Cough and Cold Preparation Toxicity 

Cough and cold suppressant medicines are widely used and favored by medical professionals and parents alike. However, minimal data support their effectiveness. In 2006, the American College of Chest Physicians found that "literature regarding over-the-counter cough medications does not support the efficacy of such products in the pediatric age group."^[1] In 2007, the US Food and Drug Administration (FDA) advisory committee recommended that the use of these medications be prohibited in children younger than 6 years.^{[2, 3]}

Despite this, approximately 4 million children younger than 12 years are treated with nonprescription cough and cold products each week in the United States. Because these medications are available over-the-counter (OTC) and are found in most households, they are frequently implicated in pediatric toxic ingestions. Although most are unintentional, the number of intentional ingestions is growing, particularly for recreational use. The most common reported calls that involve OTC medications to poison control centers are for the ingestion of acetaminophen and cough and cold preparations.

The 3 main components of most cough and cold medicines are antihistamines, decongestants, and antitussives. First-generation antihistamines can be divided into 5 different categories. The most commonly used antihistamines in OTC preparations come from the alkylamine (eg, chlorpheniramine, brompheniramine) and ethanolamine (eg, diphenhydramine, clemastine) groups. Toxicity caused by these agents is not usually due to antihistamine properties but to anticholinergic properties. The 3 most commonly used oral decongestants are pseudoephedrine, phenylephrine, and phenylpropanolamine (withdrawn from US market). These agents stimulate alpha-adrenergic receptors and cause a sympathomimetic response at toxic doses. The most common antitussive in OTC preparations is dextromethorphan.

Most poisonings are asymptomatic or mildly symptomatic and do not require specific therapy. However, the clinician may encounter severe intoxications that require prompt recognition and appropriate disposition. Involvement of the regional poison control center, as well as a medical toxicology consultant, if available, may aid in the treatment and follow-up care of these patients, and they should be contacted for all significant ingestions.

Antihistamines

Antihistamines compete with histamine at H1 receptor sites on effector cells. Histamine is not a major mediator of the common cold, and the benefits of antihistamine in relieving congestion appear to be secondary to its anticholinergic properties. Toxicity is caused by anticholinergic properties. Atropine, the prototype of anticholinergics, and other substances with anticholinergic properties competitively inhibit the muscarinic effect of acetylcholine by blocking its action in the autonomic ganglia and at the neuromuscular junctions of the voluntary muscle system. They affect the peripheral and central autonomic nervous systems. Clinical toxicity is demonstrated by central nervous system depression or agitation, hyperactivity or psychosis, blurred vision, or abdominal discomfort.

Antihistamines are generally well absorbed after ingestion. Therapeutic effects begin within 15-30 minutes and are fully developed within 1 hour. They have varied peak plasma concentrations with a range of 1-5 hours. Diphenhydramine is toxic in acute doses of more than 5 mg/kg and potentially lethal in doses more than 10 mg/kg. In children, seizures have been observed with 150 mg of diphenhydramine, and fatalities have occurred with doses of less than 500 mg.

Decongestants

Pseudoephedrine, phenylephrine, and phenylpropanolamine cause direct presynaptic catecholamine release and may also block catecholamine reuptake and influence enzymes slowing catecholamine breakdown. Blood pressure elevation often is accompanied by a reflex bradycardia caused by the baroreceptors and results in postural hypotension. Clinical manifestations result from a direct effect on adrenergic receptors in muscles and glands and stimulation of the respiratory center and CNS. This causes bronchodilation, hyperexcitability, hallucinations, seizures, psychosis, intracranial bleeding or restlessness.

One case report described a cardiomyopathy and left ventricular dysfunction as a result of persistent tachycardia from pseudoephedrine use with resolution upon its termination. Decongestants are absorbed readily from the GI tract (except for phenylephrine because of irregular absorption and first pass metabolism by the liver) and attain a high concentration in the CNS. Peak plasma concentrations are achieved within 1-2 hours after oral administration. Toxic levels of pseudoephedrine have not been identified.

Phenylpropanolamine has often been implicated in pediatric ingestion, with toxicity starting at 6-10 mg/kg. In November 2000, in an article in the New England Journal of Medicine, phenylpropanolamine was noted to increase the risk of stroke. Other effects of phenylpropanolamine are seizure, cerebral vasculitis and kidney failure.^[4] Although this study did not include children, phenylpropanolamine was removed from the OTC market in the United States. However, preparations containing this substance may still be in homes and in medications from foreign countries. All household medications should be checked for phenylpropanolamine, which should be discarded.

Antitussives

Dextromethorphan is the methylated dextro-isomer of levorphanol, a codeine analog.

It is a synthetic opioid and acts at opiate receptors in the CNS but does not have any of the other effects of typical opiates; it has no analgesic and minimal addictive properties. Dextromethorphan has shown agonist activity at the serotonergic transmission, inhibiting the reuptake of serotonin at synapses and causing potential serotonin syndrome, especially when used concomitantly with monoamine oxidase inhibitors (MAOIs).

In addition, dextromethorphan and its primary active metabolite, dextrorphan, which shows similar effects to other N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine (PCP), demonstrate anticonvulsant activity in animals by antagonizing the action of glutamate and are classified as a dissociative medication. The usefulness of quantitative determination for dextromethorphan is unclear because no correlation exists between blood levels and clinical effects. However, qualitative determination in blood or urine can demonstrate the presence or absence of dextromethorphan. The pharmacokinetics of dextromethorphan are such that a peak serum concentration of 0.1-0.2 mg/mL was reached after a single 20-mg oral dose in healthy volunteers. Five percent of persons of European ethnicity lack the ability to metabolize the drug normally, leading to toxic levels with smaller doses.

Note that adolescents have become increasingly interested in dextromethorphan for intentional intoxications. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), the rate of emergency department visits resulting from nonmedical use of dextromethorphan for those aged 12-20 years was 7.1 visits per 100,000 population, compared with 2.6 visits or fewer per 100,000 for other age groups. Effects of megadosing (5-10 times the recommended dose) are similar to that of PCP by causing ataxia, abnormal muscle movements, respiratory depression, and dissociative hallucinations at high doses. Dextromethorphan can cause false positive test-results for PCP in urine toxicologic screening tests.

The half-life of dextromethorphan is short (typical intoxication lasting 6-8 h); the mainstay of treatment is supportive care. Narcan has been used with intermittent success to reverse ataxia and respiratory depression.

Chlorpheniramine is an OTC antihistamine that is usually used in adults. However, the abuse potential of this medication by adolescents has been recently reported. Its effects in deliberate megadosing for intoxication are similar to that of dextromethorphan.

Codeine is also thought to have antitussive effects and may be prescribed in combination with promethazine (Phenergan) for cough in the pediatric population. This medication is not recommended for use in the pediatric population. Codeine is an opioid analgesic and is the most commonly ingested opioid, in toxic doses, by children younger than 6 years, as reported by the American Association of Poison Control Centers (AAPCC). Doses greater than 5 mg/kg are reported to produce respiratory and CNS depression.

Frequency

United States

The AAPCC reports that cough and cold preparations account for 111,222 total exposures, 4.5% of total human exposures (65,044 annual exposures for children younger than 6 years and 15,539 annual exposure in children aged 6-17 years) based on cumulative data reported in 2008.^[5] Although cough and cold preparations represent a large majority of exposures in the pediatric population, they are not responsible for a significant proportion of pediatric morbidity and mortality.

Mortality/Morbidity

Morbidity and mortality differ based on the 2 categories of pediatric toxic ingestion: unintentional (children < 6 y) and intentional (adolescents aged 13-19 y). Of 19 pharmaceutical-associated fatalities in the category of children younger than 6 years, 4 involved cough and cold preparations. Of 46 pharmaceutical-associated fatalities in adolescents aged 13-19 years, 2 involved cough and cold preparations.

Sex

According to the AAPCC, females represent 41% of reported pediatric toxic exposures in children aged 6-12 years and 53% of the reported exposures in teenagers.

Age

Unintentional exposures tend to occur in children younger than 6 years because they are eager to explore their environment and place objects into their mouths. Unfortunately, as many as 30% of children who experience one ingestion experience a repeat ingestion.

The peak age for childhood poisoning ranges from 1-3 years. Based on cumulative data from 1991-95, the AAPCC reported that 43% of toxic ingestions are in children younger than 6 years, the vast majority of which are unintentional. In the 2008 report, only 47% of reported adolescent ingestions were unintentional; others cases were motivated by suicidal intention or recreational abuse.^[5] Both suicidal and recreational ingestion occur with increased frequency in the teenage population and may involve multiple substances at higher doses. Studies have shown that when adolescents are surveyed their knowledge of the lethal potential of OTC medications is poor. In fact, 50% believed some, like acetaminophen, were benign.