Herbal remedies for bronchial asthma Ephedra

Often referred to by its Chinese name, ma huang, ephedra (the green stems of various Ephedra species, particularly E. sinica Stapf, E. equisetina Bunge, and others of the family Ephedraceae) has been used in China for the treatment of bronchial asthma and related conditions for more than five thousand years. Another species, E. gerardiana Wall., has been similarly employed in India. Ephedra was the first Chinese herbal remedy to yield an active constituent—in this case, ephedrine—widely used in Western medicine. 4

Ephedrine was first isolated from the herb by a Japanese chemist, N. Nagai, in 1887. Nearly forty years elapsed before K. K. Chen and his men- tor, C. F. Schmidt, of the Peking Union Medical College began to publish (1924) a series of studies on the pharmacological properties of the alkaloid. American physicians were quick to appreciate the adrenergic properties of ephedrine, and it became widely used as a nasal decongestant, a cen-

tral nervous system stimulant, and a treatment for bronchial asthma. 5 In addition to ephedrine, several other alkaloids, such as pseudoephedrine, norephedrine, and norpseudoephedrine, etc., are contained in various species of Ephedra. These possess physiological properties similar to those of ephedrine. 6

The approximately forty different species of Ephedra are grouped by Hegnauer into five geographic types based primarily on variations in their alkaloid content. 7 All North and Central American types appear to be devoid of alkaloids; thus, any activity attributed to these species must derive from compounds other than ephedrine or its derivatives. This is of particular interest in the case of E. nevadensis S. Wats., the ingredient in Mormon tea. As an American species of Ephedra, it is alkaloid free and of no value in the treatment of bronchial asthma. It should be emphasized that even special- ists often find the different species of Ephedra difficult to classify.

When a β 2 -agonist binds to the receptor on the cell membrane, a con- formational change in the receptor results in a signal transduction involving the participation of G proteins. Activation of adenylate cyclase occurs, leading to increased intracellular levels of cyclic AMP and a reduction

Chapter five: Respiratory tract problems

79 in cytoplasmic Ca ++ concentration, resulting in smooth-muscle relaxation.

Ciliary activity and liquefaction of tenacious mucus also increase, resulting in a mild expectorant action. 8

Ephedra is recommended for treating only mild forms of seasonal or chronic asthma. Due to its particular chemistry and more lipophilic properties compared to norepinephrine, ephedrine is effective when administered orally; its peak effect occurs in one hour after administration and it has a half-life of six hours. Its duration of action is more prolonged than for norepinephrine, which is not effective upon oral administration, because ephedrine is resistant to metabolism by both monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

The herb is often administered in the form of a tea prepared by steep- ing 1 heaping teaspoonful (2 g) in ½ pint of boiling water for ten minutes. 9 Prepared from plant material of good quality, this would represent 15–30 mg of ephedrine, which approximates the usual dose of the alkaloid.

Ephedra has multiple, serious adverse effects (particularly in large doses), principally because ephedrine is a nonselective adrenergic agonist. Figure 5.1 shows the effects of ephedra on adrenergic receptors in various target tissues of the body and how they translate into side effects. Central nervous system stimulation can be a problem resulting in nervousness, insomnia, hyperactivity, and irritability. Its effects on the cardiovascular system include tachycardia, premature systoles, and vasoconstriction, causing an increase in both systolic and diastolic blood pressure. Its action in the gastrointestinal tract to decrease tone, motility, and secretory activity may result in nausea and vomiting. These side effects render the indiscriminate use of ephedra highly inadvisable, particularly by persons suffering from heart conditions, hypertension, diabetes, or thyroid dis- ease. It would also be contraindicated in patients with prostatic hyperpla- sia (BPH) because of the problem of urinary retention. 10

Various products containing ephedra or ephedrine have been mar- keted with numerous unsubstantiated and potentially dangerous therapeutic claims. These include weight loss, appetite control, and as an alternative to illegal street drugs such as “Ecstasy” (MDMA or 3,4-meth- ylenedioxymethamphetamine). These claims have led to a plethora of cases of abuse with the serious consequence of more than six hundred reports in the last few years to the Food and Drug Administration (FDA) of ephedrine-related adverse reactions, along with twenty-two deaths

attributed to the drug. 11 In an attempt to control this abuse, the FDA has proposed regulations that will control the amount of ephedrine alkaloids in a product and will not allow combination products containing caffeine or caffeine-containing herbs (also central nervous system stimulants). 12

Because of its chemical structure, ephedrine can serve as a precur- sor for the illegal synthesis of methamphetamine or “speed,” a common drug of abuse. Several states have recently passed laws regulating the sale

80 Tyler's herbs of choice: The therapeutic use of phytomedicinals

Relieves bronchospasm in asthma

Relaxation

Nervousness, insomnia, hyperactivity, irritability

Increased blood pressure

Increased Stimulation

β 2 -receptors

bronchial smooth

heart rate Increased

contractile force α- and β-receptors

central nervous system

Ephedra (ephedrine)

α 1 -receptors α 2 - and β 2 -receptors trigone sphincter muscle

gastrointestinal tract urinary bladder

α 1 -receptors blood vessels

Decreases tone, Constriction

motility, and secretory activity

Vasoconstriction

Impedes urine Decreased

Nausea, ﬂow

Increased

nasal secre- blood pressure

vomiting

tion

Figure 5.1 Nonselective adrenergic agonist activity of ephedra in the human body.

of the alkaloid or products containing it. This concern overlooks the fact that today most ephedrine is produced by a chemical synthesis involving the reductive condensation of l-1-phenyl-1-acetylcarbinol with methylam- ine. This yields the desired isomer l-ephedrine, which is identical in all respects to that contained in ephedra. In view of the difficulties involved in extracting and purifying the relatively small concentrations of ephedrine from the ephedra herb and the fact that the plant serves only as a minor source of the alkaloid, anyway, restricting the availability of the herb, although well intended, seems an excessive measure. 13,14

Bitter or sour orange Citrus aurantium L., family Rutaceae (also called Seville and Neroli orange), has been vigorously promoted as a substitute for ephedra in weight-loss

Chapter five: Respiratory tract problems

81 products, following restriction of products of the latter herb by the FDA

due to their clinical association with strokes, heart attack, hypertension, and psychiatric problems. 15 Extracts are prepared from the immature fruit of C. aurantium, termed zhi shi in Chinese. The extracts contain five adrenergic amines; chief among them is synephrine, accompanied by N-methyltyramine, hordenine, octopamine, and tryamine. The extracts are usually standardized to 4 or 6 percent synephrine.

In rats, reported oral administration of 2.5–20 mg/kg of two C. aurantium fruit extracts standardized to 4 and 6 percent synephrine, respec- tively, significantly reduced food intake and body weight gain. However, mortality (not observed in controls) was present in all C. aurantium groups. Although arterial blood pressure was not modified, ECG alterations (ven- tricular arrythmias with enlargement of QRS complex) were evident in animals treated with both extracts. 16

The only published trial of a C. auranitum-containing weight-loss product utilized a combination of 975 mg C. aurantium extract (6 percent synephrine), 528 mg caffeine, and 900 mg of a St. John’s wort extract (0.3 percent hypericins) daily for six weeks received by nine subjects. Seven received a placebo and four no treatment other than dietary counseling and an exercise program. The product was found not to be

superior to placebo for weight loss. 17 There is also no evidence that synephrine and its accompanying sympathomimetic amines would have any lipolytic effect on human adipocytes at the levels found in weight- loss products.

Concern expressed over the potential for C. aurantium dietary supplements to affect drug metabolism 18 was judged groundless by the American Herbal Products Association. This organization pointed out that although bitter orange juice is claimed to be a potent inhibitor of cytochrome P450 3A4 isoenzyme and would therefore be expected to increase the blood level of many drugs, there is no evidence to support such effects from bitter orange extracts made from dried fruit or peel. 19

Thus far, there have not been any reports of adverse effects associated with consumption of bitter orange dietary supplements.

Herbal remedies for bronchial asthma Ephedra