eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Cough and Cold Preparation

Author: Jennifer Krawczyk, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Emergency Medicine, University of California at Irvine
Coauthor(s): Laleh Gharahbaghian MD, Staff Physician, Department of Emergency Medicine, University of California Irvine Medical Center; Anne Rutkowski, MD, Staff Physician, Department of Emergency Medicine, Harbor-University of California at Los Angeles Medical Center
Contributor Information and Disclosures

Updated: Jul 14, 2006

Introduction

Background

Cough and cold suppressant medicines are widely used and favored by medical professionals and parents alike. However, minimal data exist to support their effectiveness. Because these medications are available over-the-counter (OTC) and are found in most households, they frequently are implicated in pediatric toxic ingestions, both accidental and intentional. 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 usually is not 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 The 3 most commonly used oral decongestants are pseudoephedrine, phenylephrine, and phenylpropanolamine (withdrawn from US market).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.

Pathophysiology

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 generally are 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 also may 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 persistant 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 often has 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. Although this study did not include children, phenylpropanolamine was removed from the OTC market in the United States. However, preparations containing this substance still may be in homes and in medications from foreign countries. It is recommended that all household medications be checked for phenylpropanolamine and be discarded if containing any.

Antitussives

Dextromethorphan is the methylated dextro-isomer of levorphanol, a codeine analog. It is a synthetic opioid and acts at s 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 at social gatherings. The effects of megadosing are similar to that of PCP by causing ataxia, abnormal muscle movements, and respiratory depression. Dextromethorphan can cause false positive test-results for PCP in urine toxicologic screening tests. The half-life of dextromethorphan is short, with the mainstay of treatment being 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 less 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 68,943 annual exposures for children younger than 6 years and 24,703 annual exposure in children aged 6-17 years, based on cumulative data reported in 2003. 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, accidental (children <6 y) and intentional (adolescents aged 13-19 y).
• The AAPCC reported an incidence of 27 deaths per year and 27.5 deaths per million exposures in children younger than 6 years and 61 deaths per year and 523.7 deaths per million exposures in adolescents aged 13-19 years.

Sex

• According to the AAPCC, females represent 57% of reported pediatric toxic exposures in young children and 66% of the reported exposures in adolescents.

Age

• Accidental 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. Only 50% of reported adolescent ingestions are accidental, whereas 46% are motivated by suicide. Hence, suicidal ingestion occurs with increased frequency in the teenage population, and it 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.

Clinical

History

• Accidental ingestion
  • Accidental exposures tend to occur in children younger than 6 years because they are eager to explore their environment and place objects into their mouths.
  • Accidental ingestion typically represents a smaller dose of the toxic substance, and the child presents to the ED soon after ingestion.
  • Unfortunately, as many as 30% of children who experience one ingestion experience a repeat ingestion. In this age group, it is imperative to explore the possibility of child abuse or neglect.
• Intentional ingestion
  • Only 50% of reported adolescent ingestions are accidental, whereas 46% are motivated by suicide. Hence, suicidal ingestion occurs with increased frequency in the teenage population, and it may involve multiple substances at higher doses.
  • Dextromethorphan has been used as a recreational drug by adolescents

Physical

• General findings
  • Physical findings vary greatly, depending on the agent or combination of agents ingested.
  • If a single antihistamine agent has been ingested, a predominance of anticholinergic effects are demonstrated. The anticholinergic toxidrome consists of agitation; fever; urinary retention; dry, hot, flushed skin; and dilated pupils.
  • Although most cough and cold preparations are a combination of medications, a single toxidrome may not be present. The history is helpful to guide the expected physical examination findings; however, the history often is inaccurate.
• The following physical examination findings are examples of what is possible, in addition to the common findings; however, the presentation of a patient with a toxic ingestion is not always straightforward. In general, the combined effects of the various classes of drugs in OTC preparations have been broken down into the following systems based on the approach in POISINDEX.
  • Vital signs
    • Findings include hyperthermia, tachypnea, tachycardia, and hypertension.
    • Hyperthermia has been reported with ingestion of both diphenhydramine and OTC antihistamine/decongestant combinations. Case reports secondary to combination products are ascribed to the sympathomimetic component.
  • Head, ears, eyes, nose, and throat (HEENT)
    • Anticholinergic effects include mydriasis, nasal dryness and stuffiness, eye dryness, and mouth and throat dryness secondary to antihistamines.
    • Dilated and minimally reactive pupils have been seen with antihistamine toxicity related to anticholinergic effects.
    • Mydriasis and nystagmus may be observed with dextromethorphan ingestion.
• Cardiovascular
  • Abnormalities include arrhythmia (eg, AV block) and cardiac arrest.
  • ECG changes occur secondary to the antihistamine and the sympathomimetic components. Antihistamines commonly cause tachycardia.
• Respiratory: Findings include respiratory depression and adult respiratory distress syndrome.
• Neurologic: Abnormal findings include dizziness, ataxia, hyperexcitability, somnolence, seizures, dystonia, dyskinesia, toxic psychosis (anxiety, agitation, hallucination), intracranial hemorrhage, and coma.
• Gastrointestinal: Gastroenteritis (diarrhea, nausea, vomiting) can occur with the ethanolamine class of antihistamines.
• Genitourinary
  • Urinary retention is a common anticholinergic adverse effect of the antihistamines.
  • Rhabdomyolysis (ie, decreased urinary output and increased creatinine phosphokinase) has been associated with doxylamine overdose and may require treatment with IV hydration, furosemide, and urine alkalization.
• Hematologic
  • Most hematologic effects are secondary to long-term use.
  • Findings include hemolytic anemia, thrombocytopenia, and agranulocytosis
• Psychiatric: Children may experience visual hallucinations following therapeutic doses of triprolidine (antihistamine/pseudoephedrine) combinations.
• Dermatologic: Urticaria, hot dry skin
• Effects during breastfeeding: Potential changes in behavior of the infant include irritability, disturbed sleep patterns, and excessive crying.
• Other: Drug interactions between MAOIs or serotonin reuptake inhibitors with dextromethorphan may result in a serotonin syndrome. Serotonin syndrome consists of mental status changes, such as agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, headache, fever, or incoordination.

Causes

• Drug abuse
  • Drug abuse has been reported with dextromethorphan.
  • Deliberate ingestion can lead to intoxication with symptoms of euphoria, bizarre behavior, hyperactivity, auditory hallucinations, visual hallucinations, and association of sounds with colors.

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