ContextWidespread use of herbal medications among the presurgical population
may have a negative impact on perioperative patient care.ObjectivesTo review the literature on commonly used herbal medications in the
context of the perioperative period and provide rational strategies for managing
their preoperative use.Data SourcesThe MEDLINE and Cochrane Collaboration databases were searched for articles
published between January 1966 and December 2000 using the search terms herbal medicine, phytotherapy,
and alternative medicine and the names of the 16
most commonly used herbal medications. Additional data sources were obtained
from manual searches of recent journal articles and textbooks.Study SelectionWe selected studies, case reports, and reviews addressing the safety
and pharmacology of 8 commonly used herbal medications for which safety information
pertinent to the perioperative period was available.Data ExtractionWe extracted safety, pharmacodynamic, and pharmacokinetic information
from the selected literature and reached consensus about any discrepancies.Data SynthesisEchinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and
valerian are commonly used herbal medications that may pose a concern during
the perioperative period. Complications can arise from these herbs' direct
and pharmacodynamic or pharmacokinetic effects. Direct effects include bleeding
from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra;
and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions include
potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic
herb-drug interactions include increased metabolism of many drugs used in
the perioperative period by St John's wort.ConclusionsDuring the preoperative evaluation, physicians should explicitly elicit
and document a history of herbal medication use. Physicians should be familiar
with the potential perioperative effects of the commonly used herbal medications
to prevent, recognize, and treat potentially serious problems associated with
their use and discontinuation.

https://jamanetwork.com/journals/jama/articlepdf/194003/JRV10013.pdf

Herbal Medicines and Perioperative Care

Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding.

Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.

CONTEXT\nWidespread use of herbal medications among the presurgical population may have a negative impact on perioperative patient care.\n\n\nOBJECTIVES\nTo review the literature on commonly used herbal medications in the context of the perioperative period and provide rational strategies for managing their preoperative use.\n\n\nDATA SOURCES\nThe MEDLINE and Cochrane Collaboration databases were searched for articles published between January 1966 and December 2000 using the search terms herbal medicine, phytotherapy, and alternative medicine and the names of the 16 most commonly used herbal medications. Additional data sources were obtained from manual searches of recent journal articles and textbooks.\n\n\nSTUDY SELECTION\nWe selected studies, case reports, and reviews addressing the safety and pharmacology of 8 commonly used herbal medications for which safety information pertinent to the perioperative period was available.\n\n\nDATA EXTRACTION\nWe extracted safety, pharmacodynamic, and pharmacokinetic information from the selected literature and reached consensus about any discrepancies.\n\n\nDATA SYNTHESIS\nEchinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and valerian are commonly used herbal medications that may pose a concern during the perioperative period. Complications can arise from these herbs' direct and pharmacodynamic or pharmacokinetic effects. Direct effects include bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions include potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic herb-drug interactions include increased metabolism of many drugs used in the perioperative period by St John's wort.\n\n\nCONCLUSIONS\nDuring the preoperative evaluation, physicians should explicitly elicit and document a history of herbal medication use. Physicians should be familiar with the potential perioperative effects of the commonly used herbal medications to prevent, recognize, and treat potentially serious problems associated with their use and discontinuation.

Herbal medicines and perioperative care

Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC(0-8 h) and a doubling of C(max). However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a "composite" kava formulation composed of the six major kavalactones contained in the extract. K(i) values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 microM. Kava extract and kavalactones (< or =9 microM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.

https://dmd.aspetjournals.org/content/dmd/early/2005/07/20/dmd.105.004317.full.pdf

Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro

Kava is a traditional beverage of various Pacific Basin countries. Kava has been introduced into the mainstream U.S. market principally as an anti-anxiety preparation. The effects of the long-term consumption of kava have not been documented adequately. Preliminary studies suggest possible serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. As such, kava extract was nominated for the chronic tumorigenicity bioassay conducted by the National Toxicology Program (NTP). At present toxicological evaluation of kava extract is being conducted by the NTP. The present review focuses on the recent findings on kava toxicity and the mechanisms by which kava induces hepatotoxicity.

/pdf/toxicity-of-kava-kava-psd1ywe7r9.pdf

Toxicity of kava kava.

1. The metabolism in rats of several kava pyrones from Piper methysticum Forst. was studied. The compounds were the 5,6-dihydro-alpha-pyrones, dihydrokawain, kawain and methysticin, and the alpha-pyrones, 7,8-dihyroyangonin and yangonin. 2. Approx. half the dose (400 mg/kg, p.o.) of dihydrokawain was found in the urine in 48 h. About two-thirds of this was hydroxylated metabolites (three mono- and three di-hydroxylated derivatives), of which p-hydroxydihydrokawain was the most abundant. The remaining third consisted of metabolites formed by scission of the 5,6-dihydro-alpha-pyrone ring and included hippuric acid (9--13% dose). 3. Lower amounts of urinary metabolites were excreted when kawain was given, but both hydroxylated and ring-opened products were formed. 4. Methysticin gave rise to only small amounts of two urinary metabolites formed by demethylenation of the methylenedioxyphenyl moiety. 5. Urinary metabolites of the alpha-pyrones, 7,8-dihydroxyangonin and yangonin, were formed via omicron-demethylation. No ring-opened products were detected. 6. These lipophilic kava pyrones have extremely low solubility in water, which would be expected to reduce their absorption rates and appears to be responsible for the variable and low extent of metabolism observed.

Metabolism of some kava pyrones in the rat.

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Metabolism of some kava pyrones in the rat.