Clinical Toxicology Review

Clinical Toxicology Review is published monthly by the Massachusetts Poison Control System

________________________________________Vol. 18, No. 10 July 1996 ________________________________________

EPHEDRA

EPHEDRA ('MA HUANG')

In recent years, Americans have expressed an increased interest in nutritional supplements and herbal remedies. The sales of natural remedies have experienced unprecedented growth at an estimated rate of 15% annually.(1) Although herbal remedies are available without prescriptions, many of these preparations are potent drugs that may be associated with dangerous adverse effects or drug interactions. Ephedra, also known as 'ma huang,' is a herb that is widely used in products that claim to boost energy, control weight, and heighten sensations. The FDA is aware of at least 15 deaths and 395 adverse effects due to products containing ephedrine, the principal active alkaloid found in ephedra.(3) Herbal stimulants containing ephedra are easily obtained and can now be found in retail pharmacies, fitness clubs, health food stores as well as night clubs.(4,7)

For over 5000 years, the chinese have used ephedra as an herbal remedy for asthma, cough, headache, fever, allergies and the common cold.(9,15) Ephedrine was initially isolated from ephedra in 1887 by N. Nagai, a Japanese chemist. However, Western medicine did not recognize the therapeutic potential of this compound until K.K. Chen and C.F. Schmidt published their series of studies on the pharmacological properties of ephedrine.(15) Most commercially available ephedrine products utilize synthetic ephedrine that is identical to the natural compound isolated from herbal extracts. The recent interest in natural herbal remedies have lead to a resurgence in the number of products containing ephedra.

TAXONOMY

There are at least 40 species of evergreen plants that are members of the genus Ephedra (order Gnetales, family Ephedraceae). The Ephedraceae consist of small, evergreen shrubs that grow in arid regions around the world. These plants are characterized by a thick woody base and many slim, jointed branches covered with tiny scale-like leaves. The flowers are typically elongated and the fruits (cones) are globular and red or occasionally yellow.(2,11) These plants have a distinct pine odor and are reported to have a very astringent taste. The highest alkaloid content can be found in the green branches of the Ephedra species that contain alkaloids. The woody basal stem, root, flowers and fruit are almost devoid of alkaloids.(11) In addition to ephedrine, other alkaloids with sympathomimetic properties such as pseudoephedrine, norephedrine and norpseudoephedrine are found in varying quantities within the different Ephedra species.(16) Species of Ephedra that are used most commonly as medicinal agents include major, sinica, gerardiana (vulgaris), altissima, equisetina, distachya, intermedia, nevadensis and helvetica.(11,12)

The Ephedras are typically categorized into geographic groups that vary in their alkaloid content. It appears that the North American and Central American species do not contain useful alkaloids and any pharmacological activity attributed to these plants must be due to compounds other than ephedrine or its derivatives. Examples of species found in the United States that are used to make alkaloid-free beverages include E. nevadensis (Mormon tea) and E. viridis (Squaw tea).(11,15) Species commonly used to produce herbal ephedra (ma huang) preparations include E. major, E. equisetina and E. sinica. Various alkaloid-containing species of Ephedra have been considered for cultivation as an economic cash crop in the southwestern United States.(12) Ma huang may be the first of the Chinese herbal remedies to be widely used in Western medicine. Traditionally, ma huang has been used for a wide range of medical complaints including the treatment of colds and influenza, allergy, nasal congestion, coughing, wheezing, headaches, fever, chills, joint and bone pain, edema and inadequate perspiration. A decoction containing ma huang, gui zhi (cinnamon twig), gan cao (licorice root) and almond is still used today as a cold remedy that relieves fever, body aches, headaches, and coughing.(9)

CHEMISTRY/CLINICAL PHARMACOLOGY

The ephedra alkaloids are similar in structure to epinephrine. Ephedrine and its diastereoisomer, pseudoephedrine, are believed to be responsible for most of the properties of ephedra. Ephedrine can be used for the illegal synthesis of methamphetamine and the sale of ephedra alkaloids have been regulated in several states.(14) Ephedra species that contain alkaloids typically yield from 0.5% to 2.5% alkaloids, of which 30% to 90% is ephedrine. Pharmaceutical trade standards specify that dried ephedra should contain at least 1.25% ephedrine.(11) Ephedra alkaloids have been shown to be highly stable. However, storage of ephedra in a humid environment has been shown to decrease the alkaloid content.(11,12)

Ephedrine is a sympathomimetic drug that stimulates both a- and B-adrenergic receptors. In addition to its direct effects, ephedrine also releases norepinephrine from its storage sites. When used in therapeutic doses, ephedrine primarily has respiratory and cardiovascular effects. Ephedrine acts as a bronchial smooth muscle relaxant by stimulating B2-adrenergic receptors. Positive inotropic effects of ephedrine are due to the stimulation of B1-adrenergic receptors in the heart. Ephedrine can have variable effects on the vasculature and can cause either vasodilation through stimulation of the B2-adrenergic receptors or vasoconstriction through stimulation of the a1-adrenergic receptors. The administration of therapeutic doses of ephedrine typically results in cardiac stimulation and an elevated systolic and diastolic blood pressure. However, when ephedrine is administered more frequently or for prolonged periods of time, tachyphylaxis to its effects on the heart, vasculature and bronchial smooth muscle may be observed. Depletion of norepinephrine stores by ephedrine is believed to be responsible for the tachyphylaxis that develops to the cardiac and pressor effects. However, this mechanism is not responsible for the decreased response of bronchial smooth muscle to ephedrine.(10)

Other effects of ephedrine include CNS stimulation, relaxation of the smooth muscle of the GI tract, urinary retention, glycogenolysis, increased oxygen consumption and accelerated metabolic rate.(12) While ephedrine is considered to have significant abuse potential, a study of the reinforcing properties of the drug suggests that it has a lower abuse liability than amphetamines.8 Although ephedra is used in many diet aids, there is little clinical evidence to support its efficacy or safety when used for weight loss.(16) In addition, there has been at least one report of ephedrine increasing muscle strength in patients afflicted by myasthenia gravis.(10) Ephedra preparations have also been associated with diuresis and hypoglycemia in animal studies.(12)

Ephedrine is rapidly and completely absorbed after oral, intramuscular, or subcutaneous administration. Bronchodilation may be noticed within 15 to 60 minutes of oral administration. Duration of bronchodilation cardiovascular effects after oral administration is approximately 4 hours. Ephedrine is almost completely excreted in the urine as the unchanged drug. Only small quantities of the drug are metabolized in the liver. Ephedrine has a pKa of 9.6 and the elimination half-life of ephedrine may be altered by changing the urinary pH.(10) At a urinary pH of 6.3, ephedrine has an elimination half-life of approximately 6 hours. Lowering urinary pH to 5 will decrease the elimination half-life to approximately 3 hours. However, urinary acidification is not recommended for the treatment of ephedrine toxicity.

CLINICAL TOXICOLOGY

The toxic effects of ephedra are primarily due to ephedrine, and to a lesser extent, pseudoephedrine. Both active constituents of ephedra alkaloids stimulate the adrenergic system and the clinical presentation of toxicity reflects the pharmacologic activity of these agents. Ephedrine toxicity may be apparent with doses only 2 to 3 times the therapuetic range.(13) Pseudoephedrine tends to be less toxic and patients are usually asymptomatic until 4 to 5 times the therapeutic dose is taken.(5) Because the actual alkaloid content of ephedra preparation is variable, it may not be possible to determine the amount of ephedrine and pseudoephedrine actually ingested.

Because of the rapid and complete absorption of ephedrine, the onset of pharmacologic effects should be evident within 1 hour of ingestion. The clinical toxicity of ephedra affects primarily the cardiovascular system and the CNS. Unless sustained-release products are utilized, the duration of the toxic symptoms is relatively short and resolution of symptoms usually occurs within 6 hours.(5)

The major cardiovascular toxicity seen with ephedra includes hypertension and tachyarrhythmias. One report of a chronic, congestive cardiomyopathy was described in a patient who had abused ephedrine for appproximately ten years.(13) At least 2 cases of ephedrine associated intracranial hemorrhage have been reported in patients with malformations that predisposed them to cerebrovascular accidents.(3,6) In both cases, ephedrine was the only drug detected in the body by gas chromatography-mass spectrometry and it is believed that ephedrine induced hypertension caused the rupture of the malformations. A case of suspected ephedrine associated ischemic stroke has also been reported. It was hypothesized that vasculitis and vasoconstriction secondary to chronic high dose ephedrine use was responsible for the ischemic cerebrovascular accident.(6) Bradyarrhythmias rarely occur, and are usually associated with phenylpropanolamine or phenylephrine exposure.(5)

Ephedra alkaloids have a stimulant effect on the CNS. Adverse CNS effects associated with ephedrine toxicity include anxiety, insomnia, restlessness, psychosis and seizures.(11-14) These effects are especially common when multiple stimulants are involved. Additional signs of ephedrine toxicity include nausea, vomiting, headache, flushing, paresthesias, difficulty in micturation and precordial pain.(11,14) Patients with sympathomimetic toxicity are at an increased risk of rhabdomyolysis.(13) It has also been suggested that sympathomimetic drugs may precipitate thyroid storm in individuals with thyrotoxicosis.(17)

Patients presenting with ephedrine overdose usually have a history of recent ingestion of diet pills, recreational herbal preparations or decongestants. Serum drug levels have not been found to be useful and urine toxicology screens may give a false positive reading for amphetamines when sympathomimetic decongestants are present.(5)

TREATMENT

Due to the rapid absorption of ephedrine, induced emesis with syrup of ipecac is discouraged unless it can be given within a few minutes of ephedra ingestion. Inducing emesis in a symptomatic patient may exacerbate ephedrine-induced hypertension and increase risk for seizure.(2) The exposed patient should be referred to a health care facility for treatment and observation. A dose of activated charcoal with cathartic should be administered as soon as possible to reduce the absorption of ephedrine. Gastric lavage is not beneficial unless it can be performed immediately after ingestion and it is not considered necessary after activated charcoal has been administered.(5) Laboratory monitoring should include electrolytes, glucose, BUN, serum creatinine, and CPK. Monitoring the electrocardiogram is also recommended and a CT head scan should be performed if an intracranial bleed is suspected.(5)

Initial management of ephedra overdose should include supportive care. Efforts should be made to maintain the airway and assist ventilation if necessary. Seizures can be treated with diazepam or lorazepam. Lack of response to these agents may require the use of phenobarbital or phenytoin.(2,5) Hypertension should be treated aggressively if the diastolic pressure is greater than 100 mm Hg, especially in patients without a history of hypertension. Vasodilators, such as phentolamine, nitroprusside, hydralazine and nifedipine, are the preferred agents for treating ephedra-associated hypertension.(2,5) B-blockers should not be used alone to treat hypertension because a hypertensive crisis may result from the unopposed effects of the a1-receptors on the vasculature. Tachyarrhythmias are usually responsive to treatment with lidocaine, low-dose propranolol or esmolol.(2,5,14) Bradyarrhythmias are very rare with ephedrine overdose. Bradycardia in the presence of hypertension may be a compensatory response that should not be treated since it serves to limit hypertension.(5)

Dialysis and hemoperfusion are not considered to be effective for removing ephedrine.(5) Acidifying the urine will enhance the elimination of ephedrine and pseudoephedrine; however, it is not done because it is potentially hazardous to the patient. Patients with ephedra toxicity are at an increased risk for rhabdomyolysis; thus decreasing urine pH can facilitate the precipitation of myoglobin in the renal tubules and lead to acute renal failure.

David H. Tang, RPh Pharm. D. candidate, June, 1996 Massachusetts College of Pharmacy/AHS

References (lead author only)

1. Anonymous. Herbal Roulette. Consumer Reports. November 1995.

2. Anonymous. Ephedrine monograph, In: Poisindex. Micromedex Inc., 1996.

3. Anonymous. University of California at Berkeley Wellness Letter 1994. 10(12):6-7.

4. Associated Press. The Boston Globe, April 11, 1996.

5. Benowitz NL. Phenylpropanolamine and related decongestants. In Olson KR, ed. Poisoning and Drug Overdose, Appleton & Lange, 1994.

6. Bruno A. Neurology1993. 43:1313-6.

7. Burros M. New York Times, April 10, 1996.

8. Chait LS. Psychopharmacology 1994. 113:38 1-7.

9. Huang KC. Ma Huang monograph, In: The Pharmacology of Chinese Herbs. CRC Press, 1993.

10. McEvoy GK, ed., Ephedrine Monograph, In: AHFS Drug Information 1996. American Society of Health System Pharmacists, 1996.

11. Morton JF. Ephedra, In: Major Medicinal Plants - Botany, Culture and Uses. Charles C. Thomas Publishers, 1977.

12. Olin BR, ed., The Ephedras, In: The Lawrence Review of Natural Products. Facts and Comparisons, 1995.

13. Pentel P. JAMA 1984. 252(14):1898-903.

14. Sawyer Clinical Pharmacy 1982. 1:529-33.

15. Tyler V. Herbs of Choice - The Therapeutic Use of Phytomedicinals. Pharmaceutical Products Press, 1994.

16. Tyler V. The Honest Herbal - a sensible guide to the use of herbs and related remedies. Pharmaceutical Products Press, 1993.

17. Wilson BE. Case Report: The American Journal of the Medical Sciences 1993. 306(5):317-9.




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