Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 16 – Patients on Herbal Medications

Alan D. Kaye, MD, PhD, DABPM,
Jason M. Hoover, MD

  

 

Echinacea

  

 

Ephedra

  

 

Feverfew

  

 

Garlic

  

 

Ginger

  

 

Gingko Biloba

  

 

Ginseng

  

 

Kava Kava

  

 

Saw Palmetto

  

 

St. John's Wort

  

 

Alternative Medicine

  

 

Conclusion

The use of herbal medications or nutraceutical agents in the form of herbal remedies has increased significantly in the United States in recent years. The majority of consumers of herbal agents are white middle-aged women with some college education.[1] A recent study of 567 rural women found that 59.1% of the participants used herbal medications.[2] Currently, evidence is lacking regarding the effectiveness of certain herbal medications, their potential interactions with over-the-counter (OTC) or prescribed medications, and the potential side effects of herbal medications when used alone or in conjunction with OTC or prescribed medications. In addition, there seems to be an increasing trend toward the reimbursement of herbal medications by managed care organizations and insurance companies.[3]

The medical community, in general, and the anesthesiologist, in particular, should be cognizant of what data and information are available regarding herbal medications. For example, the medical community may not be aware that approximately 30% of all modern conventional therapeutic agents are derived from plants.[4] Furthermore, the clinical anesthesiologist might be interested in a recent survey of 752 patients scheduled for elective surgery that was conducted within the Department of Anesthesiology at Texas Tech University in Lubbock. The results of this study revealed that, of those surveyed, 32% were actively using at least one herbal agent and 70% of these patients did not inform their anesthesiologist of such use during the routine preoperative assessment.[5] Knowing that herbal medications can have effects on the central nervous, respiratory, cardiovascular, and gastrointestinal systems, to name a few, the importance of education in the form of a brief history and thorough examination of selected herbal medications cannot be overlooked.

The use of herbal medications, in some capacity, has occurred for centuries throughout the world. In the United States, herbal medicine use began in the early colonial days when health care was, for the most part, provided in the home. By the 19th century, the advancement of scientific methods allowed for the practice of conventional medicine to flourish and the subsequent decrease in the use of herbal medications.[3] It was not until the 1960s that herbal agents began to return in popularity, and in 1992 the Office of Alternative Medicines was established by the National Institutes of Health in Bethesda, Maryland, thus reflecting the prevalence of herbal use.

Many herbal agents are not regulated strictly as to their quality assurance and, therefore, consumers must rely on manufacturer labels.[6] Unfortunately, patients often do not consider herbal compounds to be medications and, as mentioned previously, do not convey the use of such agents during the preoperative assessment.[5] Furthermore, one estimate concluded that as many as 20% of the adult U. S. population take prescription drugs along with herbal medications. [7] [8] Herbal medications are recognized under the Dietary Supplement Health and Education Act, and this act has served to limit the regulation of such substances by the U. S. Food and Drug Administration (FDA).[1] For example, in contrast to prescription medication, the FDA must first demonstrate that an herbal agent is unsafe before it is removed from the market.[6] With savvy advertisement by herbal manufacturers, word-of-mouth popularity, and a relatively lax standardization policy by the FDA regarding these herbal compounds, the herbal industry has become a multibillion dollar industry.[3] Finally, the medical community has observed patients dissatisfied with the cost or effectiveness of their prescription medications searching for the easily obtainable and relatively inexpensive panacea of herbal medications.

A survey from 1996 of 163 health food retail stores in the United States indicated the top selling herbal medications were echinacea (Echinacea purpurea, Echinacea pallida, andEchinacea angustifolia), garlic (Allium sativum), goldenseal (Hydrastis canadenis), ginseng (Asian Panax ginseng andAmerican Panax quinquefolius), gingko (Gingko biloba), saw palmetto (Serenoa repens), aloe (Aloe species), ma huang (Ephedra sinica), and Siberian ginseng (Eleutherococcus senticosus)[6] [9] Data from 1998 revealed that St. John's wort (Hypericum perforatum), valerian (Valeriana officinalis), and feverfew(Tanacetum parthenium) were also gaining in popularity.[3] To support such conclusions, a survey of 755 patients scheduled to undergo outpatient surgery from 2000 found garlic, gingko biloba, and St. John's wort to be among the top herbal agents self-administered by patients ( Fig. 16-1 ).[10]

With the recent federal ban on ma huang (Ephedra sinica) the use of that herbal may decrease; but with the seemingly infinite number of herbal medications, it is certain that another agent will take its place. The anesthesiologist should recognize the prevalence of these compounds and their physiologic effects on the patient. For example, some herbal medications have the potential to decrease platelet aggregation and inhibit clotting ( Table 16-1 ), and their use should be included in the differential of perioperative bleeding. The risks of bleeding remain dependent on the dose and preparation of the herbal in question. The American Society of Anesthesiologists (ASA) has suggested that anyone taking an herbal medication should desist ingestion for at least 2 to 3 weeks before a surgical procedure to ensure that the herbal medication is no longer in the system. It takes five half-lives for a drug (or herbal medication) to clear the system; given the variability in the preparation and bioavailability of herbal medications, the 2- to 3-week guideline is a general estimate to cover all preparations. Furthermore, there are herbal agents that cause alteration of the cytochrome P450 system and herbal medications that are associated with hepatotoxicity and/or nephrotoxicity (Tables 16-2 and 16-3 [2] [3]). Finally, some herbal agents may potentiate the depressant effects of central nervous system anesthetics and, in the case of ginseng, inhibit the analgesic effect of opioids (Tables 16-4 and 16-5 [4] [5]).[11] In this chapter, we review popular herbal medications, their intended use, physiologic effects, side effects, and potential interactions with anesthetic agents.

 
 

FIGURE 16-1  Percentage of patients self-administering herbal medications.  (Adapted from Kaye AD, Clarke RC, et al: Herbal medicines: Current trends in anesthesiology practice—a hospital survey. J Clin Anesth 2000;12:468-471, with permission.)

 

 

 


TABLE 16-1   -- Herbal Medications Associated with Bleeding Abnormalities

  

 

Bilberry

  

 

Bromelain

  

 

Chamomile

  

 

Dandelion root

  

 

Dong quoi

  

 

Fenugreek

  

 

Feverfew

  

 

Fish oil

  

 

Flax seed oil

  

 

Garlic

  

 

Ginger

  

 

Gingko biloba

  

 

Ginseng

  

 

Grape seed extract

  

 

Horse chestnut

  

 

Kava kava

  

 

Meadowsweet

  

 

Motherworth

  

 

Red clover

  

 

Tamarind

  

 

Turmeric

  

 

Willow

 

 


TABLE 16-2   -- Herbal Medications Associated with Serum Medication Concentration Abnormalities

  

 

Echinacea

  

 

Garlic

  

 

Kava kava

  

 

St. John's wort

 

 


TABLE 16-3   -- Herbal Medications Associated with Liver and/or Renal Dysfunction

  

 

Echinacea

  

 

Kava kava

  

 

Meadowsweet

  

 

Willow

 

 


TABLE 16-4   -- Herbal Medications Associated with Excessive CNS Depression During Anesthesia

  

 

Chamomile

  

 

Hops

  

 

Kava kava

  

 

Passion flower

  

 

Valerian

 

 


TABLE 16-5   -- Common Herbal Medications, Adverse Effects, and Anesthetic Considerations

Herbal Medication

Adverse Effects

Anesthetic Considerations

Echinacea

Unpleasant taste, tachyphylaxis, cytochrome P450 alterations, potential hepatotoxicity

May potentiate barbiturate toxicity

Ephedra

Hypertension, tachycardia, cardiomyopathy, CVA, cardiac arrhythmias

May interact with volatile anesthetics, i.e., halothane, and cause ? fatal cardiac dysrhythmias. Profound intraoperative hypotension controlled with phenylephrine and not pseudoephedrine.

Feverfew

Aphthous ulcers, gastrointestinal irritability, headache

Increased risk of intraoperative bleeding; discontinue 2 to 3 weeks before surgery.

Garlic

Halitosis, prolongation of bleeding time, hypotension, cytochrome P450 alterations

Increased risk of intraoperative bleeding

Ginger

Prolongation of bleeding time

Increased risk of intraoperative hemodynamic instability

Gingko biloba

Platelet dysfunction

Increased intraoperative and postoperative bleeding tendencies. May decrease effectiveness of intravenous barbiturates

Gingko biloba

Platelet dysfunction

Increased intraoperative and postoperative bleeding tendencies. May decrease effectiveness of intravenous barbiturates

Ginseng

Hypertension, prolonged bleeding time, hypoglycemia, insomnia, headache, vomiting, epistaxis

Increased risk of intraoperative hemodynamic instability

Kava kava

Characteristic ichthyosiform dermopathy, cytochrome P450 alterations, potential hepatotoxicity

May potentiate the effect of barbiturates/benzodiazepines, thereby resulting in excessive sedation

St. John's wort

Dry mouth, dizziness, cytochrome P450 alterations, constipation, nausea

Pseudoephedrine, MAOIs, and SSRIs should be avoided

Adapted from Kaye AD, Clarke RC, Sabar R, et al: Herbal medicines: Current trends in anesthesiology practice–A hospital survey. J Clin Anesth 2000;12:468-471.

CVA, cerebrovascular accident; MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.

 

 

 


ECHINACEA

The Echinacea are members of the daisy family and grow widely throughout North America. There are nine species of Echinacea, and the medicinal preparations are primarily derived from three of these:Echinacea pallida (pale purple coneflower), Echinacea purpurea (purple coneflower), and Echinacea angustifolia (narrow leaved coneflower). [12] [13] [14] This herbal medication accounts for more than $300 million in sales each year. The recommended use of echinacea is as a prophylactic and as a treatment agent for upper respiratory tract infections, although evidence is lacking to support the former.[6]It has alkylamide and polysaccharide constituents that possess significant in-vitro and in-vivo immunostimulation properties, owing to enhanced phagocytosis and nonspecific T-cell stimulation.[15]

The consumption of echinacea at the onset of symptoms has been clinically shown to decrease both the severity and duration of the cold and flu. Investigations utilizing quantitative polymerase chain reaction to identify in-vivo alterations in the expression of immunomodulatory genes in response to echinacea have been performed.[16] Studies conducted on in-vivo gene expression within peripheralleukocytes were evaluated in six healthy nonsmoking subjects (18 to 65 years of age). Blood samples were obtained at baseline and on days 2, 3, 5, and 12 after consumption of a commercially blended echinacea product. The overall gene expression pattern at 48 hours to 12 days after taking echinacea was consistent with an anti-inflammatory response. The expression of interleukin-1β, intracellular adhesion molecule, tumor necrosis factor-α (TNF-α), and interleukin-8 was modestly decreased up through day 5 and returned to baseline by day 12. In addition, the expression of interferon-alfa consistently increased through day 12, indicating an antiviral response. Thus, the initial data yielded a gene expression response pattern consistent with the reported ability of echinacea to decrease both the intensity and the duration of cold and flu symptoms.[16]

Although different preparations of E. purpurea have been investigated for their potential to augment immune function, primarily through the activation of the innate immune responses, there are few studies available that have examined the ability for enhancement of humoral immunity. However, a study using female Swiss mice as the model found support for the acute use of E. purpurea, as suggested by anecdotal reports, and demonstrated the potential for enhancement of humoral immune responses in addition to innate immune responses.[17] Despite the anecdotal reports and immunostimulatory data associated with echinacea, the use of E. purpurea, as dosed in one study, was not effective in treating upper respiratory tract infections and related symptoms in pediatric patients, ages 2 to 11. Furthermore, the consumption of E. purpurea was associated with an increased risk of rash.[18]

Echinacea is often well tolerated, with the most common side effect being its unpleasant taste. [6] [19] Extended use of echinacea for more than 2 months may lead to tachyphylaxis.[20] Anaphylaxis has also been reported with a single dose of this herbal agent.[12] Furthermore, echinacea use has been associated with hepatoxicity if taken with other anesthetic or nonanesthetic hepatotoxic agents such as anabolic steroids, amiodarone, ketoconazole, and methotrexate.[21] Flavonoids from E. purpurea can affect the hepatic cytochrome P450 and sulfotransferase systems. [22] [23] For example, one investigation found that echinacea decreased the oral clearance of substrates of the cytochrome P450 1A2 system but not the oral clearance of substrates of the 2C9 and 2D6 isoenzymes in vivo. The herbal agent also selectively modulates the activity of the cytochrome P450 P3A isoenzyme at both hepatic and intestinal sites. The researchers, therefore, urged caution when echinacea is combined with medications dependent on the cytochrome P450 3A or 1A2 systems for elimination.[24] Finally, echinacea use should not last longer than 4 weeks, and it should not be used in patients with systemic and autoimmune disorders, patients who are pregnant, and patients who are immunocompromised. [6] [25]

Anesthesia Implications.

The immunostimulatory effects of echinacea may antagonize the immunosuppressive actions of corticosteroids and cyclosporine. Because the herb can cause inhibition of the hepatic microsomal enzymes, its concomitant use with drugs such as phenytoin, rifampin, and phenobarbital, which are metabolized by the hepatic microsomal enzymes, should be avoided, because echinacea can precipitate toxicity of these drugs.

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EPHEDRA

As previously mentioned, the recent federal ban on ephedra, also known as ma huang, may lead to a decline in its use. However, patients may still present for perioperative assessment with a history or present use of ephedra. Ma huang, an ephedra-based alkaloid, is similar in structure to amphetamines and is traditionally indicated for the treatment of various respiratory disorders, such as the common cold, flu, allergies, bronchitis, and nonrespiratory conditions such as appetite suppression.[6] Other indications are hypotension, fever, arthritis, and fluid retention. Ma huang acts as a sympathomimetic agent and exhibits potent positive inotropic and chronotropic responses. In addition to its antitussive actions, ma huang may also possess bacteriostatic properties.[26] As a cardiovascular and respiratory sympathomimetic, it utilizes an α- or β-adrenergic sensitive pathway.[27] Furthermore, recent laboratory data using the feline pulmonary vascular bed indicate that ma huang–mediated pulmonary hypertension is dependent on an α1-adrenoreceptor sensitive pathway.[28]

The appetite suppressant and metabolic enhancer effects of ma huang made it a potent ingredient of various OTC weight loss compounds. However, before the federal ban on ma huang, many herbal manufacturers advertised ephedra-free supplements as a result of its numerous reported adverse effects.

Deleterious effects of ma huang administration include hypertension, tachycardia, cardiomyopathy, cardiac dysrhythmias, myocardial infarction, stroke, seizures, psychosis, tremors, and/or death.[6]Numerous complications have been linked to the use of this herbal agent, and these outcomes have been attributed to a lack of standardization in its formulation. [29] [30] Before the federal ban of ma huang, approximately 16,000 cases of adverse events and 164 deaths had been reported to the FDA since 1994.[31] Furthermore, the Bureau of Food and Drug Safety of the Texas Department of Health reported eight fatalities, during a 21-month period between 1993 and 1995, associated with ephedra-containing compounds. Seven of these deaths were secondary to myocardial infarction or stroke.[8] Patients who are pregnant or have hypertension, coronary vascular disease, a seizure history, glaucoma, anxiety, and mania are at significant risk for ephedra-induced side effects.[6]

Anesthesia Implications.

The use of ephedrine-containing OTC products is highly relevant to the perioperative period. The possibility of hypertension causing myocardial ischemia or stroke needs to be considered. Ephedra can potentially interact with volatile general anesthetic agents (e.g., halothane, isoflurane, desflurane) and cardiac glycosides (e.g., digitalis) to cause cardiac dysrhythmias. Patients taking ephedra for prolonged periods of time can deplete peripheral catecholamine stores. Thus, under general anesthesia, these patients can potentially have profound intraoperative hypotension, which can be controlled with a direct vasoconstrictor (e.g., phenylephrine) instead of ephedrine. Use of ephedra with phenelzine or other monoamine oxidase inhibitors may result in insomnia, headache, and tremulousness. Concomitant use with oxytocin has been shown to cause hypertension.[32]

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FEVERFEW

The herbal agent feverfew is used to treat headache and fever, prevent migraines, and treat menstrual abnormalities.[33] The word is derived from the Latin word febrifugia, which means “fever reducer.”[26] Although feverfew is commonly used for migraine headaches, the literature is not conclusive with regard to its effectiveness. [34] [35] For example, one investigation sought to review evidence from double-blind randomized controlled trials to evaluate the clinical efficacy of feverfew versus placebo for migraine prophylaxis. The researchers concluded that there was insufficient evidence from the trials to suggest a benefit of feverfew over placebo for the prevention of migraine.[36] Like most herbal compounds, analyses of feverfew-based products have yielded significant variations in the parthenolide contents, a proposed active ingredient, between feverfew products.[37]

Regarding the effects of the anti-inflammatory lactone parthenolide, one German study has indicated that parthenolide may support T-cell survival by downregulating the CD95 system. The CD95 system is a critical component of the apoptotic, or programmed cell death, pathway of activated T cells. The investigators concluded that parthenolide may have some therapeutic potential as an anti-apoptotic substance against the activation-induced cell death of activated T cells.[38]

Feverfew also has demonstrated inhibition of serotonin release from aggregating platelets. This mechanism may be related to the inhibition of arachidonic acid release via a phospholipase pathway. [39] [40] [41] Furthermore, feverfew has effectively decreased 86% to 88% of prostaglandin production without exhibiting inhibition of cyclooxygenase.[42]

Adverse reactions to feverfew include aphthous ulcers, abdominal pain, flatulence, nausea, vomiting, and rebound headache with an abrupt stoppage of the herb. [26] [33] This herbal may be better tolerated than other conventional migraine medications because in clinical trials feverfew caused no change in heart rate, blood pressure, body weight, or blood chemistry like conventional migraine drugs.[33] As with many herbal agents, feverfew is not recommended in the pediatric population or pregnant or nursing patients.[43] Finally, a condition known as “post-feverfew syndrome” can occur in chronic users of feverfew and manifests as anxiety, headaches, insomnia, arthralgias, muscle and joint stiffness, and fatigue. [33] [44]

Anesthesia Implications.

Because feverfew can inhibit platelet activity, it is reasonable to avoid the concomitant use of this herb in patients taking medications such as heparin, warfarin, nonsteroidal anti-inflammatory agents (NSAIDs), aspirin, and vitamin E. [45] [46] For patients with perioperative bleeding abnormalities, the use of feverfew should be considered in the differential diagnosis. Furthermore, tannin-containing herbs like feverfew can interact with iron preparations, thereby reducing the bioavailability of such preparations.[21]

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GARLIC

Garlic is a popular herbal medication that is available in powdered, dried, and fresh forms.[6] Allicin, the main active ingredient in garlic, contains sulfur. Crushing the garlic clove activates the enzyme allinase, which results in the conversion of alliin to allicin.[12]

Recommended use has centered on treating hypercholesterolemia, hypertension, and cardiovascular disease.[6] Thus, recent studies have targeted its hypocholesterolemic and vasodilatory effects. [47] [48] [49] [50] [51] Investigations have concluded that garlic may cause inhibition of the HMG-CoA reductase and 14α-demthylase enzyme systems to exert its lipid-lowering effect.[6] Additionally, garlic derivatives may be used for their antiplatelet, antioxidant, and fibrinolytic actions. [47] [52] [53] Decreased platelet aggregation has been reported with the use of garlic in conjunction with its use for hyperlipidemia. [48] [49] [50] [51] However, there is minimal evidence corroborating the use of garlic for hypertension, because its depressor effects on systolic and diastolic blood pressure appear to range from minimal to modest. [6] [12]

Long-term oral consumption of garlic has been reported to augment the endogenous antioxidants of the heart.[54] A recent investigation hypothesized that garlic-induced cardiac antioxidants may provide protection against acute doxorubicin (Adriamycin)-induced cardiotoxicity. Using rats as the model, the researchers found in the doxorubicin group increased oxidative stress, as evidenced by a significant increase in myocardial thiobarbituric acid reactive substances (TBARS) and a decrease in myocardial superoxide dismutase (SOD), catalase, and glutathione peroxidase activity. However, in the garlic-treated rats, an increase in myocardial TBARS and a decrease in endogenous antioxidants by doxorubicin was significantly prevented. Thus, the investigators concluded that chronic garlic administration may prevent acute doxorubicin-induced cardiotoxicity.[54]

Regarding the effects of allicin in the lung vasculature, data have revealed that allicin has significant vasodilator activity in the pulmonary vascular bed of the rat and cat.[55]

Furthermore, although allicin has been found to lower blood pressure, insulin, and triglyceride levels in fructose-fed rats, it has also been considered important to investigate its effect on the weight of animals. One group of researchers used male Sprague-Dawley rats and found that the control group that was fed a diet enriched by only fructose continued to have an increase in weight. However, those groups fed allicin did not have weight gain.[56]

Evidence indicates that garlic may also be an effective treatment against methicillin-resistant Staphylococcus aureus (MRSA) infection. Using mice as the model, investigators demonstrated that the garlic extracts diallyl sulfide and diallyl disulfide exhibited protective functions against MRSA infection. Such conclusions, coupled with further study, may result in the employment of these extracts in the treatment of MRSA infection.[57]

Side effects of garlic are minimal, with odor and gastrointestinal distress being the most commonly reported.[6] However, there is a reported case of spontaneous spinal/epidural hematoma in an 87-year-old man that was thought to be associated with platelet dysfunction as a result of excessive ingestion of garlic.[58] Finally, induction of the cytochrome P450 system may occur, as evidenced by reduction of serum levels of the medication saquinavir.[6]

Anesthesia Implications.

The clinical anesthesiologist should be aware that garlic may augment the effects of warfarin, heparin, NSAIDs, and aspirin and may result in an abnormal bleeding time, which can lead to an increased risk of intraoperative or postoperative bleeding.[59] In addition, an investigation on the effects of garlic dialysate on diastolic blood pressure (DBP), heart rate (HR), and electrocardiographic (ECG) readings in anesthetized dogs, and its effects on frequency and tension of isolated rat atria was conducted.[60] The garlic dialysate led to a decrease in DBP and HR in a dose-dependent manner, and the ECG readings revealed a regular sinus bradycardic rhythm. Furthermore, the addition of garlic dialysate to isolated left rat atria resulted in a decrease in tension development in a dose-dependent manner. Finally, the results revealed that the positive chronotropism and inotropism induced by the addition of isoproterenol were partially antagonized by preincubation of the rat atria with the garlic dialysate. The investigators concluded that these findings may be explained by a depressant effect on automaticity and tension development in the heart, thus suggesting a β-adrenergic antagonist action modulated by garlic dialysate.[60]

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GINGER

Ginger (Zingiber officinale) has been used for the treatment of nausea, vomiting, motion sickness, and vertigo.[25] The effects of ginger on study subjects with vertigo found that none of the study subjects experienced nausea after caloric stimulation of the vestibular system. This finding was in contrast to those receiving the placebo.[61] Furthermore, ginger may be superior to the agent dimenhydrinate in decreasing motion sickness.[62]

A randomized, double-blind, controlled trial compared the efficacy of ginger to vitamin B6 for the treatment of nausea and vomiting during pregnancy. The investigators found the nausea score and number of vomiting episodes were significantly reduced after ginger and vitamin B6 therapy. Comparing the efficacy of ginger and vitamin B6, the researchers concluded there was no significant difference between them when used for the treatment of nausea and vomiting during pregnancy.[63] Ginger has also been effective in abating the symptoms associated with hyperemesis gravidarum.[64]

Regarding the effects of ginger on coagulation, it has exhibited potent inhibition of thromboxane synthetase. Such inhibition in activity results in a prolonged bleeding time.[65] The ability of ginger constituents and related substances to inhibit arachidonic acid-induced platelet activation in human whole blood has been studied. The data from that investigation revealed that ginger compounds and derivatives are more potent antiplatelet agents than aspirin under conditions employed in the study. Specifically, [8]-paradol, a natural constituent of ginger, was identified as the most potent antiplatelet aggregation agent and cyclooxygenase-1 inhibitor.[66]

Regarding treatment using ginger in type I diabetic rats, there was a significant increase in insulin levels and a decrease in fasting glucose levels in the rats. Administration of ginger also caused a decrease in blood pressure, serum cholesterol, and serum triglycerides in diabetic rats. The data from this investigation suggest a potential antidiabetic activity of ginger in type I diabetic rats.[67]

Side effects of ginger include bleeding abnormalities, and its use is contraindicated in patients with coagulation dysfunction or those on anticoagulant medications such as NSAIDs, aspirin, heparin, and warfarin.[25]

Anesthesia Implications.

Ginger may increase bleeding risk, enhance barbiturate effects, and, as a result of an inotropic effect, interfere with cardiac medication therapy. Large quantities of ginger may also cause cardiac arrhythmias and central nervous system depression.

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GINGKO BILOBA

Numerous active compounds are present in gingko, such as the flavonoid glycosides, terpenoids, and organic acids. The physiologic effects of the compounds vary. [6] [12] For example, the flavonoids have exhibited antioxidant activity and the terpenoids have demonstrated antagonistic ability to platelet-activating factor.[6] The extract that has received the most investigation is EGB761.

As a result of its effects, gingko is used to treat intermittent claudication, enhance memory, and treat diseases associated with free-radical production and vertigo.[8] Subjects using this herbal agent have reported decreased pain in the affected lower extremities and increased symptom-free walking distance. In addition to the inhibition of platelet-activating factor, gingko may also mediate nitric oxide release and decrease inflammation. [6] [68] [73] A recent investigation of 187 cardiology patients found that 106 of the subjects used supplements and that one of them was gingko. However, the data reported that the average low-density lipoprotein (106 vs. 108 mg/dL), average hemoglobin (Hb) A1c (8.7% vs. 7.7%), and average blood pressure (132/77 vs. 138/78 mm Hg) were not significantly different between users and nonusers of the supplements.[74]

To test the effects of gingko on dementia, a double-blind and placebo-controlled randomized trial of EGB761 was performed. The researchers found that this extract had the potential to stabilize and modestly improve cognitive performance and social functioning. [6] [75] Furthermore, the modest improvement in cognition was comparable to the effect of donepezil on dementia.[6] The beneficial effect on cognition and memory attributed to gingko may be related to its activation of the cholinergic neurotransmitter system. The data are inconclusive regarding the ability of gingko to improve memory in healthy subjects.[6]

Regarding the effects of gingko on induced-acute pancreatitis, investigators have found that prophylactic treatment of EGB761 in Sprague-Dawley rats has a significant beneficial effect on the course of acute pancreatitis.[76] Although the pathogenesis of acute pancreatitis is not well understood, there are numerous data that suggest a role for oxygen free radicals in the progression and complications of pancreatitis. Therefore, the positive influence of EGB761 on acute pancreatitis may be linked to the free radical scavenger effect of this extract.[76]

At the recommended dose, gingko is well tolerated in the healthy adult population for approximately 6 months.[6] The side effects associated with its use may be limited to mild gastrointestinal discomfort and headache.[25] However, as a potential result of gingko's anti–platelet activating factor effect, gingko biloba–induced spontaneous hyphema (bleeding from iris and the anterior chamber of the eye), spontaneous bilateral subdural hematomas, and subarachnoid hemorrhage have been reported. [6] [77] [78] [79] [80] Therefore, the use of anticoagulants and gingko should be closely monitored, if not avoided.[6] Regarding the effects of gingko on pharmacokinetics, an open-labeled and randomized crossover trial was conducted on eight healthy human volunteers to determine if ginkgo alters the pharmacokinetics of digoxin. The investigators concluded that the concomitant use of orally administered gingko and digoxin did not appear to have any significant effect on the pharmacokinetics of digoxin in healthy volunteers.[81]

Anesthesia Implications.

Concomitant use of gingko biloba with aspirin, or any NSAIDs, and anticoagulants such as warfarin and heparin is not recommended because gingko may increase the potential for bleeding in these patients. It would also be appropriate to avoid its concomitant use with anticonvulsant drugs (e.g., carbamazepine, phenytoin, phenobarbital) because gingko may decrease the effectiveness of these agents.[21] In addition, it has been recommended that gingko should be avoided in patients taking tricyclic antidepressant agents, because it might potentiate the seizure threshold-lowering action of these drugs.[21]

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GINSENG

There is a significant variation in the components of this herb. There are three main groups of ginseng that are classified based on their geographic origin.[6] These are Panax ginseng (Asian ginseng),Panax quinquefolius (American ginseng), and Eleutherococcus senticosus (Siberian ginseng), which belongs to a different genus. [6] [8] The active ingredients in ginseng are the ginsenosides. [6] [26]

Asian and American ginseng have been used for their adaptogenic properties, which allow for increased resistance to environmental stress, as a diuretic, digestion aid, immune system stimulant, and hypoglycemic agent. [82] [83] Asian ginseng may be effective in improving cognitive function when combined with gingko.[83] American ginseng has been examined for its potential to stimulate human TNF-α production in cultured human peripheral blood monocytes.[84] Direct stimulation of mononuclear cell TNF-α production in vitro occurred, as demonstrated by TNF-α mRNA gene expression, as early as 6 hours into cell incubation with ginseng. Thus, one may conclude that in-vitro immunostimulating activity of ginseng occurs when using TNF-α production as an index, and further in-vivo studies are warranted.[84] American ginseng may also possess hypoglycemic properties. [85] [86] Such effects have been observed in both normal and diabetic subjects and may be attributed to the ginsenoside Rb2 and panaxans I, J, K, and L ingredients of ginseng. [87] [88] [89] [90] [91]

Although generally well tolerated, adverse effects of ginseng use are hypertension, bleeding abnormalities secondary to antiplatelet activity, insomnia, headache, vomiting, Stevens-Johnson syndrome, abnormal vaginal bleeding, and epistaxis. [92] [93] [94] [95] [96] [97] [98] Drug interactions between Asian ginseng and calcium channel blockers, warfarin, phenelzine, and digoxin have been reported.[6]Therefore, it is recommended that ginseng be avoided in patients who are pregnant or breastfeeding, the pediatric population, and patients with cardiovascular disease. [8] [21]

Anesthesia Implications.

Ginseng should be avoided with patients on anticoagulant medications such as warfarin, heparin, NSAIDs, and aspirin. Because ginseng can cause hypertension, the clinical anesthesiologist should be focused on the clinical consequences of long-term use of this agent. Long-standing hypertension can cause end-organ damage, volume depletion, and autonomic instability. Furthermore, because many anesthetic agents can cause generalized vasodilatory effects, hemodynamic variability can be seen, including profound intraoperative hypotension. Concomitant use of ginseng with monoamine oxidase inhibitors (e.g., phenelzine sulfate) should be avoided, because manic episodes have been reported with routine use of ginseng. [99] [100] As a result of its potential to exert hypoglycemic effects, ginseng should be used cautiously in diabetic patients on insulin or oral hypoglycemic medications. It would therefore follow that the anesthesiologist would need to have appropriate evaluation of blood glucose levels perioperatively for applicable patients.

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KAVA KAVA

Kava kava, an extract of the plant Piper methysticum, is used as an anxiolytic, antiepileptic, antidepressant, antipsychotic, sedative, and muscle relaxant. [101] [102] [103] Active ingredients of kava kava include the kava lactones or kava pyrones, kawain, methysticin, dihydrokawain, dihydromethysticin, along with others. [104] [105] The kava extracts that are available commercially are formulated to contain between 30% and 70% kava lactones.[104]

The extract WS 1490 has been investigated in clinical studies to determine the effectiveness of kava kava for treatment of anxiety disorders.[104] WS 1490 has proved to be an effective treatment alternative to benzodiazepines and tricyclic antidepressants, without the associated tolerance problems with the latter two classes, in anxiety disorders.[106] Peak therapeutic effect may take as many as 4 weeks, and data have indicated treatment for 1 to 8 weeks to obtain significant improvement. [104] [107] Regarding the effects of kava kava on vasculature in the feline lung, vasodepressor effects were demonstrated and shown to be mediated or modulated by both γ-aminobutyric acid (GABA) and L-type calcium channel sensitive pathways.[108] An important side effect associated with kava kava use is hepatic dysfunction. Patients who experience hepatic adverse reactions are known as “poor metabolizers,” or those patients with a deficiency in the cytochrome P450 2D6 isozyme.[104] Therefore, it is recommended that patients who use kava kava receive routine liver function tests such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total and conjugated bililrubin to monitor for the development of hepatotoxicity.[104] Furthermore, there have been 24 documented cases of hepatotoxicity after use of this herbal agent; and in some cases, death or liver transplant occurred after only 1 to 3 months of use.[104] In countries such as Germany and Australia, kava kava use longer than 3 months is not recommended.[107]Other side effects of kava kava use include visual changes, a pellagra-like syndrome with characteristic ichthyosiform dermopathy, and hallucinations. [3] [104] [109]

The kava pyrones have demonstrated competitive inhibition of the monoamine oxidase B.[104] Inhibition of this enzyme may result in the psychotropic effects related to kava kava use.[110] However, the exact mechanism of its effects on the central nervous system is largely unknown.[104] Regarding drug interactions, kava kava may react adversely with alprazolam, central nervous system depressants, statins, rifampin, alcohol, and levodopa. [104] [111] Finally, kava kava may also affect platelets in an antithrombotic fashion by inhibiting cyclooxygenase, therefore decreasing production of thromboxane.[104]

Anesthesia Implications.

Antinociceptive effects produced by kava kava may be similar to local anesthetic responses and appear to be mediated through a non–opiate-dependent pathway. [112] [113] Ethanol can increase the hypnotic effects of kava kava.[114] It should be avoided in patients with endogenous depression and can potentiate the effect of barbiturates and benzodiazepines and cause excessive sedation.[115]

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SAW PALMETTO

The herbal agent known as saw palmetto is used primarily for benign prostatic hyperplasia.[6] The key ingredients are the free fatty acids and sterols.[6] Although the mechanism of action is currently unknown, data exist that demonstrate antagonism at the androgen receptor for dihydrotestosterone and at the 5α-reductase enzyme.[6] Furthermore, biopsies have demonstrated decreases in the transitional zone epithelia (17.8% to 10.7%) in the prostates of men treated with saw palmetto compared with placebo, although prostate size and prostate-specific antigen level are not decreased by this herbal agent.[6]Compared with the 5α-reductase inhibitor finasteride, saw palmetto has demonstrated increased urine flow and decreased side effects.[6] One prospective, randomized, open-label investigation has sought to evaluate the safety and efficacy of saw palmetto compared with finasteride in patients with prostatitis/chronic pelvic pain syndrome.[116] The study found that at the end of the trial more patients wanted to continue finasteride treatment rather than saw palmetto treatment. The researchers concluded that in patients with this condition, saw palmetto had no considerable long-term improvement, and, with the exception of voiding, the patients on finasteride therapy had significant improvement in all examined parameters.[116]

Adverse reactions to saw palmetto are rare, with occasional reports of mild gastrointestinal symptoms and headaches.[6] Finally, there are few, if any, herbal-drug interactions in the literature regarding this herbal agent.[6] Results of one investigation indicated that recommended doses of saw palmetto are not likely to alter the pharmacokinetics of coadministered medications dependent on the cytochrome P450 isoenzymes CYP2D6 or CYP3A4, such as dextromethorphan (CYP2D dependent) and alprazolam (CYP3A4 dependent).[117]

Anesthesia Implications.

Although no detailed studies have been done with regard to the anesthetic interactions, caution should be used if the patient is using benzodiazepines (e.g., alprazolam) or medications such as dextromethorphan because saw palmetto can alter pharmacokinetics of these medications. Elaborate clinical trials on anesthetic-herb interactions are warranted.

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  1. JOHN'S WORT

St. John's wort is used in the treatment of anxiety, mild to moderate depression, and sleep-related disorders. [6] [25] It has also been employed in the treatment of cancer, fibrositis, migraine headache, obsessive-compulsive disorder, and sciatica.[118] The active compounds include the naphthodihydrodianthrones hypericin and pseudohypericin, the flavonoids quercitrin, rutin, and hyperin, and the xanthones. [6] [8]

It is speculated that extracts of St. John's wort, such as WS 5570, are widely and effectively used to treat mild to moderate depression. [119] [120] The extracts are standardized based on the hypericin content and have demonstrated effectiveness superior to placebo and potentially as effective as selective serotonin reuptake inhibitors and low-dose tricyclic antidepressants.[118]

The exact mechanism of action of St. John's wort remains controversial. The herbal medication exhibits irreversible inhibition of monoamine oxidase in vitro; however, such inhibition has yet to be observed in vivo.[121] In the feline lung vasculature, St. John's wort exhibited a vasodepressor effect that was mediated or modulated by both a GABA receptor and an L-type calcium channel sensitive mechanism.[122] Studies performed in vitro have demonstrated GABA receptor inhibition by Hypericum. This mechanism may indicate that a GABA inhibitory mechanism is the cause of the antidepressant effect. [123] [124] However, other theorized pathways have included inhibition of serotonin, dopamine, and norepinephrine reuptake in the central nervous system.[6]

St. John's wort is typically well tolerated.[6] Associated side effects may include photosensitivity, restlessness, dry mouth, dizziness, fatigue, constipation, and nausea. [6] [25] Two noteworthy side effects of St. John's wort include its induction of the cytochrome P450 system (CYP 34A), which may affect serum levels of cyclosporine post organ transplantation, and the association with serotonergic syndrome in patients concurrently taking prescription antidepressants.[6] The serotonergic syndrome is characterized by hypertonicity, myoclonus, autonomic dysfunction, hallucinosis, tremors, hyperthermia, and, potentially, death. [12] [125]

Anesthesia Implications.

The concomitant use of St. John's wort is not recommended with photosensitization drugs (e.g., piroxicam, tetracycline), monoamine oxidase inhibitors, β-sympathomimetic amines (e.g., ma huang, pseudoephedrine), or selective serotonin reuptake inhibitors. There are no data regarding the multitude of potential interactions between anesthetics and St. John's wort.

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ALTERNATIVE MEDICINE

Although beyond the scope of this chapter, it is important that the anesthesiologist recognize the presence of other forms of medicine such as homeopathy, chiropractic treatment, and massage therapy, to name a few. For example, reductions in blood pressure and heart rate have been observed after massage therapy (Kaye, unpublished data). Such alterations in cardiovascular function indicate potential autonomic mechanisms that may contribute to erroneously low vital signs readings in the perioperative assessment. Therefore, as emphasized in the herbal medications section, it is necessary to obtain a complete history from the patient to identify current and past treatment with alternative medicine.

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CONCLUSION

The growing use of herbal medications in the United States warrants a better, more comprehensive understanding of these agents by the medical community. One role the anesthesiologist is charged with is regulating the patient's physiologic functions during various operative procedures. As demonstrated in this chapter, the use of herbal compounds may alter heart rate, respiratory rate, and the pharmacokinetics of various medications. Such medications may include chosen anesthetics employed during the stages of anesthesia. Thus, it is recommended that a thorough investigation be undertaken by the anesthesiologist to identify the prescribed, OTC, and herbal medications taken by the adult and pediatric patient. Furthermore, education of patients regarding the serious potential drug-herbal interactions should be a daily part of the preoperative assessment. The ASA recommends all herbal medications be discontinued 2 to 3 weeks before elective surgery.

Due to lax regulations, herbal medications are poorly categorized and not adequately standardized. This results in a high risk of adverse effects when used by uninformed/misinformed patients and the general public. There is also a lack of motivation for herbal manufacturers to conduct randomized, placebo-controlled, double-blinded safety and efficacy trials on such agents because of the lack of federal regulation. Within the past few decades, hundreds of deaths have been linked to the use of herbal medications. Furthermore, evidence suggests less than 1% of adverse effects associated with herbal supplements are reported. Such tragic outcomes may serve as the impetus for tighter standards and guidelines. However, the federal ban of ma huang may serve as a much-needed first step toward stricter regulations.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

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