Bruce H. Woolley, Pharm.D., Editor
Vol. 6, No.4
Kenneth J. Hunt, Associate Editor
INCORPORATING PHARMACOTHERAPY INTO OBESITY MANAGEMENT
Obesity is on the forefront of major health problems in the United States today. Annual health care costs directly related to obesity are in excess of $68 billion. The disease is a major contributor to type II diabetes, cardiovascular disease, stroke and gall bladder disease. It is estimated that 300,000 deaths yearly can be attributed to obesity related conditions, second only to smoking as a preventable cause of death.
There are three basic classifications of drugs according to their weight loss mechanism: those drugs which reduce energy intake; those which reduce nutrient absorption; and those which increase expenditure of energy by the process of thermogenesis.
Control of Energy Intake: Food intake may be reduced by decreasing appetite or increasing satiety. Medications which affect appetite are commonly known as anorexiants. The actions of anorexiants may not be limited to appetite control. Some researchers have proposed that anorexiants also lower the bodys set point, thus, the body will have a reduced tendency to regain the weight.
Anorexiant drugs are of two main classes: those which affect the catecholominergic system and those which affect the serotonergic system. Catecholominergic drugs increase the release of norepinephrine and dopamine from CNS nerve terminals or inhibit their reuptake. This class of compounds includes the amphetamines, phentermine, mazindol and phenylpropanolamine. Serotonergic agents stimulate the production and release of serotonin at CNS nerve endings.
Drugs in this class include fenfluramine, dexfenfluramine, and the selective serotonin reuptake inhibitors [SSRIs]. At significant recent breakthrough is sibutramine (Merida®/Knoll), a drug which suppresses the appetite by inhibiting the reuptake of both norepinephrine and serotonin.
Reduced Absorption: Medications which block absorption of fatty acids from the diet or block the action of digestive enzymes may reduce the total energy available to the body. Orlistat (Xenical®/Roche), the most common of these types of drugs, is an inhibitor of gastric and pancreatic lipase. When taken before a fatty meal, the drug will reduce the absorption of fat in the intestines.
Thermogenic Effects: The best path to increasing energy expenditure is through physical activity. Another pathway is to change the bodys thermogenic metabolism. Some commonly used substances such as ephedrine and caffeine, as well as experimental beta-3 agonists (BRL-23860 A) may accomplish this. Caution should be used when implementing this method as none of these medications is currently approved by the FDA for weight loss and side effects may be unpredictable.
Herbal Phen Fen: With the loss of the popular phen-fen diet, both consumers and marketers of weight loss drugs have sought other avenues to achieve the same end. Among the more popular alternatives is the "herbal phen-fen" program. This natural approach mimics the original drug duo in that it combines a combination of compounds, usually ephedrine and St. Johns Wort. St. Johns Wort, the common name of the herb Hypericum perforatum, is commonly sold as a mood enhancer. It has not been carefully studied as an anorexiant agent, but is meant to mimic the fenfluramine part of the original diet.
Ephedra, also known as Ma huang, can be found in many weight loss products. It saw a dramatic increase in notoriety with the popularity of herbal phen-fen. The FDA has received over 800 reports of adverse effects with the use of ephedra or other ephedrine containing compounds since 1993. Like the original drug combination, the herbal counterpart is not well studied and not approved by any recognized administration. The FDA recently issued a statement of warning to consumers of "natural" phen-fen analogs stating that they contain harmful ingredients which should not be promoted for use together.
The potency of amphetamines has led to the advent of substances which are chemical derivatives of amphetamines, but are considered safer and less addicting. Among the most popular of these compounds is phenylpropanolamine, sold as Dexatrim® or Acutrim®. These are the only FDA approved over-the-counter weight loss drugs, but are accompanied by many side effects including dry mouth, sweating and headaches.
Another phenylethylamine compound is the active ingredient of the prescription drug diethylpropion (Tenuate®/Lakeside). This compound, which is seldomly used, is not as effective as other analogs which have since been developed. One study reported an abnormally high level of psychosis in five female patients taking the drug and predicted that there are likely many cases which have gone unreported.
Leptin: Recent studies on the genetics of obesity have uncovered a product of adipose tissue called leptin. The hormone, which may be linked to the "ob"gene, is highly correlated with fat mass in humans. It is believed that leptin is secreted to interact with specific receptors in the brain and stimulate a feeling of satiety without changing the bodys metabolism. Leptin may also inhibit the release of neuropeptide Y (NPY), the effects of which will be discussed later.
A biotechnology company has purchased the rights to all research on the ob gene. They are currently developing compounds which mimic the natural product leptin in. In the process, they are isolating the specific genetic pathways of the ob gene. Though much of the research involving leptin has been conducted on mice, it has shown a great deal of promise in combating obesity.
Bromocriptine: Another biochemical approach to obesity is dopamine agonists. Dopamine agonists are believed to produce anorectic effects and perhaps even reduce body fat by increasing lipogenesis. Bromocriptine (Ergoset®/Ergo Science) is a dopamine agonist that is currently undergoing clinical trials.
Neuropeptide Y antagonist: Neuropeptide Y (NPY) is the most abundant neuropeptide in the brain12. Some NPY receptors have been shown to be associated with eating behavior. Pfizer and Neurogen, the front-runners in NPY research, halted trials on their NPY receptor antagonist, NGD 95-1, due to the discovery of elevated liver enzymes in otherwise healthy subjects in their phase I clinical trial. The companies are in the process of examining new candidates which are chemically similar to NGD 95-1, and hope to begin a new set of human linical trials over the next year.
Cholecystokinin agonists: Cholecystokinin is one of the 13 different neurotransmitters which impact our eating behavior. It is a hormone released by the wall of the stomach after a meal that communicates satiety signals to the brain. GlaxcoWellcome is developing a compound which mimics the natural CCK hormone and seems to inhibit the desire to eat.
Conclusion: Obesity is a chronic disease with vast health and social implications. Fortunately, those with the problem do not have to live uncomfortably. Once educated and motivated toward the appropriate steps, the majority of obese can achieve and maintain a safe and healthy weight level.
1. "Long-Term Pharmacotherapy in the Management of Obesity," National Task Force on the prevention and Treatment of Obesity, JAMA, Dec 18, 1996; 276:1907.
2. Colorado Health Net: Obesity: Definitions, Facts, Statistics, http://www.coloradohealthnet.org/obesity/obs_stats.html June 18, 1998.
3. Kamath V, et al. Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women. Diabetes Care 1997 Nov;20(11):1697-1701..
A GUIDE TO THE ORANGE BOOK
Over the last century, the United States Congress has enacted legislation to ensure that pharmaceutical products are safe, effective and meet a high standard of purity. These ever-changing laws have spurned a continuous evolution in the practice of pharmacy. Pharmacists are now charged with a greater responsibility than ever in terms of counseling patients, reviewing the utilization of drugs, and monitoring the origin of drugs they dispense. With this increased responsibility comes a heightened risk of liability. In selecting appropriate products, pharmacists must understand the laws and regulations governing the products they dispense; this must include therapeutic equivalence.
Beginning in the late 1970s, the Food and Drug Administration (FDA) releases an Approved Drug Products with Therapeutic Equivalence Evaluations manual which provides an authoritative source on therapeutic equivalence of FDA-approved products. This is commonly referred to as the "Orange Book" because of its orange cover. The list includes a therapeutic equivalence rating for every multi-source drug product that has met the demands of the FDAs rigorous approval process.
The Orange Book originated from concerns over the containment of Medicare costs beginning in the 1960s and has been driven by economic concerns ever since. The list was intended, in part, to help states develop and implement more rigorous drug selection laws. The drugs listed in the Orange Book are listed alphabetically by active ingredient. Products which contain multiple active ingredients are listed by the first ingredient in the combination; each additional active ingredient is cross-referenced in the entry. Each products listing contains the following items: dosage, strength, route of administration, a two-letter therapeutic equivalence rating, brand name, generic name, and the name of the company that holds the FDA approval.
The various lists in the Orange Book include prescription and OTC drugs which have been approved by the FDA under New Drug Applications or Abbreviated New Drug Applications. The manual also includes lists of drug products regulated by the Center for Biologics Evaluation and Research (CBER), a list of discontinued products, a list of orphan drug designations, and a list of drugs than must demonstrate in vivo bioequivalence only if they fail dissolution.
There are three concepts of equivalence that form the foundation for the FDAs rating of multi-source drug products listed in the Orange Book: pharmaceutical equivalence, bioequivalence, and therapeutic equivalence. Pharmaceutical equivalence defines drugs which have the same active ingredients in the same dosage form, with the same strength or concentration and the same route of administration as a product that has already been approved.
Diabetes mellitus is a disease of the pancreas affecting carbohydrate, lipid, and protein metabolism. In severe cases the concentration of glucose in the serum is markedly elevated, and large amounts of glucose are excreted in the urine. Since the kidney must excrete water along with glucose, the osmotic change leads to excessive urination, which in turn leads to thirst and weight loss.
Diabetes mellitus occurs when the body is unable to produce or utilize adequate amounts of insulin. Insulin is secreted by the beta cells of the pancreas, which are contained in cord-like clusters of hormone-secreting cells called the islets of Langerhans. Insulin regulates the level of glucose in the bloodstream by binding to cells and stimulating them to allow glucose to enter. It decreases the rate of synthesis and release of glucose by the liver while increasing the rate of glucose uptake and metabolism by other body tissues. Insulin also slows the breakdown of fat and protein.
Primary diabetes is generally subdivided into noninsulin-dependent and insulin-dependent types. The disease is caused by both genetic and environmental factors. Noninsulin-dependent diabetes mellitus (NIDDM), also called Type II diabetes mellitus is the most common form. Its frequency increases with age, which accounts for its previous designation as adult-onset diabetes. However, this name is inaccurate since teenagers and young adults also can develop NIDDM.
The majority of patients with NIDDM are obese. Patients with NIDDM frequently have higher insulin concentrations in their bloodstream than do nondiabetic individuals. However, the insulin is not as effective in lowering the blood glucose as it is in nondiabetic patients. This further increases the demand on an already failing pancreas. Since at the time of diagnosis all patients with NIDDM have some insulin in their pancreas they are not "dependent" on insulin to stay alive; hence, the name NIDDM. This disorder tends to be hereditary
Patients with insulin-dependent or type I diabetes mellitus depend on injections of insulin. Without injections, these patients develop severe hyperglycemia and life-threatening ketoacidosis. Although this can occur at any age, its peak incidence is usually in the early teens. IDDM is usually diagnosed following the onset of excessive urination, thirst, and weight loss. If these symptoms are not recognized and treatment begun, coma may rapidly ensue. Though the onset of symptoms is usually abrupt, inflammation of the beta cells of the pancreas probably will have been present for years. During this time, antibodies to insulin and/or beta cells can be found in the blood of many patients, suggesting an autoimmune process.
The prevalence of diabetes mellitus dramatically increases with age. In the United States, the number of cases increases from 1.3 per 1,000 for persons under 17 years of age to 78 per 1,000 for those 65 and older. NIDDM is particularly common in certain ethnic groups, reaching approximately 25% in Southwestern Native Americans and inhabitants of many Pacific Island nations.
Two fasting plasma glucose concentrations greater than 140 mg/dl are sufficient to establish the diagnosis of diabetes mellitus in nonpregnant adults. Slightly lower glucose concentrations may indicate diabetes mellitus in pregnant women. In certain instances, if fasting glucose concentrations do not reach the diabetic range, diabetes mellitus can be diagnosed by measuring glucose concentrations following ingestion of glucose. However, glucose tolerance tests are more useful in determining the prevalence of diabetes in a population rather than in a single individual, since the results of these tests vary from day to day and year to year in the same person.
Treatment: Patients with insulin-dependent diabetes mellitus (IDDM) must receive insulin to stay alive. Insulin may be given in the form of a subcutaneous injection by needle or by infusion with a pump. Insulin can be modified so that its absorption from the subcutaneous tissue is slowed. The number of insulin injections can vary. In general, the more frequent the insulin injections, the closer the blood glucose can be kept to values observed in nondiabetic individuals. The amount of insulin must be adjusted for food intake and exercise. A certain amount of insulin is required even if food is not eaten.
Most obese patients with NIDDM can be treated by caloric restriction. The caloric content is the most important consideration, rather than the type of food eaten; eating sugar, for example, does not cause diabetes mellitus. If caloric restriction does not satisfactorily lower blood glucose, then patients should be treated with an oral hypoglycemic agent or insulin.
Common oral agents for NIDDM patients are the sulfonylureas. These drugs act primarily by stimulating insulin secretion, although they may directly influence glucose uptake by tissues. If the pancreatic beta cells are severely damaged, sulfonylureas are not effective. The glucose concentration is generally easier to control in patients with NIDDM than in patients with IDDM, since by definition patients with NIDDM have some residual insulin secretion. Treatment with oral agents or insulin is of limited value in obese patients unless they restrict their caloric consumption.
Diabetes mellitus can have both acute and chronic complications. Diabetic ketoacidosis can occur when the insulin concentration in the blood is insufficient for the patient's needs. Omission of insulin injections or an increase in the body's need due to illness or stress may precipitate ketoacidosis. Inadequate insulin levels lead to an increase in the release of glucose and ketone bodies by the liver and a decrease in metabolism of these substances by other body tissues. Since ketone bodies are acids, the body rapidly becomes more acidic, which accounts for the term ketoacidosis. Dehydration from frequent urination and/or the underlying illness makes the body less responsive to insulin. Diabetic ketoacidosis is treated with fluids and additional insulin.
Excessive lowering of blood glucose due to either insulin or sulfonylureas can cause hypoglycemia. Since the brain is dependent on glucose for energy, low glucose (generally less than 50-55 mg/dl) results in a variety of symptoms including rapid heartbeat, nervousness, sweating, hunger, and, if not treated, coma. Hypoglycemia can be treated by ingesting small amounts of carbohydrates. Unconscious patients should be revived by giving either intravenous glucose or an injection of glucagon.
Diabetes mellitus also is associated with chronic complications. It is the leading cause of blindness. Fortunately, diabetic eye disease can be readily detected and treated by an ophthalmologist before it endangers vision. It is important, therefore, that diabetic patients have regular and frequent eye examinations.
Diabetes mellitus can cause kidney damage. It may be possible to slow or prevent kidney damage by vigorous treatment of the high blood pressure that commonly accompanies diabetes mellitus. The lowering of blood lipids that frequently is associated with lowering of high blood glucose may deter these complications. High blood glucose also may directly damage tissues. Much of the research in diabetes mellitus is directed toward slowing or preventing the chronic diabetic complications
THE SYNTHETIC THYROID HORMONE DEBATE
The primary role of the thyroid gland is the endogenous production of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). These are essential hormones which regulate the rate of many metabolic processes. The production of these two hormones is regulated by thyrotropin, also called thyroid stimulating hormone or TSH, which is secreted by the anterior pituitary. TSH is, in turn, controlled by a negative feedback involving thryoid releasing hormone (TRH) secreted by the neighboring hypothalamus. The thyroid hormones and their precursors are suppressed when exogenous hormone is intorduced at levels in escess of the glands normal production.
The thyroid hormones enhance the utilization of carbohydrate stores, stimulate protein synthesis, and lower hepatic and serum cholesterol levels. Thyroid hormones are also involved in cell growth and differentiation, brain and CNS development, and the development of bones and teeth. The exact mechanisms of action of the thyroid hormone are not clearly established, although it is known that physiologic effects are mediated at the cellular level. Thyroxine is the major components of gland secretions, although it is converted in the body to triiodothyronine, the physiologically active hormone of the two.
The synthetic or exogenous thyroid agents include levothyroxine sodium, lyothyronine sodium, and lotrix, which is a combination preparation containing a 4:1 ratio of levothyroxine to lyothyronine by weight. They are prescribed as a replacement or substitution for diminished or absent thyroid function resulting from functional deficiency or removal of the thyroid gland. They are usually taken for life except in cases of temporary hypothyroidism associated with an inflammation of the thyroid gland.
Caution should be taken in prescribing synthetic thyroid hormone to patients with any allergies or who are taking other medications. Patients with other medical problems, especially heart disease, hardening of the arteries, hypertension, or a history of problems with the thyroid, adrenal, or pituitary glands, should use thyroid replacement only under the close monitoring of a physician.
There are several trade names of thyroid hormone that are approved by the FDA. These may be different compounds or different salts of the thyroid precursors, and you should not change to another manufacturers product without discussing the change with a doctor. A change will usually require blood tests to ascertain the approximate level of levothyroxine or liothyronine in the serum in order to choose the appropriate dose.
THE PHARMACOTHERAPY OF DYSLIPIDEMIAS
Dyslipidemias are disorders of lipoprotein metabolism, including deficiency or overproduction of certain lipoproteins. These disorders exist in several forms, manifesting themselves as increased total cholesterol, raised serum LDL, high serum triglycerides, or decreased levels of serum HDL. Dyslipidemias are an area of concern as repeated studies have confirmed a causal relationship between elevated cholesterol and the initiation of coronary heart disease.
The NIH founded a National Cholesterol Education Program (NCEP) to establish guidelines for the treatment of the various dyslipidemias. The first step in treating the disorder is to eliminate secondary causes of the disease. These include hypothyroidism, obesity, and a genetic predisposition to dyslipidemias (see table). A few years down the road, those with genotypes that result in one of the familial disorders will be treatable with gene therapy. Individuals with exogenous risk factors will probably not be assisted by gene therapy.
Cholesterol levels are classified into desirable, borderline and high-risk categories. Decisions regarding the treatment of hypercholesterolemia are usually based on LDL cholesterol levels and the presence of other risk factors. The target LDL in patients with coronary heart disease is 100 mg/dl or lower. Those who have not had CHD need only be at or below 130 mg/dl if two or more risk factors are present, and below 160 mg/dl if one or fewer risk factors is identified.
Dietary considerations include a high fiber diet, which will lower LDL and triglycerides while raising HDL modestly. Antioxidants such as Vitamin C, Vitamin E and beta-carotene are also protective against atherogenesis as they block the oxidation of LDL cholesterol. The NCEP has established Step I and Step II diets for those with high serum cholesterol or triglyceride levels. The diets can reduce lipid levels by up to 20%, but there is no guarantee that there will be a significant change.
If dietary changes are ineffective or simply insufficient to achieve appropriate lipid levels, the patient may turn to an arsenal of lipid lowering agents approved for prescription use. In most patients with hypercholesterolemia, HMG-CoA reductase inhibitors are the drugs of choice as they are most effective at lowering LDL cholesterol. Nicotinic acid or fibric acid derivatives may be a better choice in patients with hypertriglyceridemia.
The HMG-CoA reductase inhibitors, or statins, inhibit cholesterol synthesis. The agents are all well tolerated; less than 1% develop elevated liver enzymes and must therefore discontinue use. These agents have been shown to reduce coronary events and lead to tremendous (22%-37%) reductions in heart attacks and mortality according to a recent trial. There are some differences among the statins; the recently approved agent atorvastatin, for example, has been demonstrated as more effective than the other agents for patients with combined hyperlipidemia and may obviate the need for multiple drug therapies in high risk patients.
HMG-CoA Reductase Inhibitors (statins)
The bile acid ion-exchange resins cholestyramine (Questran) and colestipol (Colestid) bind bile acids containing cholesterol in the small intestines. This results in increased hepatic oxidation and eventual excretion of cholesterol. These agents decrease LDL by up to 20% and do not affect hepatic metabolism; they are, therefore, a good choice in patients with hepatic disease and in young patients. One drawback to these agents is a long list of drugs with which they will bind in circulation. It is important to take these agents one hour prior or at least four hours after a bile acid dose to reduce thepotential for drug interactions.
Other common methods of lipid lowering include nicotinic acid (niacin), fibric acid derivatives (fibrates), and estrogen replacement therapy. Lifibrol is also a cholesterol lowering agent, although it is not as effective as some of the HMG-CoA reductase inhibitors. Niacin and the fibrates reduce the hepatic synthesis and release of VLDL. Both agents lower triglycerides by up to 50% and raise HDL levels by up to 35%. Fibrates are particularly useful in patients with familial hyperlipidemia and
Risk Classification of Hypercholesterolemia
|Borderline Risk||200-239mg/dl||130-159 mg/dl||>35-59mg/dl|
|High Risk||>240mg/dl||>160 mg/dl||<35-59mg/dl|
diabetes. Though Hormone Replacement Therapy is not widely studied for such actions, it has been demonstrated to lower LDL by up to 22% and raise HDL in postmenopausal women Pharmacologic therapies for dyslipidemias are effective and come with few or no side effects. It is important for patients to remember, however, that they are not a substitute for a low-fat, low-cholesterol diet and adequate exercise. Lipid levels should be monitored at least every five years in adults, and more often if levels are borderline or if there is family history of the dyslipidemias. Due to the complex web of considerations with dyslipidemias, it is important that the physician and pharmacist be aware of the diagnosis and lipid levels of each patient taking lipid lowering agents.
The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of any sponsoring organizations.