Ipecac syrup abuse, morbidity, and mortality: isn't it time to repeal its over-the-counter status?

PURPOSE: To review and address the abuse of ipecac, describing its epidemiology, toxicity, clinical characteristics, and laboratory assessment. METHODS: A Medline search (1980-2003) for Ipecac abuse and Ipecac toxicity, n = 34. RESULTS: Ipecac abuse occurs predominantly among adolescent and young adult females who are either experimenting with purging or have an eating disorder. Psychiatric comorbidity is common. Death can occur and is usually of cardiac origin. Morbidity includes myocarditis with arrhythmias, myositis, gastroesophageal pathology, including Mallory Weiss tears, diarrhea, and metabolic abnormalities (alkalosis, hypokalemia, dehydration). The injuries can reverse with cessation of ipecac use. A high index of suspicion is needed for early detection. Classic findings are abnormal EKG and echocardiography and/or elevation of muscle enzymes (CPK, adolase). Emetine, the alkaloid in ipecac, can be confirmed in serum, urine, and tissue by high performance liquid chromatography. CONCLUSIONS: Ipecac abuse is dangerous, even deadly. However, if abuse is discontinued, cardiac and muscle damage tends to reverse. Were ipecac syrup to remain an over- the-counter medication, or become a prescription medication, more stringent warning labels ought to be included and further education be provided about its toxicity and potential for abuse. Removing ipecac from the over-the-counter category would best eliminate its potential for abuse.

Urinary excretion of ipecac alkaloids in human volunteers.

Limited data are available regarding urinary excretion of ipecac alkaloids in humans. In this study, ipecac syrup was administered po to 12 healthy human volunteers at a dose of either 20 mL or 30 mL, and urinary excretions of cephaeline and emetine as well as blood and vomit concentrations were detected by HPLC. All participants showed vomiting after the 30 mL dose within 1 h, whereas 2/6 did not show vomiting within 4 h after the 20 mL dose. Percentage recovery of alkaloids in vomit were 39 +/- 38 or 76 +/- 14% after the 20 mL or 30 mL doses, respectively. In most participants, plasma alkaloids reached their maximum levels within I h and became undetectable after 6 h. Total excretions of ipecac alkaloids into the urine within the first 48 h were less than 2%, but both alkaloids were detectable in the urine at 2w in all participants and could be detected up to 12w in 1/2 participants who did not vomit. These results show that ipecac alkaloids may be detectable in urine several weeks after ingestion and suggest that their detection in urine may be helpful to identify the Munchausen syndrome by proxy using ipecac syrup.

Absorption, distribution and excretion of 3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats.

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.

High-performance liquid chromatographic assay with fluorescence detection for the determination of cephaeline and emetine in human plasma and urine.

A high-performance liquid chromatographic assay method for the quantitation of ipecac alkaloids (cephaeline and emetine) in human plasma and urine is described. Human plasma or urine was extracted with diethylether under alkaline conditions following the addition of an internal standard. Concentrations of alkaloids and internal standard were determined by octadecylsilica chromatographic separation (Symmetry C18 columns, plasma analysis; 15 cmx4.6 mm I.D., 5 microm particle size, urine analysis; 7.5 cmx4.6 mm I.D., 5 microm particle size). The mobile phase consisted of buffer (20 mmol/l 1-heptanesulfonic acid sodium salt, adjusted to pH 4.0 with acetic acid)-methanol (51:49, v/v). Eluate fluorescence was monitored at 285/316 nm. The lowest quantitation limits of cephaeline and emetine were 1 and 2.5 ng/ml, respectively, in plasma, and 5 ng/ml in urine. Intra- and inter-day relative standard deviations were below 15%. The assay is sensitive, specific and applicable to pharmacokinetic studies in humans.

Single dose pharmacokinetics of syrup of ipecac.

Syrup of ipecac (SI) has been used medicinally since the 1500s; however, little is known about the pharmacokinetics in humans of SI's active ingredients, emetine and cephaeline. The objective of this study was to evaluate the rate of absorption and the rate of elimination of emetine and cephaeline. Ten healthy, adult, human volunteers between 18 and 45 years of age who were of ideal body weight (body mass index 20-25) completed this study. After an overnight fast, 30 mL SI were ingested. Blood samples were collected 30, 45, 60, 90, 120, 150, and 180 minutes post-ingestion and urine was collected throughout the study period. Plasma and urine concentrations of emetine and cephaeline were measured by reverse-phase HPLC with fluorescence detection. In virtually all subjects, emetine and cephaeline were detected within 5-10 minutes of dosing with the time to maximum concentration being approximately 20 minutes. The mean areas under the concentration-time curve (AUC) for both emetine and cephaeline were similar; however, the ratio of mean cephaeline maximum concentration (Cmax) to emetine Cmax was approximately 1.5. Four of the ten subjects exhibited a type of concentration-time profile in which the levels of cephaeline were substantially higher than those of emetine and the levels of cephaeline were substantially higher than noted for the other six subjects. In these remaining six subjects, the levels of emetine and cephaeline were lower than 10 ng/mL at all time-points. An initial elimination phase was noted in some subjects but not in others. Individuals in whom an initial elimination phase was not observed also exhibited low levels of both alkaloids as compared with the other subjects suggestive of a slower distribution phase. Less than 0. 15% of the administered emetine and cephaeline was recovered in the urine at 3 hours. No relationship between vomiting episodes and peak concentrations of emetine or cephaeline was found. Administration of SI results in rapid appearance and disappearance of emetine and cephaeline in plasma becoming almost undetectable at 3 hours. Very little of either alkaloid is eliminated in the urine within this time period, suggesting extensive distribution. The length of time that an administered dose of SI can result in the detection of emetine and/or cephaeline in the urine has not been determined; future studies in humans are required.

Absorption of ipecac alkaloids in emergency patients.

Syrup of ipecac contains the nauseant alkaloids emetine and cephaeline. Although thousands of doses are given yearly, no data exist on the absorption of these alkaloids in man. We gave 30 mL of USP Syrup to ten adult patients. Blood and urine samples were obtained at approximately one-half and two hours after administration, and the entire volume of vomitus was saved. The samples were then analyzed for cephaeline and emetine by a high-performance liquid chromatographic (HPLC) assay developed in our laboratory. All patients vomited within 30 minutes, but the amounts of alkaloid regurgitated varied from 22 +/- 14% in six patients to 80 +/- 16% in the remaining four. Only six patients had emetine or cephaeline in their blood by two hours (range, 5 to 73 ng/mL), although ten patients had detectable concentrations of the alkaloids in their urine. Measured over two hours, no patient eliminated more than 0.5% of the dose by the urinary route. In our study ipecac was absorbed by all who received it; the extent of absorption varied widely, and elimination by the renal route was small.

High-performance liquid chromatographic analysis of emetine after oxidative activation to a fluorescent product.

A clinically useful analytical method is described for monitoring plasma levels of emetine. The drug is initially extracted from plasma with dichloromethane (0.3 volumes). The extract can be analyzed directly by paired-ion reversed-phase high-performance liquid chromatography to levels of 500 ng/ml of plasma by spectrophotometric monitoring of column effluent. For analysis of emetine at lower concentrations, the dichloromethane extracts are subjected to mild mercuric acetate oxidation prior to separation, thereby converting emetine to a fluorescent product. Spectrofluorometric monitoring of the column effluent readily extends the sensitivity of the assay to 10 ng of emetine/ml of plasma. At these levels measurements can be made with a precision of +/- 4%.