WASHINGTON, March 18 (UPI) -- Many top U.S. pediatricians say cough and cold remedies for children are not effective and can even cause harm.

A review of over-the-counter children's medicines found that elixirs like Dimetapp and Triaminic do not work as advertised and can have harmful side effects -- including infant death from accidental overdoses -- The Newark (N.J.) Star-Ledger reported.

The newspaper reported on one woman who gave her 13-year-old daughter an OTC cough remedy for children, only to have her daughter later wake up hallucinating.

Dextromethorphan and phenylephrine are two of the ingredients in most children's cough and cold remedies that are believed to be able to cause hallucinating -- as well as irregular heartbeat and other cardiovascular problems, hypertension, seizures, nervousness, dizziness, excitability, upset stomach and drowsiness, the report said.

The issue rose to the agenda after a group of prominent health officials filed a petition with the Food and Drug Administration urging drug companies to stop marketing such products."

They can cause serotonin syndrome in the same way as SSRI/SNRI antidepressants can:

http://www.emedicine.com/ped/topic2717.htm   

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 The 3 most commonly used oral decongestants are pseudoephedrine, phenylephrine, and phenylpropanolamine (withdrawn from US market).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:

• In the US: 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. ..."

History: