Pharmacology_Katzung

Pharmacology_Katzung. problems with botanical misidentification, a lack of product purity, and variations in potency and purification, which continue to be problematic even with GMP standards in place. When the new GMP standards are met, dietary supplement manufacturers should be in compliance with this legislation. However, the FDA has limited resources to investigate and oversee compliance with manufacturing standards, particularly since many ingredient suppliers are based overseas. Furthermore, the dietary supplement ingredient supply chain is complex, and federal regulators are not able to inspect all manufacturing facilities in a timely and efficient manner. Finally, the financial incentive to maximize sales ($32 billion in supplement sales in the USA in 2012) is very great, regardless of lack of evidence of product safety or efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. Because of the problems that resulted from self-regulation, another law, the Dietary Supplement and Non-Prescription Drug Consumer Protection Act, was approved in 2006. This law requires manufacturers, packers, or distributors of supplements to submit reports of serious adverse events to the FDA. Serious adverse events are defined as death, a life-threatening event, hospitalization, a persistent or significant disability or incapacity, congenital anomaly or birth defect, or an adverse event that requires medical or surgical intervention to prevent such outcomes based on reasonable medical judgment. These reports are intended to identify trends in adverse effects and would help to alert the public to safety issues.


Pharmacology_Katzung

Pharmacology_Katzung. Many US consumers have embraced the use of dietary supplements as a “natural” approach to their health care. Unfortunately, misconceptions regarding safety and efficacy of the agents are common, and the fact that a substance can be called “natural” does not of course guarantee its safety. In fact, botanicals may be inherently inert or toxic. If a manufacturer does not follow GMP, this can also result in intentional or unintentional plant species substitutions (eg, misidentification), adulteration with pharmaceuticals, or contamination.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects have been documented for a variety of dietary supplements; however, underreporting of adverse effects is likely since consumers do not routinely report, and do not know how to report an adverse effect if they suspect that the event was caused by consumption of a supplement. Furthermore, chemical analysis is rarely performed on the products involved, including those products that are described in the literature as being linked to an adverse event. This leads to confusion about whether the primary ingredient or an adulterant caused the adverse effect. In some cases, the chemical constituents of the herb can clearly lead to toxicity. Some of the herbs that should be used cautiously or not at all are listed in Table 64–1.


Pharmacology_Katzung

Pharmacology_Katzung. An important risk factor in the use of dietary supplements is the lack of adequate testing for drug interactions. Since botanicals may contain hundreds of active and inactive ingredients, it is very difficult and costly to study potential drug interactions when they are combined with other medications. This may present significant risks to patients. TABLE 64–1 Various supplements and some associated risks. 1Cases of hepatotoxicity have occurred; these cases are rare given the widespread use of black cohosh.


Pharmacology_Katzung

Pharmacology_Katzung. The three most widely used species of Echinacea are Echinacea purpurea, E pallida, and E angustifolia. The chemical constituents include flavonoids, lipophilic constituents (eg, alkamides, polyacetylenes), water-soluble polysaccharides, and water-soluble caffeoyl conjugates (eg, echinacoside, cichoric acid, caffeic acid). Within any marketed echinacea formulation, the relative amounts of these components are dependent upon the species used, the method of manufacture, and the plant parts used. E purpurea, the purple coneflower, has been the most widely studied in clinical trials. Although the active constituents of echinacea are not completely known, cichoric acid from E purpurea and echinacoside from E pallida and E angustifolia, as well as alkamides and polysaccharides, are most often noted as having immune-modulating properties. Most commercial formulations, however, are not standardized for any particular constituent. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Immune modulation—The effect of echinacea on the immune system is controversial. In vivo human studies using commercially marketed formulations of E purpurea have shown increased phagocytosis, total circulating monocytes, neutrophils, and natural killer cells, indicative of general immune modulation. In vitro, a standardized ethanol extract of the aerial (aboveground) parts of E purpurea, known as Echinaforce, inhibited the rise in pro-inflammatory cytokines and interleukins-6 and -8, and also inhibited mucin secretion caused by exposure to rhinovirus type 1A in a 3D tissue model of human airway epithelium. This type of model is intended to mimic what would be seen in vivo. The extract had no effect on cytokine actions. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Anti-inflammatory effects—Certain echinacea constituents have demonstrated anti-inflammatory properties in vitro. Inhibition of cyclooxygenase, 5-lipoxygenase, and hyaluronidase may be involved. In animals, application of E purpurea prior to application of a topical irritant reduced both paw and ear edema. Despite these preclinical findings, randomized, controlled clinical trials involving echinacea for wound healing have not been performed in humans. 3.


Pharmacology_Katzung

Pharmacology_Katzung. Antibacterial, antifungal, antiviral, and antioxidant effects—In vitro studies have reported some antibacterial, anti-fungal, antiviral, and antioxidant activity with echinacea constituents. For example, Echinaforce demonstrated virucidal activity (MIC100 < 1 mcg/mL) against influenza and herpes simplex viruses and bactericidal activity against Streptococcus pyogenes, Haemophilus influenzae, and Legionella pneumophila in human bronchial cells. In vitro, Echinaforce inactivated both avian influenza virus (H5N1, H7N7) and swine-origin influenza virus (H1N1) at doses consistent with recommended oral consumption. The extract blocked key steps (ie, viral hemagglutination activity and neuraminidase activity in vitro) involved in early virus replication and cellular entry. It was less effective against intracellular virus. Newer in vitro research in human skin fibroblasts also suggests bactericidal activity and inhibition of secretion of inflammatory cytokines produced by Propionibacterium


Pharmacology_Katzung

Pharmacology_Katzung. against intracellular virus. Newer in vitro research in human skin fibroblasts also suggests bactericidal activity and inhibition of secretion of inflammatory cytokines produced by Propionibacterium acnes with Echinaforce.


Pharmacology_Katzung

Pharmacology_Katzung. Echinacea is most often used to enhance immune function in individuals who have colds and other respiratory tract infections. Two reviews have assessed the efficacy of echinacea for this primary indication. A review by the Cochrane Collaboration involved 24 randomized, double-blind trials with 33 comparisons of echinacea mono-preparations, which are single-ingredient echinacea preparations, and placebo. Trials were included if they involved echinacea for cold treatment or prevention, where the primary efficacy outcome was cold incidence in prevention trials and duration of symptoms in treatment trials. Overall, the review did not find significant evidence of benefit for echinacea (among all species) in treating colds. Preparations made from the aerial parts of E purpurea plants and prepared as alcoholic extracts or pressed juices were discussed as possibly being preferred to other formulations for cold treatment in adults, but still having a weak overall treatment effect. In


Pharmacology_Katzung

Pharmacology_Katzung. prepared as alcoholic extracts or pressed juices were discussed as possibly being preferred to other formulations for cold treatment in adults, but still having a weak overall treatment effect. In prevention trials, pooling results suggested a small relative risk reduction of 10–20%, but no statistically significant benefit within individual trials.


Pharmacology_Katzung

Pharmacology_Katzung. A separate meta-analysis involving 14 randomized, placebo-controlled trials of echinacea for cold treatment or prevention was published in Lancet. In this review, echinacea decreased the risk of developing clear signs and symptoms of a cold by 58% and decreased symptom duration by 1.25 days. This review, however, was confounded by the inclusion of four clinical trials involving multi-ingredient echinacea preparations, as well as three studies using rhinovirus inoculation versus natural cold development. Echinacea has been used investigationally to enhance hematologic recovery following chemotherapy. It has also been used as an adjunct in the treatment of urinary tract and vaginal fungal infections. These indications require further research before they can be accepted in clinical practice. E purpurea is ineffective in treating recurrent genital herpes.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects with oral commercial formulations are minimal and most often include unpleasant taste, gastrointestinal upset, or allergic reactions (eg, rash). In one large clinical trial, pediatric patients using an oral echinacea product were significantly more likely to develop a rash than those taking placebo. In a small Norwegian mother and child cohort study, 0.5% of women reported taking any formulation of echinacea during early-stage (conception up to pregnancy week 17) or late-stage pregnancy and had no adverse pregnancy outcomes compared to pregnant women who did not use echinacea. Herbal supplements, and particularly those made from alcoholic extracts, should only be used in pregnancy and lactation after consultation with the primary health care provider.


Pharmacology_Katzung

Pharmacology_Katzung. Until the role of echinacea in immune modulation is better defined, this agent should be avoided in patients with immune deficiency disorders (eg, AIDS, cancer) or autoimmune disorders (eg, multiple sclerosis, rheumatoid arthritis). Although there are no well-documented herb-drug interactions for echinacea, in theory, it should also be avoided in persons taking immunosuppressant medications (eg, organ transplant recipients). Co-administration of an echinacea product containing E purpurea and E angustifolia root had no effect on warfarin pharmacodynamics, platelet aggregation, or baseline clotting in healthy subjects. Human studies have shown no effect of varied E purpurea preparations on the pharmacokinetics of lopinavir, ritonavir, etravirine, and darunavir.


Pharmacology_Katzung

Pharmacology_Katzung. It is recommended to follow the dosing on the package label, as there may be variations in dose based on the procedure used in product manufacture. Standardized preparations made from the aerial parts of E purpurea (Echinaforce, Echinaguard) as an alcoholic extract or fresh pressed juice may be preferred in adults for common cold treatment if taken within the first 24 hours of cold symptoms. It should not be used on a continuous basis for longer than 10–14 days.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacologic activity of garlic involves a variety of organosulfur compounds. Dried and powdered formulations contain many of the compounds found in raw garlic and will usually be standardized to allicin or alliin content. Allicin is responsible for the characteristic odor of garlic, and alliin is its chemical precursor. Dried powdered formulations are often enteric-coated to protect the enzyme allinase (the enzyme that converts alliin to allicin) from degradation by stomach acid. Aged garlic extract (AGE) has also been studied in clinical trials but to a lesser degree than dried, powdered garlic (GP). AGE contains no alliin or allicin and is odor-free. Its primary constituents are water-soluble organosulfur compounds, and packages may carry standardization to the compound S-allylcysteine.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Cardiovascular effects—In vitro, allicin and related compounds inhibit HMG-CoA reductase, which is involved in cholesterol biosynthesis (see Chapter 35), and exhibit antioxidant properties. Several clinical trials have investigated the lipid-lowering potential of garlic. The most recent meta-analysis (Ried et al, 2013) involved 39 randomized, double-blind, placebo-controlled trials with approximately 2300 patients. The investigators studied the effect of garlic mono-preparations on lipid parameters and found a moderate and significant reduction in both total serum cholesterol (–17 ±6 mg/dL) and LDL cholesterol (–9 ±6 mg/dL) when garlic was taken for 2 or more months by patients with elevated baseline cholesterol (>200 mg/dL). Subgroup analysis showed a greater effect on cholesterol reduction when AGE preparations were used than when GP preparations were used. While the benefit of garlic in lowering total cholesterol and LDL cholesterol is clinically relevant, optimal prescription


Pharmacology_Katzung

Pharmacology_Katzung. when AGE preparations were used than when GP preparations were used. While the benefit of garlic in lowering total cholesterol and LDL cholesterol is clinically relevant, optimal prescription drug therapy is far more efficacious (see Chapter 35).


Pharmacology_Katzung

Pharmacology_Katzung. Clinical trials report antiplatelet effects (possibly through inhibition of thromboxane synthesis or stimulation of nitric oxide synthesis) following garlic ingestion. A majority of human studies also suggest enhancement of fibrinolytic activity. These effects in combination with antioxidant effects (eg, increased resistance to LDL oxidation) and reductions in total cholesterol might be beneficial in patients with atherosclerosis. A randomized, controlled trial among persons with advanced coronary artery disease who consumed GP for 4 years showed significant reductions in secondary markers (plaque accumulation in the carotid and femoral arteries) as compared with patients on placebo, but primary end points (death, stroke, myocardial infarction) were not assessed. AGE preparations have similarly shown favorable effects in three small (<100 patients) randomized, double-blind, placebo-controlled trials in reducing coronary artery calcification (CAC) progression over 1 year. All trials


Pharmacology_Katzung

Pharmacology_Katzung. shown favorable effects in three small (<100 patients) randomized, double-blind, placebo-controlled trials in reducing coronary artery calcification (CAC) progression over 1 year. All trials involved patients with known coronary artery disease (CAD) or who were considered medium to high risk for CAD at baseline.


Pharmacology_Katzung

Pharmacology_Katzung. Garlic constituents may affect blood vessel elasticity and blood pressure. Several mechanisms have been proposed. Twenty placebo-controlled studies using single-ingredient preparations of GP (13 studies), AGE (5 studies), or other preparations (2 studies) were included in a meta-analysis. Significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were present when all trials were considered. Benefits were most pronounced in subjects with baseline hypertension (mean SBP reduction of 8.6 ±2.2 mm Hg and DBP reduction of 6.1 ±1.3 mm Hg), and no significant effect was observed in subjects who had normal or prehypertensive blood pressures (<140/90 mm Hg) at baseline. A Cochrane review on the effect of garlic monotherapy for prevention of cardiovascular morbidity and mortality in hypertensive patients also identified a significant reduction in systolic and diastolic pressure compared with placebo. A separate Cochrane review of the effect of garlic on


Pharmacology_Katzung

Pharmacology_Katzung. and mortality in hypertensive patients also identified a significant reduction in systolic and diastolic pressure compared with placebo. A separate Cochrane review of the effect of garlic on peripheral occlusive disease found insufficient support for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Endocrine effects—The effect of garlic on glucose homeostasis does not appear to be significant in persons with diabetes. Certain organosulfur constituents in garlic, however, have demonstrated hypoglycemic effects in nondiabetic animal models. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Antimicrobial effects—The antimicrobial effect of garlic has not been extensively studied in clinical trials. Allicin has been reported to have in vitro activity against some gram-positive and gram-negative bacteria as well as fungi (Candida albicans), protozoa (Entamoeba histolytica), and certain viruses. The primary mechanism involves the inhibition of thiol-containing enzymes needed by these microbes. A Cochrane review studying the effect of garlic on cold prevention and treatment found a significant reduction in total number of colds using a garlic supplement (with 180 mg allicin content) once daily for 12 weeks. Limited conclusions can be drawn regarding the effects observed, however, because only one trial met inclusion criteria. Given the availability of safe and effective prescription antimicrobials, the usefulness of garlic in this area appears limited.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Antineoplastic effects—In rodent studies, garlic inhibits procarcinogens for colon, esophageal, lung, breast, and stomach cancer, possibly by detoxification of carcinogens and reduced carcinogen activation. Several epidemiologic case-control studies demonstrate a reduced incidence of stomach, esophageal, and colorectal cancers in persons with high dietary garlic consumption. Current anticancer studies are focused on specific organosulfur garlic compounds in in vivo animal models of cancer and in vitro effects on human cancer cell lines. Following oral ingestion, adverse effects of garlic products may include nausea (6%), hypotension (1.3%), allergy (1.1%), and bleeding (rare). Breath and body odor have been reported with an incidence of 20–40% at recommended doses using enteric-coated powdered garlic formulations. Contact dermatitis may occur with the handling of raw garlic.


Pharmacology_Katzung

Pharmacology_Katzung. Because of reported antiplatelet effects, patients using anticlotting medications (eg, warfarin, aspirin, ibuprofen) should use garlic cautiously. Additional monitoring of blood pressure and signs and symptoms of bleeding is warranted. Garlic may reduce the bioavailability of saquinavir, an antiviral protease inhibitor, but it does not appear to affect the bioavailability of ritonavir. Dried, powdered garlic products should be standardized to contain 1.3% alliin (the allicin precursor) or have an allicingenerating potential of 0.6%. Enteric-coated formulations are recommended to minimize degradation of the active substances. A daily dose of 600–900 mg/d of powdered garlic is most common. This is equivalent to one clove of raw garlic (2–4 g) per day. A garlic bulb can contain up to 1.8% alliin. Doses of AGE most often range from 600 to 1800 mg/d, but doses up to 7200 mg daily have been safely used in clinical trials for up to 6 months.


Pharmacology_Katzung

Pharmacology_Katzung. Ginkgo biloba extract is prepared from the leaves of the ginkgo tree. The most common formulation is prepared by concentrating 50 parts of the crude leaf to prepare one part of extract. The active constituents in ginkgo are flavone glycosides and terpenoids including ginkgolides A, B, C, and J, and bilobalide. 1. Cardiovascular effects—In animal models and some human studies, ginkgo has been shown to increase blood flow, reduce blood viscosity, and promote vasodilation, thus enhancing tissue perfusion. Enhancement of endogenous nitric oxide effects (see Chapter 19) and antagonism of platelet-activating factor have been observed in animal models.


Pharmacology_Katzung

Pharmacology_Katzung. Ginkgo biloba has been studied for its effects on mild to moderate occlusive peripheral arterial disease. Among 11 randomized, placebo-controlled studies involving 477 participants using standardized ginkgo leaf extract (EGb761) for up to 6 months, a nonsignificant trend toward improvements in pain-free walking distance (increase of 64.5 meters) was observed (P = .06). The authors concluded that the standardized extract lacked benefit for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. The Ginkgo Evaluation of Memory (GEM) study and the recently published GuidAge study evaluated cardiovascular outcomes as well as incidence and mean time to Alzheimer’s dementia associated with the long-term use of ginkgo for 5–6 years in approximately 3000 elderly (age ≥70) adults with normal cognition or mild cognitive impairment. Daily use of 240 mg/d EGb761 did not affect the incidence of hypertension or reduce blood pressure among persons with hypertension or prehypertension. No significant effects in cardiovascular disease mortality, ischemic stroke or events, or hemorrhagic stroke were observed. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Metabolic effects—Antioxidant and radical-scavenging properties have been observed for the flavonoid fraction of ginkgo as well as some of the terpene constituents. In vitro, ginkgo has been reported to have superoxide dismutase-like activity and superoxide anionand hydroxyl radical-scavenging properties. The flavonoid fraction has also been observed to have antiapoptotic properties. In some studies, it has also demonstrated a protective effect in limiting free radical formation in animal models of ischemic injury and in reducing markers of oxidative stress in patients undergoing coronary artery bypass surgery. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Central nervous system effects—In aged animal models, chronic administration of ginkgo for 3–4 weeks led to modifications in central nervous system receptors and neurotransmitters. Receptor densities increased for muscarinic, α2, and 5-HT1a receptors, and decreased for β adrenoceptors. Increased serum levels of acetylcholine and norepinephrine and enhanced synaptosomal reuptake of serotonin and dopamine have also been reported. Additional possible effects include inhibition of amyloid-beta fibril formation and protective effects of Egb761 on hippocampal neurons against cell death induced by beta-amyloid.


Pharmacology_Katzung

Pharmacology_Katzung. Ginkgo has been used to treat cerebral insufficiency and dementia of the Alzheimer type. The term cerebral insufficiency, however, includes a variety of manifestations ranging from poor concentration and confusion to anxiety and depression as well as physical complaints such as hearing loss and headache. For this reason, studies evaluating cerebral insufficiency tend to be more inclusive and difficult to assess than trials evaluating dementia. A meta-analysis of ginkgo for cognitive impairment or dementia was performed by the Cochrane Collaboration. They reviewed 36 randomized, double-blind, placebo-controlled trials ranging in length from 3 to 52 weeks. Significant improvements in cognition and activities of daily living were observed at 12 but not 24 weeks. Significant improvements in clinical global assessment however, were observed at 24 but not 12 weeks. The authors concluded that the effects of ginkgo in the treatment of cognitive impairment and dementia were unpredictable and


Pharmacology_Katzung

Pharmacology_Katzung. clinical global assessment however, were observed at 24 but not 12 weeks. The authors concluded that the effects of ginkgo in the treatment of cognitive impairment and dementia were unpredictable and unlikely to be clinically relevant. However, recent meta-analyses of randomized controlled trials, 22–26 weeks in duration, using EGb761 that limited inclusion criteria to patients with dementia of the Alzheimer type (in eight studies), vascular or mixed dementia type (in six studies), or dementia with neuropsychiatric features (in four studies) showed favorable results. Significant improvements in cognition and activities of daily living were observed for ginkgo compared to placebo. Clinical global assessment of improvement also was significantly improved when EGb761 doses of 240 mg/d were used, but not doses of 120 mg/d. Because of the stricter inclusion criteria used, the overall methodologic quality of the studies was higher than that of the Cochrane review, when determining a benefit


Pharmacology_Katzung

Pharmacology_Katzung. but not doses of 120 mg/d. Because of the stricter inclusion criteria used, the overall methodologic quality of the studies was higher than that of the Cochrane review, when determining a benefit in patients with dementia. This suggests that patients with a diagnosis of dementia are more likely to benefit than patients with more mild cognitive impairment. In the GEM and GuidAge studies that included persons with normal or mild cognitive impairment, the effects of ginkgo as a prophylactic agent to prevent progression to dementia were assessed. No benefit was observed with 5–6 years of ginkgo treatment.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Miscellaneous effects—Ginkgo has been studied for its effects in schizophrenia, tardive dyskinesia, allergic and asthmatic bronchoconstriction, short-term memory in healthy, nondemented adults, erectile dysfunction, tinnitus and hearing loss, and macular degeneration. Preliminary data from eight randomized, double-blind, placebo-controlled trials suggest that EGb761 can significantly reduce the symptoms of chronic schizophrenia when used in combination with standard treatment (eg, clozapine, haloperidol, olanzapine). These trials were conducted in China, so firm conclusions about benefit in a broader population are lacking. There is insufficient evidence to warrant clinical use for the other conditions listed.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of ginkgo have been reported with a frequency comparable to that of placebo. These include nausea, headache, stomach upset, diarrhea, allergy, anxiety, and insomnia. A few case reports noted bleeding complications in patients using ginkgo. In some of these cases, the patients were also using either aspirin or warfarin.


Pharmacology_Katzung

Pharmacology_Katzung. Ginkgo may have antiplatelet properties and should not be used in combination with antiplatelet or anticoagulant medications. Other single case reports noted virologic failure when ginkgo was combined with efavirenz, sedation when combined with trazodone, priapism when combined with risperidone, and seizure when combined with valproic acid and phenytoin; all warrant further pharmacokinetic studies before firm conclusions can be drawn. Seizures have been reported as a toxic effect of ginkgo, most likely related to seed contamination in the leaf formulations. Uncooked ginkgo seeds are epileptogenic due to the presence of ginkgotoxin. Ginkgo formulations should be avoided in individuals with preexisting seizure disorders.


Pharmacology_Katzung

Pharmacology_Katzung. Ginkgo biloba dried leaf extract is usually standardized to contain 24% flavone glycosides and 6% terpene lactones. The daily dose most commonly studied and associated with a benefit in clinical trials of dementia is 240 mg daily of the dried extract in two divided doses. Ginseng may be derived from any of several species of the genus Panax. Of these, crude preparations or extracts of Panax ginseng, the Chinese or Korean variety, and P quinquefolium, the American variety, are most often available to consumers in the United States. The active principles appear to be the triterpenoid saponin glycosides called ginsenosides or panaxosides, of which there are approximately 30 different types. It is recommended that commercial P ginseng formulations be standardized to contain 4–10% ginsenosides.


Pharmacology_Katzung

Pharmacology_Katzung. Other plant materials are commonly sold under the name ginseng but are not from Panax species. These include Siberian ginseng (Eleutherococcus senticosus) and Brazilian ginseng (Pfaffia paniculata). Of these, Siberian ginseng may be more widely available in the USA. Siberian ginseng contains eleutherosides but no ginsenosides. Currently, there is no recommended standardization for eleutheroside content in Siberian ginseng products.


Pharmacology_Katzung

Pharmacology_Katzung. An extensive literature exists on the potential pharmacologic effects of ginsenosides. Unfortunately, the studies differ widely in the species of Panax used, the ginsenosides studied, the degree of purification applied to the extracts, the animal species studied, the doses or concentrations involved, and the measurements used to evaluate the responses. Reported beneficial pharmacologic effects include modulation of immune function (induced mRNA expression for interleukins-2 and -1α, interferon-γ, and granulocytemacrophage colony-stimulating factor; activated B and T cells, natural killer cells, and macrophages). Central nervous system effects included increased proliferating ability of neural progenitors and increased central levels of acetylcholine, serotonin, nor-epinephrine, and dopamine in the cerebral cortex. Miscellaneous effects included antioxidant activity; anti-inflammatory effects (inhibited tumor necrosis factor-α, interleukin-1β, and vascular and intracellular cell


Pharmacology_Katzung

Pharmacology_Katzung. dopamine in the cerebral cortex. Miscellaneous effects included antioxidant activity; anti-inflammatory effects (inhibited tumor necrosis factor-α, interleukin-1β, and vascular and intracellular cell adhesion molecules); antistress activity (ie, stimulated pituitary-adrenocortical system, agonist at glucocorticoid receptor); analgesia (inhibited substance P); vasoregulatory effects (increased endothelial nitric oxide, inhibited prostacyclin production); cardioprotective activity (reduced ventricular remodeling and cardiac hypertrophy in animal models of myocardial ischemia); antiplatelet activity; improved glucose homeostasis (reduced cell death in pancreatic beta cells; increased insulin release, number of insulin receptors, and insulin sensitivity); and anticancer properties (reduced tumor angiogenesis, increased tumor cell apoptosis). Such extensive claims naturally evoke skepticism and require careful replication.


Pharmacology_Katzung

Pharmacology_Katzung. Ginseng is most often claimed to help improve physical and mental performance or to function as an “adaptogen,” an agent that helps the body to return to normal when exposed to stressful or noxious stimuli. However, the clinical trials evaluating ginseng for these indications have shown few, if any, benefits. Some randomized controlled trials evaluating “quality of life” and “cognition” have claimed significant benefits in some subscale measures of behavior, cognitive function, or quality of life but rarely in overall composite scores using P ginseng. Better results have been observed with P quinquefolium and P ginseng in lowering postprandial glucose indices in subjects with and without diabetes. This was the subject of a systematic review in which 15 studies (13 randomized and 2 nonrandomized) were evaluated. Nine of the studies reported significant reductions in blood glucose. Some randomized, placebo-controlled trials have reported immunomodulating benefits of P quinquefolium and


Pharmacology_Katzung

Pharmacology_Katzung. were evaluated. Nine of the studies reported significant reductions in blood glucose. Some randomized, placebo-controlled trials have reported immunomodulating benefits of P quinquefolium and P ginseng in preventing upper respiratory tract infections. Use of ginseng for 2–4 months in healthy seniors may reduce the risk of acquiring the common cold as well as the duration of symptoms. Because of heterogeneity in these trials, however, the findings are insufficient to warrant a recommendation of ginseng for cold prevention. To assess effects on cardiovascular health, a systematic review and meta-analysis of 17 randomized controlled trials involving predominantly P ginseng (12 studies) and P quinquefolium (5 studies) species in persons with and without hypertension was performed. Over a mean time period of 9 weeks, no significant effect was observed of ginseng on SBP, DBP, and mean arterial pressure compared with controls. Finally, two case-control studies and a cohort study suggest a


Pharmacology_Katzung

Pharmacology_Katzung. time period of 9 weeks, no significant effect was observed of ginseng on SBP, DBP, and mean arterial pressure compared with controls. Finally, two case-control studies and a cohort study suggest a non-organ-specific cancer-preventive effect with longterm administration of P ginseng. Significant benefits in some cancer-related fatigue symptoms have been observed in both a dose-finding study and a multisite, double-blind, randomized trial using P quinquefolium, 2 g daily, versus placebo over a 2-month period. In summary, the strongest support for use of P ginseng or P quinquefolium currently relates to its effects in cold prevention, lowering postprandial glucose, nonspecific cancer prevention, and alleviating cancer-related fatigue.


Pharmacology_Katzung

Pharmacology_Katzung. Vaginal bleeding and mastalgia have been described in case reports, suggesting possible estrogenic effects. Central nervous system stimulation (eg, insomnia, nervousness) and hypertension have been reported in patients using high doses (>3 g/d) of P ginseng. Methylxanthines found in the ginseng plant may contribute to this effect. Vasoregulatory effects have not been found to be clinically significant.


Pharmacology_Katzung

Pharmacology_Katzung. Irritability, sleeplessness, and manic behavior have been reported in psychiatric patients using ginseng in combination with other medications (phenelzine, lithium, neuroleptics). Ginseng should be used cautiously in patients taking any psychiatric, estrogenic, or hypoglycemic medications. Ginseng has antiplatelet properties and should not be used in combination with warfarin. Cytokine stimulation has been claimed for both P ginseng and P quinquefolium in vitro and in animal models. In a randomized, double-blind, placebo-controlled study, P ginseng significantly increased natural killer cell activity versus placebo with 8 and 12 weeks of use. Immunocompromised individuals, those taking immune stimulants, and those with autoimmune disorders should use ginseng products with caution.


Pharmacology_Katzung

Pharmacology_Katzung. A dose of 1–2 g/d of the crude P ginseng root or its equivalent is considered standard dosage. Two hundred milligrams of standardized P ginseng extract are equivalent to 1 g of the crude root. The trademarked preparation Ginsana has been used as a standardized extract in some clinical trials and is available in the USA. The fruit and seeds of the milk thistle plant contain a lipophilic mixture of flavonolignans known as silymarin. Silymarin comprises 2–3% of the dried herb and is composed of three primary isomers: silybin (also known as silybinin or silibinin), silychristin (silichristin), and silydianin (silidianin). Silybin is the most prevalent and potent of the three isomers and accounts for 50–70% of the silymarin complex. Products should be standardized to contain 70–80% silymarin.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Liver disease—In animal models, milk thistle purportedly limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo studies indicate that silymarin reduces lipid per-oxidation, scavenges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry.


Pharmacology_Katzung

Pharmacology_Katzung. Milk thistle appears to have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase activity and reduces leukotriene formation. Inhibition of leukocyte migration has been observed in vivo and may be a factor when acute inflammation is present. Silymarin inhibits nuclear factor kappa B (NF-κB), an inflammatory response mediator. One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme’s activity, enhanced protein synthesis and cellular regeneration might occur in healthy but not malignant cells. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the fibrogenic cytokine transforming growth factor-β. If confirmed, milk thistle may have a role in the treatment of hepatic fibrosis.


Pharmacology_Katzung

Pharmacology_Katzung. In animal models, silymarin has a dose-dependent stimulatory effect on bile flow that could be beneficial in cases of cholestasis. To date, however, there is insufficient evidence to warrant the use of milk thistle for these indications. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Chemotherapeutic effects—Preliminary in vitro and animal studies of the effects of silymarin and silybinin have been carried out with several cancer cell lines. In murine models of skin cancer, silybinin and silymarin were said to reduce tumor initiation and promotion. Induction of apoptosis has also been reported using silymarin in a variety of malignant human cell lines (eg, melanoma, prostate, colon, leukemia cells, bladder transitional-cell papilloma cells, cervical and hepatoma cells). Inhibition of cell growth and proliferation by inducing a G1 cell cycle arrest has also been claimed in cultured human breast and prostate cancer cell lines. The use of milk thistle in the clinical treatment of cancer has not yet been adequately studied but preliminary trials in patients undergoing chemotherapy show that it may improve liver function (ie, reduced liver transaminase concentrations in blood). There are insufficient data to support use in patients with cancer. The antioxidant


Pharmacology_Katzung

Pharmacology_Katzung. chemotherapy show that it may improve liver function (ie, reduced liver transaminase concentrations in blood). There are insufficient data to support use in patients with cancer. The antioxidant potential of milk thistle should be taken into consideration prior to administration with chemotherapeutic agents that may be affected by antioxidant compounds.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Lactation—Historically, milk thistle has been used by herbalists and midwives to induce lactation in pregnant or postpartum women. In female rats, milk thistle increases prolactin production. As such, it is possible that it could have an effect on human breast milk production. Clinical trial data are lacking, however, for this indication, as are safety data on nursing mothers and infants. Until further data become available, milk thistle should not be used for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. Oral milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. A systematic review of 13 randomized trials involving 915 patients with alcoholic liver disease or hepatitis B or C found no significant reductions in all-cause mortality, liver histopathology, or complications of liver disease with 6 months of use. A significant reduction in liver-related mortality was claimed using the data from all the surveyed trials, but not when the data were limited to trials of better design and controls. It was concluded that the effects of oral milk thistle in improving liver function or mortality from liver disease are currently poorly substantiated. A recent multicenter, double-blind, placebo-controlled clinical trial in patients with hepatitis C refractory to interferon treatment failed to show a benefit with 24 weeks of milk thistle, 420 mg/d and 700 mg/d, on reduction of serum alanine aminotransferase


Pharmacology_Katzung

Pharmacology_Katzung. trial in patients with hepatitis C refractory to interferon treatment failed to show a benefit with 24 weeks of milk thistle, 420 mg/d and 700 mg/d, on reduction of serum alanine aminotransferase levels. Milk thistle also had no effect on mean serum hepatitis C virus (HCV) RNA levels at 24 weeks. In contrast, the intravenous use of silybinin succinate has shown some benefit in reducing HCV RNA levels and alanine aminotransferase levels in patients with treatment-resistant hepatitis C infection. Prospective pilot studies have also shown benefits with intravenous silybinin before and after liver transplantation treatment in patients with HCV cirrhosis. Potent antiviral activity was demonstrated with significant reductions in HCV-RNA levels during treatment compared to placebo or nontreated controls when given for at least 14 days before transplantation and 7 days after liver transplantation. HCV-RNA relapsed, however, after silibinin withdrawal. This suggests that formulation and poor


Pharmacology_Katzung

Pharmacology_Katzung. controls when given for at least 14 days before transplantation and 7 days after liver transplantation. HCV-RNA relapsed, however, after silibinin withdrawal. This suggests that formulation and poor oral bioavailability may influence treatment outcomes.


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Pharmacology_Katzung. Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, intravenous silybinin is marketed and used in Europe (Legalon SIL) as an antidote in Amanita phalloides mushroom poisoning. This use is based on favorable outcomes reported in case-control studies. Milk thistle has rarely been reported to cause adverse effects when used at recommended doses. In clinical trials, the incidence of adverse effects (eg, gastrointestinal upset, dermatologic, headaches) was comparable to that of placebo. At high doses (>1500 mg), it can have a laxative effect caused by stimulation of bile flow and secretion. Drug Interactions, Precautions, & Dosage


Pharmacology_Katzung

Pharmacology_Katzung. Drug Interactions, Precautions, & Dosage Milk thistle does not significantly alter the pharmacokinetics of other drugs transported by the P-glycoprotein transporter or metabolized by cytochrome enzymes. In a recent review, the impact of the herb was listed as “posing no risk for drug interactions in humans.” Recommended oral dosage is 280–420 mg/d, calculated as silybin, in three divided doses. ST. JOHN’S WORT (HYPERICUM PERFORATUM) St. John’s wort, also known as hypericum, contains a variety of constituents that might contribute to its claimed pharmacologic activity in the treatment of depression. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved. Commercial formulations are usually prepared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Antidepressant action—The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical β adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2) in a rodent model. Other effects observed in vitro include sigma receptor binding using the hypericin fraction and GABA receptor binding using the commercial extract. Interleukin-6 production is also reduced in the presence of the extract. a.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical trials for depression—The most recent systematic review and meta-analysis involved 29 randomized, double-blind, controlled trials (18 compared St. John’s wort with placebo, 5 with tricyclic antidepressants, and 12 with selective serotonin reuptake inhibitors [SSRIs]). Only studies meeting defined classification criteria for major depression were included. St. John’s wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate major depressive disorder but with fewer side effects. Most trials used 900 mg/d of St. John’s wort for 4–12 weeks. Depression severity was mild to moderate in 19 trials, moderate to severe in 9 trials, and not stated in 1 trial. In a longer but uncontrolled trial, the use of the herb for up to 52 weeks was reported to reduce depression scores in patients with mild to moderate major depression. These data and the mechanism of action data reported above suggest a


Pharmacology_Katzung

Pharmacology_Katzung. use of the herb for up to 52 weeks was reported to reduce depression scores in patients with mild to moderate major depression. These data and the mechanism of action data reported above suggest a potential role for St. John’s wort in relieving symptoms of mild to moderate major depression. Due to the short study duration of these clinical trials, efficacy beyond 12 weeks still requires further study.


Pharmacology_Katzung

Pharmacology_Katzung. b. Other mood-related conditions—St. John’s wort has been studied for several other indications related to mood, including premenstrual dysphoric disorder, climacteric complaints, somatoform disorders, and anxiety. For most of these indications, studies are too few in number to draw any firm conclusions regarding efficacy. Evidence for climacteric complaints was the subject of a recent meta-analysis. Six trials were included where two used mono-preparations of St. John’s wort and four used combinations of St. John’s wort and black cohosh, Cimicifuga racemose (note black cohosh warning in Table 64-1). St. John’s wort significantly reduced hot flashes (severity, duration, and frequency) compared to placebo when used for up to 16 weeks. Heterogeneity in these trials limits drawing firm conclusions on efficacy for this indication.


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Pharmacology_Katzung. 2. Antiviral and anticarcinogenic effects—The hypericin constituent of St. John’s wort is photolabile and can be activated by exposure to certain wavelengths of visible or ultraviolet A light.


Pharmacology_Katzung

Pharmacology_Katzung. Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given intravenously) and basal and squamous cell carcinoma (given by intralesional injection). In vitro, photoactivated hypericin inhibits a variety of enveloped and nonenveloped viruses as well as the growth of some neoplastic cells. Inhibition of protein kinase C and inhibition of singlet oxygen radical generation have been proposed as possible mechanisms. The latter could inhibit cell growth or cause cell apoptosis. These studies were carried out using the isolated hypericin constituent of St. John’s wort; the usual hydroalcoholic extract of St. John’s wort has not been studied for these indications and should not be recommended for patients with viral illness or cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Photosensitization is related to the hypericin and pseudohypericin constituents in St. John’s wort. Consumers should be instructed to wear sunscreen and eye protection while using this product when exposed to the sun. Rarely, mild gastrointestinal symptoms, fatigue, sedation, restlessness, dizziness, headache, and dry mouth have been observed. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John’s wort. When compared to SSRIs, St. John’s wort appears to be better tolerated when used to support medical treatment of major depression.


Pharmacology_Katzung

Pharmacology_Katzung. Inhibition of reuptake of various amine transmitters has been highlighted as a potential mechanism of action for St. John’s wort. Drugs with similar mechanisms (ie, antidepressants, stimulants) should be used cautiously or avoided in patients using St. John’s wort due to the risk of serotonin syndrome (see Chapters 16 and 30). The hyperforin constituent of St. John’s wort has been shown to activate the pregnane X receptor (PXR), which ultimately leads to many drug interactions by inducing hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein drug transporter. Another constituent, hypericin, which may not be present in all commercial formulations, does not have any effect on PXR, CYP, or P-glycoprotein. Case reports involving the use of St. John’s wort have suggested the herb resulted in subtherapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV protease and nonnucleoside reverse transcriptase inhibitors, warfarin,


Pharmacology_Katzung

Pharmacology_Katzung. in subtherapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV protease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants. Without knowing which constituent is present in a St. John’s wort formulation, indiscriminate combined use with other medicines should be avoided.


Pharmacology_Katzung

Pharmacology_Katzung. The most common commercial formulation of St. John’s wort is the dried hydroalcoholic extract. Products should be standardized to 2–5% hyperforin, although most still bear the older standardized marker of 0.3% hypericin. The recommended dosing for mild to moderate depression is 900 mg of the dried extract per day in three divided doses. Onset of effect may take 2–4 weeks. Longterm benefits beyond 12 weeks have not been studied. The active constituents in saw palmetto berries are not well defined. Phytosterols (eg, β-sitosterol), aliphatic alcohols, polyprenic compounds, and flavonoids are all present. Marketed preparations are dried lipophilic extracts that are generally standardized to contain 85–95% fatty acids and sterols.


Pharmacology_Katzung

Pharmacology_Katzung. Saw palmetto is most often promoted for the treatment of benign prostatic hyperplasia (BPH). Enzymatic conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase is inhibited by saw palmetto in vitro. Specifically, saw palmetto shows a noncompetitive inhibition of isoforms I and II of this enzyme, thereby reducing DHT production. In vitro, saw palmetto also inhibits the binding of DHT to androgen receptors. Additional effects observed in vitro include inhibition of prostatic growth factors, blockade of α1 adrenoceptors, and inhibition of inflammatory mediators produced by the 5-lipoxygenase pathway.


Pharmacology_Katzung

Pharmacology_Katzung. The clinical pharmacology of saw palmetto in humans is not well defined. One week of treatment in healthy volunteers failed to influence 5α-reductase activity, DHT concentration, or testosterone concentration. Six months of treatment in patients with BPH also failed to affect prostate-specific antigen (PSA) levels, a marker that is typically reduced by enzymatic inhibition of 5α-reductase. In contrast, other researchers have reported a reduction in epidermal growth factor, DHT levels, and antagonist activity at the nuclear estrogen receptor in the prostate after 3 months of treatment with saw palmetto in patients with BPH. Recent reports suggest that daily saw palmetto, as compared to daily tamsulosin (see Chapter 10), has greater anti-inflammatory activity on infiltrating prostatic cells in men with BPH-related lower urinary tract symptoms at 3 months. The anti-inflammatory effects on infiltrating prostatic cells may serve as a link between hormonal changes and the remodeling process


Pharmacology_Katzung

Pharmacology_Katzung. in men with BPH-related lower urinary tract symptoms at 3 months. The anti-inflammatory effects on infiltrating prostatic cells may serve as a link between hormonal changes and the remodeling process promoted by growth factors. The anti-inflammatory effects of saw palmetto also raise questions as to the value of early initiation of BPH therapy as well as the value of early combination therapy with 5α-reductase inhibitors (see Chapter 40).


Pharmacology_Katzung

Pharmacology_Katzung. The most recent review involved 32 randomized controlled trials in 5666 men with symptoms consistent with BPH. Seventeen trials compared saw palmetto monotherapy with placebo and found no significant improvement in most urologic symptoms (eg, international prostate symptom scores, peak flow, prostate size). Adverse effects are reported with an incidence of 1–3%. The most common include abdominal pain, nausea, diarrhea, fatigue, headache, decreased libido, and rhinitis. Saw palmetto has been associated with a few rare case reports of pancreatitis, liver damage, and increased bleeding risk, but due to confounding factors, causality remains uncertain. In comparison to tamsulosin and finasteride, saw palmetto was claimed to be less likely to affect sexual function (eg, ejaculation). Drug Interactions, Precautions, & Dosage


Pharmacology_Katzung

Pharmacology_Katzung. Drug Interactions, Precautions, & Dosage No drug-drug interactions have been reported for saw palmetto. Because saw palmetto has no effect on the PSA marker, it will not interfere with prostate cancer screening using this test. Recommended dosage of a standardized dried extract (containing 85–95% fatty acids and sterols) is 160 mg orally twice daily. The lack of positive results as noted in the review of randomized controlled studies cited above indicates that the use of saw palmetto in prostate disease cannot be recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Coenzyme Q10, also known as CoQ, CoQ10, and ubiquinone, is found in the mitochondria of many organs, including the heart, kidney, liver, and skeletal muscle. After ingestion, the reduced form of coenzyme Q10, ubiquinol, predominates in the systemic circulation. Coenzyme Q10 is a potent antioxidant and has been heavily promoted for this reason. It may have a role in maintaining healthy muscle function, although the clinical significance of this effect is unknown. Reduced serum levels have been reported in Parkinson’s disease. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Hypertension—In clinical trials, small but significant reductions in systolic and diastolic blood pressure were reported after 8–10 weeks of coenzyme Q10 supplementation. The exact mechanism is unknown but might be related to the antioxidant and vasodilating properties of coenzyme Q10. In three randomized, placebo-controlled trials, coenzyme Q10 was reported to significantly lower systolic and diastolic blood pressure by 11 mm Hg and 7 mm Hg, respectively, compared with no change in the placebo groups. However, an exaggerated treatment effect may have occurred as adequate randomization, blinding, and concealment of allocation have been questioned for these studies. Whether coenzyme Q10 can be used to lower blood pressure remains unclear. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Heart failure—Low endogenous coenzyme Q10 levels have been associated with worse heart failure outcomes, but this association is likely because low levels are a marker for more advanced heart failure, rather than a predictor of disease. Despite these findings, coenzyme Q10 is often advocated to improve heart muscle function in patients with heart failure. According to the most recent meta-analysis, coenzyme Q10 was shown to improve ejection fraction by 3.7% when used short term (2–28 weeks). It is unclear whether improvements in ejection fraction are applicable to all patients with heart failure, including those receiving the current standard of care for heart failure management. More research is required to assess the role of coenzyme Q10 in heart failure and its impact on disease severity, particularly with concomitant prescription medications. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Ischemic heart disease—The effects of coenzyme Q10 on coronary artery disease and chronic stable angina are modest but appear promising. A theoretical basis for such benefit could be metabolic protection of the ischemic myocardium by reducing proinflammatory markers (including interleukin-6 and C-reactive protein) that contribute to oxidative stress. Double-blind, placebo-controlled trials have suggested that coenzyme Q10 supplementation improved a number of clinical measures in patients with a history of acute myocardial infarction (AMI). Improvements have been observed in lipoprotein (a), high-density lipoprotein cholesterol, exercise tolerance, and time to development of ischemic changes on the electrocardiogram during stress tests. In addition, very small reductions in cardiac deaths and rate of reinfarction in patients with previous AMI have been reported (absolute risk reduction 1.5%). 4.


Pharmacology_Katzung

Pharmacology_Katzung. Prevention of statin-induced myopathy—Statins reduce cholesterol by inhibiting the HMG-CoA reductase enzyme (see Chapter 35). This enzyme is also required for synthesis of coenzyme Q10. Initiating statin therapy has been shown to reduce endogenous coenzyme Q10 levels, which may block steps in muscle cell energy generation, possibly leading to statin-related myopathy. It is unknown whether a reduction in intramuscular coenzyme Q10 levels leads to statin myopathy or if the myopathy causes cellular damage that reduces intramuscular coenzyme Q10 levels. A meta-analysis evaluating the effect of coenzyme Q10 on statin-induced myopathy as measured by muscle pain and plasma creatine kinase activity found that coenzyme Q10 supplementation (30 days to 3 months) did not demonstrate any benefit in reducing myopathy. More information is needed to determine which patients, if any, with statin-related myopathy might benefit from coenzyme Q10 supplementation, especially as it relates to the specific


Pharmacology_Katzung

Pharmacology_Katzung. myopathy. More information is needed to determine which patients, if any, with statin-related myopathy might benefit from coenzyme Q10 supplementation, especially as it relates to the specific statin, the dose, and the duration of therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Coenzyme Q10 is well tolerated, rarely leading to any adverse effects at doses as high as 3000 mg/d. In clinical trials, gastrointestinal upset, including diarrhea, nausea, heartburn, and anorexia, has been reported with an incidence of less than 1%. Cases of maculopapular rash and thrombocytopenia have very rarely been observed. Other rare adverse effects include irritability, dizziness, and headache. Coenzyme Q10 shares a structural similarity with vitamin K, and an interaction has been observed between coenzyme Q10 and warfarin. Coenzyme Q10 supplements may decrease the effects of warfarin therapy. This combination should be avoided or very carefully monitored. As a dietary supplement, 30 mg/d of coenzyme Q10 is adequate to replace low endogenous levels. For cardiac effects, typical dosages are 100–600 mg/d given in two or three divided doses. These doses increase endogenous levels to 2–3 mcg/mL (normal for healthy adults, 0.7–1 mcg/mL).


Pharmacology_Katzung

Pharmacology_Katzung. Glucosamine is found in human tissue, is a substrate for the production of articular cartilage, and serves as a cartilage nutrient. Glucosamine is commercially derived from crabs and other crustaceans. As a dietary supplement, glucosamine is primarily used for pain associated with knee osteoarthritis. Sulfate and hydrochloride forms are available, but recent research has shown the hydrochloride form to be ineffective. Endogenous glucosamine is used for the production of glycosaminoglycans and other proteoglycans in articular cartilage. In osteoarthritis, the rate of production of new cartilage is exceeded by the rate of degradation of existing cartilage. Supplementation with glucosamine is thought to increase the supply of the necessary glycosaminoglycan building blocks, leading to better maintenance and strengthening of existing cartilage.


Pharmacology_Katzung

Pharmacology_Katzung. Many clinical trials have been conducted on the effects of both oral and intra-articular administration of glucosamine. Early studies reported significant improvements in overall mobility, range of motion, and strength in patients with osteoarthritis. More recent studies have reported mixed results, with both positive and negative outcomes. One of the largest and best-designed clinical trials, which compared glucosamine, chondroitin sulfate, the combination, celecoxib, and placebo, found no benefit for glucosamine therapy in mild to moderate disease. Unfortunately the investigators studied the glucosamine hydrochloride formulation, which has been shown to be inferior to the sulfate formulation. The formulation of glucosamine appears to play a critical role with regard to efficacy, and this may be a factor contributing to the variability observed across published studies. Research suggests that use of a crystalline formulation of glucosamine sulfate leads to less pain, functional


Pharmacology_Katzung

Pharmacology_Katzung. this may be a factor contributing to the variability observed across published studies. Research suggests that use of a crystalline formulation of glucosamine sulfate leads to less pain, functional improvements in knee osteoarthritis, and an improvement in joint space narrowing at 3 years. Currently, national orthopedic and rheumatic societies do not recommend glucosamine for knee osteoarthritis primarily because of formulation variability and study heterogeneity. More research is needed to better define the ideal glucosamine formulation and patient populations that stand to benefit from glucosamine sulfate.


Pharmacology_Katzung

Pharmacology_Katzung. Oral glucosamine sulfate is very well tolerated. In clinical trials, mild diarrhea, abdominal cramping, and nausea were occasionally reported. Cross-allergenicity in people with shellfish allergies is a potential concern; however, this is unlikely if the formulation has been properly manufactured and purified. Glucosamine sulfate may increase the international normalized ratio (INR) in patients taking warfarin, increasing the risk for bruising and bleeding. The mechanism is not well understood and may be dose-related as increases in INR have occurred when the glucosamine dose was increased. Until more is known, the combination should be avoided or very carefully monitored. The oral dosage used most often in clinical trials is 500 mg three times daily or 1500 mg once daily. Glucosamine does not have direct analgesic effects, and improvements in function, if any, may not be observed for 1–2 months.


Pharmacology_Katzung

Pharmacology_Katzung. Melatonin, a serotonin derivative produced by the pineal gland and some other tissues (see also Chapter 16), is believed to be responsible for regulating sleep-wake cycles. Release coincides with darkness; it typically begins around 9 pm and lasts until about 4 am. Melatonin release is suppressed by daylight. Melatonin has also been studied for a number of other functions, including contraception, protection against endogenous oxidants, prevention of aging, treatment of depression, HIV infection, and a variety of cancers. Currently, melatonin is most often used to prevent jet lag and to induce sleep. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Jet lag—Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time, ie, hours of daylight or darkness, and the traveler’s endogenous circadian clock (internal time). The internal time regulates not only daily sleep rhythms but also body temperature and many metabolic systems. The synchronization of the circadian clock relies on light as the most potent “zeitgeber” (time giver).


Pharmacology_Katzung

Pharmacology_Katzung. Jet lag is especially common among frequent travelers and airplane cabin crews. Typical symptoms of jet lag may include daytime drowsiness, insomnia, frequent awakenings, and gastrointestinal upset. Clinical studies of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns, energy, and alertness). These outcomes are also supported by a systematic review that showed melatonin was better than placebo in helping patients fall asleep faster and to sleep better at their destination. When traveling across five or more time zones, jet lag symptoms are reduced when taking melatonin close to the target bedtime (10 pm to midnight) at the new destination. The benefit of melatonin is thought to be greater as more time zones are crossed. In addition, melatonin appears more effective for eastbound travel than for westward travel. Finally, maximizing exposure to daylight on arrival at the new destination can also


Pharmacology_Katzung

Pharmacology_Katzung. zones are crossed. In addition, melatonin appears more effective for eastbound travel than for westward travel. Finally, maximizing exposure to daylight on arrival at the new destination can also aid in resetting the internal clock.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Insomnia—Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid eye movement (REM) sleep. These observations have been applied to the development of ramelteon, a prescription hypnotic that is an agonist at melatonin receptors (see Chapter 22).


Pharmacology_Katzung

Pharmacology_Katzung. Clinical studies in patients with primary insomnia have shown that oral melatonin supplementation may alter sleep architecture. Melatonin appears effective in some patients who develop insomnia from β blockers. Subjective and objective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. Specifically, melatonin taken at the desired bedtime, with bedroom lights off, has been shown to improve morning alertness and quality of sleep as compared with placebo. These effects have been observed in both young and older adults (18–80 years of age). Interestingly, baseline endogenous melatonin levels were not predictive of exogenous melatonin efficacy. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Preand postoperative anxiety in adults—Melatonin given as a premedication has been shown to reduce preoperative anxiety in adults. Melatonin may be as effective as midazolam in reducing anxiety before a surgical procedure (measured 50–100 minutes after administration). The effect of melatonin on postoperative anxiety in adults is mixed, but studies support an overall reduction in anxiety as compared to preoperative anxiety levels. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Female reproductive function—The presence of melatonin within the female reproductive system appears widespread in mammals, and research suggests it plays a role in reducing oxidative stress. Melatonin receptors have been identified in ovarian granulosa cell membranes, and significant amounts of melatonin have been detected in follicular fluid. Some studies suggest it can be used as an adjunctive therapy in the treatment of infertility during in vitro fertilization by reducing oxidative stress and thereby improving the quality of oocytes and embryos during ovulation induction and egg retrieval. Melatonin requirements increase during pregnancy, and researchers are evaluating the role of melatonin in preeclampsia and neonatal neurologic morbidity. Importantly, melatonin has been shown to lack teratogenic effects when taken during pregnancy. Melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Male reproductive function—Melatonin receptors have been identified on spermatozoa, suggesting melatonin may play a role in sperm function. When melatonin was added to semen samples, sperm motility was increased and early apoptosis was inhibited. These findings suggest that melatonin may be important in male fertility; however, more research is needed. Melatonin appears to be well tolerated and is often used in preference to over-the-counter “sleep-aid” drugs. Although melatonin is associated with few adverse effects, some next-day drowsiness has been reported as well as fatigue, dizziness, headache, and irritability. Transient depressive symptoms and dysphoria have been reported rarely. Melatonin may affect blood pressure as both increases and decreases in blood pressure have been observed. Careful monitoring is recommended, particularly in patients initiating melatonin therapy while taking antihypertensive medications.


Pharmacology_Katzung

Pharmacology_Katzung. Melatonin drug interactions have not been formally studied. Various studies, however, suggest that melatonin concentrations are altered by a variety of drugs, including nonsteroidal anti-inflammatory drugs, antidepressants, β-adrenoceptor agonists and antagonists, scopolamine, and sodium valproate. The relevance of these effects is unknown. Melatonin is metabolized by CYP450 1A2 and may interact with other drugs that either inhibit or induce the 1A2 isoenzyme, including fluvoxamine. Melatonin may decrease prothrombin time and may theoretically decrease the effects of warfarin therapy. A dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested according to one in vitro analysis. If combination therapy is desired, careful monitoring is recommended especially if melatonin is being used on a short-term basis. Melatonin may interact with nifedipine, possibly leading to increased blood pressure and heart rate. The exact mechanism


Pharmacology_Katzung

Pharmacology_Katzung. is recommended especially if melatonin is being used on a short-term basis. Melatonin may interact with nifedipine, possibly leading to increased blood pressure and heart rate. The exact mechanism is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Jet lag—Daily doses of 0.5–5 mg appear to be equally effective for jet lag; however, the 5 mg dose resulted in a faster onset of sleep and better sleep quality than lower doses. The immediate-release formulation is preferred and should be given at the desired sleep time (10 pm–midnight) upon arrival at the new destination and for 1–3 nights after arrival. A dark room environment is important when taking melatonin and when possible, room lights should be turned off. The value of extended-release formulations remains unknown, as evidence suggests the short-acting, high-peak effect of the immediate-release formulation to be more effective. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Insomnia—Doses of 0.3–10 mg of the immediate-release formulation given orally once nightly have been used. The lowest effective dose should be used first and may be repeated in 30 minutes up to a maximum of 10–20 mg. Sustained-release formulations are effective and may be used but, as noted above, may be inferior to immediate-release formulations. Sustained-release formulations are also more costly. Agbabiaka TB et al: Serenoa repens (saw palmetto): A systematic review of adverse events. Drug Saf 2009;32:637. Ardjomand-Woelkart K, Bauer R: Review and assessment of safety data of orally used echinacea preparations. Planta Med 2016;82:17. Banach M et al: Effects of coenzyme Q10 on statin-induced myopathy: a meta- analysis of randomized controlled trials. Mayo Clin Proc 2015;90:24.


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Pharmacology_Katzung. Barnes J et al: Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): A review of their chemistry, pharmacology and clinical properties. Pharm Pharmacol 2005;57:929. Barton DL et al: Wisconsin ginseng (Panax quinquefolius) to improve cancer related fatigue: A randomized, double-blind trial, N7C2. J Natl Cancer Inst 2013;105:1230. Birks J, Evans JG: Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009;1:CD003120. Brzezinski A et al: Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005;9:41. Buck AC: Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792. Butterweck V, Schmidt M: St John’s wort: Role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr 2007;157:356.


Pharmacology_Katzung

Pharmacology_Katzung. Butterweck V, Schmidt M: St John’s wort: Role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr 2007;157:356. Capasso A: Antioxidant action and therapeutic efficacy of Allium sativum L. Molecules 2013;18:690. Chen X, Hong Y, Zheng P: Efficacy and safety of gingko biloba as an adjunct therapy in chronic schizophrenia: A systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Psychiatry Res 2015;228:121. Fotino AD, Thompson-Paul AM, Bazzano LA: Effect of coenzyme Q10 supplementation on heart failure: A meta-analysis. Am J Clin Nutr 2013;97:268. Franco OH et al: Use of plant-based therapies and menopausal symptoms. A systematic review and meta-analysis. JAMA 2016;315:2554. Fried MW et al: Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy. JAMA 2012;308:274.


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Pharmacology_Katzung. Fried MW et al: Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy. JAMA 2012;308:274. Garcia-Cazarin ML et al: Dietary supplement research portfolio at the NIH, 20092011. J Nutri 2014;144:414. Geller AI, et al: Emergency department visits for adverse events related to dietary supplements. N Engl J Med 2015;373:1531. Hansen MV, et al: Melatonin for preand postoperative anxiety in adults. Cochrane Database Syst Rev 2015;4:CD009861. Heitmann K et al: Pregnancy outcomes after prenatal exposure to echinacea: The Norwegian mother and child cohort study. Eur J Clin Pharmacol 2016;72:623. Herxheimer A, Petrie KJ: Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;2:CD001520. Ho MJ, Bellusci A, Wright JM: Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev 2009;4:CD007435.


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Pharmacology_Katzung. Ho MJ, Bellusci A, Wright JM: Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev 2009;4:CD007435. Hudson JB: Applications of phytomedicine Echinacea purpurea (Purple Coneflower) in infectious diseases. J Biomed Biotechnol 2012;2012:769896. Izzo AA et al: A critical approach to evaluating clinical efficacy, adverse effects, and drug interactions of herbal remedies. Phytother Res 2016;30:4691. Kang S, Min H: Ginseng, the immunity boost: Effects of Panax ginseng on the immune system. J Ginseng Res 2012;36:354. Kantor ED et al: Trends in dietary supplement use among US adults from 1999-2012. JAMA 2016;316:1464. Karsch-Völk M et al: Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2014;2:CD000530. Kim HJ, Kim P, Shin CY: A comprehensive review of the therapeutic and pharmacologic effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8.


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Pharmacology_Katzung. Kim HJ, Kim P, Shin CY: A comprehensive review of the therapeutic and pharmacologic effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8. Komishono AM, et al: The effect of ginseng (genus Panax) on blood pressure: A systematic review and meta-analysis of randomized controlled clinical trials. J Hum Hypertension 2016;30:619. Linde K et al: St. John’s wort for major depression. Cochrane Database Syst Rev 2008;4:CD000448. Liu YR et al: Hypericum perforatum L. preparations for menopause: A meta-analysis of efficacy and safety. Climacteric 2014;17:325. Loguercio C, Festi D: Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011;17:2288. Mastron JK et al: Silymarin and hepatocellular carcinoma: A systematic, comprehensive, and critical review. Anticancer Drugs 2015;26:475.


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Pharmacology_Katzung. Mastron JK et al: Silymarin and hepatocellular carcinoma: A systematic, comprehensive, and critical review. Anticancer Drugs 2015;26:475. Mengs U, Pohl RT, Mitchell T: Legalon SIL: The antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharmaceut Biotechnol 2012;13:1964. Natural Medicines. Therapeutic Research Center, Somerville, MA. Available from: https://naturalmedicines.therapeuticresearch.com. Subscription required to view. Newmaster SG et al: DNA barcoding detects contamination and substitution in North American herbal products. BMC Med 2013;11:222. Nicolai SP et al: Ginkgo biloba for intermittent claudication. Cochrane Database Syst Rev 2013;6:CD006888. Qaseem A et al: Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2016;164:350.


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Pharmacology_Katzung. Rambaldi A et al: Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev 2007;4:CD003620. Ried K: Garlic lowers blood pressure in hypertensive individuals, regulates serum cholesterol, and stimulates immunity: An updated meta-analysis and review. J Nutr 2016;146(suppl):389S. Ried K, Toben C, Fakler P: Effect of garlic on serum lipids: An updated meta-analysis. Nutr Rev 2013;71:282. Scheer FAJL et al: Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: A randomized controlled trial. Sleep 2012;35:1395. Schergis JL et al: Panax ginseng in randomized controlled trials: A systematic review. Phytother Res 2013;27:949. Seida JK, Durec T, Kuhle S: North American (Panax quinquefolius) and Asian ginseng (Panax ginseng) preparations for prevention of the common cold in healthy adults: A systematic review. Evid Based Complement Alternat Med 2011;2011:282151.


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Pharmacology_Katzung. Sharma M et al: Bactericidal and anti-inflammatory properties of a standardized echinacea extract (Echinaforce): Dual actions against respiratory bacteria. Phytomedicine 2010;17:563. Sharma M et al: The efficacy of echinacea in a 3-D tissue model of human airway epithelium. Phytother Res 2010;24:900. Shi C et al: Ginkgo biloba extract in Alzheimer’s disease: From action mechanisms to medical practice. Int J Mol Sci 2010;11:107. Tacklind J et al: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012;12:CD001423. Tan MS et al: Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis 2015;43:589. Van Vijven JP et al: Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: A systematic review. Osteoarthritis Cartilage 2012;20:809.


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Pharmacology_Katzung. Van Vijven JP et al: Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: A systematic review. Osteoarthritis Cartilage 2012;20:809. Vellas B et al: Long term use of standardized ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomized placebo-controlled trial. Lancet Neurol 2012;11:836. Wu D et al: Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: A meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67:585.


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Pharmacology_Katzung. Garlic has shown significant benefits in lowering total choles-terol, LDL, and systolic and diastolic blood pressure, but the effects are moderate and unlikely to be large enough to lower this patient’s values into the normal range. While this patient’s diabetes is under control, her hypertension places her at risk for microvascular complications of diabetes, thus making it necessary to reevaluate her current medication adherence, doses of benazepril for hypertension and simvastatin for hyper-lipidemia, and duration of therapy. She would benefit from meeting with a nutritionist because packaged frozen dinners can be high in sodium, and this may be elevating her blood pressure. Adding exercise to her weekly routine could also help with weight control and overall cardiovascular health. The data supporting benefits of St. John’s wort in patients with hot flashes are preliminary but show promise. Good data support use of the herb to alleviate symptoms of mild to moderate depression when


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Pharmacology_Katzung. data supporting benefits of St. John’s wort in patients with hot flashes are preliminary but show promise. Good data support use of the herb to alleviate symptoms of mild to moderate depression when used for up to 1 year. However, this patient is not a good candidate for St. John’s wort (a cytochrome P450 1A2, 2C9, 3A4 inducer) because of her prescription drug use and the potential for herb-drug interactions. Several dietary supplements reviewed in this chapter (garlic, ginkgo, and gin-seng) may have antiplatelet effects that could be additive with ibuprofen. If this patient were also taking warfarin, additional interactions could occur with coenzyme Q10 (vitamin K-like structure), St. John’s wort, and melatonin (in vitro decreased prothrombin time), leading to a decreased warfarin effect, or with glucosamine (increased international normalized ratio), leading to an increased warfarin effect.


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Pharmacology_Katzung. Paul W. Lofholm, PharmD, & Bertram G. Katzung, MD, PhD Once a patient with a clinical problem has been evaluated and a diagnosis has been reached, the practitioner can often select from a variety of therapeutic approaches. Medication, surgery, psychiatric treatment, radiation, physical therapy, health education, counseling, further consultation (second opinions), and no therapy are some of the options available. Of these options, drug therapy is by far the one most frequently chosen. In most cases, this requires the writing of a prescription. A written prescription is the prescriber’s order to prepare or dispense a specific treatment—usually medication—for a specific patient. When a patient comes for an office visit, the physician or other authorized health professional prescribes medications 67% of the time, and an average of one prescription is written per office visit because more than one prescription may be written at a single visit.


Pharmacology_Katzung

Pharmacology_Katzung. In this chapter, a plan for prescribing is presented. The physical form of the prescription, common prescribing errors, and legal requirements that govern various features of the prescribing process are then discussed. Finally, some of the social and economic factors involved in prescribing and drug use are described. Like any other process in health care, writing a prescription should be based on a series of rational steps as follows: 1. Make a specific diagnosis: Prescriptions based merely on a desire to satisfy the patient’s psychological need for some type of therapy are often unsatisfactory and may result in adverse effects. A specific diagnosis, even if it is tentative, is required to move to the next step. For example, in a patient with a probable diagnosis of rheumatoid arthritis, the diagnosis and the reasoning underlying it should be clear and should be shared with the patient. 2.


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Pharmacology_Katzung. 2. Consider the pathophysiologic implications of the diagnosis: If the disorder is well understood, the prescriber is in a much better position to offer effective therapy. For example, increasing knowledge about the mediators of inflammation makes possible more effective use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other agents used in rheumatoid arthritis. The patient should be provided with the appropriate level and amount of information about the pathophysiology. Many pharmacies, websites, and disease-oriented public and private agencies (eg, Arthritis Foundation, American Heart Association, American Cancer Society, etc) provide information sheets suitable for patients. 3.


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Pharmacology_Katzung. 3. Select a specific therapeutic objective: A therapeutic objective should be chosen for each of the pathophysiologic processes defined in the preceding step. In a patient with rheumatoid arthritis, relief of pain by reduction of the inflammatory process is one of the major therapeutic goals that identifies the drug groups that should be considered. Arresting the course of the disease process in rheumatoid arthritis is a different therapeutic goal, which might lead to consideration of additional drug groups and prescriptions. 4.


Pharmacology_Katzung

Pharmacology_Katzung. Select a drug of choice: One or more drug groups will be suggested by each of the therapeutic goals specified in the preceding step. Selection of a drug of choice from among these groups follows from a consideration of the specific characteristics of the patient and the clinical presentation, a selection process that has been emphasized as part of “precision medicine.” For certain drugs, characteristics such as age, other diseases, and other drugs being taken (because of the risk of duplicative therapy or drug-drug interactions) are extremely important in determining the most suitable drug for management of the present complaint. As the tools of precision medicine provide more detailed information (eg, mutations of drug metabolizing enzymes—pharmacogenomics), the selection process will become more focused. In the example of the patient with probable rheumatoid arthritis, it would be important to know whether the patient has a history of aspirin intolerance or ulcer disease, whether


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Pharmacology_Katzung. become more focused. In the example of the patient with probable rheumatoid arthritis, it would be important to know whether the patient has a history of aspirin intolerance or ulcer disease, whether the cost of medication is an especially important factor and the nature of the patient’s insurance coverage, and whether there is a need for once-daily dosing. Based on this information, a drug would probably be selected from the NSAID group. If the patient does not have ulcer disease but does have a need for low-cost treatment, ibuprofen or naproxen would be a rational choice.


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Pharmacology_Katzung. 5. Determine the appropriate dosing regimen: The dosing regimen is determined primarily by the pharmacokinetics of the drug in that patient. If the patient is known to have disease of the organs required for elimination of the drug selected, adjustment of the average regimen is needed. For a drug such as ibuprofen, which is eliminated mainly by the kidneys, renal function should be assessed. If renal function is normal, the half-life of ibuprofen (about 2 hours) requires administration three or four times daily. The dose suggested in this book, drug handbooks, and the manufacturer’s literature is 400–800 mg four times daily. 6.


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Pharmacology_Katzung. Devise a plan for monitoring the drug’s action and determine an end point for therapy: The prescriber should be able to describe to the patient the kinds of drug effects that will be monitored and in what way, including laboratory tests (if necessary) and signs and symptoms that the patient should report. For conditions that call for a limited course of therapy (eg, most infections), the duration of therapy should be made clear so that the patient does not stop taking the drug prematurely and understands why the prescription probably need not be renewed. For the patient with rheumatoid arthritis, the need for prolonged— perhaps indefinite—therapy should be explained, including how to obtain refills. The prescriber should also specify any changes in the patient’s condition that would call for changes in therapy. For example, in the patient with rheumatoid arthritis, development of gastrointestinal bleeding would require an immediate change in drug therapy and a prompt workup of the


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Pharmacology_Katzung. for changes in therapy. For example, in the patient with rheumatoid arthritis, development of gastrointestinal bleeding would require an immediate change in drug therapy and a prompt workup of the bleeding. Major toxicities that require immediate attention should be explained clearly to the patient.


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Pharmacology_Katzung. 7. Plan a program of patient education: The prescriber and other members of the health team should be prepared to repeat, extend, and reinforce the information transmitted to the patient as often as necessary. The more toxic the drug prescribed, the greater the importance of this educational program. The importance of informing and involving the patient in each of the above steps must be recognized, as shown by experience with teratogenic drugs (see Chapter 59). Many pharmacies routinely provide this type of information with each prescription filled, but the prescriber must not assume that this will occur. Although a prescription can be written on any piece of paper (as long as all of the legal elements are present), it usually takes a specific form. A typical printed prescription form for outpatients is shown in Figure 65–1.


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Pharmacology_Katzung. In the traditional hospital setting, drugs have been prescribed on a particular page of the patient’s hospital chart called the physician’s order sheet (POS) or chart order. In the electronic medical JOHN B. DOE, MD 1234 SOUTH NORTHEAST DR WEST CITY, CA 94999 (234) 555 6789 FOR: AD1234567 STATE LICENSE NO. ADDRESS: REFILL SIG: WARNING: OR UNTIL NO CHILDPROOF CONTAINER TIMES DATE: , MD (DRUG NAME AND STRENGTH) (QUANTITY) 10 11 98 1 2 3 4 6 7 5 12 13 14 15 16 17 FIGURE 65–1 Common form of outpatient prescription. Circled numbers are explained in the text.


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Pharmacology_Katzung. FIGURE 65–1 Common form of outpatient prescription. Circled numbers are explained in the text. records environment, prescriptions are executed via electronic order entry. The contents of that prescription are specified in the medical staff rules by the hospital’s Pharmacy and Therapeutics Committee or similar authority. The patient’s name is typed or written on the form; the orders consist of the name and strength of the medication, the dose, the route and frequency of administration, the date, other pertinent information, and the signature of the prescriber. If the duration of therapy or the number of doses is not specified (which is often the case), the medication is continued until the prescriber discontinues the order or until it is terminated as a matter of policy routine, eg, a stop-order policy. A typical chart order might be as follows: 10:30 A.M. Aspirin 0.6 g per rectum q6h prn temp over 101 [Signed] Janet B. Doe, MD


Pharmacology_Katzung

Pharmacology_Katzung. A typical chart order might be as follows: 10:30 A.M. Aspirin 0.6 g per rectum q6h prn temp over 101 [Signed] Janet B. Doe, MD Thus, the elements of the hospital chart order are equivalent to the central elements (5, 8–11, 15) of the outpatient prescription. The first four elements (see circled numerals in Figure 65–1) of the outpatient prescription establish the identity of the prescriber: name, license classification (ie, professional degree), address, and office telephone number. Before dispensing a prescription, the pharmacist must establish the prescriber’s bona fides and should be able to contact the prescriber by telephone if any questions arise.


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Pharmacology_Katzung. Element [5] is the date on which the prescription was written. It should be near the top of the prescription form or at the beginning (left margin) of the chart order. Since the order has legal significance and usually has some temporal relationship to the date of the patient-prescriber interview, a pharmacist should refuse to fill a prescription without verification by telephone if too much time has elapsed since its writing. Elements [6] and [7] identify the patient by name and address. The patient’s name and full address should be clearly spelled out.


Pharmacology_Katzung

Pharmacology_Katzung. The body of the prescription contains the elements [8] to [11] that specify the medication, the strength and quantity to be dispensed, the dosage, and complete directions for use. When writing the drug name (element [8]), either the brand name (proprietary name) or the generic name (nonproprietary name) may be used. Reasons for using one or the other are discussed below. The strength of the medication [9] should be written in metric units. However, the prescriber should be familiar with both systems now in use: metric and apothecary. For practical purposes, the following approximate conversions are useful: 1 grain (gr) = 0.065 grams (g), often rounded to 60 milligrams (mg) 15 gr = 1 g 1 ounce (oz) by volume = 30 milliliters (mL) 1 teaspoonful (tsp) = 5 mL 1 tablespoonful (tbsp) = 15 mL 1 quart (qt) = 1000 mL 1 minim = 1 drop (gtt) 20 drops = 1 mL 2.2 pounds (lb) = 1 kilogram (kg)


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Pharmacology_Katzung. The strength of a solution is usually expressed as the quantity of solute in sufficient solvent to make 100 mL; for instance, 20% potassium chloride solution is 20 grams of KCl per deciliter (g/dL) of final solution. Both the concentration and the volume should be explicitly written out.


Pharmacology_Katzung

Pharmacology_Katzung. The quantity of medication prescribed should reflect the anticipated duration of therapy, the cost, the need for continued contact with the clinic or physician, the potential for abuse, and the potential for toxicity or overdose. Consideration should be given also to the standard sizes in which the product is available and whether this is the initial prescription of the drug or a repeat prescription or refill. If 10 days of therapy are required to effectively cure a streptococcal infection, an appropriate quantity for the full course should be prescribed. Birth control pills are often prescribed for 1 year or until the next examination is due; however, some patients may not be able to afford a year’s supply at one time; therefore, a 3-month supply might be ordered, with refill instructions to renew three times or for 1 year (element [12]). Some third-party (insurance) plans limit the amount of medicine that can be dispensed—often to only one month’s supply. Finally, when first


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Pharmacology_Katzung. to renew three times or for 1 year (element [12]). Some third-party (insurance) plans limit the amount of medicine that can be dispensed—often to only one month’s supply. Finally, when first prescribing medications that are to be used for the treatment of a chronic disease, the initial quantity should be small, with refills for larger quantities. The purpose of beginning treatment with a small quantity of drug is to reduce the cost if the patient cannot tolerate it. Once it is determined that intolerance is not a problem, a larger quantity purchased less frequently is sometimes less expensive.


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Pharmacology_Katzung. The directions for use (element [11]) must be both drug-specific and patient-specific. The simpler the directions, the better; and the fewer the number of doses (and drugs) per day, the better. Patient noncompliance (also known as nonadherence, failure to adhere to the drug regimen) is a major cause of treatment failure. To help patients remember to take their medications, prescribers often give an instruction that medications be taken at or around mealtimes and at bedtime. However, it is important to inquire about the patient’s eating habits and other lifestyle patterns, because many patients do not eat three regularly spaced meals a day.


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Pharmacology_Katzung. The instructions on how and when to take medications, the duration of therapy, and the purpose of the medication must be explained to each patient both by the prescriber and by the pharmacist. (Neither should assume that the other will do it.) Furthermore, the drug name, the purpose for which it is given, and the duration of therapy should be written on each label so that the drug may be identified easily in case of overdose. An instruction to “take as directed” may save the time it takes to write the orders out but often leads to noncompliance, patient confusion, and medication error. The directions for use must be clear and concise to prevent toxicity and to obtain the greatest benefits from therapy.


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Pharmacology_Katzung. Although directions for use are no longer written in Latin, many Latin apothecary abbreviations (and some others included below) are still in use. Knowledge of these abbreviations is essential for the dispensing pharmacist and often useful for the prescriber. Some of the abbreviations still used are listed in Table 65–1. Note: It is always safer to write out the direction without abbreviating.