St. John's Wort (Hypericum perforatum)
St. John's wort is used for the short-term treatment of mild to
moderate depression.[93]
[94]
It is not effective in the treatment of major depression.[95]
[96]
It is used for other psychiatric complaints
such as anxiety, but little evidence supports its use for conditions other than depression.
The six classes of key compounds in St. John's wort are the naphthodianthrones (i.e.,
hypericin and pseudohypericin), acylphloroglucinols (i.e., hyperforin and adhyperforin),
flavonol glycosides, biflavones, proanthocyanidins, and phenylpropanes. Although
hypericin was long thought to be the primary active compound, evidence suggests that
hyperforin may be more important in the antidepressant effects.[97]
St. John's wort inhibits serotonin, norepinephrine, and dopamine
reuptake.[98]
[99]
Early in vitro data implicated monoamine oxidase inhibition as a possible mechanism
of action,[100]
but subsequent data showed this
was not the mechanism.[97]
[101]
[102]
The use of St. John's wort with or without
serotonin-reuptake inhibitors may create a syndrome of central serotonin excess.
[103]
More importantly, St. John's wort can significantly
increase the metabolism of many concomitantly administered drugs through the induction
of cytochrome P450 microsomal enzymes, roughly doubling their metabolic activity.
[104]
The most affected enzyme appears to be CYP3A4,
which is responsible for the metabolism of more than 50% of conventional medications
subject to oxidative metabolism by cytochrome P450. Interactions with the CYP3A4
substrates indinavir,[105]
ethinyl estradiol,[106]
and cyclosporin have been reported. In a series of 45 organ transplant recipients,
cyclosporin levels decreased an average of 49% after St. John's wort was taken.[107]
Two cases of acute heart transplant rejection have also been associated with this
particular pharmacokinetic interaction.[108]
Other
CYP3A4 substrates used in the perioperative period include alfentanil, midazolam
hydrochloride, lidocaine, calcium channel blockers, and serotonin receptor antagonists,
and it is reasonable to assume that metabolism of these drugs would also be increased.
St. John's wort induces CYP2C9, substrates of which include nonsteroidal anti-inflammatory
drugs, phenytoin, and warfarin. The anticoagulant effect of warfarin was reduced
in seven reported cases.[106]
St. John's wort also
lowers digoxin levels by induction of the P-glycoprotein transporter.[109]
The effect of St. John's wort on drug pharmacokinetics makes its
preoperative discontinuation important in many patients. Discontinuation is crucial
in certain patients awaiting or after organ transplantation because of the risk of
rejection. Also included are patients receiving warfarin during the perioperative
period for prophylaxis against thrombotic complications because typical warfarin
doses may not provide adequate anticoagulation for patients who take St. John's wort
preoperatively. Management of drug dosing in the immediate postoperative period
may be difficult as the metabolic function of cytochrome P450 enzymes normalize after
discontinuation. A case of delayed emergence has been attributed to St. John's wort.
[110]
The single-dose and steady-state pharmacokinetics of hypericin,
pseudohypericin, and hyperforin have been determined in humans.[111]
[112]
After oral administration, peak plasma levels
of hypericin, pseudohypericin, and hyperforin are obtained in 6.0, 3.0, and 3.5 hours,
respectively. The median elimination half-lives of hypericin, pseudohypericin, and
hyperforin are 43.1, 24.8, and 9.0 hours, respectively. These pharmacokinetic data
suggest that St. John's wort should be discontinued at least 5 days preoperatively.
