Calcium

It may be reasonable for patients to supplement their diet with calcium, because calcium supplementation has been shown to promote bone health and may be lacking in certain diets. Many women supplement with calcium to improve symptoms associated with premenstrual syndrome and premature bone breakdown.

However, calcium may interfere with a host of common drugs. The anesthesiologist must be aware of patients with cardiac problems who may be taking calcium channel blockers or beta-adrenergic blockers. The effects of calcium channel blockers may be affected by calcium supplementation; calcium has been shown to antagonize the effects of verapamil. In fact, calcium has recently been used in the successful management of calcium channel blocker overdose. Calcium supplementation may also decrease levels of β-blockers, leading to a greater chronotropic and inotropic presentation than would be expected.

Thiazide diuretics increase serum calcium concentrations, possibly leading to hypercalcemia as a result of increased reabsorption of calcium in the kidneys. Dysrhythmias may occur in patients taking digitalis and calcium together. The antibiotic effect of tetracyclines and quinolone and pharmacologic blood levels of bisphosphonates and levothyroxine may be decreased with calcium supplementation; these medications should not be taken within 2 hours of calcium intake.

Calcium supplementation may also affect the choice of anesthesia used in surgical procedures. Recent data suggest that propofol may have a protective effect on erythrocytes in patients with elevated calcium levels. Documenting the use of calcium by patients preoperatively may prevent many of these drug interactions.

Chromium

Chromium is an essential nutrient involved in metabolism of carbohydrates and lipids. Recently, chromium has received attention from consumers in the belief that it may improve glucose tolerance in diabetics, reduce body fat, and reduce atherosclerotic formation. These purported effects stem from chromium’s effect on insulin resistance. However, the evidence regarding use of chromium for insulin resistance and mildly impaired glucose tolerance is inconclusive.

A double-blind trial with 180 patients concluded that high doses of chromium supplementation (1000 mg) may have beneficial effects on hemoglobin A _1c , insulin, cholesterol, and overall glucose control in type 2 diabetic patients. The practitioner should consider asking all diabetic patients if they supplement with chromium. Because of chromium’s effects on insulin resistance and impaired glucose control, some patients will supplement with this mineral to reduce risk of cardiovascular disease. Human studies have shown decreased total cholesterol and triglyceride levels in elderly patients taking 200 μg of chromium twice daily.

Chromium is generally well tolerated; however, some patients may experience central nervous system (CNS) symptoms (e.g., perceptual, cognitive, and motor dysfunction) with doses as low as 200 to 400 μg. In addition, toxicity has been reported with chromium consumption. In one case, a woman developed anemia, thrombocytopenia, hemolysis, weight loss, and liver and renal toxicity when attempting weight loss with 1200 to 2400 μg of chromium picolinate. These problems resolved after discontinuation of chromium ingestion. A lower dose of only 600 μg was demonstrated to have resulted in interstitial nephritis in another female patient (see Table 16-1 ).

Magnesium

Magnesium plays many important roles in structure, function, and metabolism and is involved in numerous essential physiologic reactions in the human body. Supplemental magnesium has been used extensively by patients for cardiovascular disease, diabetes, osteoporosis, asthma, and migraines, although most individuals consume adequate levels in their diet. Patients with a history of these illnesses may be supplementing with magnesium and therefore should be questioned.

The most obvious anesthesia-related consideration in treating a patient taking magnesium involves its effect on muscle relaxants in the operating room (OR). The mineral can potentiate the effects of both depolarizing and nondepolarizing skeletal muscle relaxants. Therefore, it may be advisable to ask patients about their magnesium use preoperatively to avoid potential complications in the OR.

When caring for obstetric patients, the clinician must be aware of the effects of magnesium sulfate in the patient undergoing cesarean section. Duration of action of relaxant anesthetics may be affected even by subtherapeutic serum magnesium levels. Rapid inadvertent infusion of magnesium can lead to hypermagnesemia, especially during an urgent cesarean section, resulting in respiratory muscle weakness and inability to extubate safely. For this patient, an intensive care unit (ICU) stay and time will restore strength as the magnesium is cleared from the patient and will ensure a good outcome.

Magnesium may also interfere with the absorption of antibiotics such as tetracyclines, fluoroquinolones, nitrofurantoins, penicillamine, angiotensin-converting enzyme (ACE) inhibitors, phenytoin, and histamine-2 (H ₂ ) blockers. Absorption problems can be ameliorated by not taking doses of magnesium within 2 hours of these other medications. Current studies also support that intake of oral magnesium favorably affects both exercise tolerance and left ventricular (LV) function in stable patients with coronary artery disease and may be useful for high-risk surgeries in this subpopulation. Magnesium may also make oral hypoglycemics, specifically sulfonylureas, more effective when used concomitantly, thus increasing the risk of hypoglycemic episodes. Recent studies suggest magnesium supplementation for patients taking long-term proton pump inhibitors (PPIs), with the potential for hypermagnesemic or hypomagnesemic states for these patients.

Iron

In both developed and underdeveloped countries, iron deficiency is the most common nutrient deficiency. Worldwide, at least 700 million individuals have iron deficiency anemia. More than just a constituent of hemoglobin and myoglobin, iron is a key component in almost every living organism and in humans is associated with hundreds of enzymes and other protein structures. People have supplemented with iron for many reasons, including treating iron deficiency anemia, alleviating poor cognitive function in children, increasing athletic performance, and suppressing restless legs syndrome (RLS).

High concentrations of iron in the blood may worsen neuronal injury secondary to cerebral ischemia. Increased iron levels during pregnancy may lead to preterm delivery and neonatal asphyxia. These complications may occur even with normal iron intake if the patient also takes vitamin C, because high doses of vitamin C can increase iron absorption.

Iron may inhibit absorption of many drugs, including levodopa, methyldopa, carbidopa, penicillamine, thyroid hormone, captopril, and antibiotics in the quinolone and tetracycline family. Moreover, iron deficiency anemia may lead to increased risk of blood transfusion; studies have demonstrated the benefits of intravenous (IV) iron preoperatively to help decrease the risk. Some medications may decrease iron absorption and lead to decreased therapeutic levels. This includes antacids, H ₂ receptor antagonists, PPIs, and cholestyramine resin. Oral iron should not be given within 2 hours of other pharmaceuticals, to avoid alterations in drug or mineral absorption (see Table 16-1 ).

Selenium

Selenium, an essential trace element, functions in a variety of enzyme-dependent pathways, especially those using selenoproteins. Much of its supplemental efficacy results from its antioxidant properties. Glutathione peroxidase incorporates selenium at its active site, and as dietary selenium intake decreases, glutathione levels drop. Patients supplement with selenium for a variety of reasons, most notably for improvement in immune status; elderly patients may be inclined to supplement with selenium for this reason. Toxicity with selenium supplementation begins at intake greater than 750 μg/day and may manifest as garliclike breath, loss of hair and fingernails, gastrointestinal (GI) distress, or CNS changes. Few interactions with other pharmacologic agents have been found.

Zinc

Zinc deficiency was first described in 1961, associated with “adolescent nutritional dwarfism” in the Middle East. Zinc deficiency is thought to be quite common in infants, adolescents, women, and elderly populations. The most well-known use for zinc supplementation is in treatment of the common cold, caused principally by the rhinovirus. Patients self-medicating with zinc supplements may inadvertently overmedicate with zinc. Signs of zinc toxicity include anemia, neutropenia, cardiac abnormalities, unfavorable lipid profiles, impaired immune function, acute pancreatitis, and copper deficiency. Zinc supplements may interfere with the absorption of antibiotics such as tetracyclines, fluoroquinolones, and penicillamines. Zinc should not be ingested within 2 hours of antibiotics (see Table 16-1 ).

Vitamin A

The term “vitamin A” refers to a large number of related compounds, including preformed retinol (an alcohol) and retinal (an aldehyde). Vitamin A deficiency is common in teenagers, lower socioeconomic groups, and in developing countries. Furthermore, some studies indicate that diabetic patients are at an increased risk for deficiency. Vitamin A deficiency may manifest as night blindness, immune deterioration, birth defects, or decreased red blood cell (RBC) production. Purported therapeutic uses for vitamin A include diseases of the skin, acute promyelotic leukemia, and viral infections.

Retinoids are used as pharmacologic agents to treat skin disorders; psoriasis, acne, and rosacea have been treated with natural or synthetic retinoids. Moreover, retinoids are effective in treating symptoms associated with congenital keratinization-disorder syndromes. Therapeutic effects stem from their antineoplastic activity. Patients with these illnesses may be supplementing with vitamin A, and their dosages should be explored. Vitamin A may increase anticoagulant effects of warfarin, which could increase the risk of bleeding in these patients. Bleeding complications may therefore be avoided by informing the patient about this effect preoperatively.

Excess vitamin A intake during pregnancy, as well as deficiency, may lead to birth defects. Pregnant woman who are not vitamin A deficient should not consume more than 2600 IU/day of supplemental retinol. Patients using isotretinoin and pregnant women taking valproic acid are likewise at increased risk for vitamin A toxicity. Also, alcohol consumption decreases the liver toxicity threshold for vitamin A, narrowing its therapeutic window in alcoholic patients.

Vitamin B ₁₂

Vitamin B ₁₂ , the largest and most complex of all vitamins, is unique in that it contains cobalt, a metal ion. Vitamin B ₁₂ deficiency may affect almost 5% of the general adult population. B ₁₂ deficiency manifests as pernicious anemia. This syndrome includes a megaloblastic anemia as well as neurologic symptoms. The neurologic manifestations result from degeneration of the lateral and posterior spinal columns and include symmetric paresthesias with loss of proprioception and vibratory sensation, especially involving the lower extremities. The most documented use of vitamin B ₁₂ is in the treatment of pernicious anemia. Many of the neurologic, cutaneous, and thrombotic clinical manifestations have been successfully treated with oral or intramuscular (IM) cyanocobalamin.

The common anesthetic nitrous oxide (N ₂ O) inhibits vitamin B ₁₂ –dependent enzymes and may produce clinical features of deficiency, such as megaloblastic anemia and neuropathy. Some experts believe that vitamin B ₁₂ deficiency should be ruled out before N ₂ O use because many elderly patients will present to the OR with this deficiency. The colchicines as well as metformin, phenformin, and zidovudine (AZT) may decrease the levels of vitamin B ₁₂ . H ₂ receptor blockers and PPIs may decrease absorption of vitamin B ₁₂ from food, but not absorption from dietary supplements (see Table 16-2 ).

Vitamin C

Ascorbic acid, also known as vitamin C, is an essential water-soluble vitamin. The symptoms of scurvy, which include bleeding and easy bruising, can be prevented with only 10 mg of vitamin C because of its association with collagen, but it can also be used to prevent a host of other disease processes . Numerous people supplement their diet with vitamin C to prevent infection from viruses responsible for the common cold; however, research over the last 20 years conclude that vitamin C has no significant impact on the incidence of infection. A few studies show that certain groups susceptible to low dietary intake of vitamin C, such as marathon runners, may be less susceptible when supplementation is used. Furthermore, vitamin C may decrease the duration or severity of colds through an antihistamine effect when taken in large doses.

Patients taking vitamin C supplements may have a reduced anticoagulant effect from warfarin or heparin. Increased doses of these anticoagulants might be advised to achieve therapeutic levels. It is recommended that patients receiving anticoagulation therapy should limit vitamin C intake to 1 g/day. As always, the precise dosage regimen must be monitored by the appropriate laboratory studies. High doses of vitamin C may also interfere with tests, such as serum bilirubin, creatinine, and stool guaiac assay; therefore it is crucial to inquire about any OTC supplementation. Vitamin C may increase the inotropic effect of dobutamine in patients with abnormal LV function. Infusion of vitamin C into individuals with normal heart function was shown to increase contractility of the left ventricle. High doses of vitamin C may increase acetaminophen levels, whereas aspirin and oral contraceptives may lower serum levels of vitamin C. Also, vitamin C’s antioxidant effects can improve clinical outcomes in critically ill patients by optimizing cellular and microcirculatory function.

Vitamin D

Vitamin D deficiency does occur in elderly persons and shows increased incidence in people that live in northern latitudes. The main function of vitamin D is calcium homeostasis. Patients with osteoporosis frequently have vitamin D deficiency. With increasing age, vitamin D and calcium metabolism increase the risk of deficiency. Studies show a clear benefit of vitamin D and calcium supplementation for older postmenopausal women. Supplementation results in increased bone density, decreased bone turnover, and decreased nonvertebral fractures, as well as decreases in risk of falls and body sway.

Hypervitaminosis D can occur with high doses; symptoms include nausea, vomiting, loss of appetite, polydipsia, polyuria, itching, muscular weakness, and joint pain; severe cases may lead to coma and death. To prevent the syndrome, the U.S. Food and Nutrition Board has set an upper limit of supplementation at 2000 IU/day for adults.

The cardiac patient taking calcium channel blockers may present to the OR while taking supplemental vitamin D and calcium. The combination of vitamin D and calcium may interfere with calcium channel blockers by antagonizing its effect. Hypercalcemia exacerbates arrhythmias in patients taking digitalis. A state of hypercalcemia may be induced by the concomitant use of thiazide diuretics with vitamin D, which may lead to these complications. Conversely, anticonvulsants, cholesterol-lowering medications, and the fat substitute olestra may decrease the absorption of vitamin D (see Table 16-2 ).

Vitamin E

Antioxidant properties define the primary function of vitamin E. Dietary deficiency is quite prevalent, even in the developed world; therefore supplementation is reasonable. The anesthesiologist must be aware of a patient’s vitamin E supplementation because it may increase the effects of anticoagulant and antiplatelet drugs. Concomitant use of vitamin E with these drugs may increase the risk of hemorrhage. Further, preliminary evidence suggests that type 2 diabetic patients may have an increased risk of hypoglycemia because vitamin E may enhance insulin sensitivity. Cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, and the fat substitute olestra may decrease the absorption of vitamin E, leading to decreased levels in the serum.

Folate

Folic acid and folate have been used interchangeably, although the most stable form that is used by the human body is folic acid. This water-soluble, B-complex vitamin occurs naturally in foods and in metabolically active forms. Since 1998, the fortification of cereal with folate has decreased the prevalence of folate deficiency significantly. Excess folate intake has not been associated with any significant adverse effects. Patients taking large doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, experience interference in folate metabolism, although regular use shows no significant changes. Patients subject to seizures who use phenytoin for therapy may report a decrease in seizure threshold when taking folate supplements. The body’s ability to absorb or utilize folate may be decreased if taking N ₂ O, antacids, bile acid sequestrants, H ₂ blockers, certain anticonvulsants, and high-dose triamterene. Supplementation of folic acid may also correct for megaloblastic anemia because of B ₁₂ deficiency, but the neurologic damage will not be prevented. In these patients, the clinician must be careful to pinpoint the true cause of the anemia to prevent neurologic complications (see Table 16-2 ).

Saw Palmetto

Saw palmetto is used mainly for treatment of benign prostatic hyperplasia (BPH), with free fatty acids and sterols being the main components. Despite an uncertain mechanism, the literature does demonstrate antagonism at the androgen receptor for dihydrotestosterone and 5α-reductase enzyme. Although prostate size and prostate-specific antigen (PSA) level are not decreased by saw palmetto, biopsies have demonstrated decreases in transitional-zone epithelia in the prostate of men treated with this agent compared with placebo. When compared with finasteride, a 5α-reductase inhibitor, saw palmetto use resulted in fewer side effects and increased urine flow. However, one study reported that more patients with prostatitis or chronic pelvic pain opted to continue finasteride rather than saw palmetto treatment. In patients with the studied condition, saw palmetto had no appreciable long-term improvement and, with the exception of voiding, patients receiving finasteride experienced significant improvement in all other analyzed parameters.

Adverse reactions to saw palmetto are rare, with reports of mild GI symptoms and headaches. Recommended doses of saw palmetto are not likely to alter the pharmacokinetics of coadministered medications dependent on the cytochrome P450 isoenzymes 2D6 or 3A4, such as dextromethorphan and alprazolam. Further, there are few herbal-drug interactions in the literature regarding saw palmetto, but as always, care and responsibility should be exercised when taking this agent.

St. John’s Wort

St. John’s wort (Hypericum perforatum) is used to treat anxiety, mild to moderate depression, and sleep-related disorders. Other uses have included treatment of cancer, fibrositis, headache, obsessive-compulsive disorder, and sciatica. Active compounds in H. perforatum include the naphthodihydrodianthrones hypericin and pseudohypericin; the flavonoids quercitrin, rutin, and hyperin; and xanthones. Extracts of St. John’s wort, such as WS 5570, are widely used to treat mild to moderate depression. Such extracts are standardized based on their hypericin content and have demonstrated an effectiveness superior to placebo and potentially as great as selective serotonin reuptake inhibitors (SSRIs) and low-dose tricyclic antidepressants (TCAs).

The exact mechanism of action of St. John’s wort remains controversial; it demonstrates irreversible inhibition of monoamine oxidase (MAO) in vitro, but such inhibition has yet to be observed in-vivo. In the feline lung vasculature, St. John’s wort showed a vasodepressor effect mediated or modulated by both γ-aminobutyric acid (GABA) receptor and L-type calcium channel–sensitive mechanism. In vitro studies showed GABA receptor inhibition by hypericum. This finding may indicate that a GABA inhibitory mechanism is responsible for the antidepressant effect. However, another theorized pathway includes inhibition of serotonin, dopamine, and norepinephrine reuptake in the CNS, making the mechanism of action of St. John’s wort similar to traditional antidepressants.

St. John’s wort is typically well tolerated. Side effects include photosensitivity, restlessness, dry mouth, dizziness, fatigue, constipation, and nausea (see Table 16-3 ). St. John’s wort induces the CYP450 system (34A), affecting serum levels of cyclosporine in patients after organ transplantation, and the potential threat of serotonergic syndrome in patients taking prescription antidepressants. The serotonergic syndrome is characterized by hypertonicity, myoclonus, autonomic dysfunction, hallucinosis, tremors, hyperthermia, and potentially death. Specifically, use of St. John’s wort is not recommended with photosensitizing drugs such as tetracyclines, antidepressants (e.g., MAO inhibitors, SSRIs), and β-sympathomimetics (e.g., ephedra, pseudoephedrine). Studies demonstrate that the supplement greatly reduces the plasma concentrations of oral oxycodone, which may be clinically significant when treating chronic pain patients. Furthermore, anecdotal unpublished reports detail meperidine–St. John’s wort–induced serotonergic crisis, with morbidity and mortality.

Echinacea

Echinacea is part of the daisy family found throughout North America. Of nine species of Echinacea, the medicinal preparations are derived from three: Echinacea purpurea (purple coneflower), E. pallida (pale-purple coneflower), and E. angustifolia (narrow-leaved coneflower). Echinacea is recommended as a prophylactic and treatment substance for upper respiratory tract infections (URIs); current data are insufficient to support prophylaxis. Echinacea has alkylamide and polysaccharide, which possess significant in vitro and in vivo immunostimulation properties from enhanced phagocytosis and nonspecific T-cell stimulation.

The consumption of echinacea at the onset of symptoms has been clinically shown to decrease both the severity and the duration of the “cold” and the “flu.” Quantitative polymerase chain reaction (PCR) has identified in vivo alterations in expression of immunomodulatory genes in response to echinacea. In vivo gene expression within peripheral leukocytes was evaluated in six nonsmoking healthy subjects. Blood samples were obtained at baseline and subsequent to consumption of a commercial echinacea product. The overall gene expression pattern between 48 hours and 12 days after taking echinacea was consistent with an anti-inflammatory response. The expression of interleukin-1 beta (IL-1β), intracellular adhesion molecule, tumor necrosis factor alpha (TNF-α), and interleukin-8 was modestly depressed up through day 5, and returned to baseline by day 12. Further, the expression of interferon-α consistently increased through day 12, thus indicating an antiviral response. Therefore, initial data yielded a gene expression response pattern consistent with the ability of echinacea to decrease both intensity and duration of cold and flu symptoms.

Aside from the effects of Echinacea on innate immunity, few studies have examined the ability for enhancement of humoral immunity. Using female Swiss mice as the model, however, one study found support for the use of E. purpurea, as suggested by anecdotal reports, and demonstrated potential enhancement of humoral immune responses, in addition to innate immune responses. However, it is important to note that the use of E. purpurea, as dosed in one study, was not effective in treating URIs and related symptoms in pediatric patients, age 2 to 11 years. Further, consumption of E. purpurea was associated with an increased risk of rash.

Echinacea is usually well tolerated, with the most common side effect being its unpleasant taste. Echinacea use longer than 2 months may lead to tachyphylaxis. Anaphylaxis has also been reported with a single dose of this herbal agent. Further, echinacea use has been associated with hepatotoxicity if taken with hepatotoxic agents, including anabolic steroids, amiodarone, ketoconazole, and methotrexate. Further, flavinoids from E. purpurea can affect the hepatic CYP450 and sulfonyltransferase systems. For example, one investigation found that echinacea decreased the oral clearance of substrates of CYP1A2 but not the oral clearance of substrates of 2 C9 and 2D6 isoenzymes in vivo. The herbal also selectively modulates the activity of the CYP3A isoenzyme at both hepatic and intestinal sites. The researchers therefore urged caution when echinacea is combined with medications dependent on CYP3A or 1A2 systems for elimination. Drug levels may become elevated with concomitant use of Echinacea. Some drugs metabolized by CYP3A enzyme include lovastatin, clarithromycin, cyclosporine, diltiazem, estrogens, indinavir, and triazolam. Taking midazolam and Echinacea together seems to increase levels of the sedative. Echinacea use should not exceed 4 weeks, and it should not be used in patients with systemic or autoimmune disorders, pregnant women, or immunocompromised patients.

The immunostimulatory effects of echinacea may antagonize the immunosuppressive actions of corticosteroids and cyclosporine. Echinacea may also lead to inhibition of the hepatic microsomal enzyme system; as such, its use with drugs such as phenobarbital, phenytoin, and rifampin, which are metabolized by these enzymes, should be avoided because toxicity may result (see Table 16-3 ).

Feverfew

Feverfew is used to treat headache, fever, rheumatism, asthma, stomach pains, and other conditions related to inflammation. The name is derived from the Latin febrifugia, “fever reducer.” Although feverfew is often used for migraine headaches, the literature is inconclusive regarding its efficacy. A review of double-blind randomized controlled trials (RCTs) of the clinical efficacy of feverfew versus placebo for migraine prophylaxis found insufficient evidence to suggest a benefit of feverfew over placebo for the prevention of migraine. As with most herbal compounds, analyses of feverfew-based products have yielded significant variations in the parthenolide contents, believed to be the active ingredients. The anti-inflammatory lactone parthenolide may support T-cell survival by downregulating the CD95 system, a critical component of the apoptotic, or programmed cell death, pathway of activated T cells. Further, pathenolide may have therapeutic potential as an antiapoptotic substance blocking the activation-induced death of T cells. 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. Also, feverfew decreases 86% to 88% of prostaglandin production without exhibiting inhibition of the cyclo-oxygenase (COX) enzyme.

Adverse reactions to feverfew include aphthous ulcers, abdominal pain, nausea, and vomiting. A rebound headache may occur with abrupt cessation of this herbal. Better tolerance to feverfew than to conventional migraine medications has been suggested because feverfew use resulted in no alteration in heart rate, blood pressure, body weight, or blood chemistry as did conventional migraine drugs. A condition known as “post-feverfew syndrome” can occur in long-term users, manifesting as fatigue, anxiety, headaches, insomnia, arthralgias, and muscle/joint stiffness.

Feverfew may inhibit platelet action; therefore it is reasonable to avoid its concomitant use in patients taking heparin, warfarin, NSAIDs, aspirin, and vitamin E. Further, herbs such as feverfew can interact with iron preparations, reducing their bioavailability (see Table 16-3 ).

Ephedra

Since the U.S. Government’s ban on ephedra-based products, there has been an obvious decline in its use. However, patients may still present for anesthesia evaluation with a history of ephedra use or of taking related compounds, many of which are readily available and possess potent dose-dependent increases in heart rate and in blood pressure. 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 flu, common cold, allergies, and bronchitis. Additionally, ma huang is commonly used as an appetite suppressant. Ma huang, or ephedra, acts as a sympathomimetic agent and exhibits potent positive ionotropic and chronotropic responses. In addition to its antitussive actions, ephedra may also possess bacteriostatic properties. As a cardiovascular and respiratory sympathomimetic, ephedra uses an α- or β-adrenergic sensitive pathway. Data using the feline lung vascular bed indicate that ephedra-mediated pulmonary hypertension depends on α ₁ -adrenoreceptor–sensitive mechanisms.

The appetite suppressant and metabolic enhancer effects of ma huang made it a potent ingredient of various OTC weight loss compounds. However, even before the U.S. Federal ban on ma huang, many herbal manufacturers were already promoting their ephedra-free supplements because of the numerous reported adverse effects of ephedra.

Dangerous side effects of ma huang include systemic hypertension, pulmonary hypertension, tachycardia, cardiomyopathy, cardiac dysrhythmias, myocardial infarction (MI), cerebrovascular accident (CVA, stroke), seizures, psychosis, and death. Many of these complications have been attributed to a lack of standardization in formulations and their varied potency. Moreover, studies show ephedra’s weight loss effect is mostly negative in the long term. Before the U.S. ban on ma huang, approximately 16,000 cases of adverse events, including 164 deaths, had been reported to the U.S. Food and Drug Administration (FDA) since 1994. Further, the Bureau of Food and Drug Safety of the Texas Department of Health reported eight ephedra-associated fatalities during a 21-month period (1993–1995); seven secondary to MI or stroke. Many large lawsuits for ephedra-linked MI, CVA, and pulmonary hypertension were filed in recent years. Those at highest risk of side effects include pregnant women and patients with hypertension, coronary vascular disease, seizures, glaucoma, anxiety, or mania.

The use of ma huang, still available over U.S. borders, is highly relevant to the practitioner in the perioperative period. The possibility of hypertension causing myocardial ischemia or stroke needs to be considered. Further, ephedra or similar compounds readily available OTC may interact with general anesthetic agents (halothane, isoflurane, desflurane) or cardiac glycosides (digitalis) to cause cardiac dysrhythmias. Patients taking ephedra for prolonged periods can also deplete their peripheral catecholamine stores. Therefore, under general anesthesia, these patients might experience profound intraoperative hypotension, which can be controlled with a direct vasoconstrictor (e.g., phenylephrine) instead of ephedrine. Use of ephedra with phenelzine or other MAO inhibitors may result in insomnia, headache, and tremulousness. Concurrent use with the obstetric drug oxytocin has resulted in hypertension. The synthetic analog of ephedra, ephedrine, is a sympathomimetic amine that has been used by anesthesiologists to raise blood pressure intraoperatively for about 85 years.

Ginger

Ginger has been used to treat nausea, vomiting, motion sickness, and vertigo. A study of the effects of ginger found that no subjects with vertigo taking ginger experienced nausea after caloric stimulation of the vestibular system, in contrast to those taking placebo. Ginger may be superior to dimenhydrinate in decreasing motion sickness. For vomiting episodes, ginger has also been effective in decreasing symptoms associated with hyperemesis gravidarum.

The effect of ginger on the clotting pathway has also been investigated. Ginger has exhibited potent inhibition of thromboxane synthetase, which increases bleeding time and may cause morbidity. The ability of ginger constituents and related substances to inhibit arachidonic acid–induced platelet activation in human whole blood has been studied as well (see Box 16-1 ). The data revealed that ginger compounds and derivatives are more potent antiplatelet agents than aspirin under the conditions employed. [8]-Paradol, a constituent of ginger, was identified as the most potent antiplatelet aggregation agent and COX-1 inhibitor. In another study, administration of ginger resulted in decreases in blood pressure, serum cholesterol, and serum triglycerides in diabetic rats. Further investigation into these effects in diabetes is warranted.

Adverse effects of ginger include bleeding dysfunction, and its use is contraindicated in patients with coagulation abnormalities or those taking anticoagulants (NSAIDs, aspirin, warfarin, heparin). Ginger may increase bleeding risk, enhance barbiturate effects, and, as a result of an inotropic effect, interfere with cardiac medications. Large quantities of ginger may also cause cardiac arrhythmias and CNS depression (see Table 16-3 ).

Garlic

Used prevalently, garlic is available in powdered, dried, and fresh forms. Allicin, the main active ingredient in garlic, contains sulfur, and crushing the clove activates the enzyme allinase, thus facilitating the conversion of alliin to allicin. Recommended uses for garlic have focused on treating hypercholesterolemia, hypertension, and cardiovascular disease, targeting its hypocholesterolemic and vasodilatory activity. Garlic may lead to inhibition of the HMG-CoA reductase and 14α-demethylase enzyme systems, exerting a lipid-reducing effect. Garlic may also be used for its antiplatelet, antioxidant, and fibrinolytic actions. Data are minimal to support the use of garlic for hypertension; its depressor effects on systolic and diastolic blood pressure appear to range from minimal to modest.

Chronic oral use of garlic has been reported to augment the endogenous antioxidants of the heart. A recent study hypothesized that garlic-induced cardiac antioxidants may provide protection against acute doxorubicin (Adriamycin)–induced cardiotoxicity. Using the rat model, researchers discovered an increase in 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 in the doxorubicin group. In the garlic-treated rats, however, the increase in myocardial TBARS and a decrease in endogenous antioxidants by doxorubicin were significantly attenuated. Therefore, garlic administration may help prevent this form of drug-induced cardiotoxicity.

Allicin has shown significant vasodepressor activity in the pulmonary vascular bed of the rat and cat. Further, 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.

Data indicate garlic may be an effective treatment against methicillin-resistant Staphylococcus aureus (MRSA) infection. The garlic extracts diallyl sulfide and diallyl disulfide showed protective qualities against MRSA infection in mice. Such conclusions, coupled with further investigation, may result in the use of such extracts in MRSA infection treatment.

Side-effects of garlic are minimal, with odor and GI discomfort most common. Induction of the CYP450 system may occur, as evidenced by reduction of serum levels of one medication. Pain prevention practitioners must be aware that garlic may augment the effects of warfarin, heparin, or aspirin and may result in an abnormal bleeding time. This effect can result in increased risk of perioperative hemorrhage or catastrophic hematoma on interventional pain procedures.

Ginkgo biloba

There are many active components present in ginkgo, including the flavonoid glycosides and terpenoids. The flavonoids demonstrate antioxidant activity and the terpenoids, antagonism to platelet action. Ginkgo (Ginkgo biloba) has been used to treat intermittent claudication and vertigo and to enhance memory. Subjects report decreased pain in the affected lower extremities and increased symptom-free distance in ambulation. In addition to inhibiting platelet-activating factor, ginkgo may also mediate nitric oxide release and decrease inflammation.

To evaluate the efficacy of ginkgo biloba on dementia, a double-blind placebo-controlled RCT found that the extract EGB761 had the potential to stabilize and modestly improve cognitive performance and social functioning. In addition, the improvement in cognition was comparable to the effect of donepezil on dementia. This effect on cognition function and memory may be related to activation of cholinergic neurotransmitters. However, data are inconclusive regarding the ability of this herbal to improve memory in subjects without dementia.

Although the pathogenesis of acute pancreatitis is not well understood, numerous data suggest a role for oxygen free radicals in the progression and complications of pancreatitis. The effects of EGB761 have shown a positive effect on acute pancreatitis, which may be linked to a free-radical scavenger effect by ginkgo.

Ginkgo is generally well tolerated in healthy adults for about 6 months. However, aside from the mild GI distress, the potential effect of ginkgo on antiplatelet activating factor has resulted in G. biloba –induced spontaneous hyphema (bleeding from iris, anterior chamber of eye), spontaneous bilateral subdural hematomas, and subarachnoid hemorrhage. Therefore, use of anticoagulants and ginkgo should be strictly monitored and possibly avoided when patients are scheduled for surgery.

An open-label crossover RCT was conducted on healthy human volunteers to determine if ginkgo alters the pharmacokinetics of digoxin. Concurrent use of oral ginkgo and digoxin had no significant effect on digoxin in the subjects. Concomitant use of G. biloba with aspirin, NSAIDs, warfarin, or heparin is not recommended because ginkgo may increase the potential for bleeding in these patients. It is also advisable to avoid ginkgo with anticonvulsant drugs such as carbamazepine, phenytoin, and phenobarbital because the herbal may decrease the effectiveness of these medications. Concurrent use of ginkgo and TCAs is also not advised because of the potential to lower the seizure threshold in these patients (see Table 16-3 ).

Kava

Kava (or kava kava), an extract of the Piper methysticum plant, is employed for its proposed anxiolytic, antiepileptic, antidepressant, antipsychotic, and sedative properties. Some of the active ingredients of kava include the lactones or pyrones, kawain, methysticin, dihydrokawain, and dihydromethysticin. Kava extracts available commercially are usually found to contain 30% to 70% kava lactones. The extract WS 1490 has been shown effective in anxiety disorders as a treatment alternative to benzodiazepines and TCAs, without the problems associated with these two drug classes. However, therapeutic effect may take up to 4 weeks, with treatment for 1 to 8 weeks to obtain significant improvement.

Although the exact mechanism of kava kava’s effects on the CNS is largely unknown, the pyrones have demonstrated competitive inhibition of the MAO-B. Inhibition of this enzyme may result in the psychotropic effects related to kava use because MAO-B is responsible for the breakdown of amines that play a role in psychoses.

Patients who experience hepatic adverse reactions are known as “poor metabolizers.” Typically, these patients have a deficiency in the CYP2D6 isozyme. Therefore, it is recommended that patients who use kava receive routine liver function tests to monitor for hepatotoxicity. Furthermore, 24 cases of hepatotoxicity after use of kava kava were documented as of 2002, and death or liver transplant occurred after 1 to 3 months of use in some patients. In countries such as Germany and Australia, kava kava use longer than 3 months is not recommended. Other side effects of kava use include visual changes, a pellagra-like syndrome with characteristic ichthyosiform dermopathy, and hallucinations.

Kava may react adversely with the benzodiazepine alprazolam, other CNS depressants, statins, alcohol, and levodopa, resulting in excessive sedation and other side effects. Therefore the supplement should be avoided in patients with endogenous depression. Kava may also affect platelets in an antithrombotic manner by inhibiting COX and thus attenuating thromboxane production. Pain relief mechanisms utilized by kava may be similar to local anesthetic responses and might depend on a nonopiate-sensitive pathway.

Ginseng

There are three main groups of ginseng that are classified based on their geographic origin. These are Asian ginseng, American ginseng, and Siberian ginseng, with the pharmacologically active ingredient in ginseng being ginsenosides. Asian and American ginsengs have been used to increase resistance to environmental stress, promote diuresis, stimulate the immune system, and aid digestion. Further, while Asian ginseng has shown promise in improving cognition when combined with the herbal agent ginkgo, American ginseng has been studied for its potential to stimulate human TNF-α production in cultured white blood cells. American ginseng may also possess hypoglycemic activity. Such effects have been observed in both normal and diabetic subjects and may be attributed to ginsengs components, specifically ginsenoside Rb2 and panaxans I, J, K, and L.

Typically, ginseng is well tolerated, but side effects such as bleeding abnormalities secondary to antiplatelet effects, headache, vomiting, Stevens-Johnson syndrome, epistaxis, and hypertension have been reported. Drug interactions between Asian ginseng and calcium channel blockers, warfarin, phenelzine, and digoxin have also been noted. Ginseng should be avoided in patients receiving anticoagulants (warfarin, heparin, aspirin, NSAIDs). Further, because of ginseng’s association with hypertension and the deleterious outcomes linked to chronic hypertension, the anesthesiologist should be aware of which patients and for how long they may have been taking this herbal product. Since many agents can cause generalized vasodilation, hemodynamic lability may be seen.

Regarding ginseng’s interaction with antidepressants (e.g., MAO inhibitors), concurrent use of ginseng with phenelzine should be avoided because manic episodes have been reported with routine use of both. Because it can cause decreased blood glucose levels, ginseng should be used cautiously in diabetic patients taking insulin or other oral hypoglycemic agents, and levels should be monitored (see Table 16-3 ).

Cloves

Cloves, also known as clove oil, have been used orally for stomach upset, its antiplatelet effect, and as an expectorant. Cloves may also be used topically for pain relief from mouth and throat inflammation, as well as athlete’s foot. Its constituent, eugenol, has long been used topically for toothache, but the FDA has classified this drug into category III (inadequate data to support efficacy). More evidence is necessary to rate cloves for this purpose. Topically, cloves can cause tissue irritation and in some people even allergic dermatitis. Moreover, repeated oral application may result in gingival damage and skin and mucous membrane irritation. The eugenol constituent in cloves may theoretically increase the risk of bleeding in some people who are concomitantly using herbs such as garlic, ginger, ginkgo, and white willow bark. Likewise, patients taking antiplatelet agents such as aspirin, clopidogrel, dipyridamole, ticlopidine, heparin, and warfarin may also experience an increase risk of bleeding.

Black Pepper

Black pepper, also known as Piper nigrum, has been used to treat upset stomach, bronchitis, and even cancer. Some have used black pepper topically to treat pain associated with neuralgia and skin irritation, and it may also possess antimicrobial and diuretic properties. The putative compounds include volatile oils (sabinene, limonene, caryophyllene, β-pinene, α-pinenes), acid amines (e.g., piperines), and fatty acids. Eye contact with black pepper may lead to redness and swelling. Large amounts have even been reported to cause death secondary to aspiration.

Black pepper may decrease the activity of the CYP3A4 enzyme, increasing levels of drugs metabolized by the enzyme (e.g., phenytoin, propranolol, theophylline). The piperine constituent of pepper seems to inhibit CYP3A4 in vitro. Other drugs that may be affected include calcium channel blockers, chemotherapeutic agents, antifungals, glucocorticoids, cisapride, alfentanil, fentanyl, losartan, fluoxetine, midazolam, omeprazole, and ondansetron. Caution is advised if patients are taking these drugs concomitantly because their doses may need to be decreased.

Capsicum annuum

Capsicum (Capsicum annuum), also known as cayenne pepper, has been used orally for upset stomach, toothache, poor circulation, fever, hyperlipidemia, and heart disease prevention. Capsicum can be used topically to treat pain associated with osteoarthritis, shingles, rheumatoid arthritis, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, fibromyalgia, and back pain. Others have used capsicum for relief of muscle spasms and even as a gargle for laryngitis.

Capsaicinoids, carotinoids, flavonoids, and steroid saponins are the putative compounds involved. The mechanism of action involves the binding of nociceptors in the skin, which initially causes neuronal excitation and heightened sensitivity (itching, burning) followed by cutaneous vasodilation. Selective stimulation of afferent C fibers, which act as thermoreceptors and nociceptors, and release of substance P, a sensory neurotransmitter that mediates pain, are implicated. This excitatory period is followed by a refractory period with reduced sensitivity, possibly from desensitization secondary to substance P depletion. Cough, dyspnea, nasal congestion, and eye irritation may occur through stimulation of unmyelinated, slow C-fibers of the sensory nervous system.

About 10% of patients who use capsaicin topically discontinue its use secondary to adverse effects such as burning, stinging, and erythema. Exacerbation of ACE inhibitor cough has been reported in patients using topical capsaicin and taking ACE inhibitors. Skin contact with fresh capsicum fruit can cause irritation or contact dermatitis. Furthermore, concomitant use of herbs and supplements (garlic, ginseng, ginkgo, cloves) may increase the risk of bleeding by decreasing platelet aggregation (see Table 16-3 ).

White Willow Bark

From the family of salicylates, white willow bark is used to treat headache, mild feverish colds, influenza, muscle and joint pain caused by inflammation, arthritic conditions and systemic connective tissue disorders. Preliminary research suggests that willow bark extracts have analgesic, anti-inflammatory, and antipyretic effects.

Evidence demonstrates that willow bark extract providing 120-240 mg of the salicin constituent daily can reduce low back pain in some patients with the higher concentration being more effective. Of note, it may take up to 1 week for significant relief. Salicin’s therapeutic effect had in fact been reported to be comparable to rofecoxib (Vioxx – now discontinued) for low back pain.

Research is conflicting concerning white willow bark’s efficacy on osteoarthritis, with some studies suggesting a moderate analgesic effect while others consider it similar to placebo. More studies must be conducted to identify its use in these conditions.

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  Flavonoids, tannins, and salicylates are attributed to the antiinflammatory, antipyretic, and antiuricosuric activities of white willow bark. Salicin is eventually metabolized to salicylic acid, which then shares the same metabolic pathway as aspirin.

  
  
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  An ethanolic extract of willow bark seems to inhibit cyclooxygenase (COX)-2 indirectly by mediating prostaglandin release, while other constituents of white willow bark may have lipoxygenase-inhibiting and antioxidant properties that could contribute to analgesia. Moreover, other literature suggest that they may also prevent prostaglandin and cytokine release.

Willow bark inhibits platelet aggregation, but to a lesser degree than aspirin, thus, concomitant use with other herbals such as ginkgo, ginseng, garlic, or cloves may increase the risk of bleeding, as will use with anticoagulants and antiplatelet drugs.

Devil’s Claw

Devil’s claw has been used to treat pain symptoms from osteoarthritis, rheumatoid arthritis, gout, myalgia, fibrositis, lumbago, tendonitis, pleuritic chest pain, and gastrointestinal upset. The active constituent, harpagoside, seems to reduce nonspecific low-back pain when used in a dose range from 50 to 100 mg. In fact, its use in this range has been compared to 12.5 mg of the discontinued drug, rofecoxib. Additionally, oral dosing of devil’s claw either alone or in combination with NSAIDs may lessen pain associated with osteoarthritis and may even need lower doses of NSAIDs to achieve the same level of pain relief. More evidence is needed to substantiate its use or disuse for rheumatoid arthritis-related pain although preliminary data suggests it may be ineffective.

Besides containing harpagoside, devil’s claw contains iridoid glycoside constituents and procumbide that add to its effect, as well as the phenylethanol derivatives acteoside (verbascoside) and isoaceteoside, and the oligosaccharide stachyose. The iridoid glycoside constituents seem to provide an anti-inflammatory effect. Current evidence implies that harpagoside inhibits both the cyclo-oxygenase (COX) and lipoxygenase inflammatory pathways. Devil’s claw seems to inhibit only COX-2, not COX-1, and also inhibits the inflammation modulating enzyme nitric oxide synthetase. An increased synthesis and release of tumor necrosis factor alpha (TNF-α) by compounds other than harpagoside aid in the anti-inflammatory effect; however, research in humans shows no effect of devil’s claw on the arachidonic acid pathway.

The most common reported side effect of devil’s claw is diarrhea, but the supplement is generally well tolerated. Other generalized complaints include nausea, vomiting, and abdominal pain, headache, tinnitus, anorexia, and loss of taste. Some people have experienced dysmenorrhea and hemodynamic instability.

Possible drug interactions may stem from devil’s claw ability to inhibit CYP2C9, although the effect has not been reported in humans. Drugs metabolized by CYP2C9 such as nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac, ibuprofen, meloxicam [Mobic], and piroxicam [Feldene]); celecoxib (Celebrex); amitriptyline (Elavil); warfarin (Coumadin); glipizide (Glucotrol); losartan (Cozaar); and others may need to be reduced or even eliminated (see Table 16-3 ).

Boswellia

Boswellia, also known as Indian frankincense (Boswellia serrata) , has been used to manage pain associated with osteoarthritis, rheumatoid arthritis (RA), rheumatism, bursitis, and tendonitis. Non-pain related uses include ulcerative colitis, dyspepsia, asthma, allergic rhinitis, sore throat, syphilis, pimples, and cancer.

There is preliminary evidence that taking Indian frankincense extract orally might reduce osteoarthritis symptoms such as knee pain and swelling, while its use in rheumatoid arthritis is controversial. More evidence is needed for use of boswellia in both these conditions.

The principal constituents, boswellic acid and α- and β-boswellic acid, come from the resin. These constituents have anti-inflammatory properties that aid in pain management with arthritic patients, but not all extracts of Indian frankincense show antiarthritis, anti-inflammatory, or antipyretic effects. The mechanism behind boswellic acids comes from inhibition of 5-lipoxygenase and leukotriene synthesis, along with the inhibition of leukocyte elastase. Some have suggested that the acids may have disease modifying effects, thereby decreasing glycosaminoglycan degradation and cartilage damage. Boswellia seems to decrease production of antibodies and cell-mediated immunity.

Side effects include GI upset such as epigastric pain, nausea, and diarrhea, while topical use may cause contact dermatitis. Not enough studies have been done to comment on pharmacologic interactions with other drugs (see Table 16-3 ).