Ephedrine
Ephedrine International Programme on Chemical Safety Poisons Information Monograph 209 Pharmaceutical 1. NAME 1.1 Substance Ephedrine 1.2 Group 1.3 Synonyms Ephedrinum; Hydrated ephedrine, Eedrynum hidratum; Ephedrina; Ma-huang; 1.4 Identification numbers 1.4.1 CAS 229-42-3 (anhydrous) 1.4.2 Other numbers50906-05-3 (hemihydrate) ATC codes: R01AA03 S01FB02 1.5 Main brand names Amidrin; Daral; Fluidin; Kidargol; Rhinamide; Tedral; Tenfril; Vicks decongestive cough syrup 1.6 Main manufacturers and/or importers Farmacéutica Uruguaya Lab. Andrómaco Roussel-Labur 2. SUMMARY 2.1 Main risks and target organs Cardiovascular: heart and arterial vessels CNS stimulation Chronic use can lead to tolerance with dependence 2.2 Summary of clinical effects Digestive disorders: nausea, vomiting. Cardiovascular impairment: tachycardia, severe hypertension and secondary myocardial infarction and/or stroke. Central effects: anxiety, tremor, irritability, hallucinations, psychotic states, seizures, intracerebral haemorrhage. Metabolic dysfunction: hyperglycaemia, hypokalaemia (intracellular shift). 2.3 Diagnosis Diagnosis is based on history and/or the presence of nausea, vomiting, tachycardia, headache, elevated blood pressure. Ephedrine and its metabolites can be analyzed in blood and urine by gas chromatography. 2.4 First aid measures and management principles Gastrointestinal decontamination Supportive and symptomatic care; administration of propranolol in patients with severe arterial hypertension. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Ephedra species (particularly E. sinica) contain chiefly two alkaloids: ephedrine and pseudoephedrine, which is a stereoisomer of ephedrine. Ephedra species have been used as a source of ephedrine; ephedrine is also prepared synthetically. Ephedra is sold as a traditional Chinese medicinal herb under the name Ma-huang. (Parfitt, 1999) 3.2 Chemical structure Molecular formula: C10 H15 NO1 Molecular mass: 165.2 Structural name: (1R,2S)-2-methylamino-1-phenylpropan-1-ol 3.3 Physical properties 3.3.1 Colour Colourless or white 3.3.2 State/form Solid-crystals Solid-powder 3.3.3 Description Bitter taste; odourless or slight aromatic odour. In warm weather it slowly volatilizes. The anhydrous substance melts at 36°C and the hemihydrate melts at 42°C. It is a weak base, with a pKa = 9.6 Ephedrine decomposes with light. Solutions in oil can have a garlicky odour. It is soluble in water (1 in 20) and in alcohol, chloroform, ether, glycerol, olive oil and in liquid paraffin (Windholz, 1983). Ephedrine and its optical isomer pseudoephedrine are structurally very similar to methamphetamine. In illicit drug laboratories simple dehydrogenation is used to make methamphetamine from ephedrine (Kelley 1998). 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions Protect from light. Temperatures must not exceed 8EC in containers. 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description The most important uses are: - as a bronchodilator - nasal decongestant - other uses: syndrome of Stokes-Adams; as a mydriatic and hypertensor in the spinal-anesthesia. It is also used as an herbal diet supplement under the name "Ma-huang" as an anorectic and CNS stimulant. 4.2 Therapeutic dosage 4.2.1 Adults 15 to 60 mg of ephedrine hydrochloride or sulphate 3 or 4 times daily as a bronchodilator 4.2.2 Children 500 (g/kg body weight of ephedrine hydrochloride or sulphate 3 or 4 times daily (Parfitt, 1999). 4.3 Contraindications Cardiovascular disease; hypertension; hyperthyroidism; phaeochromocytoma and closed angle glaucoma. Ephedrine should not be given in patients being treated with MAOI (or have stopped treatment in the last 14 days) (Dukes, 1988; Parfitt, 1999; Dawson et al., 1995). It should be used with caution in patients with prostatic enlargement or with renal impairment 5. ROUTES OF EXPOSURE 5.1 Oral Abuse of ephedrine-containing diet pills is a common occurrence (MMWR, 1996). 5.2 Inhalation Ephedrine salts are used as nasal drops or sprays in the relief of nasal congestion associated with cold or rhinitis. Ephedrine can be abused by the nasal route by subjects who have developed dependence to its vasoconstrictive effect (Bismuth, 2000). 5.3 Dermal As an ointments well absorbed. 5.4 Eye Eye-drops at 0.1% are effective in congestion of conjunctival allergy. 5.5 Parenteral Subcutaneous or intramuscular injections. 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure Ephedrine is readily and completely absorbed from the gastrointestinal tract; plasma peak concentrations are reached an hour after ingestion A single oral dose of 24 mg produced an average peak plasma concentration of 0.10 mg/L (Goldfrank, 1990). 6.2 Distribution by route of exposure The volume of distribution is about 3L/kg; patients with toxicity are not good candidates for haemodialysis (Kelley 1998). 6.3 Biological half-life by route of exposure It has a plasma half-life ranging from 3 to 6 hours depending on urinary pH (Parfitt, 1999). No change in half-life from that seen with therapeutic dosing was observed in an otherwise healthy patient with massive overdose (Snook et al., 1992). The ephedrine concentrations in three fatalities were 3.49; 7.85 and 20.5 mg/L (Ellenhorn, 1988). 6.4 Metabolism Only a small amount of ephedrine is metabolized in the liver. 6.5 Elimination by route of exposure It is largely excreted unchanged in the urine, with some deaminated metabolites and N-demethylated metabolites. Elimination is enhanced in acid urine. (Parfitt, 1999) Less than 10% of ephedrine is excreted as norephedrine. In normal subjects 70-80% of a dose is eliminated unchanged in the urine within 48 hours. 4% is present as norephedrine (Baselt and Cravey 1995) 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics Ephedrine can produce stimulation at the adrenergic receptors and neuronal norepinephrine release (Kelley 1998). 7.1.2 Pharmacodynamics Ephedrine has both alpha- and beta-adrenergic activities, and both direct and indirect effects on receptors. It raises blood pressure both by increasing cardiac output and inducing peripheral vasoconstriction (Shufman et al., 1994; Parfitt, 1999). It can produce bronchodilation. In local application it causes pupils dilation. The main metabolic effects in overdose are hyperglycaemia and hypokalaemia. Ephedrine is a centrally acting respiratory stimulant and can increase motor activity. 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults The ephedrine concentrations in three fatalities were 3.49, 7.85, and 20.5mg/L (Kelley 1998). However survival at levels of 23mg/L has been reported (Baselt and Cravey 1995) 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity No data available 7.4 Teratogenicity No data available 7.5 Mutagenicity No data available 7.6 Interactions A serotonin syndrome has been reported in a patient taking paroxetine and an over-the-counter cold medicine containing ephedrine (Skop et al., 1994). Combination of ephedrine and a MAOI can produce life-threatening reactions (Dawson et al., 1995). It should also be avoided in patients undergoing anaesthesia with cyclopropane, halothane or other volatile anaesthesia. An increased risk of arrhythmias may occur if given to patients receiving cardiac glycosides, quinidine or tricyclic antidepressants, ergot alkaloids, oxytocin (Parfitt 1999). 7.7 Main adverse effects Central effects of sympathomimetic agents include: tremor, fear, anxiety, confusion, irritability, insomnia, and psychotic states. Paranoid psychosis, delusions and hallucinations may also follow ephedrine overdose. Effects on the cardiovascular system are complex: vasoconstriction, hypertension, or hypotension and bradycardia, tachycardia, palpitations, cardiac arrest. It can cause local ischaemia in chronic topical use (Parfitt, 1999). 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.1.3.6 8.2 Toxicological analyses and their interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple qualitative test(s) 8.2.1.2 Advanced qualitative confirmation test(s) 8.2.1.3 Simple quantitative method(s) 8.2.1.4 Advanced quantitative method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple qualitative test(s) 8.2.2.2 Advanced qualitative confirmation test(s) 8.2.2.3 Simple quantitative method(s) 8.2.2.4 Advanced quantitative method(s) 8.2.2.5 Other dedicated method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.2 Urine "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses "Basic analyses" "Dedicated analyses" "Optional analyses" 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Early clinical manifestations of ingestion of high doses of ephedrine consist of nausea and vomiting, followed by insomnia, cardiac arrhythmia, myocardial ischemia, agitation, psychosis and seizures. 9.1.2 Inhalation No data available 9.1.3 Skin exposure No data available 9.1.4 Eye contact No data available 9.1.5 Parenteral exposure The parenteral use of ephedrine may cause intracerebral haemorrhage as a result of a rise in arterial pressure. Ventricular arrhythmias have been described (Ellenhorn 1988). 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion Neurological symptoms that have been described include headache, anxiety, tremor, insomnia, dizziness, seizures (MMWR, 1996). Several cases of psychosis have been reported (Roxanas & Spalding, 1977; Shufman et al., 1994; Copwell, 1995; Doyle & Kargin, 1996; Jacobs & Kirsch, 2000). Cardiovascular disorders associated with the chronic use of ephedrine may include chest pain, hypertension, arrhythmia, myocardial infarction, cerebral vascilitis and stroke (MMWR, 1996). 9.2.2 Inhalation No data available 9.2.3 Skin exposure Local applications of ephedrine may cause contact dermatitis (Tomb et al., 1991). 9.2.4 Eye contact No data available. 9.2.5 Parenteral exposure The intravenous use of ephedrine causes similar effects as oral ingestion. 9.2.6 Other The vasoconstrictive effects of ephedrine applied topically as nasal spray or drops may cause local ischaemia (Parfitt, 1999). 9.3 Course, prognosis, cause of death Early clinical manifestations of ephedrine overdose consist of nausea and vomiting, followed by headache, agitation, anxiety, tremor, seizures, tachycardia and hypertensive crisis. Severe rise in blood pressure may produce cerebral haemorrhage and myocardial infarction. Ventricular arrhythmia may progress to cardiac arrest and death. Although fatalities have been reported the prognosis is usually good (Burkhart, 1992; Snook et al., 1992; MMWR, 1996; Backer et al., 1997; Theoharides, 1997; Hedetoft et al., 1999). 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular The most common symptoms are arterial hypertension and tachycardia; ventricular arrhythmia, chest pain, myocardial infarction, ischaemic or haemorrhagic stroke, cardiac arrest may rarely occur (Burkhart, 1992; Snook et al., 1992; MMWR, 1996; Parfitt, 1999; Matthews et al., 1997; Hedetoft et al., 1999) 9.4.2 Respiratory Respiratory stimulation, bronchodilation, pulmonary oedema apnea (Parfitt, 1999). 9.4.3 Neurological 9.4.3.1 CNS CNS stimulation: anxiety, agitation, tremor, mental confusion, hallucinations, mania, paranoid psychosis may occur; convulsions have been reported. (Roxanas & Spalding, 1977; Snook et al., 1992; Shufman et al., 1994; Copwell, 1995; Doyle & Kargin, 1996; Jacobs & Kirsch, 2000). 9.4.3.2 Peripheral nervous system No data available. 9.4.3.3 Autonomic nervous system Ephedrine causes stimulation of the sympathetic nervous system acting on both alpha and beta receptors. Symptoms include tachycardia, arterial hypertension, tremor, sweating, mydriasis. 9.4.3.4 Skeletal and smooth muscle Ephedrine produces relaxation of smooth muscle. In overdose it may also cause rhabdomyolysis (Salmon and Nicholson 1988) 9.4.4 Gastrointestinal Nausea and vomiting are common. 9.4.5 Hepatic No data available. 9.4.6 Urinary 9.4.6.1 Renal No data available. 9.4.6.2 Other Ephedrine relaxes the vesical detrusor muscle, and increases contraction of the vesical sphincter (alpha agonist action), and can produce acute retention of urine (Parfitt, 1999). 9.4.7 Endocrine and reproductive systems Inhibition of insulin secretion. 9.4.8 Dermatological No data available 9.4.9 Eye, ear, nose, throat: local effects Chronic administration of nasal drops or spray can result in rebound nasal congestion and rhinorrhoea (Parfitt, 1996; Bismuth, 2000). 9.4.10 Haematological Leukopenia. 9.4.11 Immunological No data available. 9.4.12 Metabolic 9.4.12.1 Acid base disturbancesMetabolic acidosis. 9.4.12.2 Fluid and electrolyte disturbancesHypokalaemia resulting from intracellular shift. 9.4.12.3 OthersHyperglycaemia. 9.4.13 Allergic reactions Contact dermatitis after local application. Sensitization and systemic allergic reactions (severe eczema) have been reported after oral administration (Audicana et al., 1991; Tomb et al., 1991). 9.4.14 Other clinical effects 9.4.15 Special risks Ephedrine is present in breast-milk in sufficient concentrations to be harmful to the baby, and is contraindicated in women who are breast-feeding. Patients with ischaemic heart disease, hypertension, acute angle glaucoma, hyperthyroidism, prostatic enlargement, or taking MAOI antidepressants should also avoid ephedrine. 9.5 Other Chronic use can lead to tolerance with dependence. Ephedrine abuse is a common occurrence and has been associated with several deaths (Roxanas & Spalding, 1977; Copwell, 1995; Doyle & Kargin, 1996; Gualtieri & Harris, 1996; MMWR, 1996; Theoharides, 1997; Jacobs & Kirsch, 2000). 9.6 Summary 10. MANAGEMENT 10.1 General principles Establish airway patency, breathing and circulation. Establish baseline blood pressure and pulse. Treatment is primarily supportive. ECG monitoring is necessary. Monitor urine output. Gastrointestinal decontamination may be indicated There is no antidote. 10.2 Life supportive procedures and symptomatic/specific treatment Severe hypertension and tachycardia should be treated with the intravenous administration of a short-acting, selective beta-blocker such as esmolol (Burkhart, 1992; Bismuth, 2000). (Care should be taken as hypertension may be aggrevated with use of beta-blockers owing to unopposed alpha-agonist effects). Alternative treatments for hypertension include nitroprusside or nitroglycerin infusion In the treatment of ventricular dysrhythmias, lidocaine or bretylium may be required. Convulsions require administration of intravenous diazepam. 10.3 Decontamination Gastric lavage may be performed within 2 hours of ingestion but can also increase intracranial pressure. Emesis is contra-indicated Administration of activated charcoal. 10.4 Enhanced elimination Maintenance of adequate urine output is essential; although ephedrine elimination is best achieved in acidic urine, however the risk of this procedure in this setting probably outweighs the potential benefits (Kelley 1998); there is no evidence of the usefulness of forced diuresis, hemodialysis or peritoneal dialysis in enhancing ephedrine elimination. 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature A 20 y-o woman ingested 300 diet pills containing a total of 7.5 g of ephedrine in a suicide attempt. She presented to the ED two hours post ingestion, with a HR of 116, BP 146-60 mmHg, she was agitated and anxious, with tremor and vomiting. Treatment included gastric lavage, activated charcoal, and 1 mg propranolol. Serum ephedrine level was 22.8 nanog/mL (therapeutic range: 0.04-0.08 nanog/mL) at 90 minutes post ingestion. The patient made an uneventful recovery (Snook et al., 1992). After ingesting 17500 mg of ephedrine, a 29 y-o female developed a BP of 168-106. Her BP was 124-90 five minutes after IV propranolol (Burkhart, 1992). A 19 y-o woman ingested 1000 mg of ephedrine in combination with 10000 mg of caffeine. She developed severe toxic manifestations from the heart, CNS, muscles, liver and kidneys leading to multiorgan failure, cardiac arrests and died subsequently of cerebral oedema on the fourth day of hospitalization (Hedetoft et al., 1999). A 57 y-o woman had been taking a usual dose of ephedrine for bronchial asthma (50 mg 3 times a day) for more than 30 years. When her husband died she developed depression, for which she tried to use ephedrine as an antidepressant, increasing the dose to 500 to 1000 mg a day over the course of half a year. She developed paranoid psychosis with delusions of persecution and auditory hallucinations. Recovery was rapid after ephedrine was gradually reduced to 200 mg a day (Shufman et al., 1994) 12. ADDITIONAL INFORMATION 12.1 Specific preventive measures 12.3 Other 13. REFERENCES Audicana M, Urrutia I, Echechipia S, Munoz D, Fernandez de Corres L (1991) Sensitization to ephedrine in oral anticatarrhal drugs. Contact Dermatitis, 24: 223 Backer R, tautman D, Lowry S, Harvey CM, Poklis A (1997) Fatal ephedrine intoxication. J Forensic Sci, 42: 157-159 Bacelt RC, Cravey RH. (1995) Disposition of toxic drugs and chemicals in man. 4th Edition. Pub Chemical Toxicology Institute, California, pp290-291 Bismuth C Ed. (2000) Toxicologie clinique, 5ème Ed, Flammarion, Paris Burkhart KK (1992) Intravenous propranolol reverses hypertension after sympathomimetic overdose: two case reports. J Toxicol Clin Toxicol, 30: 109-114 Copwell RR (1995) Ephedrine-induced mania from an herbal diet supplement. Am J Psychiatry, 152: 647 Dawson JK, Earnshaw SM, Graham CS (1995) Dangerous monoamine oxidase inhibitor interactions are still occurring in the 1990's. J Accid Emerg Med, 12: 49-51 Doyle H & Kargin M (1996) Herbal stimulant containing ephedrine has also caused psychosis. BMJ, 313: 756 Dukes, MNG (1988) Meylers Side effects of drugs, 11th ed., 259-260. Ellenhorn MJ, Barceloux DG (1988) Medical Toxicology - Diagnosis and treatment of human poisoning, 521-543. Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA (1990) Toxicological Emergencies 4th ed, 422. Goodman y Gilman (1986) Las Bases Farmacológicas de la Terapéutica, 7a ed 155-175. Gualtieri J & Harris C (1996) Dilated cardiomyopathy in a heavy ephedrine abuser. Clin Toxicol, 34: 581 (abstract) Hedetoft C, Jensen CH, Christensen MR, Christensen O (1999) Fatal poisoning with Letigen. Ugeskr Laeger, 161: 6937-6938 Jacobs KM & Kirsch KA (2000) Psychiatric complications of Ma-huang. Psychosomatics, 41: 58-62 Kelley MT (1998). Chapter 39 Sympathiomimetics. In Clinical Management of Poisioning and Drug Overdose 3rd Edition. Eds Haddad, Shannon, Winchester. Pub WB Saunders Company Philidelphia, pp1082-1083 Matthews G, Smolinske S, White S (1997) Ephedrine-related stroke in a teenager. Clin Toxicol, 35: 555 (abstract) MMWR Morb Mortal Wkly Rep (1996) Adverse events associated with ephedrine-containing products-Texas, December 1993-September 1995. 45: 689-693 Parfitts K. (1999) The Extra Pharmacopoeia, 31 Ed, The pharmaceutical Press, London Roxanas MG & Spalding J (1977) Ephedrine abuse psychosis. Med J Aust, 2: 639-640 Salmon J, Nicholson D. DIC and rhabdomyolysis following pseudoephedrine overdose. Am J Emerg Med 1988;6:545-546 Shufman NE, Witztum E, Vass A (1994) Ephedrine psychosis. Harefuah, 127: 166-8, 215 Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM (1994) The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy and vascular disease. Am J Emerg Med, 12: 642-644 Snook C, Otten M, Hassan M (1992) Massive ephedrine overdose: case report and toxicokinetic analysis. Vet Human Toxicol, 34: 335 (abstract) Theoharides TC (1997) Sudden death of a healthy college student related to ephedrine toxicity from a Ma-huang-containing drink. J Clin Psychopharmacol, 17: 437-439 Tomb RR, Lepoittevin JP, Espinassouze F, Heid E, Foussereau J (1991) Systemic contact dermatitis from pseudoephedrine, Contact Dermatitis, 24: 86-88 Windholz M ed. (1983) 10 ED The Merck Index: an encyclopaedia of chemicals, drugs and biologicals, Rahway, New Jersey Merck and Co., Inc. 14. AUTHOR(S), REVIEWER(S) DATA (INCLUDING EACH UPDATING), COMPLETE ADDRESSES Author: Dr Mabel Burger Address: CIAT - Piso 7E Hospital de Clinicas Avenida Italia s/n Montevideo Uruguay Tel: (598 2) 80 40 00 (598 2) 47 03 00 Fax: (598 2) 47 03 00 Date: July 1991 Update: MO Rambourg Schepens, September 2000 Reviewed at INTOX 12, Erfurt, Germany, November 2000 Reviewers M. Balali-Mood, W. Temple, B. Groszek, N. Langford.See Also: Toxicological Abbreviations