HEALTH AND MEDICAL PRODUCTS:DECONGESTANTS

DECONGESTANTS

Several of the bones located within the skull contain air-filled chambers known as sinuses. These sinuses lighten the various skull bones and are lined by a specialized mucus membrane epithelium, which produces mucus that helps to moisten and clean the air in and around each sinus. Specifically, the nasal complex includes the bones that enclose the nasal cavities and the paranasal sinuses. The paired paranasal sinuses (e.g., maxillary, ethmoidal, frontal, palantine, and sphenoidal) all drain their mucus secretions directly (or indirectly in the case of the palantine) into the nasal (nose) cavity. The mucus within the nasal cavity allows inhaled air to become warmed and humidified and also provides a “sticky” medium for dust or microorganisms to become trapped. The movement of the cilia (cellular membrane extensions located within the nasal cavity epithelial lining) usually passes the mucus backward toward the throat, where it is eventually swallowed into the digestive system. Thus, this drainage system normally protects the fragile respiratory tract from exposure to foreign particulate matter.

Sinus congestion (also referred to as “nasal congestion” or “rhinitis”) involves the blockage of one or more of the five pairs of paranasal sinus passageways in the skull. The blockage may result from inflammation and swelling of the nasal tissues, obstruction by one of the small bones of the nose (e.g., in the case of a deviated septum), or the presence of excess mucus (e.g., decreased ciliary activity). While acute (short-term) sinus congestion is frequently caused by the common cold virus (e.g., rhinovirus), chronic (long-term) sinus congestion usually results from exposure to environmental irritants such as tobacco smoke, food allergens, inhaled allergens, or foreign matter within the nasal cavity. Sinus congestion impairs the flow of mucus within the sinuses and further pre- disposes individuals to secondary bacterial infections that usually cause sinusitis. Sinusitis is an inflammation of the sinuses. The inflammatory response process involves the release of numerous inflammatory chemicals into the extracellular fluid space around cells. The liberated chemicals promote dilation (an increase in diameter) of small blood vessels in the vicinity, increase the permeability of local blood capillaries, and cause exudate (fluid-containing proteins) to seep from the bloodstream into the tissue spaces. The presence of the exudate then causes local edema, or swelling. As the swelling occurs, the drainage passageways narrow, the movement of mucus slows, congestion increases, and the individual experiences headaches and a feeling of pressure within the facial bones.

The sympathetic nervous system is a subdivision of the autonomic nervous system (or visceral motor system), which provides automatic, in- voluntary regulation of smooth muscle, cardiac muscle, and glandular activity or secretions. Sympathetic nerve fibers reach the nasal mucosa, and when stimulated, sympathetic nerve terminals release norepinephrine, which binds to and activates two types of adrenergic receptors [e.g., and a.2; receptors activated by adrenaline(epinephrine)], or substances with similar activity, on the vascular smooth muscle fibers. a.1 receptors tend to be concentrated on postcapillary venules, which act as capacitance vessels, and decrease mucosal and blood volume when activated.

receptors are concentrated on precapillary arterioles and decrease mucosal capillary blood flow when activated. Thus, when a.-adrenergic receptors in the mucosa of the upper respiratory system (e.g., within the paranasal sinuses) are stimulated, there is vasoconstriction (decrease in the diameter of blood vessels) of the mucosal capillaries, with additional shrinkage of swollen mucosal tissue. Drugs that target these adrenergic receptors produce effects similar to those produced by natural stimulation of the sympathetic nervous system. These drugs are referred to as being “sympathomimetic,” as they mimic the effects of stimulating post- ganglionic adrenergic sympathetic nerves.

Nasal decongestants are adrenergic sympathomimetic drugs that allow for vasoconstriction within the parasinus mucosal lining, thereby causing a decrease in swelling, release of exudate, and airway obstruction. Decongestants act to provide relief by stimulating the a.-adrenergic receptors of the vascular smooth muscle, constricting the dilated arteriolar network within the nasal mucosa, reducing blood flow in the engorged swollen nasal area, and thereby improving ventilation within the nasal cavity. Both topical (e.g., nasal spray) and oral forms of over-the-counter decongestants are currently available. Topical decongestants act as potent a.-adrenergic agonists (stimulants) that constrict blood vessels within the nasal mucosal lining, causing a decrease in swelling and improved mucus drainage. Active ingredients in such topical decongestants include oxymetazoline hydrochloride, xylometazoline hydrochloride, propylhexedrine, and phenyl- ephrine hydrochloride. Oxymetazoline hydrochloride (3-[(4,5-dihydro- 1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethylphenol hydro- chloride; C16H24N2O·HCl) and xylometazoline hydrochloride (2-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]methyl]-4,5-dihydro-1H-imidazole hydrochloride; C16H24N2·HCl) are both sympathomimetic imidazoline derivatives. These two drugs are often the active ingredients of long-acting (twelve-hour) nasal sprays, which are recommended for use no longer than three consecutive days. Chronic use of such products, and thus continuous sympathetic tone, creates a certain level of vasoconstriction and relief from swollen nasal tissues; however, constant sympathetic stimulation triggers the brainstem to produce the nasal cycle, leading to a re- bound of nasal congestion and stuffiness. This may then lead the individual to continue using the spray long after the recommended duration, which can lead to drug dependency. It is the prolonged stimulation of a.2- adrenergic receptors that is theorized as a mechanism for this rebound

effect. Interestingly, oxymetazoline hydrochloride is thought to be such an a2 receptor agonist. Other sympathomimetic imidazoline derivatives, including naphazoline and tetrahydrozoline, also act as potent vasocon- strictors and may be found as active ingredients within both nasal decongestant formulations and eyedrop redness-relief treatments. Propylhexedrine (1-cyclohexyl-2-methylaminopropane;C10H21N), a sympathomimetic amine, also acts as an a-adrenergic agonist. Structurally related to the central nervous system stimulant amphetamine [a synthetic compound patterned after the chemical structure of naturally occurring epinephrine(adrena- line)], propylhexedrine replaced amphetamine in popular nasal inhalers starting in 1949 as a drug with weaker stimulant properties.

Phenylephrine hydrochloride ((-)-m-hydroxy-a-[(methylamino)methyl] benzyl alcohol hydrochloride; C9H13NO2·HCl) is an active vasoconstric- tor ingredient in both topical and oral over-the-counter decongestants. Chemically related to epinephrine and ephedrine, this drug is a synthetic sympathomimetic amine that is considered a relatively selective a1- adrenergic agonist. Pseudoephedrine hydrochloride ([S-(R*,R*)]-a-[1- methylamino)ethyl]benzene methanol hydrochloride; C10H15NO·HCl), an active ingredient of oral decongestants, is an a-adrenergic receptor agonist (sympathomimetic) that produces vasoconstriction by stimulat- ing a-receptors within the mucosa of the respiratory tract and also by causing the release of norepinephrine from storage sites. Pseudoephe- drine shrinks swollen mucus membranes, reduces exudate release and nasal congestion, and thereby increases normal nasal airway exchange. Drainage of sinus secretions is increased, and any mucus obstruction within the eustachian tube (the tube connecting the middle ear to the throat) is alleviated. A physiologically active stereoisomer of ephedrine, the vasoconstriction action of pseudoephedrine is similar to that of ephedrine but produces comparatively less tachycardia (increased heart rate), increased blood pressure, and central nervous system stimulation. After the oral administration of pseudoephedrine, nasal decongestion usually occurs within thirty minutes and persists for four to six hours. Systemic administration of decongestants eliminates possible damage to the nasal mucosa compared with the use of nasal decongestant sprays.