Pharmacological Effects

Studies have shown that resultant effects are similar, regardless of whether pure synthetic ephedrine or naturally occurring ephedra is ingested (24,25). There are, however, significant enantioselective differences between the enantomers in both pharmacokinetic and pharmacodynamic effects. All of the ephedra alkaloids have important effects on the cardiovascular and respiratory systems, but not to the same degree.

Ephedrine, the predominant alkaloid in ephedra, is both an a and p stimulant. It directly stimulates a2 and px; receptors and, because it also causes the release of norepinephrine from nerve endings, it also acts as a p2 stimulant. The resultant physiological changes are variable, depending on receptor distribution and receptor regulation (26). Tolerance to ephedrine's p agonist actions emerges rapidly, which is why ephedrine is no longer the preferred agent for treating asthma; receptor downregulation quickly occurs and the bronchodilator effects are lost (27,28).

Receptor distribution probably explains why ephedrine has no effect on diastolic pressure, and only minimal effect on systolic. P2 Stimulation of vessels in peripheral muscles results in peripheral vasodilation and "diastolic runoff," which more than cancels ephedrine's other inotropic effects (29). The absence of any significant effect on blood pressure was firmly established during the late 1970s and early 1980s in dozens of double-blind, placebo-controlled studies performed to compare the effectiveness of ephedrine with that of newly synthesized adrenergic agents (30-60).

The pharmacokinetic and toxicokinetic behavior of any isomer cannot be used to predict that of any other ephedrine isomer. The (+) isomer of meth-amphetamine, for example, is a potent CNS stimulant, but the (-)-isomer is merely a decongestant. There is a tendency in the literature to lump together all "ephedrine alkaloids" and use the term "class effect" to assume that all the different drugs in that class exert the same effects on the same biological targets. In fact, some of the drugs in the class will be similar in some regards and different in others.

The affinity of the various ephedrine isomers for human ^-receptors has been measured and compared (as indicated by the amount of cyclic adenosine monophosphate produced compared to that of isoproterenol) in tissue culture. Activity of the different isomers is highly stereoselective, i.e., the different isomers had very different receptor-binding characteristics. For p1-receptors, maximal response (relative to isoproterenol = 100%) was greatest for ephedrine (68% for 1R,2S-ephedrine and 66% for the 1S,2R-ephedrine isomer). Both of the pseudoephedrine isomers had much lower affinities (53%). When binding to p2-receptors was measured, the rank order of potency for 1R,2S-ephedrine was 78%, followed by 1R,2R-pseudoephedrine (50%), followed by 1S,2S-pseudoephedrine (47%). The 1S,2R-ephedrine isomer had only 22% of the activity exerted by isoproterenol, but was the only isomer that showed any significant agonist activity on human p3-receptors (31%) (61). Stimulation of p3-receptors, which are thought to be located only in fat cells, may account for ephedrine's ability to cause weight loss (62-64).

Ephedrine is also an a agonist and, as such, is capable of stimulating bladder smooth muscle. At one time, it was used to promote urinary continence (65,66). In animal models, when compared to norepinephrine, ephe-drine is a relatively weak a-adrenergic agonist, possessing less than one-third the activity of norepinephrine (67). Ephedrine's usefulness as a bronchodila-tor is limited by the number of ^-receptors on the bronchi. The number of P

receptors located on human lymphocytes (which correlates with the number found in the lungs) decreases rapidly after the administration of ephedrine; the density of binding sites drops to 50% after 8 days of treatment and returns to normal 5 to 7 days after the drug has been withdrawn (27).

6. Clinical Studies 6.1. Bronchodilation

Banner et al. summarized studies where the effects of ephedrine and ephedra were compared to placebo in controlled studies in humans. None of the controlled trials disclosed any evidence of cardiovascular toxicity when ephedrine was given in doses as high as 1 mg/kg, even when it was administered to severe asthmatics with known cardiac arrhythmias (57). The trial reported by Banner et al. studied the respiratory and circulatory effects of orally administered ephedrine sulfate, 25 mg, aminophylline, 400 mg, terbutaline sulfate, 5 mg, and placebo in 20 patients with ventricular arrhythmia by a double-blind crossover method. The study was comprised of 20 patients, with an average age of 60 years and a preexisting history of both asthma and heart disease (as evidence by the presence of frequent premature ventricular contractions). The bronchodilator effect of terbutaline was similar to that of aminophylline over 4 hours but superior to ephedrine at hour 4. Both terbutaline and ephedrine exhibited chronotropic effects, with the effect of terbutaline greater than that of ephedrine at hour 4. The effect of amino-phylline on heart rate (HR) did not differ from placebo. Only terbutaline was associated with an increase in ventricular ectopic beats. Ventricular tachycardia occurred in three patients treated with terbutaline and in one patient with ephedrine (which occurred before he was given ephedrine). There were no significant changes in blood pressure. Orally administered terbutaline should not be regarded as safer than orally administered ephedrine or aminophylline in patients with arrhythmias.

In 1992, Astrup studied the effects of ephedrine and caffeine in a group of obese patients (68). In a randomized, placebo-controlled, double-blind study, 180 obese patients were treated by diet (4.2 mJ/day) and either an ephedrine/ caffeine combination (20 mg/200 mg), ephedrine (20 mg), caffeine (200 mg), or placebo three times a day for 24 weeks. Withdrawals were distributed equally in the four groups, and 141 patients completed the trial. Mean weight losses was significantly greater with the combination than with placebo from week 8 to week 24 (ephedrine/caffeine, 16.6 ± 6.8 kg vs placebo, 13.2 ± 6.6

kg [mean ± standard deviation {SD}], P = 0.0015). Weight loss in both the ephedrine and the caffeine groups was similar to that of the placebo group. Side effects (tremor, insomnia, and dizziness) were transient and after 8 weeks of treatment they had reached placebo levels. Systolic and diastolic blood pressure fell similarly in all four groups.

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