Pharmacology of Cough and Cold Medicines

Decongestants 

The decongestants found in children’s OTC cold medication are either pseudoephedrine or phenylephrine. Systemic decongestants are adrenergic receptor agonists (sympathomimetics) that produce vasoconstriction within the mucosa of the respiratory tract, temporarily reducing the swelling associated with inflammation of the mucous membranes. Sympathomimetic drugs work on the α receptors in the vascular smooth muscle causing vasoconstriction and pressor effects and on the β-adrenergic receptors in the heart causing increased heart rate and force of contraction. Because of the cardiac effects, these agents should be used with caution in children with congenital heart disease, hypertension, or cardiac arrhythmias without consulting the patient’s pediatric cardiologist. Pseudoephedrine (Sudafed) and phenylephrine (Sudafed PE) may have mild central nervous system (CNS) stimulant effects in patients sensitive to sympathomimetics. Oral decongestants also should be used with caution in patients with hyperthyroidism and diabetes mellitus.

Topical decongestant products are applied topically to the nasal tissues via spray or drops. Topical decongestants stimulate the α-adrenergic receptors in the arterioles of the nasal mucosa, leading to vasoconstriction and shrinkage of nasal tissues. There is minimal systemic absorption if used as directed. Therapy should not exceed 3 to 5 days because of the development of rebound congestion with α-adrenergic receptor agents. If congestion persist, normal saline nose drops may be substituted for the vasoactive drugs for 3 to 5 days, then another trial of active drug may be attempted if necessary. Two topical decongestants currently are available OTC in the United States: phenylephrine (Neo-Synephrine) and oxymetazoline (Afrin).

The use of isotonic saline nose drops and gentle aspiration can be effective in the temporary relief of nasal obstruction in infants. Also useful is the general humidification of room air. Moisture tends to dilute tenacious nasal mucus so that it is easier to remove.

Cough Suppressants 

Dextromethorphan is the cough suppressant found in OTC cough medications, and it often is combined with the expectorant guaifenesin. Dextromethorphan, the D isomer of the codeine analogue levorphanol, acts centrally in the cough center in the medulla to suppress cough. Drowsiness, dizziness, nausea, and gastrointestinal upset also may be seen with dextromethorphan use.

Diphenhydramine, an antihistamine, also is marketed as a cough suppressant for children (PediaCare Children’s Long-Acting Cough). The exact mechanism of action of first-generation antihistamines antitussive effects is unknown, although it is thought that the CNS depression effects of first-generation antihistamines may depress respiratory reflexes, thus suppressing cough (McLeod et al., 1998).

Expectorants 

Guaifenesin is the most commonly prescribed oral mucolytic agent as an expectorant in the United States. Its mechanism of action is to reduce the surface tension and viscosity of the mucus, which increases the ease of expectoration. Respiratory mucus removal is facilitated by increased flow of the thinned secretions via ciliary action. Studies on the efficacy of guaifenesin have failed to demonstrate either improved pulmonary function or decreased sputum viscosity. Hence, its clinical usefulness is questionable.

Antihistamines 

Diphenhydramine, chlorpheniramine, and brompheniramine are the antihistamines found in children’s cold and allergy formulas. Antihistamines, also known as H1 receptor antagonists, compete for and block the action of histamine at the H1 receptor site on cells in the respiratory tract, gastrointestinal tract, and blood vessels. In the respiratory tract, antihistamines decrease congestion related to allergies.

Naclerio and colleagues (1988) studied the response of inflammatory mediators to induced viral infections. All variables except histamine grew stronger in direct relationship with the symptoms as the cold increased in severity. This finding indicates that antihistamines have no role in the treatment of the common cold; they will not shorten the period of symptoms. They are helpful, however, in the treatment of the symptoms of allergic rhinitis. Lastly, in young infants, sympathomimetic-antihistamine mixtures are particularly dangerous because they may cause respiratory depression.

Antipyretics 

Some multi-symptom cold formulas contain acetaminophen or ibuprofen as an antipyretic and analgesic. Acetaminophen acts centrally to inhibit the synthesis prostaglandins in the CNS and peripherally to block pain impulse generation. Antipyretic activity is due to its action against prostaglandin E2 in the CNS, which increases in fever (Aronoff & Neilson, 2001). Ibuprofen is a cyclo-oxygenase (COX) enzyme inhibitor. COX is needed for prostaglandin synthesis, and inhibiting COX leads to antipyretic activity because of decreased prostaglandin E synthesis in the CNS.

Lack of Evidence for Effectiveness of Cough and Cold Medications in Children 

Evidence is lacking for the effectiveness of cough and cold medications in children. A recent Cochrane review of the use of decongestants to treat nasal congestion associated with the common cold found a small (6%) but statistically significant improvement in congestion in adults (Taverner & Latte, 2007). The review found insufficient evidence in the literature regarding the effectiveness of decongestants to treat the common cold in children and recommended that decongestants not be used in children younger than 12 years (Taverner & Latte). A Cochrane review of the use of cough medications for acute cough in children found a lack of evidence for the use of OTC cough medications in children, including antitussives, expectorants, and antihistamines (Schroeder & Fahey, 2004). The American College of Chest Physicians evidence-based practice guidelines note limited efficacy of cough suppressants in patients with cough due to the common cold and do not recommend the use of cough suppressants for upper respiratory infections (Bolser, 2006). This guideline is consistent with the American Academy of Pediatrics (AAP) policy, which states there are no well-controlled scientific studies regarding the efficacy and safety of antitussives in children (AAP Committee on Drugs, 1997).

Safety of OTC Cough and Cold Medications in Infants and Children 

Concerns regarding the safety of cough and cold medications can be found in the scientific literature for at least 15 years. Case reports of infants presenting to the emergency department with OTC cold medication toxicity appear in Pediatrics as early as 1992, with the authors noting that in 1990, 1 in 15 calls to the Maryland Poison Center were regarding cough and cold medications (Gadomski & Horton, 1992). During 2004 and 2005, an estimated 1519 children younger than 2 years were treated in emergency departments for either overdose or other adverse event associated with cough and cold medications (Centers for Disease Control and Prevention [CDC], 2007).

In the past 5 years, multiple studies pointing to OTC cold medications as the cause of death in infants have been published. The Montgomery County Ohio Coroner reported a series of 10 infant deaths in 8 months with toxicology findings confirming the presence of ingredients found in OTC cold medications (Marinetti et al., 2005). The authors note toxicology reports confirm that combination cold products were administered by parents or caregivers in nine of the 10 infant deaths (Marinetti et al.). The Philadelphia Medical Examiners Office reported on a series of 15 deaths of infants and toddlers between February 1999 and June 2005 in which pseudoephedrine was present in the blood or tissues of all the cases (Wingert, Mundy, Collins, & Chmara, 2007). Pseudoephedrine was confirmed to have contributed to or caused the death in eight of the 15 infants, with high levels of pseudoephedrine present in two other cases, with the primary cause of death listed as pneumonia in one case and undetermined cause in the second (Wingert et al.). A survey of 15 medical examiners from 12 states by the National Association of Medical Examiners identified three infant deaths in 2005 associated with cold medications, specifically pseudoephedrine that was found in high levels on postmortem toxicology reports of all three infants (CDC, 2007).

A consistent finding in the reports of infant deaths is the high levels of medication found during postmortem toxicology reports. Several possible reasons for this finding are suggested in the literature, including lack of dosing guidelines for infants and toddlers, product labeling that is confusing to parents, multiple active ingredients in products that lead to accidental overdosing, and multiple caregivers administering medication to children, leading to accidental overdose.

Recommendations for Use of Cough and Cold Medications 

Pediatric nurse practitioners (PNPs) need to be familiar with the safety and efficacy of cold medications in children, including appropriate dosing for different aged children. Parents need to be educated regarding the appropriate use of cough and cold medications in children. Establishing a culture of safety around the use of OTC cough and cold medications will encourage appropriate use and decrease the likelihood of accidental overdose.

Prescribing Cough and Cold Medications 

Evidence is lacking regarding the effectiveness of cough and cold medications in children; therefore, PNPs need to rethink their prescribing practice if they currently recommend these products. Understanding the rationale for following FDA labeling recommendations is crucial for patient safety. An understanding of the risks and benefits of prescribing these medications and providing parents with the correct dose for their child will improve safety when cough and cold medications are prescribed.

Off-label prescribing 

Off-label prescribing is the practice of prescribing medications outside of the FDA-approved label recommendations. To pass through the FDA labeling process, drug manufacturers need to provide pharmacokinetic, safety, and efficacy data for all populations they want the product label to reflect. Historically, a large number of pediatric medications have been prescribed off-label in children because studies were never done in this population. Adult data were extrapolated to determine pediatric dosing with little attention to the developmental pharmacokinetic differences in children. The FDA Modernization Act of 1997 and the Best Pharmaceuticals for Children Act of 2003 encourages pharmaceutical companies to perform pediatric studies on medications, awarding a 6-month extension on the patent if pediatric studies are done. These acts allowed the FDA to issue a request to pharmaceutical companies for medications that may be used in children. As a result, 138 medications have had pediatric pharmacokinetic, safety, and efficacy data updated and have been relabeled. The first medication to have labeling changes to add prescribing information for 2- to 6-year-olds was ibuprofen suspension (Advil, Motrin) in 1998. The only cough or cold products that have gone through this relabeling process as of November 2007 are Advil Cold and Motrin Cold suspensions (ibuprofen/pseudoephedrine).

Off-label prescribing is not illegal because the FDA only approves drugs to enter the market and relabels when drug manufactures submit additional data. When choosing to prescribe outside the FDA approved label, providers need to reflect on whether there is strong evidence in the literature supporting off-label use of medications. Using current prescribing references such as The Harriet Lane Handbook, Micromedex, or Lexicomp’s Pediatric Dosage Handbook will determine the community standard of practice regarding off-label prescribing of specific medications, recognizing that even in the Harriett Lane Handbook, more than 25% of the medications in the formulary lack FDA labeling recommendations (Novak & Allen, 2007). In the case of children’s cough and cold medications, the literature is clear regarding lack of evidence regarding efficacy of these medications, with clear recommendations from the FDA and national organizations against use of cough and cold medications in infants and young children.

Appropriate dosing in pediatric patients 

With the myriad of cough and cold formulas available, if a provider chooses to prescribe them for children, it is critical to accurately dose the medication, whether writing a prescription or educating parents about medications. I recommend that PNPs follow the FDA and AAP recommendations that cough and cold medications not be prescribed to children younger than 2 years. There is some concern by pediatric experts regarding the safety of these medications in children younger than 6 years, and while official statements have not been issued, caution should be taken when prescribing for children ages 2 to 6 years. Table 1 provides dosing information for commonly used cough and cold products. If making recommendations to parents, a dose in milligrams (mg) with clear instructions regarding dosing interval will decrease the likelihood of accidental overdose. The differences between formulations such as infant drops, elixirs or suspensions, chewable tablets, and quick dissolve strips should be discussed, and it should be recommended that parents look at the strength of each medication before administering it. To encourage safe use of medications, it is important to encourage parents to contact the provider (or advise nurse) before administering any new OTC medication to their child.

TABLE 1. Dosing of common cough and cold medications

	Drug	Age of child	Dosing	Maximum/24 h
	Oral decongestants
	Pseudoephedrine	<2 y	Not recommended
		2-5 y	15 mg q 6 h*	60 mg/24 h
		6-12 y	30 mg q 6 h	120 mg/24 h
		>12 y	60 mg q 6 h	240 mg/24 h
	Phenylephrine (Sudafed PE)	<2 y	Not recommended
		2-5 y	5 mg q 4 h*
		6-12 y	10 mg q 4 h
		>12 y	10-20 mg q 4 h
	Topical decongestants
	Phenylephrine (Neo-Synephrine)	6-12 y	2-3 drops each nostril or 1-2 sprays of 0.25% solution q 4 h
		>12 y	2-3 drops each nostril or 1-2 sprays of 0.25% or 0.5% solution q 4 h
	Oxymetazoline (Afrin)	>6 y	2 sprays each nostril q 12 h
	Cough suppressants
	Dextromethorphan	<2 y	Not recommended
		>2-6 y	2.5 to 7.5 mg q 4 to 8 hrs⁎	30 mg/24 h
		7-12 y	5-10 mg q 4 h or 15 mg q 6 to 8 h	60 mg/24 h
		>12 y	10-30 mg q 4 to 8 h	120 mg/24 h
	Expectorants
	Guaifenesin	<2 y	Not recommended
		2-5 y	50-100 mg q 4 h	600 mg/24 h
		6-11 y	100-200 mg q 4 h	1.2 gm/24 h
		>12 y	200-400 mg q 4 h	2.4 gm/24
	q, Every.

⁎ Cough and cold medications should be used with caution in children younger than age 6 years.

Summary 

It is clear from the literature that the use of cough and cold medications in infants and young children is not recommended. Evidence is lacking for effectiveness in the treatment of cough and congestion due to the common cold, with real concerns for the safety of using these medications in children younger than 2 years. PNPs should review their practice regarding recommending OTC cough and cold medications to determine if their practice aligns with the standard of practice set by the AAP. PNPs should report suspected overdose or adverse events from cough and cold medications to the FDA Med Watch program (Box 3). Proactively educating parents regarding the safety and efficacy of these products in infants and young children will counter pharmaceutical advertising to parents. Offering nonpharmacologic symptom control techniques will encourage parents to hold off on reaching for cough and cold medications, yet still provide them with “something to do” for URI symptoms. These steps will ensure that OTC cough and cold medications are used appropriately in pediatric patients.