial upper respiratory tract infections (URIs), usually characterized by a mild general malaise and a runny, stuffy nose. Other symptoms include sneezing, possible sore throat, cough, and possibly some chest discomfort. Allergic rhinitis and serious illnesses such as influenza, acute bronchitis, and infections of the lower respiratory tract are not included in this discussion. Influenza, or the “flu,” caused by the influenza virus is associated with symptoms of fever, headache, general muscle ache, and extreme fatigue or weakness. Onset of symptoms is usually rapid. The fever and systemic symptoms of influenza are contrasted with symptoms of the common cold in Table 15-1.

TABLE 15-1

Differences in Symptoms between the Common Cold and Influenza

SIGNS AND SYMPTOMS	COLD	INFLUENZA
Fever	Rare	Typical, high
Chills	None	Typical
Cough	Present, hacking	Nonproductive, may be severe
Headache	Rare	Prominent
Fatigue	Mild	Early and severe
Myalgia	None or slight	Usual, may be severe
Nasal congestion	Common	Occasional
Sneezing	Common	Occasional
Sore throat	Common	Occasional

Four classes of agents can be distinguished in cold remedies, used individually or in combination, as follows:

• Sympathomimetics: For decongestion

• Antihistamines: To reduce (dry) secretions

• Expectorants: To increase mucus clearance

• Antitussives: To suppress the cough reflex

The above-listed four classes of cold medications target the primary symptoms caused by the cold virus in the respiratory tract; this is illustrated conceptually in Figure 15-1. Each class is discussed briefly, with representative agents listed. In addition to these four types of ingredients, an analgesic such as acetaminophen may be included, as in Sinutab, which consists of 30 mg of pseudoephedrine (decongestant) and 325 mg of acetaminophen (analgesic).

Figure 15-1 Cold medications include four classes of drugs, targeted at the symptoms produced by this upper respiratory viral infection, along with analgesics.

Sympathomimetic (adrenergic) decongestants

! KEY POINT

Adrenergic agents act to vasoconstrict and relieve nasal congestion.

Sympathomimetic (adrenergic) agents are discussed as bronchodilators in Chapter 6, and the general effects of sympathetic stimulation are outlined in Chapter 5. In cold remedies, sympathomimetics are intended for a decongestant effect, which is based on their α-stimulating property and resulting vasoconstriction.

Sympathomimetics such as pseudoephedrine are found under brand names such as Sudafed and Dimetap and can be taken orally. As a result of changes in the U.S. Patriot Act, single agents or combination drugs using pseudoephedrine are placed behind the counter in pharmacies and regulated sales are documented because the drug has been overpurchased for use in the illegal production of methamphetamines. Manufacturers have turned to phenylephrine as a substitute; however, the 10-mg dose that has been approved by the U.S. Food and Drug Administration (FDA) has little effect on nasal decongestion when used orally because of the drug’s high first-pass effect. In a meta-analysis by Hatton and associates,¹ it was found that 10 mg of phenylephrine was no more effective than placebo. Oxymethazoline, a sympathomimetic with brand names such as Afrin and Vicks Sinex, can be used topically for the nasal mucosa. Topical applications generally require lower dosages than oral use. Problems can occur with either route of administration. Table 15-2 lists sympathomimetic agents used as nasal decongestants in cold remedies.

TABLE 15-2

Examples of Adrenergic Agents Used as Nasal Decongestants

DRUG	ROUTE
Phenylephrine (Sudafed PE)	Topical, oral
Pseudoephedrine HCl (Sudafed, various)	Oral
Pseudoephedrine sulfate (Afrinol)	Oral
Xylometazoline (Otrivin)	Topical
Naphazoline (Privine)	Topical
Tetrahydrozoline (Tyzine)	Topical
Oxymetazoline (Afrin)	Topical

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.

Antihistamine agents

Histamine occurs naturally in the body and is contained in tissue mast cells and blood basophils. The role of the mast cell in releasing histamine with allergic asthma is discussed in Chapters 11 and 12.

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:

1. H₁ receptors: Located on nerve endings and smooth muscle and glandular cells. H₁ receptors are involved in inflammation and allergic reactions, producing wheal and flare reactions in the skin, bronchoconstriction and mucus secretion, nasal congestion and irritation, and hypotension in anaphylaxis.²

2. H₂ receptors: Located in the gastric region. H₂ receptors regulate gastric acid secretion and feedback control of histamine release.²

3. H₃ receptors: Located primarily in the central nervous system (CNS). H₃ receptors may be autoreceptors for cholinergic neurotransmission in the airway at the autonomic ganglia, involved in CNS functioning and feedback control of histamine synthesis and release.²^,³

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

! KEY POINT

Antihistamines dry secretions through an anticholinergic effect and by blockade of H₁ receptors.

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.

TABLE 15-3

Major Groups of Antihistamines with Representative Agents by Nonproprietary and Brand Names

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GROUP	DRUG
First Generation (Nonselective)
Ethanolamine derivatives	Diphenhydramine HCl (Benadryl)
	Clemastine (Tavist)
	Carbinoxamine
Piperazine	Hydroxyzine (Vistaril)
Piperidine derivatives	Cyproheptadine
Phenothiazine derivatives