Co-Director, Meharry Medical College School of Medicine
Thiazolidinedione-associated weight gain is likely because of subcutaneous adipocyte differentiation and fluid retention arrhythmia prognosis buy genuine valsartan. Although a greater number of small adipocytes may be advantageous from an insulin sensitivity standpoint heart attack ne demek cheap valsartan 80mg amex, weight gain in patients with prediabetes is of concern because many of these patients are already likely to be overweight blood pressure jumps up purchase valsartan once a day. Fluid retention and edema contribute to the increased risk of congestive heart failure associated with these agents arrhythmia 10 discount 160mg valsartan amex. As such, both rosiglitazone and pioglitazone carry black box warnings about congestive heart failure. Data from a metaanalysis of rosiglitazone clinical studies also suggest that rosiglitazone increased the odds of myocardial infarction and cardiovascular death compared with other diabetes drugs or placebo. Acarbose, an a-glucosidase inhibitor that decreases postprandial glucose concentrations, has also been investigated as a diabetes prevention agent. In addition, acarbose reduced the relative risk of cardiovascular event and new cases of hypertension by 49% and 34%, respectively. Acarbose is associated with a high incidence of gastrointestinal adverse effects and has a cumbersome dosing schedule. Thus, although the data on the ability of acarbose to prevent diabetes and reduce cardiovascular risk are intriguing, lack of patient adherence may limit its routine use in clinical practice. These patients deserve special attention for intensive management of hyperglycemia and other metabolic syndrome risk factors to decrease the risks of both microvascular and macrovascular complications. Metformin improves hepatic insulin sensitivity and, unlike most other antihyperglycemic agents, is weight neutral, or even induces modest weight loss. Sulfonylurea-associated weight gain (about 2 kg) may prompt more aggressive lifestyle modification strategies in obese patients with metabolic syndrome. The insulin-sensitizing and anti-inflammatory effects of the thiazolidinediones target the underlying pathophysiology Pharmacotherapy Self-Assessment Program, 6th Edition 119 of metabolic syndrome. Pioglitazone reduces triglycerides by about 20%, whereas rosiglitazone either has no effect or modestly increases triglyceride concentrations. The dipeptidyl peptidase-4 inhibitor, sitagliptin, is the newest oral antidiabetic agent. Sitagliptin has modest antihyperglycemic efficacy, producing a mean reduction in hemoglobin A1C of 0. In addition, sitagliptin does not appear to adversely affect blood pressure or lipid concentrations. Prothrombotic and Pro-inflammatory State Lifestyle changes leading to weight loss can result in a reduction in high-sensitivity C-reactive protein concentrations, suggesting that inflammation is reduced with weight reduction. Therapy with statins can also reduce highsensitivity C-reactive protein concentrations. Treatment with rosuvastatin 20 mg/day reduced the incidence of major cardiovascular events compared with placebo for an average follow-up of 1. Therapy with low-dose aspirin is indicated in patients with existing cardiovascular disease to reduce the risk of secondary thrombosis. Preventive Services Task Force updated its recommendations for aspirin use in March 2009. Aspirin therapy is also routinely recommended in patients with diabetes, although the evidence supporting this recommendation has been recently challenged by results from recent trials. Other Agents That Target Metabolic Syndrome Pathophysiology Rimonabant the endocannabinoid system has been implicated in the pathophysiology of metabolic syndrome, playing a role in both central and peripheral energy metabolism balance. Discovery of these receptors led to the development of endocannabinoid system antagonists, most specifically, rimonabant. Despite these findings, rimonabant was not shown to affect the percent atheroma volume measured by intravascular ultrasonography compared with placebo in a randomized trial of patients with metabolic syndrome. Psychiatric events have been more common with rimonabant than placebo, and two deaths from suicide in patients taking rimonabant have been reported. Based on these concerns, development programs for muraglitazar and tesaglitazar have been discontinued. By mimicking glucagon-like peptide-1, exenatide promotes glucosedependent insulin secretion and decreases glucagon secretion during states of hyperglycemia. Furthermore, exenatide delays gastric emptying, reduces food intake, and improves satiety. Considering that exenatide is an expensive subcutaneous injection, substantial benefits will likely have to be demonstrated for this agent to be used in patients without diabetes. Patient Education Metabolic Syndrome 120 Patient education is an important component in the treatment of patients with metabolic syndrome and can prevent the development of metabolic syndrome in those with risk factors. Because the syndrome is often the result of physical inactivity and obesity, patient education must focus on selfchange in lifestyle behaviors. For the tools and information to be used fully, it is important for the pharmacist to introduce the patient to the Web site and review some of the material available. To be maximally effective, any educational material used must be a supplement to a structured dietary and physical activity regimen prescribed by a health care professional. Although the predictive usefulness of metabolic syndrome will continue to be debated, it does have practical utility in the clinical setting.
Diseases
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The method for deriving a guideline is dependent upon the type of chemical as well as duration and frequency of exposure arteria femoralis profunda order valsartan online now. It is also important to make the distinction between an experimental dose (mg/kg) and an environmental concentration (mg/m3 or ppm) heart attack x factor buy 80mg valsartan with mastercard. In order to make safety decisions blood pressure chart bottom number valsartan 40mg fast delivery, exposure guidelines are presented as concentrations so that these values can be compared to concentrations measured by air monitoring instrumentation heart attack 90 blockage order valsartan 160 mg on-line. Short-term effects (or acute effects) have a relatively quick onset (usually minutes to days) after brief exposures to relatively high concentrations of material (acute exposures). This site is usually the skin or eyes, but includes the lungs if irritants are inhaled or the gastrointestinal tract if corrosives are ingested. Systemic effects are those that occur if the toxicant has been absorbed into the body from its initial contact point, transported to other parts of the body, and cause adverse effects in susceptible organs. Long-term effects (or chronic effects) are those with a long period of time (years) between exposure and injury. These effects may occur after apparent recovery from acute exposure or as a result of repeated exposures to low concentrations of materials over a period of years (chronic exposure). Health effects manifested from acute or chronic exposure are dependent upon the chemical involved and the organ it effects. These organs are known as target organs which are more sensitive to that particular chemical than other organs. The organs of the body and examples of effects due to chemical exposures are listed below. The respiratory tract is the only organ system with vital functional elements in constant, direct contact-with the environment. The lung also has the largest exposed surface area of any organ on a surface area of 70 to 100 square meters versus 2 square meters for the skin and 10 square meters for the digestive system. The respiratory tract is divided into three regions: (1) Nasopharyngeal-extends from nose to larynx. They filter out large inhaled particles, increase the relative humidity of inhaled air, and moderate its temperature. These passage ways are lined with ciliated epithelium coated by mucous, which serves as an escalator to move particles from deep in the lungs back up to the oral cavity so they can be swallowed. These ciliated cells can be temporarily paralyzed by smoking or using cough suppressants. The alveoli, of which there are 100 million in humans, contact the pulmonary capillaries. Less than 1 micron particles are deposited in the alveolar region by diffusion and Brownian motion. However, certain small inorganic particles, settle into smaller regions of the lung and kill the cells which attempt to remove them. Many chemicals used or produced in industry can produce acute or chronic diseases of the respiratory tract when they are inhaled (Table 5). The toxicants can be classified according to how they affect the respiratory tract. Chemical asphyxiants are gases that prevent the tissues from getting enough oxygen. Cyanide prevents the transfer of oxygen from blood to tissues by inhibiting the necessary transfer enzymes. Constriction of the airways occurs and may lead to edema (liquid in the lungs) and infection. Fibrosis producers: Chemicals that produce fibrotic tissue which, if massive, blocks airways and decreases lung capacity. Allergens: Chemicals that induce an allergic response characterized by bronchoconstriction and pulmonary disease. Solvents, such as benzene and tetrachloroethane, anesthetic gases, and many other chemical compounds can be absorbed through the respiratory tract and cause systemic effects. It provides a barrier between the environment and other organs (except the lungs and eyes) and is a defense against many chemicals. In the dermis are sweat glands and ducts, sebaceous glands, connective tissue, fat, hair follicles, and blood vessels. Chemicals can penetrate through the sweat glands, sebaceous glands, or hair follicles. Although the follicles and glands may permit a small amount of chemicals to enter almost immediately, most pass through the epidermis, which constitutes the major surface area. The top layer is the stratum corneum, a thin cohesive membrane of dead surface skin. This layer turns over every 2 weeks by a complex process of cell dehydration and polymerization of intracellular material. Below the epidermis lies the dermis, a collection of cells providing a porous, watery, nonselective diffusion medium. Melanocytes (skin pigment): Prevent damage from ultraviolet radiation in sunlight. The ability of skin to absorb foreign substances depends on the properties and health of the skin and the chemical properties of the substances. Increasing temperature of skin which causes sweat cells to open up and secrete sweat, which can dissolve solids. Adding agents which will damage skin and render it more susceptible to penetration. Absorption of a toxic chemical through the skin can lead to local effects through direct contact, such as irritation and necrosis, and systemic effects.
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These are initiated in various ways through the following three pathways (Table 5-2): 1 heart attack one direction lyrics order valsartan 160mg line. Activation of Complement Normally heart attack blues discount 40mg valsartan mastercard, complement components are present in the circulation in an inactive form blood pressure medication common discount valsartan 80mg with visa. Enzyme Activation After complement is initially activated prehypertension what to do buy valsartan cheap, each enzyme precursor is activated by the previous complement component or complex, which is a highly specialized proteinase. This converts the enzyme precursor to its catalytically active form by limited proteolysis. Alternative Pathway Microbe the pathways leading to the cleavage of C3 are triggered enzyme cascades. During this activation process, a small peptide fragment is cleaved, a membrane-binding site is exposed, and the major fragment binds. Because each enzyme can activate many enzyme precursors, each step is amplified until the C3 stage; therefore, the whole system forms an amplifying cascade. Classical Pathway Microbe Lectin Pathway Microbe Mannose Mannose binding lectin C4 C2 Binding of complement proteins to microbial cell surface or antibody C3 C3b C1 IgG antibody C4 C2 C4b 2a C4b 2a Formation of C3 convertase C3b Bb C3 convertase C4b 2a C3 convertase C4b 2a C3 convertase C3b Bb Cleavage of C3 C3 C3b C3a C4b 2a C3 C3b C3a C4b 2a C3 C3b C3a Covalent binding of C3b to microbe; Formation of C5 convertase C3b Bb C3b C5 C5 convertase C4b 2a C3b C5 C5 convertase C5b C5a C5b C5a C4b 2a C3b C5 C5 convertase C5b C5a A Late steps of complement activation Figure 5-1 Early steps of complement activation. In addition to the function of complement as a major effector of antigen-antibody interaction, physiologic concentrations of complement have been found to induce profound alterations in the molecular weight, composition, and solubility of immune complexes. The activation of complement may also play a role in mediating hypersensitivity reactions. In either case, activation of complement components from C3 onward leads to the generation of anaphylatoxins in an immediate-hypersensitivity reaction. The sequence of component activation-C1, 4, 2, 3, 5, 6, 7, 8, and 9-does not follow the expected numeric order. C3 is present in the plasma in the largest quantities; fixation of C3 is the major quantitative reaction of the complement cascade. Although the principal source of synthesis of complement in vivo is debatable, the majority of the plasma complement components are made in hepatic parenchymal cells, except for C1 (a calcium-dependent complex of the three glycoproteins C1q, C1r, and C1s), which is primarily synthesized in the epithelium of the gastrointestinal and urogenital tracts. In the classic pathway, the first step is initiation of the pathway triggered by recognition by complement factor C1 of antigenantibody complexes on the cell surface. A single IgM molecule is potentially able to fix C1, but at least two IgG molecules are required for this purpose. The amount of C1 fixed is directly proportional to the concentration of IgM antibodies, although this is not true of IgG molecules. C1s is weakly proteolytic for free intact C2, but is highly active against C2 that has complexed with C4b molecules in the presence of magnesium (Mg2+) ions. The resultant C2a fragment joins with C4b to form the new C4bC2a enzyme, or classic pathway C3 convertase. A smaller C2b fragment from the C2 component is lost to the surrounding environment. The functions of these receptors depend on the type of cell and often are incompletely understood. Effects of Complement Activation the activation of complement and the products formed during the complement cascade have a variety of physiologic and cellular consequences. Physiologic consequences include blood vessel dilation and increased vascular permeability. The most important biologic role of complement in blood group serology is the production of cell membrane lysis of antibody-coated targets. B, the properties of the proteins of the late steps of complement activationarelisted. The complement cascade reaches its full amplitude at the C3 stage, which represents the heart of the system. The C4bC2a complex, the classic pathway C3 convertase, activates C3 molecules by splitting the peptide, C3 anaphylatoxin, from the N-terminal end of the peptide of C3. Consequently, clusters of C3b molecules are activated and bound near the C4bC2a complex. Each catalytic site can bind several hundred C3b molecules, even though the reaction is very efficient because C3 is present in high concentration. Only one C3b molecule combines with C4bC2a to form the final proteolytic complex of the complement cascade. Other bound C3b molecules not involved in the C4b2a3b complex form an opsonic macromolecular coat on the erythrocyte or other target, which renders it susceptible to immune adherence by C3b receptors on phagocytic cells. The C5bC6 complex is hydrophilic but, with the addition of C7, it has additional detergent and phospholipid-binding properties as well. The presence of hydrophobic and hydrophilic groups within the same complex may account for its tendency to polymerize and form small protein micelles (a packet of chain molecules in parallel arrangement). It can attach to any lipid bilayer within its effective diffusion radius, which produces the phenomenon of reactive lysis on innocent so-called bystander cells. Once membrane bound, C5bC6C7 is relatively stable and can interact with C8 and C9. The C5bC6C7C8 complex polymerizes C9 to form a tubule (pore), which spans the membrane of the cell being attacked, allowing ions to flow freely between the cellular interior and exterior. This tubule is a hollow cylinder with one end inserted into the lipid bilayer and the other projecting from the membrane. A structure of this form can be assumed to disturb the lipid bilayer sufficiently to allow the free exchange of ions and water molecules across the membrane. The consequence in a living cell is that the influx of sodium (Na+) ions and H2O leads to disruption of osmotic balance, which produces cell lysis.
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