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Adverse Reactions

In clinical trials, all doses of colesevelam were generally well tolerated. Colesevelam is not absorbed in the digestive tract, reducing the potential for systemic adverse side effects. Also, its water-retaining ability creates a soft, gelatinous material that minimizes the potential for gastrointestinal irritation. The most common side effects reported by patients in clinical trials of colesevelam HCl were flatulence (12% for colesevelam vs. 14% for placebo) and constipation (11% for colesevelam vs. 7% for placebo). The incidence of gastrointestinal side effects was less than that associated with other drugs in its class. Less than 3% of the trial patients discontinued colesevelam therapy as a result of GI tract adverse reactions. There were no clinically significant changes in serum chemistry parameters from baseline to the end of treatment. In general, the change from baseline for indicators of kidney and liver function did not differ among treatment groups, with the exception of a modest, non-dose-related increase in alkaline phosphatase. No clinically significant changes were noted during clinical trials to date for hematologic parameters, serum levels of vitamins A and E, prothrombin time, partial thromboplastin time, estradiol levels, body weight, pulse, and systolic and diastolic blood pressure.

Drug Interactions

In clinical studies, coadministration of colesevelam with atorvastatin, lovastatin, or simvastatin did not interfere with the lipid-lowering activity of the HMG-CoA reductase inhibitor. Colesevelam is reported to decrease the C_max and AUC of sustained-release verapamil (Calan SR) by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. Colesevelam HCl was found to have no significant effect on the bioavailability of digoxin, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy, monitoring drug levels or effects should be considered.

Dosage, Administration and Patient Information

Colesevelam is supplied as an off-white tablet containing 625 mg of the active drug. The recommended initial dose of colesevelam monotherapy is three tablets twice daily or six tablets once daily. Colesevelam should always be taken with a liquid and a meal. The dose of colesevelam may be increased to seven tablets, depending upon the desired therapeutic effect. When used with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily. Colesevelam and the HMG-CoA reductase inhibitor do not need to be administered at the same time. Patients should be instructed to adhere to their National Cholesterol Education Program recommended diet and inform their physicians if they are pregnant, are intending to become pregnant, or are breastfeeding. Colesevelam is contraindicated in individuals with bowel obstruction and in individuals who have shown hypersensitivity to any of the components of the drug product.

Pharmacology and Pharmacokinetics

Bile acids are formed from cholesterol in a series of reactions regulated by the enzyme 7-alpha- hydroxylase. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids are then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed (less than 0.05% absorption) from the GI tract. It binds bile acids in the intestine, impeding their reabsorption and facilitating elimination. As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-alpha-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in both increased transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increased numbers of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects result in increased clearance of LDL-C from the blood, thereby decreasing serum LDL-C levels. Furthermore, studies have shown that the combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone.

Therapeutics

The effectiveness of colesevelam in lowering LDL-C has been demonstrated in a number of controlled clinical trials involving approximately 1,400 patients who were treated for 4–50 weeks. Colesevelam taken alone was found to be effective for patients with mild-to-moderate hypercholesterolemia, producing a maximum therapeutic response within two weeks; this effect was maintained during long-term therapy. In a study in patients with LDL-C between 130 and 220 mg/dL (mean 158 mg/dL), colesevelam was given for 24 weeks in divided doses with the morning and evening meals. In this study, the mean LDL-C reductions were 15% with a 3.8 g dose of colesevelam and 18% with a 4.5 g dose. The mean total-C reductions were 7% and 10%, respectively, and the mean Apo B reductions were 12% in both treatment groups. Colesevelam at both doses also resulted in a 3% increase in HDL-C. There were also small increases in triglycerides (TG) at both colesevelam HCl doses but these were not statistically different from placebo.

In a study of nearly 100 patients with LDL-C between 145 and 250 mg/dL (mean 169 mg/dL), 3.8 g of colesevelam was given for six weeks as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the three dosing regimens, respectively. The reductions with these three regimens were not statistically different from one another. Coadministration of colesevelam and an HMG-CoARI (atorvastatin, lovastatin, or simvastatin) produced an additive reduction of LDL-C in several clinical studies. Colesevelam doses of 2.3 g to 3.8 g resulted in additional 8% to 16% reductions in LDL-C above that seen with the HMG-CoARI alone. It should be noted that the specific effects of colesevelam, either alone or with an HMG-CoA reductase inhibitor, on cardiovascular morbidity and mortality have not been determined at this time.

Based on these studies, colesevelam, administered alone or in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet and exercise for the reduction of elevated LDL-C in patients with primary hypercholesterolemia who are at significant increased risk for atherosclerotic vascular disease. Prior to initiating colesevelam therapy, it is necessary to first exclude secondary causes of hypercholesterolemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease or other drug therapy. Also, a lipid profile should be obtained to assess total-C, HDL-C, and TG and periodic serum cholesterol levels, determined as outlined in the National Cholesterol Education Program (NCEP) guidelines to confirm a favorable initial and long-term response. Colesevelam should be used with caution in patients with gastrointestinal disorders (e.g., dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery) since the safety and efficacy of this drug has not been established in such patients.

What does the pharmacist need to know to counsel patients about colesevelam?

Development

Epidemiological studies have established that elevated levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipo-protein B (Apo B), as well as decreased levels of HDL-cholesterol (HDL-C), are associated with an increased risk of atherosclerosis and cardiovascular-related mortality. Furthermore, it has been documented through numerous trials that aggressive reduction of lipid levels can significantly reduce the risk of cardiovascular disease. It is estimated that more than 50 million Americans currently have at least mild elevations of cholesterol (hyper-cholesterolemia or Fredrickson Type IIa hyperlipidemia) and would benefit from some form of lipid-lowering therapy. Diet and lifestyle changes generally represent the initial approach toward lipid reduction, but these often produce small and inconsistent results. For patients who continue to have elevated cholesterol levels following diet and lifestyle modifications, drug therapy is recommended. Currently available lipid-lowering drugs include the “statin” hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoARIs), the bile acid sequestrants, nicotinic acid, the fibric acids (gemfibrozil, clofibrate) and probucol. The lipid-lowering market is one of the fastest growing in the nation, generating over $6 billion in sales and nearly 95 million prescriptions over the past year.

For initial cholesterol-lowering therapy, the National Cholesterol Education Program (NCEP) recommends bile acid sequestrant drugs used alone or in combination with other drugs, such as the statin HMG-CoARIs. The safety and efficacy of cholestyramine resin and colestipol hydrochloride, the most commonly prescribed bile acid sequestrants, have been demonstrated repeatedly. These bile acid sequestrants alone reduce LDL-C concentrations by 10% to 30%. Combination therapy of bile acid sequestrants with niacin or an HMG-CoARI produces even larger LDL-C reductions of up to 60%. Despite their proven efficacy and the lack of systemic effects resulting from nonabsorption from the gastrointestinal tract, the bile acid sequestrants currently available have a high drug discontinuation rate due, in large measure, to intolerable GI side effects. Constipation occurs in up to 39% of patients taking currently available bile acid sequestrants and in severe cases, this may result in fecal impaction. Other gastrointestinal side effects, such as bloating, flatulence, and cramping, also occur in a large percentage of patients who are treated with currently available bile acid sequestrants. Therefore, the development of effective cholesterol-lowering agents with greater tolerability than currently available bile acid sequestrants has been a priority of hypercholesterolemic drug research.

Colesevelam (WelChol/Sankyo) is a new, nonabsorbed polymer (water-absorbing hydrogel) that has been specifically designed to bind to bile acids in the GI tract. It is a poly-allylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and brom hexyltrimethylammonium bromide. Colesevelam has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that colesevelam has superior bile acid binding efficacy compared to cholestyramine. Furthermore, its water-retaining characteristic creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation relative to other bile acid sequestrants.

Patient Counseling
Pharmacists can take on a variety of roles in the management of lipid disorders. Several reports have described pharmacists’ involvement in the management of dyslipidemias. Particularly in the community setting, pharmacists are uniquely positioned to assist with screening, managing, and educating patients with lipid disorders. Typically, pharmacists’ activities include interviewing patients to assess medical histories, ascertaining risk factors and other pertinent information, assessing lipid profiles, tressing the treatment, and providing patient education and follow-up.

Hypertension and Diabetes Risk Factors in the African American Population
The high prevalence of hypertension and diabetes in African Americans increases their risk for CHD. The presence of cholesterol abnormalities (i.e., increased LDL, triglycerides, and decreased HDL) in conjunction with these two major risk factors puts this population at an even greater risk for cardiovascular morbidity and mortality. It is imperative that pharmacists recognize this population as one requiring special considerations with regard to monitoring and counseling. Hypertension appears to increase with the prevalence of certain lifestyles. In the rural South (as well as in other areas), certain cultural food preferences still exist. For example, chitterlings, salt back, pickled pig parts, fat back, sweet potato pie, and boiled peanuts are major components of many African American diets. Many of these foods are high in fat and sodium, and low in potassium. Diets high in fried foods and low in fruits, vegetables, and grains pose significant challenges for the patient with dyslipidemia, making lifestyle modifications more critical. The assistance of a dietitian may be particularly useful for recommending low-fat, low-sodium alternatives to the patient.

To prevent hypertension, African Americans should increase consumption of high-potassium foods (such as fresh fruits and vegetables), use low-fat dairy products, and avoid salt. The Dietary Approaches to Stop Hypertension (DASH) diet is particularly effective in significantly lowering high blood pressure in African Americans. This diet is low in cholesterol, high in dietary fiber, potassium, calcium, and magnesium, and moderately high in protein, and has been shown to lower blood pressure even when an individual’s weight and salt intake remained constant. One major obstacle facing many African Americans in the treatment of hypertension, is the cost of medications. Many of the newer medications are more effective and have fewer side effects than older medications, but they are costly. In addition, many African Americans do not receive proper medical care until hypertension has been present for some time. This results in otherwise avoidable damage to the kidneys and other organs. It may also account for the high rate of hypertension-related morbidity and mortality that exists among African Americans.

It should also be taken into consideration that African Americans tend to respond differently than other populations to treatment for high blood pressure. Because African Americans experience higher rates of diabetes, renal insufficiency and heart failure, they may benefit more from aggressive treatments to lower blood pressure.

Conclusion
Dyslipidemia is a major risk factor in the development of coronary heart disease. This risk factor, as well as other risk factors, can be altered through pharmacologic, dietary and other lifestyle modifications. Cultural norms affecting health among African Americans do exist and should not be overlooked by healthcare providers. Increased awareness by the pharmacist and the use of culturally sensitive information and materials can greatly enhance patient understanding and adherence to the prescribed regimen.
Pharmacists have a responsibility to assist in the management of lipid disorders. This can be accomplished by developing individual or collaborative practices in various healthcare settings. Pharmacists interested in strengthening their skills in this area can enroll in courses offered by several organizations.

Heart disease is the leading cause of death among adults in the United States. Specifically, coronary heart disease (CHD) is the single largest killer of American males and females. Seven million Americans suffer from CHD, and about a half million people die each year from heart attacks caused by CHD. One out of two men, and one out of three women will develop heart disease sometime in their life. CHD is also the leading cause of death among African Americans, affecting this population disproportionately when compared to whites. In 1996 CHD death rates were 120.2 per 100,000 for white males, 125.4 for black males, 58.9 for white females, and 80.0 for black females. For those aged 35–74, the age-adjusted death rate from CHD for black women is nearly 72% higher than that of white women.

Both epidemiologic and clinical trials have documented the prevalence of lipid disorders, and have proven that elevated levels of low-density lipoprotein (LDL) cholesterol and decreased levels of high-density lipoprotein (HDL) are associated with an increased risk of CHD. (Pharmacists should be aware that certain diseases and medications are also capable of affecting cholesterol levels. Therefore, patient medication profiles and medical histories should be reviewed thoroughly to rule out these possible secondary causes of dyslipidemia.) In addition to elevated cholesterol, other risk factors for CHD have been identified:

• Age: Male 45 years or older; female 55 years or older, or experiencing premature menopause without estrogen replacement therapy
• Family history: History of premature CHD (definite myocardial infarction or sudden death before age 55 in father or other male first-degree relative, or before age 65 in mother or other female first-degree relative)
• Current cigarette smoking
• Hypertension (blood pressure 140/90 mmHg or greater) or taking antihypertensive medicine
• Diabetes mellitus

Management of Elevated Cholesterol
The National Cholesterol Education Program (NCEP) of the National Heart, Lung and Blood Institute (NHLBI) has established guidelines for the prevention and treatment of lipid disorders. According to the NCEP guidelines, all patients at least 20 years of age should have an initial cholesterol measurement. It is recommended that the initial laboratory test measure both total and HDL cholesterol. The American Diabetes Association (ADA) recommends that diabetic patients receive a complete lipid profile (i.e., LDL, HDL and triglycerides) annually. Further evaluation of the patient is based on the results of these initial tests. The goals of lipid-lowering interventions vary depending on whether the focus is primary or secondary prevention of CHD. In primary prevention the goal is to prevent the onset of CHD; secondary prevention focuses on avoiding further CHD events. Treatment should be modeled after NCEP recommendations. These guidelines include nonpharmacologic, lifestyle modifications (e.g., diet, exercise, smoking cessation), and pharmacologic measures. Table 1 outlines the LDL treatment goals based on the number of CHD risk factors present.

Lifestyle Modification: Dietary therapy is the first line of treatment for elevated cholesterol levels. NCEP recognizes dietary modification as the cornerstone in the management of dyslipidemia. The general goal of dietary therapy is to reduce elevated serum cholesterol while maintaining a nutritionally appropriate eating pattern. A reduction in saturated fat and cholesterol in the diet, as well as regular physical activity, are two important lifestyle changes that pharmacists must emphasize to patients. Dietary therapy is a two-step process. Step I begins the process of reducing intake of saturated fat and cholesterol. The diet should involve an intake of 10% of total calories from saturated fat, 30% or less of calories from total fat, and 300 mg or less of cholesterol per day (Table 2). If the goals of therapy are not achieved with Step I, patients should be advanced to the Step II diet. Step II requires further reduction in saturated fat and cholesterol. For this step, a registered dietitian should assist with management.

Both physical activity and weight reduction are considered essential components in the nonpharmacologic management of elevated serum cholesterol. A program of physical activity for at least 20 minutes three times weekly provides significant cardiovascular benefit. The benefits of physical activity include an increase in HDL and a decrease in weight, especially for obese and overweight patients. It may also lead to a reduction in triglyceride levels. Patients should be advised to consult their physician prior to initiating an exercise program.
Smoking cessation should also be encouraged. Pharmacists should have information available, and be able to direct patients to local smoking cessation programs. They should be knowledgeable about the various smoking cessation aids available (e.g., nicotine gum and patches).

Pharmocologic Measures: The goal of drug therapy is to reduce the LDL cholesterol to below 160 mg/dL or to below 130 mg/dL if two other risk factors are present. Drug therapy is considered for the adult patient who has an LDL cholesterol level of 190 mg/dL or greater without two other risk factors; or 160 mg/dL or greater with two other risk factors. Table 3 outlines the NCEP guidelines for treatment, and Table 4 summarizes patient counseling information specific to each lipid-lowering agent available.

Many factors that put individuals at risk for stroke have been identified, including physical inactivity, high cholesterol, obesity, use of alcohol or cigarettes, diabetes and high blood pressure. For the first time, researchers have identified a psychological factor that also affects stroke risk — depression.

A study published in the July/August issue of Psychosomatic Medicine reports that increasingly, levels of depression are associated with increasing levels of risk for later stroke. This was true even for those who had only moderate symptoms of depression, and who might not actually be diagnosed with clinical depression.

“The suggestion of an increasingly strong relationship between level of depressive symptoms and stroke indicates that reducing depression may be important for everyone, not just those whose symptoms may have clinical implications,” stated Dr. Bruce S. Jonas of the National Center for Health Statistics in Hyattsville, Maryland, part of the Centers for Disease Control and Prevention (CDC).

Jonas and colleagues looked at a nationally representative sample of more than 6,000 adults, ages 25 to 74, when the National Health and Nutrition Examination Survey began in the early 1970s. The researchers surveyed participants periodically for an average of 18 years. They analyzed the information collected to see if symptoms of depression reported at the beginning of the study were related to incidence of stroke over the following decades. They discovered a strong relationship.

Scores on the depression questionnaire were sorted into high, medium and low. People who reported high levels of depressive symptoms were 73 percent more likely to have a stroke over the next two decades than those with low levels. Even those with moderate levels of symptoms had a 25 percent increase in risk.

To see if their findings were influenced by the other known risk factors for stroke, Jonas and colleagues tried several different analyses. However, even when they accounted for age and the existence of other risk factors, the results were similar. The researchers even tried excluding people who had strokes within a few years of completing the depression questionnaire, to see if changes that were already happening to their bodies might influence the relationship — but depression still predicted later stroke.

Jonas and colleagues also report gender and racial differences in the association between depression and stroke. Among white men, white women, and all African-Americans (there weren’t enough to group the sexes separately), higher levels of depressive symptoms were significantly related to an increased risk of stroke, regardless of whether age and other risk factors were taken into account. No differences, however, were found between those 25 to 59 years of age and those 60 to 74.

These findings do not mean that the other risk factors aren’t important, Jonas points out. “Risk factors such as baseline age, gender, smoking status, systolic blood pressure, serum cholesterol level, history of diabetes and history of heart disease remain strong predictors of developing stroke,” he explained. “However, this study indicates that depression levels may also play an important role.”

The researchers point out that depression increased the risk of stroke about as much as would a 40-point increase in systolic blood pressure.

Overall, 9.1 percent of study participants reported high levels of depressive symptoms, and 32.7 percent reported moderate levels. Among African Americans, 15.7 percent reported high and 35.6 percent moderate, levels.

Researchers don’t fully understand the connection between depression and stroke. The changes in brain chemical activity seen in people with depression may affect the body’s ability to regulate itself and handle stress. Other research has found that depression appears to alter the hormonal and immune systems. Still other studies report increases in platelet activity among depressed people. Depression also appears to be a risk factor for high blood pressure and heart disease, both of which contribute directly to stroke risk.

Clearly, a lot more research is needed to understand how depression affects the risk for stroke. In the meantime, however, the current findings suggest that helping people with symptoms of depression may not only increase their immediate quality of life, but also decrease their risk of having a stroke further down the line.

Coronary heart disease (CHD), chest pain, heart attack – they all occur in your chest, right? Well, according to recent research, various forms of heart disease may actually start in your head.

Medical research linking these two topics clearly depicts a bi-directional path of symptom development and disease progression. For instance, previous research has shown that depression is a common problem in patients with coronary heart disease. Major depression is found in nearly 20 percent of patients who have recently had a heart attack. Minor depression is found in more than 25 percent of them. It is also estimated that within one year of a heart attack, one out of three patients will experience major depression.

A study from the University of Munich recently reported that a depressive mood paired with heart disease can intensify perceived chest pain. Patients diagnosed with high levels of depression in the period immediately after a heart attack were three times more likely to experience anginal pain six months later. The authors suggest that their findings point to a pain trigger that may be unrelated to the usual (i.e., nervous) sources. They recommend more broad-based therapeutic interventions following a heart attack, rather than solely conventional anti-anginal treatments.

Depression has also been related to an increased risk for coronary death. These results, uncovered by researchers at the Duke University Medical Center, link depression with impaired baroreflex sensitivity (BRS). BRS refers to the ability of the circulatory system to manage changes in blood pressure. In the Duke study, patients who were severely depressed had a 30 percent reduction in BRS function compared with patients with little or no depressive symptoms. Although based on a small sample, these results suggest that the inability of depressed patients to respond appropriately to blood pressure changes may render them more vulnerable to adverse cardiac events such as heart attack.