VA Class:AU100

AHFS Class:

• alpha- and beta-Adrenergic Agonists 12:12.12

Generic Name(s):

• Ephedrine Hydrochloride

• Ephedrine Sulfate

Chemical Name:

• [ R -( R *, S *)]-α-[1-(Methylamino)ethyl]-benzenemethanol hydrochloride

• [ R -( R *, S *)]-α-[1-(Methylamino)ethyl]-benzenemethanol sulfate

Molecular Formula:

• C₁₀H₁₅NO • HCl

• (C₁₀H₁₅NO)₂ • H₂SO₄

Ephedrine is a sympathomimetic agent that occurs naturally in plants of the genus Ephedra ; ephedrine stimulates both α- and β-adrenergic receptors.172,178,200

Hypotension During Anesthesia

Ephedrine is used parenterally as a vasopressor for the treatment of hypotension during anesthesia.178,200,247,249,250,251,252,255 Ephedrine sulfate injection is labeled by the US Food and Drug Administration (FDA) for the treatment of clinically important hypotension occurring in the setting of anesthesia.200 Because ephedrine sulfate injection was introduced into the US market before 1962 without an approved new drug application (NDA), some commercially available preparations may not be approved by the FDA.178,256,257

Evidence supporting the efficacy of ephedrine for this indication is based principally on data from the published literature demonstrating that the drug increases systolic and mean arterial blood pressures when administered as a direct IV (“bolus”) injection following the development of hypotension in patients undergoing neuraxial (spinal/epidural) and/or general anesthesia.178,200,252 In these studies, ephedrine was administered as either the sulfate or hydrochloride salt forms of the drug; however, only ephedrine sulfate is commercially available in the US as a parenteral preparation.178,200,252 Although IM use of ephedrine also has been evaluated in this setting, results of studies using IM ephedrine have been equivocal.255 The majority of patients who received ephedrine for the treatment of hypotension in these clinical studies were pregnant women undergoing cesarean section with neuraxial anesthesia.200,252 Although ephedrine historically has been considered the vasopressor of choice for the treatment of hypotension in obstetric anesthesia, there is some evidence suggesting that phenylephrine may provide a more favorable fetal acid-base balance.247,248,249,250,251,255 Experts currently recommend the use of either IV ephedrine or phenylephrine for the treatment of hypotension during neuraxial anesthesia; however, consideration should be given to selection of phenylephrine in the absence of maternal bradycardia because of improved fetal acid-base status in uncomplicated pregnancies.255

Ephedrine also has been used with limited success for the prevention of hypotension† in patients undergoing spinal anesthesia;250,253 however, routine prophylactic use of vasopressors has been questioned because hypotension does not always occur during spinal anesthesia and treatment can readily be instituted if necessary. In addition, IV ephedrine has been associated with an increased incidence of hypertension when given prophylactically.200

Bronchospasm

Asthma

Ephedrine is used orally as a bronchodilator for the symptomatic treatment of asthma.176,198,220,221,222 Preparations containing ephedrine hydrochloride or ephedrine sulfate in fixed-combination with guaifenesin are used as self-medication for the temporary relief of mild symptoms of intermittent asthma (e.g., wheezing, chest tightness, shortness of breath).176,198,199 Once a diagnosis of asthma has been confirmed by a clinician, use of a nonprescription (over-the-counter, OTC) bronchodilator may be appropriate in patients with mild symptoms of intermittent asthma; because asthma may be life-threatening, those with more severe asthma (i.e., persistent asthma) or worsening asthma (symptoms not relieved within 60 minutes or with maximum recommended dosages of ephedrine, increasing frequency of asthma attacks) should consult a clinician for other treatment options.199 A single-ingredient oral ephedrine sulfate preparation no longer is commercially available in the US.175 Ephedrine sulfate also has been used parenterally for the treatment of bronchial asthma; however, currently available parenteral preparations of the drug are not FDA-labeled for this use.178,200

While oral ephedrine was once widely used for its bronchodilating effects in the management of reversible airway obstruction,221,224 the drug generally has been replaced by more selective and rapid-acting agents (e.g., inhaled β₂-adrenergic agonists); ephedrine is not recommended as a drug of choice for the rapid relief of asthma in current asthma management guidelines.176,198,199,223,224,225 In the stepped-care approach to antiasthmatic therapy, most experts currently recommend use of a selective, short-acting inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) on an intermittent, as-needed basis in all patients with asthma to control acute symptoms (e.g., cough, wheezing, dyspnea).191,192 Alternatives to short-acting inhaled β₂-agonists recommended by some clinicians for relief of acute asthma symptoms include an inhaled anticholinergic agent (e.g., ipratropium), a short-acting oral β₂-agonist, or a short-acting theophylline (provided extended-release theophylline is not already used), but these alternatives have a slower onset of action and/or a greater risk of adverse effects.193

Expectorants such as guaifenesin are used in combination with ephedrine to help loosen and thin bronchial secretions and facilitate the removal of mucous from bronchial passageways.176,177,198 However, use of expectorants in the management of asthma has been questioned by the FDA because of insufficient evidence supporting their use and inconsistency of such treatment with the pathogenesis of the disease.177 Increased sputum production is not a common feature of asthma; thus, patients with mild asthma (the population for whom self-medication with OTC drugs may be appropriate) generally do not require expectorant therapy.177 Furthermore, expectorants are not recommended in current asthma management guidelines.177 Based on these factors, FDA currently believes that there is no role for expectorants in the routine pharmacologic management of asthma and no longer considers the combination of an oral bronchodilator (i.e., ephedrine) and an expectorant (i.e., guaifenesin) rational therapy for patients with mild asthma.177

Ephedrine also has been administered concomitantly with theophylline in the treatment of asthma;28,221 however, the combination of ephedrine and theophylline was shown in a study in asthmatic children to be no more effective than theophylline alone and was associated with an increased incidence of adverse effects.28,29

Nasal Congestion

Ephedrine has been administered orally as a nasal decongestant, but is of doubtful value when used for this condition. Extensive clinical experience indicates that ephedrine produces nasal decongestion when solutions of 0.5-3% (nasal solution no longer commercially available in the US) are applied topically to the nasal mucosa; however, controlled clinical studies supporting its effectiveness are lacking. Rebound congestion and tachyphylaxis may occur within a few days when ephedrine is used topically as a nasal decongestant.

As part of its ongoing review of OTC drug products, FDA has determined that any cough and cold preparation containing an oral bronchodilator active ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any other ephedrine salt) in combination with any analgesic, analgesic/antipyretic, anticholinergic, antihistamine, oral antitussive, or stimulant (e.g., caffeine) active ingredient generally is not recognized as safe and effective for self-medication .174 Such a combination is considered by the FDA to be a new drug and misbranded, and cannot be marketed for OTC cough and cold use unless it is the subject of an approved new drug application.174

Obesity

Because of its anorexigenic effects, ephedrine alone or combined with caffeine129,130 has been used for self-medication in the management of exogenous obesity†.181,184,185 (See Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations under Uses: Misuse and Abuse.)

Efficacy and safety of ephedrine and dietary supplements containing ephedra (a plant that contains several ephedrine alkaloids) have been assessed in numerous controlled studies involving several hundred individuals receiving the preparations for exogenous obesity†.181,184,185 Retrospective analysis of pooled data from these studies indicates that short-term (8 weeks up to 4 months) use of ephedrine (high doses), ephedrine combined with caffeine, or dietary supplements containing ephedra with or without herbs containing caffeine was associated with statistically significant, albeit modest, short-term weight loss when compared with placebo.181,184,185 The addition of caffeine to ephedrine moderately increases short-term weight loss.181,185 There is no evidence that the effect on short-term (up to 4-6 months) weight loss of dietary supplements containing ephedra combined with caffeine differs from that of ephedrine combined with caffeine; use of both drug combinations was associated with increased weight loss (about 0.9 kg more per month) compared with placebo.181,185 Safety and efficacy of long-term (i.e., more than 6 months) use of ephedrine for management of obesity have not been established.181,184,185 Because substantial weight loss (5-10% of baseline body weight) and long-term weight maintenance are necessary to improve health outcomes and reduce the risk of morbidities associated with obesity, the benefit of short-term weight loss associated with ephedrine or ephedra on health outcomes currently is not known.181,184 (See Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations under Uses: Misuse and Abuse.)

Other Uses

Ephedrine has reportedly been used orally with good results for the management of peripheral edema secondary to diabetic neuropathy† in a few patients with type 1 diabetes mellitus.100

Ephedrine has been used in patients with myasthenia gravis†.178,226 Limited data suggest that the drug may improve muscle weakness, fatigue, and quality of life in some patients with myasthenic conditions; however, randomized controlled studies are needed to further evaluate these potential benefits.178,226

Ephedrine also has been used as a CNS stimulant in the treatment of narcolepsy† or depressive states†; however, the cardiovascular effects of the drug limit its usefulness in these conditions, and it has been largely replaced by other CNS stimulants.

Ephedrine sulfate also has been used in the treatment of Stokes-Adams disease†; when used for this condition, ephedrine provides a similar benefit to that of epinephrine.178

Misuse and Abuse

Enhancement of Athletic Performance

Because of its stimulant effects, ephedrine has been misused and abused by athletes, bodybuilders, weight lifters, and others, including high school- and college-aged individuals engaged in sports.181 Evidence from several surveys indicates that about 4% of student athletes and 13-25% of individuals attending a gymnasium use ephedrine.181 (See Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations under Uses: Misuse and Abuse.)

Studies evaluating the safety and efficacy of dietary supplements containing ephedra for enhancement of athletic performance† are lacking.181,185 In addition, the few studies evaluating safety and efficacy of ephedrine for this use generally have included only a limited number of fit individuals (i.e., young male military recruits) and have assessed effects of ephedrine only for very short-term use (for immediate performance) rather than for long-term, repeated use as seen in the general population.181,185 These data support a modest effect of ephedrine used in combination with caffeine on very short-term athletic performance.181 Limited data also indicate that addition of caffeine to ephedrine is necessary for the modest enhancement of athletic performance.181 However, the effect of sustained use of ephedrine on improvement of athletic performance has not been assessed.181 Therefore, safety and efficacy of dietary supplements containing ephedrine or ephedra, as they have been used in the general population to promote enhancement of athletic performance, have not been established.185 (See Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations under Uses: Misuse and Abuse.)

CNS Stimulation

Over-the-counter ephedrine has been abused by some users including adolescents and young adults for its CNS stimulating action.110 (See Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations under Uses: Misuse and Abuse.) Ephedrine (as the primary precursor) also has been used in the clandestine synthesis of methamphetamine (see Chronic Toxicity in the Amphetamines General Statement 28:20.04) and methcathinone (both potent CNS stimulants with great potential for habituation and physical and/or psychic dependence). 102,103,104,105,106,107,108,109,110,111,112,119 Abuse of ephedrine has produced psychic dependence (characterized by compulsion, obsession, and preoccupation) and worsened mental disorders (e.g., depressive anxiety, thought disorders).110 Acute overdosage of the drug has been associated with tachycardia, difficulty in breathing, and death. (See Acute Toxicity.)110

Issues and Regulations Associated with Misuse and Abuse of Ephedrine-containing Preparations

Because use of dietary supplements that contain ephedrine or ephedra, alone or in combination with caffeine, may be associated with substantial adverse health effects and toxicity113,181 (see Dietary Supplements under Cautions: Adverse Effects), FDA issued a final regulation in February 2004 prohibiting the manufacturing, distribution, and sale of all dietary supplements containing ephedrine alkaloids after April 12, 2004.189,190 (See Regulations Governing Dietary Supplements under Adverse Effects: Dietary Supplements, in Cautions.) In April 2005, a federal judge in a Utah district court overturned part of the FDA ruling, declaring the agency could not ban the sale of dietary supplements containing ephedrine dosages of 10 mg or less without proving that such low dosages are unsafe;195,196,197 this ruling partially lifted FDA's ban, allowing products with 10 mg or less of active ingredient to return to the US market.201 However, in August 2006, a 3-judge panel of the US Court of Appeals for the 10^th Circuit in Denver reversed the lower Utah district court decision and upheld FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated.207,208 FDA then reiterated its position that no dosage of dietary supplements containing ephedrine alkaloids is considered safe, and the sale of these products in the US is illegal and subject to FDA enforcement action.207

Transactions (e.g., distribution, receipt, sale, use, importation, exportation) involving ephedrine-containing drug products also have been restricted under the Chemical Diversion and Trafficking Act of 1988, the Domestic Chemical Diversion Control Act of 1993, and the Comprehensive Methamphetamine Control Act of 1996 (MCA [US Public Law 104-237]).102,103,104,105,106,107,108,109,110,111,112,119,212 Under MCA, effective October 1997, 24 g of ephedrine (in terms of the base) was the limit for a single transaction for drug products containing ephedrine in combination with other drugs (regardless of the form in which these drugs are packaged) that could be sold by retail distributors (e.g., grocery stores, general merchandise stores, drug stores).111,112,119,180,212 As of October 1997, mail-order distribution of ephedrine-containing drug products must be reported monthly to the US Attorney General according to applicable regulations.111,112,119,180,212 In addition, under regulations finalized by the Drug Enforcement Administration (DEA), effective April 2002, nonprescription preparations containing ephedrine had to be stored behind the counter in retail settings that were open to the public to ensure that only employees have access to these products so that their availability to the general public could be more closely controlled.119,180

Despite the enactment of MCA and other stringent laws, methamphetamine abuse remains a serious problem.206,212,213 In March 2006, the Combat Methamphetamine Epidemic Act (CMEA) of 2005 (Title VII of the USA Patriot Act Improvement and Reauthorization Act of 2005) was signed into law, which effectively amends the Federal Controlled Substances Act of 1970 to tighten control over the sale and distribution of nonprescription ephedrine and pseudoephedrine.204,205,206,209,210,211 This law creates a new class of products called “scheduled listed chemical products,” which are defined in the law as products containing ephedrine, pseudoephedrine, or phenylpropanolamine (no longer commercially available in the US) or any salt, optical isomer, or salt of an optical isomer of these drugs that are lawful nonprescription products in the US, and sets additional requirements for their sale.210,212 Effective September 30, 2006, the law requires pharmacies and other retail distributors to store ephedrine- and pseudoephedrine-containing preparations behind the counter or in locked cabinets; requires purchasers to provide approved photographic identification and sign a written or electronic logbook for each purchase; requires pharmacies and other retail distributors to keep information about the purchasers (e.g., name, address, signature) and purchases (e.g., name of product, quantity sold, date and time of sale) for at least 2 years; and limits the amount of ephedrine that can be purchased to no more than 3.6 g per day or 9 g per month.204,205,209,210,211 The law exempts requirements of a written or electronic logbook for any purchase of single-dose packages that contain no more than 60 mg of pseudoephedrine; however, these single-dose packages also must be stored behind the counter.209 To comply with CMEA, pharmacies and other retail distributors selling preparations containing ephedrine are required to submit to the Attorney General a statement regarding self-certification and employee training on the requirements of this new law and to maintain records relating to such training at their place of operation.209,210 Additional information about legal and regulatory requirements under CMEA may be obtained at the website of the Office of Diversion Control of the US Drug Enforcement Administration (DEA) ([Web]), including specific requirements for various sellers (e.g., pharmacies, mail-order sellers) and employee training materials developed by DEA.212,213,214 (See Uses: Misuse and Abuse, in Pseudoephedrine 12:12.12.)

Use of ephedrine in some states may be subject to additional controls, since some states had restricted the prescription, dispensing, and distribution of ephedrine (e.g., as a controlled substance or a prescription drug) prior to passage of the federal law.102,104,106,109,202,203,209,212 For example, in the state of Oregon, legislation was enacted in August 2005 that required the Oregon State Board of Pharmacy to classify ephedrine, pseudoephedrine, and phenylpropanolamine as schedule III drugs by July 2006, which effectively moved these drugs from the nonprescription to the prescription-only category in that state.206 Where such state laws are more stringent than the provisions of CMEA, the state requirements also must be followed.209,212,213

Administration

Oral Administration

Ephedrine (as the hydrochloride or sulfate salt) is administered orally as fixed-combination preparations containing guaifenesin.176,177,198

Parenteral Administration

Ephedrine sulfate is administered by IV injection.178,200 The drug also has been administered by IM† or subcutaneous† injection.178

Ephedrine sulfate injection (Akovaz^®) is administered by direct IV (“bolus”) injection.200,252 Prior to IV administration, the commercially available solution for injection must be diluted.200 The manufacturer recommends that a 5-mg/mL solution be prepared by diluting 1 mL of the 50-mg/mL injection concentrate with 9 mL of 0.9% sodium chloride injection or 5% dextrose injection.200 Vials of the drug are for single-use only; unused portions should be discarded.200

Ephedrine sulfate injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.178,200

Dosage

Ephedrine is commercially available as ephedrine hydrochloride or ephedrine sulfate; dosage is expressed in terms of the salt.176,178,198,200

Oral Dosage

When ephedrine hydrochloride or ephedrine sulfate is administered orally for self-medication as a bronchodilator (in fixed combination with guaifenesin) in adults and children 12 years of age and older, the usual oral dosage is 12.5-25 mg every 4 hours as needed, not to exceed 150 mg in 24 hours.176,198 Ephedrine should be used in children younger than 12 years of age only under the direction of a clinician.176,198

Parenteral Dosage

When used as a pressor agent, ephedrine should be administered in the lowest effective dosage for the shortest possible time. The recommended initial adult dose of ephedrine sulfate for the treatment of clinically important hypotension during anesthesia is 5-10 mg by IV bolus injection; additional bolus doses should be administered as needed (up to a total dose of 50 mg) to achieve the desired blood pressure response.200 Other parenteral dosage regimens have been recommended in adults, including a dose of 5-25 mg by slow IV injection (repeated in 5-10 minutes if necessary) and an IM† or subcutaneous† dose of 25-50 mg.178,250

In children†, parenteral ephedrine sulfate doses of 0.5 mg/kg or 16.7 mg/m² have been administered every 4-6 hours by subcutaneous† or IM† injection;178 however, safety and efficacy of ephedrine sulfate injection have not been established in pediatric patients.200,252

When used parenterally to relieve severe, acute bronchospasm, ephedrine sulfate doses of 12.5-25 mg usually have been given in adults.

Adverse Effects

The CNS-stimulating effects of ephedrine may result in nervousness, anxiety, restlessness, or insomnia, especially with large doses.176,178,200 Vertigo also may occur.178 Prolonged abuse of ephedrine may cause symptoms of paranoid schizophrenia.178 Ephedrine also may cause headache, sweating, mild epigastric distress, anorexia, nausea, or vomiting.178,200

Ephedrine increases the work of the heart and probably myocardial oxygen consumption. In patients with coronary insufficiency and/or ischemic heart disease, the drug can induce anginal pain. Ephedrine increases the irritability of the heart muscle and may alter the rhythmic function of the ventricles. Palpitation and tachycardia may result.178 Extrasystoles and potentially fatal arrhythmias including ventricular fibrillation may occur, especially in patients with organic heart disease or those receiving other drugs that sensitize the heart to arrhythmias including cardiac glycosides, cyclopropane, or halogenated hydrocarbon anesthetics. (See Drug Interactions.) Precordial pain also may occur following administration of ephedrine sulfate injection.178

Acute urinary retention may occur in men with prostatism; increased vesicular sphincter tone may cause difficult and painful urination.178 Some patients may require catheterization.

Ephedrine may cause tachyphylaxis with repeated administration.200 Although tolerance to ephedrine may develop with prolonged or excessive usage, addiction to the drug does not occur.178 Temporary cessation of ephedrine and subsequent reinitiation of therapy restores the drug's effectiveness.178

Dietary Supplements

Ephedrine alkaloid-containing dietary supplements (frequently combined with caffeine) were previously promoted for various uses (e.g., weight loss, body building, energy enhancement, increased mental concentration, increased sexual sensations, euphoria, alternative to illicit drugs); although these products constituted less than 1% of all dietary supplement sales, they accounted for 64% of adverse events associated with dietary supplements.183,184,186 Use of ephedrine alkaloid-containing dietary supplements has been associated with a twofold to threefold increased risk of nausea, vomiting, adverse psychiatric effects (e.g., anxiety, mood changes), autonomic hyperactivity, and palpitations.181,185 Serious adverse effects (e.g., cardiovascular and nervous system effects) and deaths have been reported in individuals receiving ephedrine or ephedra-containing dietary supplements. 113,114,115,117,131,118,120,134,144,160,172,181,183 Such adverse effects, including irregular heart rate, palpitations, increased blood pressure, chest pain, anxiety, nervousness, tremor, hyperactivity, headache, and insomnia,113,117,118,144,166 usually were associated with clinically serious conditions (e.g., myocardial infarction, stroke, psychoses, seizures, nephrolithiasis, death)113,117,118,120,161,162,166 and frequently were reported in young (i.e., 30 years of age or younger) to middle-aged adults (over 70% of whom were females) using the supplements, mainly for weight loss or energy enhancement.113,120,166,172,181 Many such adverse effects occurred within 2 weeks of first use,113 although they were reported on the first day of use in some cases.161 Most individuals who developed such adverse effects claim that they used the dietary supplements according to labeled instructions.161,166

Source of Ephedrine in Dietary Supplements

The labeled source of ephedrine in dietary supplements varied from raw botanicals to powdered plant material, sometimes pharmaceutical ephedrine alkaloids, but mainly consisted of concentrated extracts of the amphetamine-like Ephedra species (usually listed on labels as ma huang, ephedra, Chinese ephedra, Ephedra sinica, ephedra herb powder, epitonin, ephedrine, or ephedrine alkaloids).113,115,116,117,118,161,166,172 Small amounts of ephedrine alkaloids also are found in Sida cordifolia .113,118 Plants of the genus Ephedra may contain ephedrine alkaloids as single ingredients; however, ephedrine alkaloids usually are combined with other compounds.113,120 Although some dietary supplements contained only Ephedra as a labeled ingredient, most dietary supplements contained other ingredients, many of which have known or suspected physiologic and pharmacologic activities that have the potential of interacting with ephedrine alkaloids and thus increasing their effects.113,120

Regulations Governing Dietary Supplements

Although the quality and consistency of prescription and nonprescription drugs in the US generally are ensured by strict FDA regulations concerning drug uniformity, purity, and labeling accuracy, dietary supplements (e.g., herbal preparations, vitamins and minerals, amino acids, tissue extracts) are regulated as foods under the Dietary Supplement Health and Education Act (DSHEA) of 1994.131,132,133,134,136,146,153,160,161 Therefore, FDA bears the burden to prove that a marketed dietary supplement is unsafe when used according to the conditions of use on the label or as commonly consumed.136,161 These requirements are in contrast to FDA regulations concerning prescription and nonprescription drugs that stipulate that a drug has to be proven safe and effective (for a particular indication) before it is approved for marketing.132,133,134,136

Serious adverse effects (e.g., cardiovascular and nervous system effects) and deaths have been reported with ephedrine or ephedra-containing dietary supplements.113,114,115,117,118,166,172 As a result, FDA has proposed strict regulations for these preparations since 1997 to protect the public health.190 In 1997, the agency proposed regulations to limit the amount of ephedrine alkaloids that dietary supplement preparations contain113,114,115,117,118 and to change labeling and marketing practices for these supplements.113,114,115,116,117,118,133 In 2001, FDA seized drug products containing synthetic ephedrine hydrochloride labeled as dietary supplements.190 In 2003, with the emergence of new scientific evidence (including approximately 18,000 adverse event reports received overall by FDA and a comprehensive evaluation of the scientific literature through 2002 conducted by the RAND corporation),181,182 FDA proposed additional changes to labeling to emphasize the risks of using ephedrine-containing dietary supplements.190 In addition, the agency also proposed rules to establish GMPs for all dietary supplements and issued warnings prohibiting manufacturers from making unsubstantiated efficacy claims (e.g., enhancement of athletic performance, street drug alternative) for these preparations.190

In February 2004, FDA finally concluded that dietary supplements containing ephedrine alkaloids pose a risk of serious adverse events (e.g., heart attack, stroke, death), and that these risks are unreasonable in light of any benefits that may result from the use of these products.189 Therefore, the agency issued a final regulation declaring that dietary supplements containing ephedrine alkaloids are adulterated under the Federal Food, Drug, and Cosmetic Act.189 Under this rule, manufacturing, distribution, and sale of all dietary supplements containing ephedrine alkaloids (e.g., Ephedra spp. [“ma huang”], Sida cordifolia , Pinellia spp.) were prohibited after April 12, 2004.189,190 This regulation does not apply to traditional Chinese herbal remedies or products regulated as conventional foods (e.g., herbal teas).190 Ephedra is not generally recognized as safe for foods and not approved for use as a food additive.190

In April 2005, about one year after issuance of FDA's final ruling, a federal judge in a Utah district court overturned part of the ruling, declaring that the agency cannot ban the sale of dietary supplements containing ephedrine dosages of 10 mg or less without proving that such low dosages are unsafe;195,196,197 this ruling partially lifted FDA's ban, allowing products with 10 mg or less of active ingredient to return to the US market.201 However, in August 2006, a 3-judge panel of the US Court of Appeals for the 10^th Circuit in Denver reversed the lower Utah district court decision and upheld FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated.207,208 FDA then reiterated its position that no dosage of dietary supplements containing ephedrine alkaloids is considered safe, and the sale of these products in the US is illegal and subject to FDA enforcement action.207

Precautions and Contraindications

Ephedrine may cause hypertension.178,200 The drug should be used with caution in patients with hypertension, cardiovascular disease, angina, diabetes mellitus, hyperthyroidism, or prostatic hyperplasia, and in those receiving digoxin.178 An increased risk of hypertension has been observed in patients receiving ephedrine sulfate injection for the prevention of hypotension during anesthesia.200 Serious postpartum hypertension, in some cases resulting in stroke, has been reported in patients receiving a vasopressor (e.g., ephedrine) and an oxytocic agent (e.g., ergonovine, methylergonovine) concomitantly.200

Patients considering self-medication with ephedrine as a bronchodilator should be advised that the drug be used only if they have been diagnosed by a clinician as having asthma, and that self-medication not be undertaken if they ever have been hospitalized for asthma or are currently receiving a prescription drug for the management of this condition unless otherwise directed by a clinician.176,198 These patients also should be advised not to use the drug if they have cardiovascular disease, hypertension, diabetes mellitus, thyroid disease, angle-closure (narrow-angle) glaucoma, seizures, a psychiatric or emotional condition, or difficulty urinating because of prostatic hyperplasia unless directed by a clinician.176,198 In addition, patients should be advised not to exceed recommended dosages or frequency of administration unless otherwise instructed by a clinician.176,198 Patients should contact their clinician if symptoms are not improved within 1 hour or become worse, more than the recommended dosage of ephedrine is required, or asthma attacks become more frequent (i.e., more than 2 asthma attacks in a week).176,198 Patients also should be cautioned that ephedrine can cause hypertension and tachycardia, which could increase the risk of cardiovascular disease, stroke, or death.176,198 Foods, beverages, and dietary supplements that contain stimulants (e.g., caffeine) should be avoided.176,198

Prolonged use of parenteral ephedrine may produce a syndrome resembling an anxiety state.178 Tolerance to ephedrine also may develop with repeated administration of the drug; in some cases, effectiveness may return after the drug is temporarily withheld.178,200 If ephedrine sulfate injection is used for the treatment of hypotension during anesthesia, clinicians should be aware of the possibility of tachyphylaxis and be prepared to use an alternative vasopressor agent in the event that an unacceptable response to ephedrine occurs.200

Because ephedrine is substantially excreted by the kidneys, patients with impaired renal function may eliminate the drug more slowly, consequently prolonging its pharmacologic effect and potentially increasing the risk of adverse effects.200 Patients with renal impairment should be carefully monitored after administration of the initial IV dose of ephedrine.200

Misuse or abuse of ephedrine can result in potentially serious adverse effects. (See Uses: Misuse and Abuse.) Serious adverse effects also have been reported with dietary supplements containing ephedrine alkaloids. In February 2004, FDA issued a final regulation prohibiting the manufacturing, distribution, and sale of all dietary supplements containing ephedrine alkaloids (effective April 12, 2004).189,190 Effective August 2006, no dosage of dietary supplements containing ephedrine alkaloids is considered safe, and the sale of these products in the US is illegal and subject to FDA enforcement action.207 (See Dietary Supplements under Cautions: Adverse Effects.)

Some manufacturers state that ephedrine is contraindicated in patients with known hypersensitivity to the drug or other sympathomimetic agents, although allergic reactions to ephedrine are rare.178

Pediatric Precautions

Ephedrine sulfate injection is not FDA-labeled for use in pediatric patients.200,252 Although the drug has been used in children,178 safety and efficacy have not been established in this patient population.200

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.215,216 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the FDA) for the symptomatic treatment of cold and cough have not been established.215 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions, in Pseudoephedrine 12:12.12.

Geriatric Precautions

Clinical studies of ephedrine sulfate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.200 Clinical experience to date has not identified any differences in response between geriatric and younger patients.200 If ephedrine is used in geriatric patients, dosage should be selected carefully, usually starting at the low end of the dosage range, since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group.200

Ephedrine is known to be substantially excreted by the kidneys and the risk of ephedrine-induced adverse effects may be increased in patients with impaired renal function; because geriatric patients may have decreased renal function, it may be useful to monitor renal function in such patients.200

Pregnancy and Lactation

Pregnancy

Animal reproduction studies have not been performed to date with ephedrine sulfate injection; it is not known whether the drug can cause fetal harm or miscarriage when administered during pregnancy. 178,200,252 However, ephedrine has been used in pregnant women for the treatment of hypotension during spinal anesthesia, and the available data support the efficacy and safety of ephedrine sulfate injection for such use.253,254 There is some evidence indicating that fetal acidosis is more likely to occur with maternal administration of ephedrine compared with phenylephrine.252 Low umbilical artery pH (7.2 or less) has been reported at the time of delivery in neonates whose mothers were exposed to ephedrine.200 Newborn infants with such maternal exposure should be assessed for their acid-base status and monitored for signs and symptoms of metabolic acidosis.200

Lactation

Limited data indicate that ephedrine is distributed into human milk; however, there is no information regarding the effects of the drug on the breast-fed infant or on milk production.178,200 The known benefits of breast-feeding should be considered along with the mother's clinical need for ephedrine and any potential adverse effects of the drug or underlying maternal condition on the infant.200

- and Beta-Adrenergic Blocking Agents

Administration of an α-adrenergic blocking drug reduces the vasopressor response to ephedrine.200 Phentolamine, by blocking the α-adrenergic effects of ephedrine, can cause vasodilation. However, because of the cardiac stimulating effects of ephedrine, a pressor response may be achieved if sufficient doses are administered.

As with other sympathomimetic drugs having cardiostimulating effects, administration of a β-adrenergic blocking drug such as propranolol may block the cardiac and bronchodilating effects of ephedrine.200

Blood pressure should be monitored in patients receiving ephedrine concomitantly with an α- or β-adrenergic blocking agent.200

Cardiac Glycosides

Cardiac glycosides (e.g., digoxin) can sensitize the myocardium to the effects of sympathomimetic drugs and increase the risk of arrhythmias; patients receiving such concomitant therapy should be carefully monitored.178,200

Diuretics

Administration of furosemide or other diuretics may decrease arterial responsiveness to pressor drugs such as ephedrine.

Epidural Anesthesia

Ephedrine may decrease efficacy of epidural blockade by facilitating the regression of sensory analgesia.200 Patients should be monitored for this effect and treated accordingly.200

General Anesthetics

Some manufacturers state that concurrent use of ephedrine with general anesthetics, especially cyclopropane or halogenated hydrocarbons, can sensitize the myocardium to the effects of ephedrine and possibly increase the risk of arrhythmias.178

Monoamine Oxidase Inhibitors

By increasing the quantity of norepinephrine in adrenergic nervous tissue, monoamine oxidase (MAO) inhibitors may potentiate the pressor effects of indirectly acting sympathomimetic drugs such as ephedrine. Potentiation is approximately the same following IV or oral administration of ephedrine. A hypertensive crisis and subarachnoid hemorrhage occurred in a patient receiving an MAO inhibitor after 50 mg of ephedrine was administered orally.

Blood pressure should be carefully monitored in patients receiving ephedrine and an MAO inhibitor concomitantly.200 Some manufacturers recommend that ephedrine not be used in patients currently receiving, or for 2 weeks after discontinuance of, an MAO inhibitor.176,178,198

Oxytocic Drugs

Concomitant use of a vasopressor (e.g., ephedrine) with an oxytocic drug (e.g., ergonovine, methylergonovine) may increase the pressor effect and cause severe postpartum hypertension, which may lead to stroke.178,200 Blood pressure should be carefully monitored in patients receiving such concomitant therapy.200

Rocuronium

Ephedrine may reduce the onset time of rocuronium-induced neuromuscular blockade for intubation when administered simultaneously with anesthetic induction.200

Theophylline

Concomitant use of ephedrine and theophylline may increase the frequency of nausea, nervousness, and insomnia.200 Patients receiving such concomitant therapy should be monitored for these symptoms and treated accordingly.200

Other Drugs

Other drugs that may potentiate the pressor effect of ephedrine include clonidine, propofol, and atropine.200 Other drugs that can antagonize the pressor effect of ephedrine include reserpine and quinidine.200 Blood pressure should be carefully monitored in patients receiving such concomitant therapy.200

Acute Toxicity

Manifestations

Overdosage of ephedrine can cause a rapid increase in blood pressure.200 Hypertension may develop initially, followed later by hypotension accompanied by anuria.178 Careful monitoring of blood pressure is recommended in the event of an overdosage.200 Another principal manifestation of ephedrine overdosage is the development of seizures.178 Acute overdosage of ephedrine also may result in nausea, vomiting, chills, cyanosis, irritability, nervousness, fever, suicidal behavior, tachycardia, dilated pupils, blurred vision, opisthotonos, spasms, pulmonary edema, gasping respirations, coma, and respiratory failure.178

Treatment

If respirations are shallow or cyanosis is present, one manufacturer recommends initiation of assisted respiration.178 In the presence of cardiovascular collapse, blood pressure should be maintained; however, vasopressors are contraindicated.178

Parenteral antihypertensives may be administered at the discretion of the clinician for the management of severe hypertension.200 One manufacturer recommends administration of 5 mg of phentolamine mesylate diluted in 0.9% sodium chloride injection and administered slowly by IV injection; alternatively, 100 mg of the drug may be given orally (an oral dosage form of phentolamine is not commercially available in the US).178 Seizures may be controlled with diazepam; pyrexia may be managed with external cooling and IV dexamethasone (1 mg/kg administered slowly).178

Pharmacology

Ephedrine stimulates both α- and β-adrenergic receptors through direct and indirect mechanisms.172,178,200,250 It is believed that β-adrenergic effects result from stimulation of the production of cyclic adenosine 3',5'-monophosphate (cAMP) by activation of the enzyme adenyl cyclase, whereas α-adrenergic effects result from inhibition of adenyl cyclase activity. Ephedrine also exerts an indirect effect by releasing norepinephrine from its storage sites.178,250 With prolonged or excessive use, ephedrine may deplete norepinephrine stores in sympathetic nerve endings and tachyphylaxis may develop.178,200,250 Tachyphylaxis to the bronchial effects of the drug may also occur, but it is not the result of norepinephrine depletion. The main effects of therapeutic doses of ephedrine are relaxation of the smooth muscle of the bronchial tree, and when norepinephrine stores are not depleted, cardiac stimulation and increased systolic and usually increased diastolic blood pressure.178,198 Unlike epinephrine and norepinephrine, ephedrine produces bronchodilation and possibly increased blood pressure and has pronounced CNS activity following oral administration.

Respiratory Effects

Ephedrine relaxes bronchial smooth muscle by stimulation of β₂-adrenergic receptors.178,200 Bronchodilation produced by oral ephedrine occurs more slowly, is less pronounced, and is more prolonged than that achieved with epinephrine administered subcutaneously or by oral inhalation.

Cardiovascular Effects

The cardiovascular effects of ephedrine are mediated by its α- and β-adrenergic properties and the overall clinical response is based on the balance between α₁-mediated vasoconstriction, β₂-mediated vasoconstriction, and β₂-mediated vasodilation.178,200 Ephedrine increases heart rate, increases cardiac output, and variably increases peripheral vascular resistance, resulting in an increase in systemic blood pressure.178,200

Ephedrine acts on β₁-adrenergic receptors in the heart, producing a positive inotropic effect on the myocardium when single low doses are administered. This effect contributes to, and may be principally responsible for, the pressor effects of the drug when venous return to the heart is adequate. Although the drug also produces a positive chronotropic effect through the sinoatrial node, this effect may be overcome by increased vagal activity occurring as a reflex to increased arterial blood pressure. Bradycardia, tachycardia, or unchanged heart rate has been reported. Cardiac output usually is increased, especially after IV administration. Because of its positive inotropic effects, ephedrine increases cardiac work and probably myocardial oxygen consumption, and usually increases pulmonary arterial pressure.

Ephedrine increases the irritability of the heart muscle and may alter the rhythmic function of the ventricles, especially when the heart has been sensitized to this action by other drugs including digitalis glycosides or certain anesthetics. Arrhythmias including ventricular tachycardia, extrasystoles, and fibrillation may result. As with epinephrine, arrhythmias may be more likely to occur if large doses are given or if the patient has acute myocardial infarction.

Ephedrine may dilate coronary blood vessels. As with epinephrine, coronary artery vasodilation may be indirect, caused by enhanced cardiac metabolism due to direct cardiac stimulation. Ephedrine may increase coronary artery blood flow; as with other sympathomimetic drugs, increased coronary blood flow may result from increased systemic blood pressure as well as indirect coronary artery vasodilation. However, decreased coronary artery blood flow has also been reported and the effects of the drug on coronary circulation may be dose dependent.

Like epinephrine, ephedrine can produce both vasodilation by its effect on β₂-adrenergic receptors and vasoconstriction by its effect on α-adrenergic receptors. The drug constricts arterioles in the skin, mucous membranes, and viscera, and dilates arterioles in the skeletal muscle. Either constriction or dilation of pulmonary and cerebral vessels may occur. Peripheral vascular resistance may be increased, decreased, or unchanged after administration of the drug. Conditions causing an increase or decrease in vascular resistance have not been identified. Pressor responses to parenteral ephedrine occur more slowly but are more prolonged than those achieved with epinephrine or norepinephrine. Increased blood pressure may be caused by vasoconstriction as well as by cardiac stimulation; however, when peripheral vascular resistance is decreased, elevation of blood pressure is due entirely to increased cardiac output. Ephedrine may constrict both arterial and venous blood vessels; peripheral venous pressure also is increased. Ephedrine may decrease circulating plasma volume. This may result from loss of fluid into extracellular spaces caused by postcapillary vasoconstriction.

Constriction of renal blood vessels by parenteral ephedrine decreases renal blood flow. In hypotensive patients, ephedrine may initially decrease urine flow and excretion of sodium and potassium. If the patient is not hypovolemic, renal blood flow and glomerular filtration rate increase as the systemic blood pressure is raised toward normal levels; however, renal blood flow and glomerular filtration rate again decrease if blood pressure is further increased toward hypertensive levels.

Ephedrine may constrict dilated blood vessels in the nasal mucosa and produce nasal decongestion following topical application; however, rebound congestion may occur. There is insufficient evidence that the drug is effective as a nasal decongestant when administered orally in usual doses.

Other Effects

Ephedrine has CNS stimulating effects similar to those of amphetamines but less pronounced. (See Cautions: Adverse Effects.)

Ephedrine generally relaxes smooth muscles of the GI tract.178 Ephedrine contracts the urinary bladder trigone and sphincter; relaxation of the detrusor muscle is not prominent.178 (See Cautions: Adverse Effects.) The drug usually decreases the activity of the uterus; however, an excitatory effect has also been reported. Use of ephedrine during delivery to correct maternal hypotension resulting from spinal anesthesia may result in improved uterine blood flow. In experimental animals, the drug has corrected fetal hypoxia, hypercapnia, acidosis, and bradycardia resulting from maternal hypotension.

Blood glucose concentrations are not increased as much by ephedrine as by epinephrine, and usual doses of ephedrine are not likely to produce hyperglycemia. Ephedrine increases oxygen consumption and metabolic rate, probably as a result of central stimulation.

Administration of ephedrine to patients with myasthenia gravis may result in increased muscle strength.178 The mechanism by which ephedrine acts in these patients is not known.178

Pharmacokinetics

Absorption

Bronchodilation occurs within 15-60 minutes after oral administration of the drug and appears to persist for 2-4 hours. The duration of pressor and cardiac responses to ephedrine is 1 hour after IV administration of 10-25 mg or IM or subcutaneous administration of 25-50 mg and up to 4 hours after oral administration of 15-50 mg of the drug.

There appears to be a wide variation in ephedrine plasma concentrations associated with bronchodilation. In one study, therapeutic plasma concentrations were reported to range from 20 ng/mL to more than 80 ng/mL.

Following oral administration of ephedrine as conventional ephedrine hydrochloride capsules containing 25 mg of ephedrine base (no longer commercially available in the US) or as 3 dietary supplement preparations of Ephedra (a botanical source of ephedrine alkaloids referred to as ma huang, no longer commercially available in the US) assayed as containing the equivalent of 23.6, 25.6, or 27 mg of ephedrine base in a randomized, crossover pharmacokinetic study in healthy fasting adults, the absorption rate and area under the serum concentration-time curve (AUC) were similar among the 4 preparations, although the absorption of one of the dietary supplements and AUC of another differed substantially from the remaining preparations.120 Mean peak serum ephedrine concentrations of about 73.4, 86, and 100 ng/mL were achieved in about 3, 2.6, and 2.7 hours following oral administration of the 23.6-, 25.6-, or 27-mg dose of ephedrine, respectively, compared with a mean peak serum concentration of 86.5 ng/mL at about 2.81 hours with the 25-mg dose of ephedrine administered as the conventional capsules (no longer commercially available in the US).120 Most of these dietary supplements contained other ingredients besides ephedrine and these ingredients may have increased the rate but not the extent of absorption of ephedrine from the GI tract.120

Distribution

Ephedrine is presumed to cross the placenta and distribute into milk.178,200,253

In one study in healthy fasting adults comparing oral administration of conventional ephedrine hydrochloride capsules (no longer commercially available in the US) with botanical preparations (ma huang, Ephedra , no longer commercially available in the US) containing the drug, the apparent steady-state volume of distribution ranged from about 220-240 L.120

Elimination

The metabolic pathway of ephedrine has not been completely elucidated.200,253 However, some data suggest that small quantities of ephedrine are slowly metabolized in the liver by oxidative deamination, demethylation, aromatic hydroxylation, and conjugation. The metabolites have been identified as p -hydroxyephedrine, p -hydroxynorephedrine, norephedrine, and conjugates of these compounds.

Ephedrine and its metabolites are excreted in urine. Most of the drug is excreted unchanged. The rate of urinary excretion of the drug and its metabolites is dependent upon urinary pH. In one study, 74-92% of an oral dose and 87-99% of an IV dose of 25 mg of ephedrine hydrochloride were excreted as ephedrine and 8-10% of the oral dose and 3-7% of the IV dose were excreted as norephedrine within 24 hours when the urine was acidified to pH 5 by administration of ammonium chloride. When the urine was alkalinized to pH 8 by administration of sodium bicarbonate, 22-35% of a 25-mg oral dose of ephedrine hydrochloride was excreted as ephedrine and 11-24% of this dose was excreted as norephedrine within 24 hours. Approximately 70-80% of a 25-mg oral dose of ephedrine sulfate was excreted in urine within 48 hours when the urine pH averaged 6.3. The ratio of ephedrine to norephedrine excreted in this study was not determined.

The elimination half-life of ephedrine has been reported to be about 3 hours when the urine is acidified to pH 5 and about 6 hours when urinary pH is about 6.3. In a study in healthy fasting adults comparing oral administration of conventional ephedrine hydrochloride capsules (no longer commercially available in the US) with botanical preparations (ma huang, Ephedra , no longer commercially available in the US) containing the drug, elimination half-life ranged from 4.85-6.47 hours, with apparent clearances of 25.5-34.1 L/hour; urinary pH was not reported.

Chemistry and Stability

Chemistry

Ephedrine is a sympathomimetic drug that occurs naturally in plants of the genus Ephedra , most commonly E. sinica .172,179 Ephedra spp., known in traditional Chinese medicine as “ma huang,” contains 6 ephedrine alkaloids (sometimes collectively referred to as “ephedra”),172 including ephedrine, pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine, and methylpseudoephedrine.179 The total ephedrine alkaloid content of E. sinica is approximately 1-2%, with ephedrine being the most abundant alkaloid.131 Although the content may vary between samples, ephedrine and pseudoephedrine together generally constitute more than 80% of the alkaloid content of the dried herb.179 In dietary supplements, the ephedrine alkaloid content was typically expressed as a standardized percentage of total herb content.131 However, results of one study evaluating the content of 20 dietary supplements labeled as containing botanical sources of ephedrine alkaloids indicate that considerable discrepancies exist between the labeled amount of ephedrine alkaloid content and the assayed amount, and that ephedrine alkaloid contents vary from lot to lot.131 (See Dietary Supplements under Cautions: Adverse Effects.) FDA issued a final regulation in February 2004 prohibiting the manufacturing, distribution, and sale of all dietary supplements containing ephedrine alkaloids after April 12, 2004.189,190 (See Regulations Governing Dietary Supplements under Adverse Effects: Dietary Supplements, in Cautions.)

Ephedrine is commercially available as the hydrochloride or sulfate salt.176,178,198,200 Ephedrine hydrochloride and ephedrine sulfate occur as fine, white, odorless crystals or powders. Ephedrine hydrochloride has solubilities of approximately 0.33 g/mL in water and 71 mg/mL in alcohol at 25°C. Ephedrine sulfate has solubilities of approximately 0.77 g/mL in water and 11 mg/mL in alcohol at 25°C. Ephedrine sulfate injection has a pH of 4.5-7.200

Stability

Ephedrine sulfate injection should be stored at 20-25°C but may be exposed to temperatures of 15-30°C.178,200 Ephedrine salts and preparations containing the drugs gradually decompose and darken on exposure to light and must be stored in light-resistant containers.

Ephedrine injections have been reported to be incompatible with various drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

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