Pharmacological Toxicological Effects 51 Pharmacology

C. aurantium contains the adrenergic amines (18) synephrine, octopamine, and tyramine, and many flavones and glycosylated flavanones

(19). These sympathomimetic molecules can be found in normal human plasma

(20) and are known to be involved in alternate metabolic pathways of common biogenic amines (21). Of the three active adrenergic molecules in C. aurantium, synephrine is present in amounts at least 100-fold greater than either octopamine or tyramine found in the fresh fruit, dried extracts, or herbal medicines (18).

The locations of the substituents on the phenylethylamine backbone play an integral role in determining the observed pharmacological effects of sym-pathomimetic molecules (Table 1). Substitution of a hydroxyl group on the P-carbon tends to increase activity toward both a and P receptors, but decreases activity in the central nervous system (CNS) (23). Substitution of hydroxyl groups in any place in the phenylethylamine structure increases the hydrophi-licity, and thus decreases the propensity of the molecule to enter the CNS (23). Ephedrine, for example, is a weaker CNS stimulant than amphetamine but is a stronger bronchodilator and has greater effect on increasing heart rate and blood pressure (23). The relatively polar epinephrine is essentially devoid of CNS activity aside from anxiety related to other systemic effects (23). Hydroxyl groups at both the 3 and 4 position provides the most a and P activity (23). Also, substitution at the amino position generally enhances the effect on P receptors (23). This accounts for the strength of epinephrine for P2 receptor subtype relative to that of norepinephrine and is probably important in interpreting the potential cardiovascular effects of C. aurantium (23).

Although the effects of synephrine and C. aurantium differ slightly in hemodynamic studies, the relative content of synephrine compared to octopamine and tyramine (at least 100 times more synephrine) in C. aurantium products substantially outweighs the effects of octopamine and tyramine (18). Although synephrine is found endogenously in the adrenal glands (24), the function is still unclear (20). The binding of synephrine to various adrenergic receptors is shown in Table 2.

Table 1

Chemical Structures of Selected Sympathomimetic Molecules a

Epinephrine

3-OH,4-OH

OH

H

CH

Norepinephrine

3-OH,4-OH

OH

H

H

Synephrine

4-OH

OH

H

CH

Octopamine

4-OH

OH

H

H

Tyramine

4-OH

H

H

H

Ephedrine

OH

ch3

CH3

Amphetamine

H

ch3

H

Phenylpropanolamine

OH

H

H

Adapted from ref. 23.

Adapted from ref. 23.

Table 2

Synephrine Binding and Activity in Adrenergic Receptors

Table 2

Clinical hemodynamic

Activated

Binding relative

response to receptor

Receptor

by synephrine

to norephinephrine

Reference

activation (23)

a1

Yes

¿15X

25,26

Constrict vessels throughout body

a2

Yes

?

26,27

Constrict coronary/renal arteries and systemic veins

ß1

No

?

28

Increase heart reate, contractility, conduction velocity

ß2

No, yes

¿100X

28,29

Dilate coronary/renal/ skeletal/pulmonary arties and systemic veins. Also same heart effects as p1

ß3

Yes

?

30

Lypolysis and thermogenesis

There seems to be general agreement that synephrine is an active agonist of Pj, p2, and p3 adrenergic receptors. There are conflicting reports, however, as to whether synephrine possesses any pr or p2-receptor-agonist activity (28,29). The effects observed in studies and case reports of C. aurantium use are consistent with that of both a- and P-receptor activation. Also, the published study demonstrating lack of P-adrenergic activation (28) was conducted in guinea pig atria/trachea, whereas the study demonstrating activation of p receptors was conducted in cloned human p2 adrenergic receptors (29). Drugs such as phenylephrine, which primarily exhibit a-agonist activity, induce a rise in blood pressure and a dose-related increase in peripheral vascular resistance (23). Associated with these actions is a sinus bradycardia caused by vagal reflex (23). Epinephrine, on the other hand, exhibits both a- and p-agonist activity. Effects seen with norepinephrine infusion are tachycardia, a moderate increase in systolic blood pressure, a rise in cardiac output, and shorter and more powerful cardiac systole (23). The p2 effect relaxes skeletal muscle vasculature, leading to a lowering of peripheral resistance and diastolic blood pressure (23).

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