Possible herbal medicine-drug interactions in the perioperative period.
This assumption leads to the unwary use of these medicines in special risk groups, e.g. children, the elderly, pregnant/lactating women, and patients with liver and kidney failure. The herbal medicines are used in pregnant women as it is believed that they are natural and safe for the unborn child.
The use of herbal medicines extends to children who present for 'day-case' anaesthesia, especially those with chronic conditions, e.g. asthma or eczema or those perceived by caregivers to be 'sickly' and in need of immune or energy boosters. Increasingly, the herbal medicines are used by HIV-positive patients and cancer patients in combination with their prescribed drugs.
As the public perceive the medicines as natural products, they neglect to mention their use. Alternatively, they deliberately hide the fact that they use herbal or 'traditional' medicines as they think that their medical practitioners may be prejudiced against their use. In the perioperative period, several agents may be given in a short period of time and anaesthetists may not be aware that their patients are taking herbal medicines. These herbal medicines can have clinically significant interactions with conventional drugs.
Modern medical practice allows for patients to be seen on the day of their surgery. This review article will address potential herb-drug interactions between commonly used herbal medicines and drugs used in the perioperative period. The aim is to create an awareness of these potential interactions.
Potential herbal medicine-drug interaction and possible mechanisms
Herbal medicines have pharmacokinetic and pharmacodynamic interactions with conventional drugs. Pharmacokinetic interactions involve drug absorption, distribution, metabolism and excretion. Most herbal medicines and conventional drugs are orally administered. Most orally administered drugs are lipophilic and need to be transformed into water-soluble compounds. The liver is the principal site for drug biotransformation. Phase I reactions such as oxidation, reduction and hydrolysis transform drugs into inactive or active metabolites. Typically, these metabolites are then conjugated by phase II reactions such as glucuronidation, sulphation or methylation to form less toxic, water-soluble metabolites which are more readily excreted in bile and urine. Phase I metabolism occurs mainly via the cytochrome P450 (CYP450) mixed oxidase enzyme system. CYP450 is a large family of isoenzymes found mainly in the liver (can also be found elsewhere, e.g. gut). Conventional drugs and herbal medicines can be substrates, inhibitors or inducers of the CYP450 enzyme system. The CYP3A isoenzyme metabolises more than half of drug metabolised by the CYP450 enzyme system. Inhibitors increase the bioavailability of the substrate, which can result in toxicity. The inducers, on the other hand, increase their metabolism, leading to decreased efficacy and therapeutic failure.
An important site for pharmacokinetic interaction is the drug transporter P glycoprotein. P glycoprotein is an energy-dependent efflux pump expressed in cell membranes found in the gastrointestinal tract and sites of excretion (e.g. liver and kidney, blood-brain barrier). In the gut, it pumps xenobiotics (including herbal medicines or drugs) back into the lumen. It enhances drug elimination at the excretion sites. Conventional drug and herbal medicines can be substrates, inducers or inhibitors. Inhibitors result in increased bioavailability and decreased excretion of substrates while inducers result in decreased bioavailability and increased excretion.
Pharmacodynamic interactions involve biochemical and physiological effects (therapeutic or adverse) of the co-administered drugs on the body. The interactions can either be synergistic or antagonistic. These can be herb drug or herb-herb interactions, as some commercially available formulations contain more than one herb.
Herbal medicines with clinical implications in the perioperative period
Herbal medicines are usually used for curing diseases or as dietary supplements, alone or in combination with conventional medicines. The indications for their use vary from treatment of common colds or flu, pain relief, depression, to treatment of serious diseases like cancer or HIV/AIDS-related illnesses.
Table I lists indications for herbal medicines with clinical implications in the perioperative period. In vivo data are lacking, and most data come from in vitro and animal studies. The limited clinical data come from case reports rather than randomised controlled trials.
St John's wort is one of the few herbal remedies that has been tested in vitro, and pharmacokinetic and clinical studies have shown that it reduces drug concentrations of midazolam, alprazolam, cyclosporin, tacrolimus, amitriptyline, selective serotonin re-uptake inhibitors (SSRIs), digoxin, warfarin, theophylline, dextromethorphan, simvastatin, anticonvulsants, chemotherapy, some antiretrovirals, oral contraceptives, etc. This is due to potent induction of cytochrome P450. It is important to note that when combined with SSRIs, it increases the risk of the potentially fatal serotonin syndrome. Other drugs that may increase this risk in combination with St John's wort are the commonly used analgesics tramadol and pethidine.
Garlic, most commonly used in HIV patients as a dietary supplement, has been reported to increase bleeding tendency due to a direct anticoagulation activity. The active compound allicin inhibits platelet aggregation.
Ginkgo biloba has antiplatelet effects and has been reported to cause spontaneous bleeding. It may interact with nonsteroidal anti-inflammatory drugs, e.g. ibuprofen. Combination with warfarin may increase the risk of spontaneous bleeding. Ginseng has been reported to cause hypoglycaemia. Ginseng lowers glucose levels by increasing the number of insulin receptors and enhancing insulin release. This is especially important in diabetic patients who are fasted preoperatively. It also inhibits platelet aggregation and therefore increases the risk of bleeding.
Kava kava and valerian are used for anxiolysis and sedation and may cause prolonged sedation when combined with benzodiazepines, anaesthetic agents and the analgesics.
Ephedra contains alkaloids including ephedrine, pseudoephedrine, norephedrine, methylephedrine and norpseudoephedrine. Ephedrine is the predominant active component and is usually found in stimulants and diet pills. It causes dose-dependent tachycardia and hypertension and potentiates arrhythmias and uncontrolled hypertension when combined with halothane and other sympathomimetics respectively. This could lead to fatal cardiovascular events, e.g. myocardial infarction and cerebrovascular accidents.
Table II lists the commonly used herbal medicines that have clinical interactions in the perioperative period and recommendations regarding discontinuation. However, as there is lack of clinical data regarding discontinuation of these medicines, the conservative approach by the American Society of Anaesthesiologists suggests discontinuation 2 weeks before elective surgery. This may be challenging as most patients are preoperatively assessed the day before or on the day of surgery. What is required is collaboration between attending clinicians and anaesthesiologists as to whether patients are using herbal remedies, as well as awareness of these potentially harmful interactions.
Ang-Lee MK, Moss J, Yuan C. Herbal medicines and perioperative care. JAMA 2001; 286: 208-216.
Ernst E. The risk-benefit profile of commonly used herbal therapies: Ginkgo, St John's Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern Med 2002; 136: 42-53.
Johnston SJB. Herbal medications--harmless or harmful? SAJAA 2003; 9: 16-17.
Skalli S, Zaid A, Soulaymani R. Drug interactions with herbal medicines. Ther Drug Monit 2007; 29: 679-686.
Van den Bout-van den Beukel C, Koopmans PP, van den Ven AJAM, De Smet PAGM, Burger DM. Possible drug-metabolism interactions of medicinal herbs with antiretroviral agents. Drug Metabolism Reviews 2006; 38: 477-514.
PHUMLA SINXADI, MB ChB, DA (SA) MARC BLOCKMAN, MB ChB, BPharm, Dip Int Res Ethics, MMed (Clin Pharmacol)
Division of Clinical Pharmacology, University of Cape Town
Table I. Indications for herbal medicines with clinical implications in the perioperative period Herbal medicine (common name) Commercial use Echinacea purpura (echinacea) Common colds and flu Ephedra sinica (ma huang) Weight loss, energy booster, asthma and bronchitis Allium sativum (garlic) Immune booster, lipid lowering and prevention of atherosclerosis Ginkgo biloba (gingko) Peripheral vascular diseases, cognitive disorders, macular degeneration, intermittent claudication Panax ginseng (ginseng) Diabetes, protection against stress Piper methysticum (kava) Anxiolysis and sedation Hypericum perforatum Clinical depression (St John's wort) Valeriana officinalis (valerian) Sedation and hypnosis Table 11. Clinically important effects and perioperative concerns of 8 herbal medicines and recommendations for discontinuation of use Herb: common name(s) Relevant pharmacological effects Echinacea: purple Activation of cell-activated cone-flower root immunity Ephedra: ma huang Increased heart rate and blood pressure through direct and indirect sympathomimetic effects Garlic Inhibition of platelet aggregation (maybe irreversible); increased fibrinolysis; equivocal antihypertensive effects Ginkgo: duck foot tree, Inhibition of platelet- maiden hair tree, silver activating factor apricot Ginseng: american, Lowers blood glucose; asian, chinese, korean inhibition of platelet ginseng aggregation (maybe irreversible); increased prothrombin time/partial thrombloplastin time in animals; many other diverse effects Kava: awa, intoxicating Sedation, anxiolysis pepper, kawa St John's wort: amber, Inhibition of neurotransmitter goat weed, hardhay, reuptake, monoamine hypericum, klamathe weed oxidase inhibition unlikely Valerian: all heal, garden Sedation heliotrope, vandal root Herb: common name(s) Perioperative concerns Echinacea: purple Allergic reactions; decreased cone-flower root effectiveness of immunosuppressants, potential for immuno-suppression with long-term use Ephedra: ma huang Risk of myocardial ischaemia and stroke from tachycardia and hypertension, ventricular arrhythmias with halothane; long-term use depletes endogenous catecholamines and may cause intraoperative haemodynamic instability, life-threatening interactions with mono amine oxidase inhibitors Garlic Potential to increase risk of bleeding, especially when combined with other medications that inhibit platelet aggregation Ginkgo: duck foot tree, Potential to increase risk of bleeding, maiden hair tree, silver especially when combined with other apricot medications that inhibit platelet aggregation Ginseng: american, Hypoglycaemia; potential to increase asian, chinese, korean risk of bleeding; potential to decrease ginseng anticoagulation effect of warfarin Kava: awa, intoxicating Potential to increase sedative effects pepper, kawa of anaesthetics, potential for addiction, tolerance withdrawal after abstinence unstudied St John's wort: amber, Induction of cytochrome P450 enzymes, goat weed, hardhay, affect- ing cyclosporine, warfarin, hypericum, klamathe weed steroids, protease inhibitors, and possibly benzodiazepines, calcium channel blockers, and many other drugs; decreased digoxin levels Valerian: all heal, garden Potential to increase sedative effect of heliotrope, vandal root an- aesthetics; benzodiazepine-like withdrawal; potential to increase anaesthetic requirements with long-term use Herb: common name(s) Preoperative discontinuation Echinacea: purple No data cone-flower root Ephedra: ma huang At least 24 hours before surgery Garlic At least 7 days before surgery Ginkgo: duck foot tree, At least 36 hours maiden hair tree, silver before apricot Ginseng: american, At least 7 days before asian, chinese, korean surgery ginseng Kava: awa, intoxicating At least 24 hours pepper, kawa before surgery St John's wort: amber, At least 5 days before goat weed, hardhay, surgery hypericum, klamathe weed Valerian: all heal, garden No data heliotrope, vandal root
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|Title Annotation:||Clinical pharmacology|
|Author:||Sinxadi, Phumla; Blockman, Marc|
|Publication:||CME: Your SA Journal of CPD|
|Date:||Mar 1, 2008|
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