Dietary Supplements & Herbal Medications: Introduction
Dietary supplements, which include substances known as botanical and herbal medications, are available without prescription and, unlike over-the-counter medications, are considered to be nutritional supplements rather than drugs. These substances are marketed in the United States without FDA or other governmental premarketing review of efficacy or safety, and with little government oversight of purity, variations in potency, or adverse effects. Purified nonherbal nutritional supplements such as dehydroepiandrosterone (DHEA) and melatonin are also used widely by the general public in pursuit of "alternative medicine." In the case of many herbal products and nutritional supplements, evidence from controlled clinical studies for their medical effectiveness is incomplete or nonexistent. A summary of the intended uses of some herbal products and nutritional supplements is presented in Table 60-1.
TABLE 60-1 Common intended uses of some botanical or nutritional supplements.
Botanical or Nutritional Supplement Common Intended Use Echinacea Decrease duration and intensity of cold symptoms Ephedra (ma huang) Treatment of respiratory ailments such as bronchitis and asthma, and as a CNS stimulant Garlic For cholesterol lowering and atherosclerosis Ginkgo Treatment of intermittent claudication, and cerebral insufficiency and dementia Ginseng Improvement of physical and mental performance Milk thistleLimitation of hepatic injury and as an antidote to Amanita mushroom poisoning Saw palmetto Improvement in symptoms of benign prostatic hyperplasia St. John's wortTreatment of mild to moderate depression Coenzyme Q10Improvement of ischemic heart disease and for Parkinson's disease Glucosamine Reduction of pain associated with osteoarthritis MelatoninDecrease jet lag symptoms and as a sleep aid
High-Yield Terms to Learn
Alternative medicine Treatments that are not generally recognized by the medical community as standard or conventional medical approaches Controlled clinical trial A clinical trial that compares a group of subjects who are receiving a treatment with a closely matched group of individuals who are not receiving a treatment. Chapter 5 describes clinical trials in more detail Herbal medication Plants or plant extracts that people use to improve their health Nutritional supplement A substance that is added to the diet to improve health and which usually contains dietary ingredients such as vitamins, minerals, amino acids, and enzymes Placebo An inactive medication made to resemble the investigational formulation as much as possible
Botanical Substances
Echinacea
Nature
Leaves and roots of echinacea species (eg, Echinacea purpurea) contain flavonoids, polyacetylenes, and caffeoyl conjugates.
Pharmacology
In vitro studies have shown that echinacea has cytokine activation and anti-inflammatory properties. There is some evidence for the efficacy of aerial (above-ground) parts of E purpurea plants in the early treatment of colds.
Toxicity and Drug Interactions
Unpleasant taste and gastrointestinal effects may occur, sometimes with dizziness or headache. Some preparations have a high alcohol content, but no drug interactions have been reported.
Ephedra (Ma Huang)
Nature
Ma huang is one of many names given to various plants of the genus Ephedra, the major chemical constituents of which are ephedrine and pseudoephedrine (see Chapter 9). Ephedrine is a prescription drug in the United States; pseudoephedrine is available in over-the-counter decongestants. In the United States, the FDA has banned the marketing of dietary supplements containing ephedrine alkaloids, which are considered to pose an unreasonable cardiovascular risk. The ban is not applicable to Chinese herbal remedies.
Pharmacology
The actions of ephedra products are those of ephedrine and pseudoephedrine, which are indirect-acting sympathomimetics that release norepinephrine from sympathetic nerve endings (see Chapter 9). In addition to nasal decongestion, the established clinical use of ephedrine is as a pressor agent. Ephedra herbal products are commonly used for treatment of respiratory dysfunction, including bronchitis and asthma, and as mild CNS stimulants. In Chinese medicine, ephedra products are also used for relief of cold and flu symptoms, for diuresis, and for bone or joint pain. Dietary supplements containing ephedrine alkaloids have been widely promoted for weight loss and for enhancement of athletic performance.
Toxicity and Drug Interactions
Toxic effects are those of ephedrine and include dizziness, insomnia, anorexia, flushing, palpitations, tachycardia, and urinary retention. In high doses, ephedra can cause a marked increase in blood pressure, cardiac arrhythmias, and a toxic psychosis. Contraindications are those for ephedrine and include anxiety states, bulimia, cardiac arrhythmias, diabetes, heart failure, hypertension, glaucoma, hyperthyroidism, and pregnancy. As a weak base, renal elimination of ephedrine in overdose can be facilitated by urinary acidification.
Garlic
Nature
Garlic (Allium sativum) contains organic thiosulfinates that can form allicin (responsible for the characteristic odor) via enzymes activated by disruption of the garlic bulb.
Pharmacology
In vitro studies show that allicin inhibits hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase and angiotensin-converting enzyme (ACE), blocks platelet aggregation, increases nitric oxide (NO), is fibrinolytic, has antimicrobial activity, and reduces carcinogen activation. There is some evidence from clinical trials that garlic is more effective than placebo at lowering total cholesterol, although a trial in adults with moderately elevated low-density lipoprotein (LDL) cholesterol failed to find an LDL cholesterol-lowering effect. A randomized study of garlic in patients with advanced coronary artery disease showed a reduction in plaque accumulation but primary end points (death, stroke, myocardial infarction) were not studied.
Toxicity and Drug Interactions
Nausea, hypotension, and allergic reactions may occur. Possible antiplatelet action warrants caution in patients receiving anticoagulants or conventional antiplatelet drugs.
Ginkgo
Nature
Prepared from the leaves of Ginkgo biloba, ginkgo contains flavone glycosides and terpenoids.
Pharmacology
In in vitro studies, ginkgo exhibits antioxidant and radical-scavenging effects and increases nitric oxide formation. Animal studies have revealed reduced blood viscosity and changes in CNS neurotransmitters. At the clinical level, ginkgo may have value in intermittent claudication, and its use as a pretreatment may reduce markers of oxidative stress associated with coronary artery bypass surgery. Although several studies have shown a mild benefit of ginkgo in patients with cognitive impairment and dementia, the effects are unpredictable and unlikely to be clinically significant. A large trial investigating ginkgo as a prophylactic agent for dementia failed to show a benefit after 6 yrs of treatment.
Toxicity and Drug Interactions
Gastrointestinal effects, anxiety, insomnia, and headache occur. Possible antiplatelet action suggests caution in patients receiving anticoagulants or antiplatelet drugs. Ginkgo may be epileptogenic and should be avoided in persons with a history of seizure disorders.
Ginseng
Nature
Most ginseng products are derived from plants of the genus Panax, which contain multiple triterpenoid saponin glycosides (ginsenosides). Siberian or Brazilian ginseng does not contain these chemicals.
Pharmacology
Ginseng is purported to improve mental and physical performance, but the clinical evidence for such effects is limited. There is some evidence that ginseng may have some effect in cold prevention and in lowering postprandial glucose.
Toxicity and Drug Interactions
Estrogenic effects include mastalgia and vaginal bleeding. Insomnia, nervousness, and hypertension have been reported. Ginseng should be used cautiously in patients receiving anticoagulant, antihypertensive, hypoglycemic, or psychiatric medications.
Milk Thistle
Nature
Milk thistle is derived from the fruit and seeds of Silybum marianum, which contain flavonolignans such as silymarin.
Pharmacology
In vitro studies show that milk thistle reduces lipid peroxidation, scavenges free radicals, enhances superoxide dismutase, inhibits formation of leukotrienes, and increases hepatocyte RNA polymerase activity. In animal models, milk thistle protects against liver injury caused by alcohol, acetaminophen, and Amanita mushrooms. A systematic review of randomized trials of milk thistle in patients with alcoholic liver disease or viral hepatitis found no significant reduction in all-cause mortality, liver histopathology, or complications of liver disease. A commercial preparation of silybin (an isomer of silymarin) is available in some countries as an antidote to Amanita phalloidesmushroom poisoning.
Toxicity and Drug Interactions
Other than loose stools, milk thistle does not cause significant toxicity, and there are no reports of drug interactions.
St. John's Wort
Nature
St. John's wort is made from dried flowers of Hypericum perforatum, which contains the active constituents hypericin and hyperforin.
Pharmacology
In vitro studies with hyperforin have shown decreased activity of serotonergic reuptake systems. In animals, chronic treatment with commercial extracts led to downregulation of adrenoceptors and upregulation of 5-HT receptors. Some (but not all) clinical trials of the extract in patients with mild to moderate depression have shown efficacy that is greater than placebo and, in some trials, similar to those of prescription antidepressants for mild or moderate depression. Hypericin, when photoactivated, may have antiviral and anticancer effects.
Toxicity and Drug Interactions
Mild gastrointestinal side effects occur, and photosensitization has been reported with St. John's wort. It should be avoided in patients using selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors and in those with a history of bipolar or psychotic disorder. Constituents in St. John's wort induce the formation of cytochrome P450 isoforms and P-glycoprotein drug transporters. Decreases in effectiveness of birth control pills, cyclosporine, digoxin, HIV protease inhibitors, and warfarin have been reported in patients who regularly use St. John's wort.
Saw Palmetto
Nature
Saw palmetto is derived from the berries of Serenoa repens or Sabal serrulata and contains phytosterols, aliphatic alcohols, polyprenes, and flavonoids.
Pharmacology
In vitro studies have shown inhibition of 5
-reductase and antagonistic effects at androgen receptors. Clinical trials of saw palmetto in benign prostatic hyperplasia (BPH) have been mixed. Some have shown improvement in urologic function and in urinary flow. Others, including a recent well-controlled, double-blind 1-yr study in moderate to severe BPH, have shown no significant effects on symptoms or objective measures.
Toxicity and Drug Interactions
Abdominal pain with gastrointestinal distress, decreased libido, headache, and hypertension occur; overall incidence was less than 3%. Saw palmetto has no effect on the prostate-specific antigen (PSA) marker.
Skill Keeper: Drugs from Plant Sources
Many conventional drugs, strictly regulated by governmental agencies such as the FDA, originated from plant sources. How many of these compounds can you identify? The Skill Keeper Answer appears at the end of the chapter.
Purified Nutritional Substances
Coenzyme Q10
Nature
Coenzyme Q10, also known as ubiquinone, is a benzoquinone that serves as a cofactor in the mitochondrial electron transport chain and, in its reduced form of ubiquinol, serves as an important antioxidant. After ingestion, the reduced form predominates in the circulation.
Pharmacology
Coenzyme Q10 may have a small degree of efficacy in reducing systolic and diastolic blood pressure and in treating coronary artery disease and chronic stable angina, but it does not appear to be useful as adjunctive therapy of heart failure. Coenzyme Q10 may have some efficacy in reducing muscle pain in patients with statin-related myopathy.
Toxicity
Coenzyme Q10 is well tolerated. The most common adverse effect is gastrointestinal disturbances. Rare effects include rash, thrombocytopenia, irritability, dizziness, and headache. Coenzyme Q10 has structural similarity to vitamin K and can decrease the effects of warfarin.
Glucosamine
Nature
Glucosamine is an amino sugar that serves as the precursor of nitrogen-containing sugars, including the glycosaminoglycans that are a major constituent of connective tissue, including the cartilage in joints.
Pharmacology
Glucosamine is primarily used for pain associated with osteoarthritis. The many clinical trials examining the use of oral or intra-articular glucosamine have produced mixed results. Although some early trials and a meta-analysis found a beneficial effect in osteoarthritis, a recent large placebo-controlled, double-blind trial failed to find a benefit for glucosamine in treating osteoarthritis.
Toxicity
Glucosamine can occasionally cause diarrhea and nausea but otherwise is well tolerated. Because glucosamine is commercially prepared from crustaceans, there is some concern about cross-allergenicity in people with shellfish allergy.
Melatonin
Nature
Melatonin is a serotonin derivative produced mainly in the pineal gland. It appears to regulate sleep-wake cycles, and its release coincides with darkness (9 PM to 4 AM). Other purported activities include contraception, prevention of aging, protection against oxidative stress, and the treatment of cancer, major depression, and HIV infection.
Pharmacology
Melatonin has been used extensively for jet lag and insomnia. In jet lag, clinical studies have shown subjective improvements in mood, more rapid recovery times, and reductions in daytime fatigue. Melatonin improves sleep onset, duration, and quality when given to patients with sleep disorders. Ramelteon, an agonist of melatonin receptors, has been FDA approved for insomnia (see Chapter 22).
Toxicity
Sedation and next-day drowsiness and headache have been reported. Melatonin can suppress the midcycle surge of luteinizing hormone (LH) and should not be used in pregnancy or in women attempting to conceive. Because it can decrease prolactin levels, melatonin should not be used by nursing mothers. In healthy men, chronic melatonin use decreases sperm quality.
Skill Keeper Answer: Drugs from Plant Sources
The clinical application of drugs that originated from plant sources has contributed greatly to conventional medicine. Such compounds include aspirin, atropine, cocaine, codeine, colchicine, digoxin, ephedrine, etoposide, methysergide, morphine, nicotine, physostigmine, pilocarpine, quinidine, quinine, reserpine, scopolamine, taxanes (eg, paclitaxel), tubocurarine, vinblastine, and vincristine.
Checklist
When you complete this chapter, you should be able to:
Contrast the regulations in the United States of botanicals and nutritional supplements with those of therapeutic drugs with regard to efficacy and safety.
List several of the most widely used botanical products, and describe their purported medical uses, adverse effects, and potential for drug interactions.
Describe the proposed medical uses and adverse effects of several purified nutritional supplements.