Ephedra
Botanical Names: Ephedra sinica Stapf., Ephedra equisetina Bunge., Ephedra intermedia Shenk and CA Meyer.
Pharmacopoeial Name: Ephedrae herba.
Common Names: Ephedra, Ma-huang, Ma huang , jointfir.
| Drug/Class Interaction Type | Mechanism and Significance | Management | Acetazolamide
Urinary pH modifiers
 / 
| Probable pharmacokinetic interaction.
Significance not established.
Drug may increase herb levels by renal retention.
| Avoid. | Caffeine, Theophylline
Methylxanthines
| Well-established additive increase in sympathetic adverse events by multiple mechanisms. | Coadministration requires professional assessment and monitoring. | Dexamethasone
Corticosteroids, oral glucocorticosteroids
| Possible pharmacokinetic increase in drug clearance during coadministration.
Significance and applicability to other steroidal drugs unknown.
| Avoid. | Guanethidine
Peripheral adrenergic blockers
| Herb reduces drug action and may greatly increase hypertension when coadministered. | Avoid. | Phenelzine
MAO inhibitors
| Potential for increased sympathetic adverse effects by multiple mechanisms. | Avoid. | Reserpine, clonidine
Sympatholytics
| Herb and drug have directly conflicting pharmacodynamic mechanisms.
Coadministration (unlikely) will impair therapeutic efficacy of drug or herb.
| Avoid. | MAO , Monoamine oxidase. |
Related Species
The three main Ephedra spp. ( E. sinica, E. equisetina, E. intermedia ) are official in the Chinese and Japanese pharmacopoeias. Commercial sources also include E. distachya L. and E. geradiana Wall. ex Stapf. The latter is common in medicinal use in India. The North American species known as Mormon or Brigham Tea ( E. nevadensis S. Wats.) contains little or no alkaloid and is not used medicinally.
Habitat and Cultivation
Widespread perennial shrub native to China, Mongolia, Tibet, Siberia, Japan, India, Pakistan, and Afghanistan; it is also extensively cultivated.
Parts Used
Dried aerial parts (stems); the roots and rhizomes, known as Ma Huang gen , are a separate medicinal agent in Chinese medicine with distinct actions and uses.
Common Forms
- Tincture: 1:4, 45% alcohol (BHP).
- Standardized Extracts: Unavailable.
Alkaloid content of ephedra-containing dietary supplement combinations in the United States and elsewhere are often not accurately labeled, and significant product variability has been demonstrated. Crude herb extracts are subject to seasonal and species variations in alkaloid content. Ephedra is a component of several commercially available Chinese standard formulae.
Overview
Ephedra has a long history of use in Chinese medicine, dating from 3100BCE. Some authorities consider ephedra to be the mythical soma plant of the Vedas. Traditionally, ephedra, or Ma Huang, has been used as a bitter warming herb for feverish and catarrhal conditions of the respiratory tract. Currently, regulatory restrictions permitting, it continues to be used clinically for its traditional indications, including bronchial asthma, allergic rhinitis, and as a diaphoretic in colds and influenza in both Western and Chinese medical formulations.
The activity of the crude herb is dominated by sympathomimetic phenethylamine alkaloid constituents, principally ephedrine and pseudoephedrine. Synthetic (racemic) ephedrine itself was produced by Merck in 1926 and introduced into clinical medicine as a treatment for pediatric asthma in 1927; thereafter it rapidly replaced epinephrine because it could be orally administered. Then, as now, the undesirable central stimulating effects of ephedrine were considered limiting factors on its clinical use.
Ephedra monographs by both the World Health Organization (WHO) and the German Commission E support its traditional use for catarrhal conditions of the respiratory tract. The clinical literature on ephedra appears extensive but actually is dominated by a persistent confusion of the crude herb with isolated ephedrine alkaloid. To a limited degree, pharmacokinetic and pharmacodynamic data suggest a similarity between crude ephedra and ephedrine, and the general sympathomimetic activity of ephedra is broadly correlated with ephedrine content. However, aspects of ephedra pharmacology, such as cytotoxicity or phosphodiesterase inhibition, cannot be attributed to ephedrine alone. In answer to the question of whether there is full equivalence between synthetic ephedrine and ephedra, eminent German phytotherapist Weiss replied, “On the whole yes, but not quite.”
The problems of literature interpretation and data comparison are compounded by the variable ingredients and combinations of agents contained in dietary supplements marketed as “weight loss” products that have been used in clinical trials. Caffeine or caffeine-containing herbs such as guaraná (Paullinea cupana) may be present, with aspirin or salicylate-containing herbs such as willow bark (Salix alba) sometimes combined with micronutrients such as trivalent chromium. Most recent trials have invariably examined these combination products and often incorrectly describe the results as referring to “ephedra.” This in turn casts some methodological doubts on metastudies such as the Cantox and RAND reports, and although both reviews acknowledged the problem, their conclusions should be critically qualified in this regard.
In the U.S., ephedra-containing supplements previously permitted under the Dietary Supplement Health and Education Act (DSHEA) have been banned since 2003, largely because of inappropriate consumption of ephedrine-containing weight loss and “natural stimulant” products resulting in a significant number of adverse events (see Note: Regulation, Safety, and Ephedra Weight Loss Products).
Historical/Ethnomedicine Precedent
Chinese traditional uses include acute wind-cold syndromes (characterized by chills, mild headaches, fevers without sweating, runny or stuffy nose, and body or joint aches) as well as bronchial asthma and allergic rhinitis. Several millennia-old classical Chinese formulae contain Ma Huang, including Ma Huang Tang (ephedra decoction), She Gan Ma Huang Tang (belamcanda and ephedra decoction), Ge Gan Tang (pueraria decoction), and Xiao Qing Long Tang (minor blue dragon decoction). In these combinations, ephedra comprises 15% to 25% of the total prescription, delivering 60 to 90 mg total alkaloid daily at normal adult dose levels.
In Chinese medicine, a further distinction is made between the stems of the plant, Ma Huang, and the root, Ma Huang gen . The roots contain dimeric flavonols and macrocyclic alkaloids not found in the aerial parts. In Chinese medicine the root is considered antisudorific, used for night sweats and excessive perspiration, whereas the stem is diaphoretic.
Known or Potential Therapeutic Uses
Asthma, coryza of common colds, fevers, allergic and vasomotor rhinitis, hives, and topical use for insect bites, stings, and allergic irritations of the skin and enuresis.
A recent comprehensive meta-analysis of these trials supports a moderate short-term weight loss effect from ephedra alkaloids when combined with stimulants such as caffeine. Ephedrine and pseudoephedrine are approved for use in over-the-counter (OTC) bronchodilator and nasal decongestant products. Ephedrine has limited use in the hospital setting for the management of hypotension during epidural block and inhalational anesthesia in the operating room (intravenous and intramuscular). Ephedrine has been historically used as a mydriatic and also as a pharmacotherapeutic agent for Stokes-Adams heart block, for enuresis, and for myasthenia gravis, in which latter its mechanism of action is unclear. Some herbal texts also mention the latter two indications, but these are not general practice today, although some urologists continue to investigate the use of ephedrine for enuresis.
Key Constituents
Phenylethylamine alkaloids, from approximately 0.5% to more than 2.4% total. (See Note.)
Catechin tannins, including epicatechin and epigallocatechin as well as catechin and gallocatechin.
Volatile oil, including terpinol, cineole, and tetramethylpyrazine; biflavonols.
The roots contain dimeric flavonols and spermine alkaloids not found in the stems.
Note: Proportions of the different alkaloids vary. The majority is 1R,2S-ephedrine (up to 80%), which occurs alongside the optical isomer 1S,2S-pseudoephedrine and their corresponding nor- and methyl- derivatives. The ratio of ephedrine to pseudoephedrine is variable and even reversed in some minor species of Ephedra . Alkaloid composition can be used to “fingerprint” product samples containing ephedra herb because of the four possible optical isomers of ephedrine, only 1R,2S-ephedrine and 1S,2S-pseudoephedrine occur naturally.
Therapeutic Dosing Range
Adults
- Dried prepared herb for traditional decoction: 3 to 9 g daily. Typical recommended doses in Chinese and Western herbal practice deliver between 60 to 90 mg total alkaloid daily.
- Commission E: 15 to 30 mg single dose and maximum of 300 mg daily total ephedra alkaloid.
- OTC ephedrine: Up to 150 mg alkaloid daily.
- OTC pseudoephedrine: Up to 240 mg alkaloid daily.
Children
Not to be administered to children under 6 years of age.
Pediatric dose up to 0.5 mg total alkaloid per kg body weight daily; according to Commission E and WHO figures.
Strategic Considerations
Ephedra alkaloids act as combination direct and indirect sympathomimetic agents at all alpha and beta adrenoceptor subtypes and have multiple effects on catecholamine pathways. As a result, ephedra may interact with a variety of drugs that directly target the sympathetic nervous system. They may also indirectly interact with other classes of drug, such as antihypertensives or antiarrhythmics that do not directly affect the adrenergic pathways.
Within an integrative medical setting, however, the use of ephedra-containing formulae for traditional indications is limited and largely unproblematic when used by professionals trained in botanical medicine. Using traditional formulation models, ephedra is combined with other herbs that mitigate its “warming” energetics and the central nervous system (CNS) stimulatory aspects of its actions. The proportion of ephedra in a given formula is rarely more than approximately 15% to 20% of the total. Administered at therapeutic doses for traditional indications, ephedra is generally considered safe. This is supported by the complete absence of adverse event reports associated with administration of the crude herb or crude herb extracts either alone or in traditional formulations, as opposed to isolated alkaloid in multi-ingredient commercial preparations. Ephedra alkaloids are not degraded by monoamine oxidase, lacking the necessary hydroxyl configuration, and are excreted almost entirely unchanged renally, with a half-life of 3 to 5 hours.
Adverse effects of the herb result from the CNS stimulatory actions and sympathomimetic actions and include insomnia, anxiety, tachycardia, tremors, and at higher doses, arrhythmias and increased blood pressure. Prolonged and repetitive use may induce tachyphylaxis, but suggestions of “dependency” are not corroborated by clinical reports. Nonclinical toxicological data is based on studies of the isolated alkaloids, principally ephedrine. Clinical data on safety are derived from adverse drug reactions (ADRs) noted in clinical trials on weight loss, and anecdotal reports following initial use or with abuse of ephedrine-containing combination weight loss products.
Assuming normal clinical practice and basic professional physiology and pharmacology knowledge, ephedra herb and its crude extracts do not present any hazardous interactions issues, despite the recent increases in adverse reports related to weight loss dietary supplements and isolated alkaloids (see Note: Regulation, Safety; and Ephedra Weight Loss Products). Professional management of ephedrine interactions for therapeutic purposes also occurs within the hospital setting, typically in relation to management of anesthesia-induced hypotension.
Acetazolamide (Diamox, Diamox Sequels), aluminum hydroxide, ammonium chloride, kaolin clay, sodium bicarbonate. | | Adverse Drug Effect on Herbal Therapeutics—Strategic Concern | | Interaction Likely but Uncertain Occurrence and Unclear Implications |
Probability:
4. PlausibleEvidence Base:
EmergingEffect and Mechanism of Action
This pharmacokinetic interaction causes retention of ephedrine and pseudoephedrine (and amphetamine) by means of reduced urinary elimination under alkaline conditions. As pH rises, the p Ka of ephedrine favors the nonionic association form, which is more lipophilic and reabsorbable at the nephron. This effectively reduces clearance and increases half-life.
Research
The mechanism of this interaction has been experimentally established in animals and humans using ephedrine and ammonium chloride, as well as with pseudoephedrine and ammonium hydrochloride.
Reports
Reports of this ADR in patients are rare. After encountering the interaction in a patient with persistently alkaline urine, Brater et al. studied ephedrine and pseudoephedrine excretion in normal patients and those with renal acidosis. They concluded that the rate of flow of urine as well as pH affected the elimination of ephedrines.
Clinical Implications and Adaptations
Although acetazolamide is usually listed as the interacting agent, this is an extrapolation from the studies with inorganic alkalizing compounds. The further extension from ephedra alkaloids to ephedra herb adds an additional layer of imponderability to the clinical significance and implications of this interaction, which is therefore of unknown or problematic status.
- Caffeine (Cafcit, Caffedrine, Enerjets, NoDoz, Quick Pep, Snap Back, Stay Alert, Vivarin); combination drugs: acetylsalicylic acid and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA, codeine, butalbital, and caffeine (Fiorinal); acetaminophen, butalbital, and caffeine (Fioricet).
- Theophylline/aminophylline (Phyllocontin, Slo-Bid, Slo-Phyllin, Theo-24, Theo-Bid, Theocron, Theo-Dur, Theolair, Truphylline, Uni-Dur, Uniphyl); combination drug: ephedrine, guaifenesin, and theophylline (Primatene Dual Action).
| | Minimal to Mild Adverse Interaction—Vigilance Necessary |
Probability:
1. CertainEvidence Base:
0 ConsensusEffect and Mechanism of Action
The effects of ephedrine on weight loss through thermogenesis, lipolysis, and appetite suppression are potentiated by caffeine. Frequency and severity of sympathomimetic adverse events, principally palpitations, tachycardia, agitation, and insomnia, are also increased when theophylline or caffeine are coadministered with ephedrine.
Research
Numerous studies have shown the combination of caffeine and ephedrine moderately increases weight loss, whereas the agents administered separately show little or no effect. The mechanism of the interaction is multifactorial. Methylxanthines antagonize adenosine receptors and are phosphodiesterase (PDE) inhibitors. Their action on the cardiovascular system is complex, mediated by brainstem vasomotor and vagal centers as well as by direct effects on the vascular and cardiac tissues, mediated by both catecholamines and the renin system. At higher doses, caffeine and theophylline definitely induce tachycardia and are proarrhythmic, with sensitive individuals likely to experience premature ventricular contractions (PVCs). As with the ephedra alkaloids, caffeine is also centrally stimulating, and in methylxanthine-naive individuals, administration of caffeine or theophylline can cause elevation of circulating epinephrine and initial hypertension; however, tolerance rapidly develops. Caffeine alone is not associated with increased frequency of arrhythmia in normal subjects or those with history of ventricular ectopy.
In a recent study on a proprietary formulation (Metabolife 356) containing 12 mg ephedra extract and 48 mg caffeine, among several other ingredients, single dosing caused significant prolongation of QTc interval, at levels associated with possible torsades de pointes arrhythmia in conventional drugs (∼30 msec prolongation). However, a long-term rodent study showed no effects on metabolic cardiac parameters after 1 year of ephedrine-caffeine administration at 10 times the normal human dose. Interestingly, crude ephedra has been shown to have PDE inhibitory activity that is not exhibited by pure ephedrine. Theophylline is generally more potent than caffeine in its effects; it was often combined with ephedrine in nasal decongestant products before more selective adrenergic blockers became available. An early study found the theophylline-ephedrine combination no more effective than theophylline alone in 23 asthmatic children, whereas the ADR rate was higher for the combination than for theophylline. Another study of asthmatic children, however, showed no additional adverse effects from the combination.
Reports
Shekelle et al. reviewed hundreds of ADR reports from the ephedrine-caffeine combination in the RAND study and concluded the quality of data was too poor to draw conclusions about a causal association of the ADRs with the combination. At the same time, they noted that clinical data suggest that the combination is associated with a significant risk of nausea, vomiting, anxiety, mood changes, autonomic hyperactivity, and palpitations. Other researchers, however, have concluded that adverse effects during trials involving the combination are not significant.
Clinical Implications and Adaptations
Any synergy of effect on weight loss from the ephedrine-caffeine combination is largely offset by associated increase in adverse effects. Professional management, screening of at-risk patient groups, and therapeutic monitoring might largely preclude the development of serious adverse effects from the combination. However, pharmacotherapy for obesity does not generally favor use of herbal combination products, and integrative approaches to obesity do not emphasize pharmacotherapy. In traditional use, ephedra is not combined with other stimulants, and obesity is not considered an indication for ephedra herb. Therefore the notoriety attached to the interaction of these agents is incommensurate with the significance of the issue in informed clinical practice.
- Evidence: Dexamethasone (Decadron).
- Related but evidence lacking for extrapolation: Betamethasone (Celestone), cortisone (Cortone), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol), prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort).
| | Interaction Likely but Uncertain Occurrence and Unclear Implications |
Probability:
3. PossibleEvidence Base:
EmergingEffect and Mechanism of Action
A pharmacokinetic interaction is possible whereby the clearance of dexamethasone is increased during concurrent ephedrine administration.
Research
The mechanism of this interaction was experimentally established in nine asthmatic patients, comparing the effects of ephedrine, theophylline, and placebo on airway symptoms. The interaction apparently does not occur between theophylline and dexamethasone. This finding helped tilt bronchodilator products for asthmatic patients away from ephedrine and toward theophylline.
Reports
Despite some cautions in the drug interactions literature, the importance and significance of this interaction remain problematic, and extension to other glucocorticoids has not been established.
Clinical Implications and Adaptations
The implications of this interaction are unclear, other than monitoring concurrent corticosteroid and ephedra use.
- Evidence: Guanethidine (Apo-Guanethidine, Ismelin).
- Similar properties but evidence lacking for extrapolation: Betanidine (Esbatal, Regulin), bretylium, debrisoquine, guanadrel (Hylorel).
| | Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability:
1. CertainEvidence Base:
0 ConsensusEffect and Mechanism of Action
Guanethidine and related drugs are prevented from entering, and are displaced from adrenergic neurons by, sympathomimetics. This abolishes the hypertensive effect of the blockading drug and also results in superadditional hypertensive effects because of the release of norepinephrine from the presynaptic terminal by ephedrine-induced indirect stimulation.
Research
The mechanism of this established interaction has been confirmed experimentally in humans and cats with amphetamine. In a clinical study involving 16 hypertensive patients maintained on 25 to 35 mg guanethidine, Gulati et al. observed abolition of the effects of guanethidine, as well as hypertension in excess of the treatment level, when subjects were treated concurrently with a range of oral sympathomimetics, including ephedrine.
Reports
Despite clinical confirmation of the underlying mechanism of the interaction, recent reports of its occurrence are lacking. Also, it is unclear to what extent this is an issue with the combination of sympathomimetic alkaloids in ephedra herb or crude extracts. The German Commission E suggests that the interaction may “enhance the sympathomimetic effect,” which presumably refers to the experimentally confirmed fact that peripheral adrenergic blockade causes a hypersensitization of the postsynaptic receptors to directsympathomimetic stimulation. The significance of this in practice with mixed sympathomimetics is unknown, although guanethidine and epinephrine are known to result in exaggerated pressor and mydriatic responses.
Clinical Implications and Adaptations
Although this must be viewed as a serious and an established interaction, the poorly tolerated guanethidine is no longer in widespread use for hypertension as it was in the 1970s. The newer derivatives are restricted to use in cases where other blocking agents (e.g., reserpine, methyldopa) have unacceptable CNS adverse effects. The clinical significance of the interaction is therefore limited in practice, although it is usually often cited without qualification as a principal ephedra-drug interaction in the herbal literature.
- MAO-A inhibitors:Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).
- MAO-B inhibitors:Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl), rasagiline (Azilect).
| | Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability:
1. CertainEvidence Base:
0 ConsensusEffect and Mechanism of Action
As indirect and direct sympathomimetics, ephedra alkaloids have “double” potential to cause rapid elevations of epinephrine at adrenergic and noradrenergic terminals if cytosolic monoamine oxidase (MAO) is inhibited. Monoamine oxidase inhibitors (MAOIs) cause presynaptic epinephrine accumulation. Ephedra will both promote release of the accumulated presynaptic epinephrine and simultaneously have a direct stimulating effect on the postsynaptic receptors itself. Exaggerated pressor responses will result, with possible hypertensive crisis or hemorrhagic stroke.
Research
The sympathomimetic action of ephedra alkaloids is well established. However, the literature seldom mentions that ephedrine, pseudoephedrine, and norephedrine are themselves all unlabeled MAOIs, although weak and reversible in character. Thus, they may also affect levels of 5-hydroxytryptamine (5-HT, serotonin) and dopamine both centrally and peripherally, as well as interact with tyramine-containing foods such as aged cheese and red wine. The manufacturers of serotonin agonists such as sibutramine caution against combining with ephedra alkaloids. Although a theoretical basis for this may exist because of the MAOI-like action of ephedra, the risk of serotonin syndrome is apparently low, and reports are lacking. Theoretically the newer, selective MAO-A or MAO-B drugs should be less interactive, but reports show that moclobemide increases the pressor action of ephedrine twofold to fourfold in healthy volunteers. On the other hand, a recent case report describes ephedrine and phenylephrine being used uneventfully to control hypotension during epidural anesthesia in a patient taking moclobemide.
Reports
The standard drug interactions literature through the 1960s and 1970s contains isolated reports of fatal intracranial and subarachnoid hemorrhage, but these refer to amphetamines combined with older MAOI drugs. More recently, concerns have been raised about a renewed increase in occurrence of this interaction caused by the increased use of ephedrine-containing weight loss products.
Clinical Implications and Adaptations
The older, nonselective, irreversible MAOIs, whether prescribed for hypertension or depression, should never be combined with indirect sympathomimetics. Even the newer, selective, reversible MAOIs should not be combined with sympathomimetics. This established and serious drug interaction can be plausibly extended to ephedra. After use of irreversible MAOIs, renewed MAO synthesis takes time, and 2 weeks has been suggested as a safe period after which ephedrine can be administered.
- Clonidine (Apo-Clonidine, Catapres Oral, Catapres-TTS Transdermal Dixarit, Duraclon, Novo-Clonidine, Nu-Clonidine); combination drug: clonidine and chlorthalidone (Combipres); methyldopa (Aldomet); combination drugs: methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); reserpine (Harmonyl).
| | Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability:
3. PossibleEvidence Base:
EmergingEffect and Mechanism of Action
Although each of these agents has somewhat different mechanisms of action, they can be considered as a group because their interaction is theoretically likely to induce the adverse effect of hypertension. The rauwolfia alkaloids exert their sympatholytic effects through depletion of epinephrine and norepinephrine at the presynaptic vesicles. This has the dual effect of sensitizing the postsynaptic receptors to direct sympathomimetics and rendering indirect (presynaptic) sympathomimetics ineffective. Mixed direct and indirect sympathomimetics are likely to have mixed effects in combination with reserpine. Clonidine is a central alpha agonist that reduces peripheral sympathetic outflow; methyldopa may act in a similar manner.
Research
Early experiments in dogs, in vivo and in vitro, suggest that the pressor effects of indirect sympathomimetics are reduced or abolished by reserpine. Human data are sparse, but patients undergoing ocular surgery who were already taking reserpine were found to have blood pressure elevations of +30/+13 mm Hg after administration of phenylephrine eyedrops. There are no data on the methyldopa-ephedrine combination; however, an 80-patient trial, in which subjects were pretreated with clonidine, showed a blood pressure augmentation when given intravenous ephedrine at 0.1 mg/kg in both anesthetic and waking control groups.
Reports
Clinical reports of ADRs from interactions involving these combinations are unavailable.
Clinical Implications and Adaptations
There are obvious pharmacological implications of combining sympatholytics with sympathomimetics. Concurrent prescription would be unusual, which may account for the lack of adverse effect reports. Reserpine is rarely used in hypertension treatment, although rauwolfia herbal extracts are frequently used in natural medicine as short-term hypotensives, usually with a holding strategy while implementing long-term lifestyle and dietary changes. The methyldopa interaction remains speculative, and the clonidine interaction is of questionable practical importance.
Deslanoside (cedilanin-D), digitoxin (Cystodigin), digoxin (Digitek, Lanoxin, Lanoxicaps; purgoxin), ouabain (g-strophanthin).
Commission E suggests the interaction between ephedra and cardiac glycosides, citing increased risk of arrhythmias. Despite the large repertoire of known interactions associated with digoxin, there are no reported interactions between digoxin (or other cardiac glycosides) and ephedrine (or other sympathomimetics) in the drug interaction literature. In clinical practice the interaction is unlikely.
Desflurane (Suprane), enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), sevoflurane (Sevorane, Ultane).
Commission E warns that ephedra interacts with halothane. Halothane was a primary inhalational anesthetic for more than 25 years. It has largely been replaced by related halogenated derivatives (enflurane, isoflurane, desflurane, sevoflurane) because of concerns of postoperative hepatic necrosis associated with halothane. The ability of these agents to sensitize the myocardium to arrhythmia is well known in anesthesiology and probably underlies Commission E's position, although this is not stated.
The halothane “interaction” is arguably a misleading one, especially in the context of consumer-oriented literature. Administration of intramuscular or intravenous ephedrine remains the best choice in management of anesthetic-induced hypotension, both for epidural block and with propofol and sevoflurane. In other words, the interaction is beneficial with appropriate management. Advice to disclose ephedra use, along with any other relevant herbs and supplements, before surgery is more appropriate to anesthesia management issues than repeating solemn warnings to the general public about the danger of interactions with an inhalational anesthetic that is no longer generally used.
Oxytocin (Pitocin, Syntocinon).
Commission E lists the interaction between ephedra and oxytocin. Oxytocin causes vascular relaxation and hypotension with reflex tachycardia. There are no reports of oxytocin and ephedrine interactions, and the probability of concurrent administration clinically is remote because induction of labor is an unlikely context for ephedrine use. This interaction may be regarded as speculative.
Buformin (Andromaco Gliporal, Buformina), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol; Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase, Glynase Prestab, Micronase, Pres Tab), insulin (animal-source insulin: Iletin; human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin), metformin (Dianben, Glucophage, Glucophage XR); combination drugs: glipizide and metformin (Metaglip), glyburide and metformin (Glucovance); phenformin (Debeone, Fenformin), tolazamide (Tolinase), tolbutamide (Orinase, Tol-Tab).
An antagonistic interaction between ephedra and hypoglycemics such as insulin has been implied by some secondary sources. There is no evidence for this interaction, and, in fact, ephedra extracts have hypoglycemic activity and pancreatic islet regenerative effects.
Commission E suggests an interaction between ephedra and “secale alkaloids” (i.e., ergotamine derivatives from the rye grass fungus Clavicepsspp.), presumably based on theoretical additive pressor effects. Because ergotamine derivatives are primarily used in postpartum hemorrhage or as migraine prophylaxis, the interaction is clinically improbable. The drug interactions literature lacks any reports of this interaction, and its repetition by secondary sources is presumably derived from the original, unsubstantiated claim in Commission E.
Ephedrine-containing dietary supplements sold as weight loss aids have been associated with numerous adverse event reports in the U.S., including hypertension, tremors, myocardial infarction and hemorrhagic stroke. After a long controversy, this led the Food and Drug Administration (FDA) to invoke a sweeping restriction on the public sale of ephedra-containing products in 2003, directed specifically at commercial weight loss supplements. Subsequent clarification has effectively granted limited access to licensed practitioners of Chinese medicine. As of 2007, this regulation remains in force. In the context of practitioner-level information, political and regulatory concerns over weight loss products containing ephedra alkaloids are of secondary importance; the primary interactions issue is the underlying ephedra alkaloids–methylxanthine interaction.
Two major comprehensive reviews of safety and toxicity data on ephedrine-containing weight loss products are available. The RAND report of Shekelle et al. also reviewed efficacy trials for weight loss and athletic performance enhancement. None of these clinical trials or case reports involved ephedra crude herb alone, but only combinations of herbal extracts or isolated ephedrine with stimulants such as caffeine. The RAND report analyzed adverse event data from both clinical trial reports and postmarketing pharmacosurveillance sources, including reports to the FDA's MEDWATCH, and data from the customer files of a major weight loss product manufacturer (HerbaLife). The reviewers concluded that ephedrine-containing formulations are associated with a significant risk of nausea, vomiting, anxiety, mood changes, autonomic hyperactivity, and palpitations. Their meta-analysis of the clinical trials on weight loss confirmed that products combining ephedrine with caffeine were capable of producing short-term weight loss of about 1 kg (2.2 lb) per month compared with placebo.
The possible role of adrenoceptor (AR) polymorphisms as an explanatory factor in the variability of weight loss data has not been considered by these reviewers, despite its known relevance to obesity. The precise contribution of direct receptor interaction, indirect release of endogenous catecholamines, or reuptake inhibition to the overall action of ephedrine remains unclear. Recently, ephedrine has been shown to act directly on the human beta-3 AR, which is involved in lipolysis in human brown adipose tissue as well as thermogenesis, which may explain the moderate effects on short-term weight loss, especially combined with the central anorectic properties of the phenylethylamines. The emerging pharmacogenomic data on AR polymorphisms may partially explain the variable results with obesity and could theoretically support more effective drug targeting of ephedrine in obese patient populations. However, the “therapeutic gap” between current AR polymorphism data and their implications for clinical practice remains sizable.
Several sympathomimetic agents are licensed as prescription medications for short-term use (<12 weeks) in weight loss, including benzphetamine and phendimetrazine, both of which are FDA Schedule III because of their abuse potential. Phenylpropanolamine (PPA), which is identical to norpseudoephedrine found in ephedra, was recently withdrawn from the market because of concerns about hemorrhagic stroke in women. However, the norpseudoephedrine content in ephedra is generally very low, and although a small proportion of ephedrine may also be metabolized to norephedrine, the threshold dose of PPA considered to constitute a risk for hemorrhagic stroke is 75 mg/day. A recent case-control study found no association between ephedrine use and hemorrhagic stroke.
Meanwhile, research and trials continue on new pharmacological interventions for obesity, with recent emphasis on selective beta-3 AR agonist drugs. Despite the prevalence of overweight and obesity and the alarming rate of increase in obesity-related conditions, the overall understanding of this multifactorial condition and the efficacy of current pharmacological treatments remain limited.
The adverse events reviewed by RAND and others can be extrapolated to ephedra herb with some minor qualifications. The crude herb contains tannin constituents that have angiotensin-converting enzyme (ACE)–inhibiting activity, as well as multiple constituents that include organic acids, flavonoids, and volatile oils that will modulate the alkaloid-fraction effects. It is plausible that extrapolations from ephedrine effects will be overly conservative with respect to the crude herb. Again, these studies used combinations with caffeine or caffeine-containing herbs.
Classic pressor responses have been established for the crude herb, but the dose-response kinetics are significantly slower than for pure ephedrine, and the pressor response is small, with considerable individual variation. Nephrolithiasis has been reported recently after crude herb consumption; the urologists’ search of the Louis C. Herring and Company kidney stone database show that this is an endemic complication of ephedrine, with hundreds of previous episodes. At the same time, one experimental study has showed a significant reduction of uremic toxins after administration of aqueous crude herb extract in an animal model of renal failure.
The recent banning of ephedra-containing weight loss products by the FDA has changed the degree to which undisclosed use of ephedra may be a potential danger in most cases. The market for weight loss products remains active, and “ephedra-free” formulations are available to the public that attempt to circumvent regulatory restrictions, based on extracts of Citrus aurantium(bitter orange), which contains the mildly sympathomimetic alkaloid synephrine. Lipolytic effects in human adipocytes have been demonstrated, but convincing evidence for efficacy of the extract as a weight loss aid is not currently available.
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