Cat Carlson

Ephedrine

Cat Carlson

INTRODUCTION

Body image is an increasing issue in today’s society. Never before has the idea of having the “perfect body” been so stressed and because of this, several supplements have found their way onto the market to help obtain the “perfect body.” The use of dietary supplements and metabolic enhancers are relatively new and unstudied. More specifically, supplements containing the stimulant ephedra are becoming increasingly popular and controversial.

For more than 5,000 years, ephedra, (a.k.a.: ephedrine, Ma Huang, pseudoephedrine), an herbal stimulant found in an evergreen plant from central Asia, has been utilized by the Chinese for asthma and other respiratory disorders [1]. As of recently, in the United States this herbal stimulant in has been added to many of the popular weight loss products including Metabolife, Hydroxycut, Ripped Fuel, Ultimate Orange, Yellowjacket, Diet Fuel, Trim Fast, Thermagene, and Xenadrine RF1 [2]. Although ephedra has long since been an ingredient in nasal decongestants and asthma medications, the increasing use of ephedra for weight loss by the general population, and athletes in particular, is leading to investigations. Also, a number of deaths have been linked to ephedra in the last few years, enhancing the need for more research.

Over the last several years, products containing ephedra have been linked to serious cardiovascular toxicity. The side effects of ephedra include increased blood pressure, increased heart rate, heart palpitations, nervousness, dry mouth, insomnia, irritability, dizziness, hepatitis, stroke, myocardial infarction, psychosis, seizures, and death [3, 4]. According to an article published by Reuters Health, the American Association of Poison Control Centers found that in the year 2001, 64% of bad reactions to herbal products reported in the U.S. were due to ephedra use. In comparison to other herbal supplements, out of a total of 1,306 reports of adverse effects, 1,178 were due to ephedra, 28 to gingko biloba, 31 to St. John’s Wort, and 69 to Echinacea [5]. Also, the Food and Drug Administration reported that weight loss products containing ephedra have been linked to 88 deaths.

BANNING

Due to the extreme side effects and its recent correlation with numerous deaths, the FDA is investigating the safety and usage of ephedra. Several deaths of athletes, ranging from high school to professional levels, have been publicized and linked to the use of ephedra. Currently, the NFL, NCAA, and Olympics ban the usage while the NBA, NHL, and the MLB do not.

The Dietary Supplement Health and Education Act (DSHEA) of 1994 define dietary supplements as vitamins, minerals, amino acids, enzymes, and herbs and other botanicals. Because ephedra is a botanical, it is considered a “dietary supplement” and cannot be banned or regulated by the Food and Drug Administration (FDA). In 1997, the FDA’s proposal to restrict access to ephedra was denied because there was not sufficient evidence to prove that the use of ephedra is linked to serious adverse effects. On February 28, 2003, the FDA and Department of Health and Human Services addressed several concerns regarding ephedra and its side effects. The FDA plans to move for the banning and/or restriction of ephedra due to the recent increase in awareness of its serious cardiovascular toxicity.

CHEMICAL/STRUCTURAL BACKGROUND

Ephedrine, C₁₀NH₁₅, is found the form of four isomers: 1R, 2S-ephedrine, 1S, 2R-ephedrine, 1R, 2R-pseudoephedrine, and 1S, 2S-pseudoephedrine. Both 1S, 2S-pseudoephedrine and 1R, 2S-ephedrine exist as the naturally occurring isomers. Ephedrine is a β-adrenergic agonist that affects the central nervous system (CNS) through the release of epinephrine and/or norepinephrine and by its attachment to β_1,β₂, and β₃-adrenergic receptors. Ephedrine is also a lipid soluble compound that is capable of crossing the blood/brain barrier (BBB).

Fig. 1: Four Ephedrine Isomers and Epinephrine

ADRENERGIC RECEPTORS

Adrenergic receptor agonists (a.k.a. sympathomimetic drugs), such as ephedrine, affect the sympathic nervous system which is responsible for regulating the activity of smooth muscle, cardiac muscle, and glandular cells. Sympathomimetic drugs essentially mimic the actions of norepinephrine and epinephrine in a direct and indirect manner. Directly, agonists activate adrenoreceptors and indirectly, they facilitate the release of epinephrine and/or norepinephrine (catecholamines).

β-adrenergic receptors, also known as serpentine receptors, are integral proteins composed of seven membrane-spanning hydrophobic regions of 20-28 amino acid residues [6]. β₁-adrenoreceptors are found in the cardiac muscle/tissues and are responsible for the force and rate of contractions of the heart. β₂-adrenoreceptors, found in smooth muscle (bronchial, vascular, gastrointestinal, genitourinary) and skeletal muscle tissues, are responsible for muscle relaxation and glycogenolysis. β₃-adrenoreceptors are found in the adipose tissue and regulate lipolysis.

MECHANISM

Fig. 2: Structure of epinephrine vs. ephedrine

As previously stated, ephedrine acts in a direct and indirect manner. Directly, ephedrine activates the adrenergic receptors, which eventually leads to the specific response based on the activated β-AR. Structurally, ephedrine is similar to epinephrine (Fig. 2). Thus binding of ephedrine on β –adrenergic receptors results in the same response. Indirectly, ephedrine stimulates the release of epinephrine and the consequent activation of β-adrenergic receptors eventually leading to the increase of cyclic AMP (cAMP).

Under normal conditions, epinephrine (a.k.a. adrenaline) is released by the adrenal glands above the kidneys in response to stressful stimuli. Once released, epinephrine travels throughout the blood stream until it binds to specific receptors. A G stimulatory protein (Gs) is coupled to the β –adrenergic receptor. It has three subunits (α, β, and γ) and guanosine 5’-diphosphate (GDP) is bound to the subunit. Binding of epinephrine (or ephedrine) to the receptor causes a conformational change in the intracellular domain which allows the replacement of GDP bound to G_sα with GTP (guanosine 5-triosphosphate). As the β and γ subunits of G_s dissociate, active G_sα moves to adenylyl cylase (AC) and activates it. The activation of AC catalyzes the synthesis of cAMP from ATP. The increase in cystolic [cAMP] then goes on to activate PKA, which in turn phosphorylates specific cellular proteins, leading to the specific responses. An example of the binding of epinephrine to a β₁-adrenergic receptor is shown in Fig. 3. For this specific receptor, the binding of epinephrine controls the force of contraction of the heart muscles and increases the heart rate.

Fig. 3: β1-adrenergic receptor

STUDY 1: EPHEDRA’S EFFECT ON β-ADRENORECEPTORS

Vansel et. al. investigated the direct effects of the four ephedrine isomers on human β-adrenoreceptors (β-AR) expressed in Chinese hamster ovary (CHO) cells [7]. Table 1 summarizes the percent of activity for each isomer on the three β-adrenoreceptors. Intrinsic activities are expressed as percent responses to that of (-)-isoprotenol (3x10^-8 =100%).

Table 1: I.A. of ephedrine isomers

	Intrinsic Activity (%)
	β₁-AR	β₂-AR	β₃-AR
1S, 2R-Ephedrine	66	21	22
1R, 2S-Ephedrine	68	78	31
1S, 2S-Pseudoephedrine	53	47	7
1R, 2R-Pseudoephedrine	53	50	17

A summary of the rank order potency of ephedrine on human β-AR from the table is as follows:

β₁-AR: 1R, 2S-ephedrine > 1S, 2R-ephedrine > 1S, 2S-pseudoephedrine = 1R,

(heart) 2R-pseuodephedrine

β₂-AR: 1R, 2S-ephedrine > 1R, 2R-pseudoephedrine =

(smooth muscle 1S, 2S-pseudoephedrine > 1S, 2R-ephedrine

lining)

β₃-AR: 1R, 2S-ephedrine > 1S, 2R-ephedrine* > 1S, 2S-pseudoephedrine* = 1R,

(adipocytes) 2R-pseudoephedrine*

(*-The intrinsic activity was determined to be too low to be significant)

1R, 2S-ephedrine was the most potent isomer on the human β-AR’s in CHO cells. In comparing the intrinsic activity of each isomer, 1R, 2S-ephedrine was the most potent towards β₂-AR, supporting the high incidence of increased heart rate as a side effect.

Because most dietary supplements containing ephedra claim to promote weight loss, and the β₃-AR is responsible for modifying lipolysis, the activity of ephedra isomers on the β₃-AR was further investigated. Of the four isomers, 1R, 2S-ephedrine was the only isomer to show activity. However, the exposure was at such high concentrations not typical to a normal dosage, that the results proved to be insignificant. Thus, the experiment demonstrated the most potent isomer to be 1R, 2S-ephedrine and its primary activity is on β₁/β₂ adrenoreceptors with insignificant effects on the β₃ adrenoreceptor. It is important to note that had ephedrine shown a significant effect (high intrinsic activity) on the β₃-AR, it could cure obesity.

STUDY 2: THE PHARMACOLOGY OF EPHEDRA

Due to the increasing incidence of cardiovascular toxicity related to the use of dietary supplements containing ephedra, the pharmacology of the dietary supplement was investigated [8]. After an overnight fast, eight “healthy adults” were given a single dose of Metabolift, labeled to contain 20 mg ephedrine and 200 mg caffeine. Subjects varied in weight from 52.0 kg to 88.9 kg. Plasma and urine samples were analyzed via liquid chromatography-tandem mass spectrometry for the ephedrine and caffeine concentrations. Heart rates and blood pressures were monitored, as well as complaints of adverse effects.

A single capsule of Metabolift is labeled to contain 10 mg ephedrine alkaloids from ma huang extract, 100 mg caffeine, 50 mg L-carnitine, and 100 μg chromium picolinate. Analysis of a single dose (two capsules of Metabolift) revealed an average of 17.3 mg ephedrine, 5.3 mg pseudoephedrine (a total of 23.7 mg ephedrine alkaloids) and 175 mg caffeine [8].

The average time to maximum plasma concentration for ephedrine, pseudoephedrine, and caffeine were 142.5 minutes, 146.3 minutes, and 94 minutes, respectively. The average elimination half life (t_1/2) for ephedrine was 6.06 hours, 6.26 hours for pseuodephedrine, and 8.1 hours for caffeine. Also, increased urine pH was correlated with an increased t1/2. Subject 7, a 54.6 kg female reported to be taking oral contraceptives, experienced the highest maximum plasma concentrations (Cmax) of ephedrine, pseudoephedrine, and caffeine with 80.0 ng/mL, 29.1 ng/mL, and 6.61 μg/mL, respectively. The mean values of Cmax for ephedrine, pseudoephedrine, and caffeine were 63.5 ng/mL, 24.1 ng/mL, and 1.26 μg/mL [8].

Serious complaints were limited to 2 complaints of palpitations. The average baseline heart rate of the eight subjects was 67 BPM and the mean maximum heart rate was 82 BPM, which occurred at an average of 6 hours after ingestion. One subject had reported tachycardia, defined as an extremely rapid heart rate of over 100 BPM, at two time intervals, 6 and 11 hours, with a maximal heart rate of 108 BPM. The greatest heart rate change in a single individual occurred at 6 and 8 hours with a baseline heart rate of 53 BPM and a peak heart rate of 90 BPM. The mean systolic and diastolic blood pressures were 115 mm Hg and 72 mm Hg, respectively. The average change in systolic blood pressure was an increase in 14 mm Hg, occurring at 90 minutes after ingestion. The average change in diastolic blood pressure was an increase of 6mm Hg, occurring at 30, 90, and 120 minutes. Of the eight subjects, three had reported mild cases of hypertension: 2 with diastolic blood pressure measurements of 90 mm Hg, and 1 with a systolic blood pressure measurement of 143 mm Hg.

As well as monitoring the plasma concentrations, heart rates, and blood pressure, subjects filled out questionnaires regarding their mood, emotional feelings, and physical symptoms, rating their symptoms as “none,” “slight,” or “strong.” Symptoms included headaches, chest pain, shakiness, dizziness, irritable, energetic, sweating, restlessness, heart pounding, shortness of breath, etc. The most common symptoms reported were restlessness, heart pounding, and shakiness. Of the 21 categorized symptoms, only three were reported to be of strong intensity a one hour after of ingestion: two reported shakiness, two reported restlessness, and one reported heart pounding. After five hours of ingestion, only one symptom was reported as “strong” intensity: shakiness. The majority of mood and emotional feelings were of stronger intensity five hours after ingestion, including irritable, relaxed, happy, and energetic. Very few physical symptoms were reported after 1 hour (only 3 out of the 21 categorized symptoms), with an increase in “slight” intensity at 5 hours.

The overall purpose of this study was to demonstrate the effects of ephedrine ingestion as related to cardiovascular toxicity. Based on the changes in heart rate, blood pressure, and the reported symptoms, it can be said that ephedrine does in fact lead to adverse effects and can cause strain on the heart. A few cases of hypertension and tachycardia were reported, as well as several reports of shakiness, heart pounding, and palpitations.

CONCLUSION

Ephedrine is the center of several current controversial issues. It is included in dietary supplements that promote weight loss but is also linked to serious cardiovascular toxicity. Although ephedrine is marketed to promote fat loss/breakdown (lipolysis), it is concluded that it does not actually do so. Lipolysis is stimulated by the activation of β3-adrenergic receptors; however, as shown in the first case study, ephedrine has insignificant effects on β3-AR, even at extremely high concentrations. Ephedrine does cause significant response of the β1 and β2 AR’s, which control the force and rate of contractions of the heart and muscle relaxation of skeletal and smooth muscle, as well as glycogenolysis. The effect of ephedrine on the latter β-AR’s is supported by case study 2 in which an increase in heart rate, blood pressure, and adverse effects were recorded.

With the ingestion of Ephedra it will either act directly by binding to the receptor site or indirectly by stimulating the release of epinephrine and/or norepinephrine. Both pathways eventually lead to an increase in cystolic [cAMP] and the specific cellular response, such as lipolysis or glycogenolysis. Time, concentration, and external stimuli (stress, heat, and exhaustion) are a few factors that must be carefully monitored when taking ephedrine. Because it is marketed as being a fairly safe dietary supplement and little significant research has been done on ephedrine in dietary supplements, the use of ephedra is risky. Although it has been banned in the NFL, NCAA, and the Olympics, the NBA, NHL, and MLB still have not recognized it as a dangerous stimulant. The FDA is pushing to regulate the use and sales of ephedra due to recent deaths linked to its usage. In all, ephedra does not promote lipolysis, but does however increase glycogenolysis and heart contractions. The benefits of using ephedra should be carefully weighed against the side effects and possibility of death before committing either way.