Physiological Actions

Ephedrine and the other alkaloids are sympathomimetic amines that have both direct and indirect actions at a- and h-adrenergic receptors in the brain and peripheral nervous system (12). The physiological actions of the ephedra alkaloids depend on their relative affinities for these receptors, which provide a molecular basis to explain their different profiles of action and adverse effects. For example, (—)-ephedrine appears to have relatively more direct agonist effects and greater central nervous system affinity than either pseu-doephedrine or norephedrine (22-24).

The primary action of the ephedra alkaloids is as indirect sympathetic nervous system stimulants acting to increase release of stored norepinephrine in sympathetic nerve terminals, which then diffuses into the synapse and binds to postsynaptic a- and h-adrenergic receptors (Fig. 2). These agents also can have direct agonist actions at both central and peripheral a1, h1, and h2 postsynaptic receptors (22-24). Their a1-adrenergic agonist activity produces vascular smooth-muscle contraction that results in vasoconstriction and increased peripheral vascular resistance. Stimulation of a1 receptors in the radial pupillary muscle of the eye results in mydriasis. There are also a1 receptors in the urethral sphincter, bladder base, and prostate that promote urinary continence. Stimulation of a1-adrenergic receptors in the appetite

Figure 2 Schematic of molecular mechanisms of action of ephedra alkaloids. (a) Indirect release of stored neurotransmitters, primarily norepinephrine. (b) Direct action at postsynaptic a1-adrenergic receptors in the brain and peripheral nervous system. (c) Direct action at postsynaptic h1-, h2-, and h3-adrenergic receptors in the heart, smooth muscle, liver, and adipose tissue. NT= neurotransmitter, including norepinephrine, dopamine, and serotonin. A = agonist. G= membrane-bound G protein. AC= membrane-bound adenyl cyclase enzyme. cAMP= cyclic adenosine monophosphate. ATP= adenosine triphosphate.

Figure 2 Schematic of molecular mechanisms of action of ephedra alkaloids. (a) Indirect release of stored neurotransmitters, primarily norepinephrine. (b) Direct action at postsynaptic a1-adrenergic receptors in the brain and peripheral nervous system. (c) Direct action at postsynaptic h1-, h2-, and h3-adrenergic receptors in the heart, smooth muscle, liver, and adipose tissue. NT= neurotransmitter, including norepinephrine, dopamine, and serotonin. A = agonist. G= membrane-bound G protein. AC= membrane-bound adenyl cyclase enzyme. cAMP= cyclic adenosine monophosphate. ATP= adenosine triphosphate.

center of the hypothalamus is believed to be responsible for the anorexigenic effects of the centrally acting ephedra alkaloids (25).

Stimulation of hradrenergic receptors, found mostly in the heart, results in increased rate and force of contraction, leading to greater cardiac output. To a lesser extent, stimulation of a1-receptors in the heart contributes to increased cardiac contractility. Stimulation of h2-adrenergic receptors relaxes vascular, respiratory, and uterine smooth muscle, and increases liver glycogenolysis. h3-Adrenergic receptors are located primarily in white adipose tissue, liver, and skeletal muscle, and activation of these receptors will increase lipid oxidation (26).

Agents with both a- and h-adrenergic stimulant actions will generally have a net effect of increasing blood pressure because the a1 vasoconstrictive action typically supersedes h2-mediated vascular relaxation. However, h2-mediated bronchial smooth-muscle relaxation is not opposed by a1-ago-nist activity, and therefore, ephedra alkaloids with h2 activity will relieve bronchoconstriction.

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