Elavil

Lynne M. Yancey, MD, FACEP

• Assistant Professor
• Division of Emergency Medicine
• University of Colorado Denver School of Medicine
• Aurora, Colorado

Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality joint pain treatment options order generic elavil on-line, cardiovascular disease back pain treatment yahoo elavil 50mg free shipping, and type 2 diabetes: Systematic review and meta-analysis of observational studies pain treatment and wellness center greensburg effective 10 mg elavil. Low-carbohydrate diets and all-cause and cause-specific mortality: Two cohort studies heel pain treatment youtube generic elavil 75mg line. Efficacy of and Patient Compliance with a Ketogenic Diet in Adults with Intractable Epilepsy: A Meta-Analysis pain treatment for bursitis order cheap elavil on line. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors: Low carbohydrate diets and cardiovascular risk factors pain medication for shingles pain buy elavil without a prescription. Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: A systematic review and meta-analysis. Low-carbohydratehigh-protein diet and long-term survival in a general population cohort. Founded in 1961 by a group of physicians concerned about the impact of nuclear proliferation, psR shared the 1985 nobel peace prize with international physicians for the prevention of nuclear War for building public pressure to end the nuclear arms race. Coal combustion in particular contributes to diseases affecting large portions of the u. In addition, the report addresses another, less widely recognized health threat from coal: the contribution of coal combustion to global warming, and the current and predicted health effects of global warming. Detrimental development, a higher standard of living, and health effects are associated with every aspect an increased life expectancy. Railroad tion, the discharge of carbon dioxide into the atengines and trucks together release over 600,000 mosphere associated with burning coal is a major tons of nitrogen oxide and 50,000 tons of particucontributor to global warming and its adverse eflate matter into the air every year in the process of fects on health worldwide. Coal combustion contributes to smog surface mining technique, used widely across through the release of oxides of nitrogen, which southern appalachia, damages freshwater aquatic react with volatile organic compounds in the presecosystems and the surrounding environment by ence of sunlight to produce ground-level ozone, the burying streams and headwaters. Coal combustion is also death, and slurry injected underground into old responsible for more than 30% of total u. Children are particularly susceptithe term used to describe that physiological ble to the development of pollution-related asthma state. It may also be due to the immaturity of atherosclerosis, hypertension, rheumatoid their enzyme and immune systems, which assist in arthritis, diabetes mellitus, and neuro– detoxifying pollutants, combined with incomplete degenerative disorders such as Alzheimer’s pulmonary development. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem and exacerbations is greatest among those with severe Cell Biology 2007; 39: 44–84. Coal pollutants trigger asthma attacks in comCoal pollutants play a role in the development bination with individual genetic characteristics. Conversely, long-term improvements with the development of19 and mortality from20, 21, 22 in air pollution reduce mortality rates. Recent research suggests that nitrogen oxides several studies have shown a correlation beand Pm2. In ated with hospital admissions for potentially fatal medicare patients, ambient levels of Pm2. But coal combustion also of childbearing age have blood A continued reliance has indirect health effects, through mercury levels that would cause its contribution to greenhouse gas on coal combustion them to give birth to children emissions. Global warming is already with mercury levels exceeding the for electricity will negatively impacting public health ePa’s maximum acceptable dose contribute to the and is predicted to have widespread for mercury. Because coal-fred power dren with mercury-related neuroconsequences of global plants account for more than one third of Co emissions in the u. Researchers have estimated a major contributor to the predicted that between 317,000 and 631,000 health impacts of global warming. Coal combustion contribelectricity production will contribute to the preutes to diseases already affecting large portions dicted health consequences of global warming. Based on that assessment, PsR fnds it essential  the ePa should establish a standard, based to translate our concern for human health into on maximum achievable Control technology, recommendations for public policy. In place of investment in coal (including pollution coming from coal subsidies for the extraction and complants. When our nation establishes a health-driven  there should be no new construction of coalenergy policy, one that replaces our dependence fred power plants, so as to avoid increasing on coal with clean, safe alternatives, we will prevent health-endangering emissions of carbon dioxthe deterioration of global public health caused ide, as well as criteria pollutants and hazardous by global warming while reaping the rewards in air pollutants. Characterization of particulate matter (Pm10) in particulate air pollution and the triggering of myocardial Roda, Virginia. Fine particulate air pollunet/public/25/10670/features/documents/2009/04/23/ tion and hospital admission for cardiovascular and respiratory document pm 01. Human and ecological risk assessment of coal combuson total mortality: results from 29 european cities within the tion wastes: draft, august 6, 2007. Fine particulate air pollution and hospital admission for cardiovascular and respiratory 14;57(45):1229–32. Infant mortality statistics from the 2005 period linked birth/infant death data set. Westport, Ct: Report of the Intergovernmental Panel on Climate Change Praeger; 2008. Impact of assessment Report of the Intergovernmental Panel on Climate regional climate change on human health. Historical warnings of future food inseimpacts of climate variability and change for the united states: curity with unprecedented seasonal heat. Introduction lmost half of the energy used to generate electricity in the united states comes from burning coal, as shown in a Figure 1. Coal is a major component of the economy and forms the center around which political, economic, health, and environmental considerations coalesce. With the passage of time, more and more adverse health effects have been attributed to the increasing reliance on coal. In 1952, the infamous killer fog been a number of sentinel events that link episodes in london, lasting four days, sent death rates of severe air pollution to a variety of illnesses. In the year that followed, black smoke ardous air pollutants (HaPs) emitted from coal concentrations declined by 70% plants, but did not address particulates or oxides of nitrogen and sulfur (noX and soX), now referred to as criteria pollutants. By considerhealth and any single pollutant or any single ing coal’s impact on the respiratory system, the source of the pollutant, notably burning coal, difcardiovascular system, and the central nervous fculties arise due to multiple sources of the pollutsystem, we replace a piecemeal approach with a ant in question and multiple health impacts. Big coal: the dirty secret behind america’s energy 6 energy Information administration. Coal’s Life Cycle lthough people have burned coal for hundreds of years, the demand for coal exploded during the industrial revolua tion. Initially, coal powered the steam engine and therefore became the essential fuel for transportation during the nineteenth century, when steamships and railroads fourished. By the middle of the 1800s, coal replaced charcoal in the production of iron and steel, thus flling another key role in driving industrialization. Coal became a source of energy for the generation of electricity at the end of the 1800s. Because more subjected to heat and pressure over millions of than 25% of the world’s recoverable coal reserves years. High-carbon coals produce the exemplifed by the dozens of new coal plants curmost energy when burned and low-carbon coals rently in the planning or construction stage. Rank Appearance content uses reserves production producers lignite brown, soft, 25–35 power generation 17 7 texas, north faky Dakota subbrownish-black, 35–45 power generation, 30 44 Wyoming bituminous soft cement manufacture, (powder River industrial uses basin) bituminous black, hard 45–86 power generation, 52 49 West virginia, cement manufacture, Kentucky, industrial uses pennsylvania Anthracite black, hard, 86–97 Domestic/industrial 1 less than pennsylvania glossy uses 0. In this method, vegetation, topsoil, and electricity generation provides many benefts rock are blasted and removed down to the level worldwide, and is synonymous with economic of the coal seam, which is then mined. It involves blasting ing, preparation at the power plant, combustion, down to the level of the coal seam—often hunand the disposition of post-combustion wastes. Both types of mines where the average incidence rate of nonfatal injury involve excavating shafts hundreds of feet deep, was 5. Black lung dissurface mining accounts for 69% of the coal ease is caused by inhalation of respirable coal mined in the u. When mines are abandoned, deaths may result from physical damage to surrainwater reacts with exposed rock to cause the rounding communities due to blasting at surface oxidation of metal sulfde minerals. Both slurry disposal stratein 2005 that mountaintop removal mining had gies—the construction of surface impoundments adversely impacted 1,200 miles of streams in a and underground injection into closed mines— study area that included parts of Kentucky, West may leach chemicals into groundwater supplies. Impoundment streams had been directly buried by valley fll relatfailures in the past have caused death and injury, ed to mountaintop removal mining through 2001. Coal is hauled to production and carbon content but also in pollutplants by train, truck, barge, and conveyor. Diesel engines curportionate share of electric utility-related pollurently produce approximately 1. Coal plants emit approximately 87% of total nox and 63,000 tons of small particles (less than utility-related nitrogen oxide pollution, 94% of 2. Coal trains and trucks also reeconomic sectors, coal plants are responsible for lease coal dust into the air as they move, degrading a large share of human-caused air pollution: they air quality and exposing nearby communities to are the single largest source of sulfur dioxide, merdust inhalation. Coal combustion harmful pollutants designated under the Clean releases over 70 harmful chemicals into the enviair act. Gas byproducts are emitted into the ants: nitrogen oxides, ozone, sulfur oxides, paratmosphere through smokestacks. Health effects populations ozone ozone is a highly ozone is formed Rapid shallow breathing, children, elderly, corrosive, invisible when nitrogen airway irritation, coughpeople with asthma gas oxides (nox) react ing, wheezing, shortness or other respiratory with other pollutants of breath. Sulfur so2 is a highly corso2 is formed in the coughing, wheezing, children and adults Dioxide rosive, invisible gas. Nitrogen A family of chemical nox is formed when nox decreases lung funcelderly, children, oxides compounds includcoal is burned. Mercury A metal that occurs mercury is released Developmental effects in Fetuses and children naturally in coal. Coal-fred associated with emissions of nitrogen oxides, sulpower plants are responsible for two thirds of the fur dioxide, and Pm from coal-fred power plants nation’s sulfur dioxide emissions. It found that opposed to allowable ambient air levels, are set damage to human health or the environment was by the ePa. NoteS mercury is the HaP of greatest concern emitted through coal combustion, due to its impacts on 1 Goodell J. Relations between health indicators and residential proximity to coal mining in West Virginia. Power plant emissions: particulate matter-related 19 national Research Council Committee on Coal Waste Imhealth damages and the benefts of alternative emission repoundments. Costs and Benefts of energy Production and Consumption; natural Resources Defense Council, 2007. Coal’s Effects on the Respiratory System irtually all airborne or less of the predicted value, children exposed to pollutants gain acthe highest levels of particulates were almost fve cess to the body via times more likely to fall into the abnormal range V the respiratory tract. Various measures of lung function were made periodically and correlated with their exposure to various pollutants. During normal development, the amount of air that can be forcibly exhaled in one second (FeV1) increases with age. We now know of Ros can be increased through exposure to that some of these free radicals exert critical environmental substances such as air pollucontrols over normal cellular metabolic process tion, tobacco smoke, pesticides, and solvents. Free radicals and antioxidants in normal physiological funcof one molecule of hydrogen and two moletions and human disease. Reactive oxygen species, such as ignore early symptoms of an asthma exacerbation free radicals and oxygen ions, appear to be cenand fail to seek treatment, leading to attacks of tral to this process. It matters little whether the infammation is caused by particulates or other pollutants. In the those authors conducted a prospective cohort asthmatics, the concentration of glutathione, an study of 271 children younger than 12 who had antioxidant that protects cells from free radicals, physician-diagnosed asthma. Rigorous made the children less able to withstand oxidative statistical techniques were used to examine the stress and more susceptible to the development of relationship between ozone levels below ePa stanan asthmatic attack. Fine particulate increases combustion of coal, the pollutants they studied inof 10 μg/m3 were associated with an 8% increase in cluded those produced by coal burned by electrical lung cancer mortality. While smoking toas the consequence of burning coal, it is possible bacco, radon and other radioactive gases, secondthat burning coal places those exposed to coalhand smoke, asbestos, arsenic, nickel compounds, related pollutants at greater risk for developing and other airborne organic compounds have been lung cancer. NoteS First among these was a study of seventh Day adventists who lived in California. J allergy Clin Immunol 2005; were also found, however only the association with 115(4):689–699. Pulmonary infammaIn the Harvard six Cities study, lung cancer tion by ambient air particles is mediated by superoxide anion. Coal’s Effects on the Cardiovascular System he american Heart death in the united states. By convention, and for purposes of monitors has been the most important factor in the detoring air to evaluate compliance with air quality clines in death rates attributable to coronary heart standards, the Pms of greatest concern are those disease over the past decades. First event 700,000 animal studies are well suited to studying pulRecurrent event 500,000 monary infammation and oxidative stress, mechanisms that may be important in cardiac disease congestive heart failure 550,000 pathogenesis. In a study of hyperlipidemic rabbits, suwa, et immunological and infammatory responses and al. Defbrillation how cardiovascular is transient but quite painful, and occurrence that can found in hospital emergency room records or examinadisease relates to patients are instructed to seek medition of defbrillator data extracted cal attention after an event. Peters and her colleagues also investigated the relationship between acute myocardial infarctions (mI) and air pollutants. Compared to control Percent rate increase Admission Lag (95% confdence periods, there was an increase in the probability of diagnosis days* interval) an mI in association with elevations in Pm2. In addition, there was a delayed response to a peak occurring a full day before an heart failure 0 1. Fine particulate air two large studies using health outcomes such pollution and hospital admission for cardiovascular and respiraas mortality in relation to day-to-day changes in tory diseases. However, the results were Files to look for associations between particulate remarkably similar to those observed in the u. Cities with high no2 concentrations found increases in all categories, with the largest had death rates that were approximately four found for congestive heart failure, where a 1. Circulation 2004; late concentration of 10 μg/m3 was associated with 109(21):26552671. Inhalation of fne particulate air pollution and ozone the cardiovascular health of the u.

Phenylbutyrate is combined with benzoate knee pain treatment purchase elavil on line, which undergoes conjugation with glycine and thus further drains the liver’s nitrogen pool [203] pain management for my dog discount elavil 10mg free shipping. In addition to organic acids pain medication for dogs after neuter buy 25mg elavil mastercard, defects of urea cycle enzymes other than arginase are also treated with citrulline or arginine joint and pain treatment center lompoc ca buy elavil master card, which both reduce free ammonia pain management in uti buy 75 mg elavil amex. Citrulline is used with enzyme defects that are located upstream of itself within the cycle pain treatment for dogs with cancer buy elavil line, and so do not interfere with its conversion to arginine. Arginine is used in enzyme defects that disrupt this conversion, except in arginase deficiency [202]. Citrulline contains only one of the two nitrogen atoms that will eventually be found in urea. Utilization of exogenous citrulline by the urea cycle will therefore result in a net elimination of nitrogen. In contrast, arginine already contains both nitrogens destined for urea synthesis; exogenous arginine thus cannot directly improve the nitrogen balance. It follows that the reduction of ammonia by arginine must be due to some regulatory effect. A possible answer involves the anaplerotic conversion of glutamate to ornithine (reactions 10 and 11 in Figure 10. The throughput of this pathway must in some way be controlled by the current level of urea cycle intermediates. This may occur through inhibition either by arginine directly or by ornithine, which is produced from arginine by arginase. In either case, a low level of arginine would disinhibit synthesis of ornithine from glutamate. Since glutamate inhibits glutaminase [204], consumption of glutamate would then stimulate its own replenishment by glutaminase, and with it the release of ammonia. The depletion of lymphocytes leads to severe combined immunodeficiency syndrome, that is to defects of both cellular and humoral immunity. Since lymphocytes originate in the bone marrow, the problem can be addressed by allogenic bone marrow transplantation, which, however, is a severe intervention and requires 10. Nucleotides can enter and leave cells by facilitated diffusion, so that they can encounter the enzyme in the extracellular space. The enzyme therefore does not have to enter the cells to be effective, which makes this form of therapy relatively straightforward. Since the enzyme used for therapy is not of human origin, repeated application is prone to induce antibodies, which will inactivate the enzyme and may cause allergic reactions. The phosphorylation of deoxyadenosine is catalyzed both by deoxyadenosine kinase and, although that enzyme’s name does not suggest it, also by deoxycytidine kinase. When lysosomal enzymes from such degradative pathways are deficient, the corresponding substrates accumulate, which typically results in organ enlargement and in loss of organ function. Depending on the particular 226 10 Intermediate metabolism, diabetes and atherosclerosis substrate and enzyme, the defect can be manifest in a specific organ, or it may affect a range of organs or tissues. Gene therapy is still mostly experimental, and drug therapy is applicable in only a few cases. Lysosomal enzymes are active only in the acidic milieu of the phagolysosomes, which is also the place where the substrates are transported to . Therefore, therapeutically applied enzymes must enter the phagolysosomes as well in order to be useful. In several cases, this is facilitated by the glycosyl moieties of the enzymes, which are recognized by cellular carbohydrate receptors that mediate endocytosis. Pompe disease the defective enzyme in this disease is acid maltase, which cleaves α-1,4-glucosyl bonds and functions in the lysosomal degradation of glycogen particles. Depending on the specific mutation present, the enzyme defect can vary in severity, and muscle weakness can accordingly become clinically manifest in early childhood or only during adolescence. The disease is treated with enzyme replacement therapy using the recombinantly expressed human enzyme. Cellular uptake and lysosomal targeting are mediated by mannose6-phosphate receptors on the target cells. For expression of the enzyme, cell cultures have been genetically engineered so as to maximize the number of mannose-6-phosphate residues incorporated into the enzyme molecule during posttranslational modification [207]. Gaucher disease the enzyme defect in Gaucher disease concerns glucocerebrosidase, which cleaves the glucose headgroup from glucocerebroside, a sphingolipid that occurs in cell membranes (Figure 10. Only a small fraction of the surplus organ mass consists of accumulated lipid; the pathogenetic mechanism that leads to the additional organ enlargement is not exactly understood. Since macrophages originate in the bone marrow, transplantation of bone marrow is an effective and established therapeutic option, and gene therapy of bone marrow stem cells an experimental one. Enzyme therapy again requires uptake of the enzyme molecules into the phagolysosomes. Macrophages have multiple classes of cell surface receptors that trigger endocytosis. One class are lectins, which bind to the cell surface oligosaccharides of microbes and initiate their ingestion. To facilitate this interaction, the enzyme is partially deglycosylated so as to expose the mannose residues contained within its native glycosyl moiety (see Figure 10. In addition to enzyme therapy, Gaucher patients are being treated with inhibitors of glucocerebroside synthesis such as miglustat (Figure 10. A: Lysosomal β-glucosidase or glucocerebrosidase cleaves the glucose moiety from glucocerebroside (glucosylceramide), a membrane lipid. C: Plasma clearance of native β-glucosidase, and of a partially deglycosylated enzyme in which all sugar moieties distal of the mannose residues were removed. The rate of disappearance from the plasma reflects uptake by macrophages via mannose receptors. D: Structure of miglustat, an inhibitor of glucocerebroside synthesis that is used in the treatment of Gaucher disease. Serendipitously, miglustat was also found to inhibit spermatogenesis in mice, raising hopes for a new approach for male contraception. Monosodium urate is poorly soluble, and at elevated levels it forms crystals in connective tissues, particularly within joints. Urate crystals trigger inflammation by a recently elucidated mechanism [210], which leads to the characteristic gouty arthritis. While inflammation occurs acutely and intermittently, the underlying deposition of urate crystals is a long-term process. It is subject to glomerular filtration and to both reuptake and active secretion by tubular epithelial cells. The reaction carried out by adenosine deaminase is shown in red, and the two successive reactions catalyzed by xanthine oxidase are shown in blue. Typically, when present in the lumen of the tubule, they will compete with urate reuptake; this is the mode of action of uricosuric drugs such as benzbromarone or probenecid. On the other hand, when present inside the tubular epithelial cells, they may become substrates for exchange and therefore increase the rate of urate reuptake, as is the case with the metabolites of pyrazinamide (see Figure 10. The sugar moieties are utilized, while the pyrimidine and purine bases are mostly degraded and excreted. Gout is promoted by food and beverages that are rich in nucleic acids or nucleosides, such as, for example, meat and beer. Accordingly, dietary restrictions placed on such foods are a cornerstone of therapy. Fructose has been linked to increased uric acid production both statistically [212] and experimentally [213, 214]. Fructokinase, the first enzyme in fructose degradation, produces fructose-1-phosphate more rapidly than it is utilized. The transiently sequestered phosphate will eventually be brought back into circulation by the degradation of fructose-1-phosphate, which starts with aldolase B. The severe liver cell damage characteristic of this disease is again due to phosphate sequestration, which, however, is much more pronounced in this case. While heterozygous carriers of the enzyme defect don’t suffer acute liver damage, they still have an increased likelihood to develop gout in response to a diet rich in fructose or sucrose. Since gout is typically associated with an overly rich diet, one may be surprised to learn that it also afflicts patients with anorexia nervosa [215], who compulsively starve themselves to an often dangerous degree. Gout in anorectics is not due to increased synthesis of uric acid but rather to its increased retention. In starvation, triglycerides are broken down and converted to acetoacetate and β-hydroxybutyrate, the so-called ketone bodies, which serve as surrogate substrates for glucose. In addition, the acidosis (accumulation of acids) that goes with ketone body formation lowers the pH value of the urine, which promotes urate reuptake by way of nonionic diffusion. Alcoholic beverages are often assumed to promote gout, but this is not uniformly the case; beer does it, while wine does not [216], suggesting that ingredients other than alcohol itself are important. At high dosages, alcohol promotes acidosis by stimulating both lactate and ketone body formation, which should again promote gout through increased renal retention of uric acid. Degradation then stops at the level of hypoxanthine or xanthine, which are more readily excreted, presumably because they are exempt from tubular reuptake. Treatment of acute inflammatory episodes uses colchicine, cyclooxygenase inhibitors, and corticosteroids. It inhibits actin polymerization and with it cellular motility, including the migration and secretory activity of leukocytes. The molecular mode of action resembles the cancer drug vinblastine (see Section 12. As suggested by this similarity, colchicine treatment can cause considerable toxicity. Colchicine is an alkaloid that inhibits actin polymerization and exerts anti-inflammatory effects. Benzbromarone inhibits the tubular reuptake of uric acid and so increase its renal elimination. Salicylic acid as well as the metabolites of the tuberculostatic drug pyrazinamide, pyrazinoic acid and 5-hydroxypyrazinoic acid, act as exchange substrates for uric acid in tubular reuptake and therefore reduce its renal elimination. It is particularly common in acute lymphomas and leukemias, in which no surgery is performed that would remove the bulk of the malignant cell mass before application of cytotoxic chemotherapy (see Chapter 12). The rapid destruction of a large number of tumor cells by chemotherapy, followed by the degradation of the nucleic acids contained within, produces a flood of uric acid that precipitates within the tubules of the kidney. However, under this regimen, xanthine may reach excessive levels and also precipitate within the kidneys, again causing an acute and potentially lethal nephropathy [217]. A therapeutic option that avoids accumulation of xanthine is enzyme therapy with urate oxidase, which catalyzes the conversion of uric acid to allantoin, a more water-soluble substance that is also excreted with the urine. Since the capacity of the kidneys for tubular reuptake of glucose is limited, excess glucose in the primary filtrate passes down the nephron, taking water along with it by way of osmosis. The two major forms of diabetes are both related to insulin, the major hormone controlling glucose transport and metabolism. In type 1 diabetes, the insulin-producing β cells of the pancreatic islets are destroyed by an immunological cross-reaction, which is triggered by infection with certain serotypes of Coxsackievirus. According to its typical age of onset, type 1 diabetes is also named juvenile diabetes. Here, the β cells are not destroyed, and in the early stage insulin secretion may be even higher than normal. The underlying molecular mechanism of insulin insensitivity is not yet fully understood, but one aspect is the reduced degree of activation of the insulin receptor in response to hormone binding. This triggers a number of phosphorylation cascades, at the end of which the activities of glucose-utilizing enzymes and glucose transporters are upregulated, whereas pathways that provide glucose are inhibited. Regulation by insulin occurs both through the phosphorylation of existing enzyme molecules and at the transcriptional level. The complete pathway comprises two enzymes in addition to urate oxidase [218], but the reactions catalyzed by these occur also without enzymatic catalysis. Nerve cells, red blood cells, and some other cell types strictly require glucose and import it with or without insulin. If insulin activity is lacking, these major tissues cease to consume glucose, which causes it to accumulate in the blood. Metabolism Dysregulation of metabolic pathways further amplifies the accumulation of glucose and also causes additional metabolic turmoil. In the liver, glucose production is ramped up by the activation of glycogen breakdown and gluconeogenesis. Muscle cells break down protein and release amino acids, which are utilized for gluconeogenesis in the liver. Fat cells break down triglycerides and release fatty acids, which the liver converts to ketone bodies. The acidosis that accompanies ketone body formation,1 as well as the increased osmotic activity of the blood plasma due to the high glucose levels can impair the function of the brain, resulting in diabetic coma. This can occur in fresh, undiagnosed and untreated cases of diabetes, as well as in patients who are adequately treated but whose metabolism becomes derailed by infectious diseases or other causes. Long-term complications Long-term complications of diabetes are ascribed mostly to the effects of chronically elevated blood glucose. The lens of the eye suffers cataract; this is due to insulin-independent uptake of glucose and its subsequent conversion to sorbitol by aldose reductase. A similar pathogenic mechanism has also been assumed for other kinds of diabetic organ damage such as polyneuropathy, that is, degeneration of peripheral nerves. This hypothesis has motivated the development of aldose reductase inhibitors, but these have not demonstrated a major clinical benefit. Excess blood glucose can be converted to triglycerides and cholesterol in the liver, which will give rise to elevated blood lipoproteins. Such concentrations can be reached with ketogenic diet, which is useful in epilepsy that is refractory to conventional drug treatment [219]. The possibility that acetone narcosis is a causative factor in diabetic ketoacidotic coma has been considered and dismissed [221]. Type 2 diabetics frequently require it, too, although in the early stages dietary carbohydrate restriction and oral antidiabetic drugs may be sufficient. The various forms and modes of application of insulin are considered in Section 14.

Effects of testosterone replacement in testosterone pain research treatment impact factor discount generic elavil uk, from the second to the fifth decade of hypogonadal men southern california pain treatment center pasadena buy 10 mg elavil mastercard. He compounds typically use 100 to 200 times the noris a good athlete who would like to get a college mal dose and will cycle or stack multiple anabolic scholarship and thinks that if he can increase his compounds together in an effort to enhance the bimuscle strength pain diagnostic treatment center sacramento best order for elavil, he will get better and win a scholological effect chronic pain treatment guidelines discount 75mg elavil free shipping. He knows of some other athletes who are Common endocrine side effects of these comusing anabolic steroids and requests your help pain management shingles head discount 75 mg elavil with mastercard. Surveys inhepatotoxicity hip pain treatment exercises buy cheap elavil, suppression of high-density lipoprodicate that in the United States 6% of high school tein cholesterol, increased cardiovascular risk, inathletes, 20% of college athletes, and more than sulin resistance, and decreased thyroid hormone 50% of professional athletes in certain sports use or production. However, it compounds does result in increased muscle mass, is important to educate him about the risk–benefit strength, and endurance. Several classes of drugs have been associated with aging, but that is not entirely accurate. It has a shorter onset of action and can be used dal artery, and three major sets of veins, superficial, inin smaller doses than sildenafil. The pudendal nerve is the major sothe pharmacological agents useful in this disorder may matic pathway innervating the male genitalia. Such a classification system takes into acripheral nerves, central neural pathways are involved in count the mode of drug action, the route of administrathe process. These central mechanisms interact during tion, and the means by which target organ selectivity is normal sexual activity and require complex coordinaachieved. A therapeutic taxonomy of treatment for erectile dysfunction:An evolutional imperative. The injection does not appear to produce plications were frequently required for satisfactory any long-term side effects on penile smooth muscle. Compounds with relatively short dura(alprostadil urethral suppository or medicated urethral tion of action were found to be less than satisfactory in system for erection) is also an effective therapeutic maintaining penile erections. The intracavto take advantage of the differing onset and duration of ernosal injection of alprostadil. Dopamine appears to have an imporexerts a number of effects, including systemic vasodilatant role in normal erectile function. Apomorphine is a tion, inhibition of platelet aggregation, and stimulation D1-like, D2-like dopamine receptor agonist. Apomorphine can be the drug of choice in depends on its being injected intracavernosally or adpatients with coexisting benign prostatic hyperplasia ministered transurethrally or intraurethrally. Attempts to buffer papaverine to render it more suitable for intracaverAndrogens: Testosterone nosal injection have not been entirely satisfactory, and Androgen deficiency can lead to decreases in nocturnal such delivery may still lead to intracorporeal scarring. Hypogonadism is associated with impotence, yet erection in response to visual stimulaPhentolamine tion is preserved in men with hypogonadism, suggesting that androgens are not essential for erection. Phentolamine (Vasomax) is a nonselective couraged unless the cause is clearly related to hypogoadrenoceptor blocking agent (see Chapter 11), and like nadism. Androgen replacement regimens for treating tration, phentolamine has a plasma half-life of about 30 male hypogonadism include long-acting intramuscular minutes and a duration of action of 2 to 4 hours. Androderm) and topical testosterone gel (Androgel) are Phentolamine has been used in combination with also available. Transdermal delivery systems can provide a may cause orthostatic hypotension, reflex tachycardia, more constant serum testosterone level than do intracardiac arrhythmias, and rarely, myocardial infarction. Other -adrenoceptor receptor antagonists include yohimbine, phenoxybenzamine, and thymoxamine. Papaverine is particularly both 1and 2-adrenoreceptors, although it has a greater known as a smooth muscle relaxant and vasodilator. All three of these -receptor principal pharmacological action is as a nonspecific vablocking drugs can induce penile erection, but their efsodilator of smooth muscles of the arterioles and capilfects are generally less consistent and less effective than laries. Yohimbine is only moderately efspond differently to papaverine administration both in fective in treating patients with organic impotence, and intensity and duration. Papaverine decreases the resistside effects may include postural hypotension, heart palance to arterial inflow and increases the resistance to pitations, fine tremors, and cavernosal fibrosis, especially venous outflow. Papaverine–phentolamine combinations have been used in self-injection procedures. Sildenafil (Viagra) was developed more than 10 years Papaverine doses may range from 15 to 60 mg. It 64 Drugs Used in the Treatment of Erectile Dysfunction 739 proved ineffective in these applications but was shown tric oxide. Injected intracavernosally it can produce peto affect the smooth muscles of the penis. Sildenafil enhances erection by Minoxidil, an antihypertensive agent, produces arteaugmenting nitric oxide–mediated relaxation pathways. An initial dose of 50 mg is dose-related increase in penile arterial inflow, cavtaken about an hour prior to sexual activity to induce ernous smooth muscle relaxation, cavernous outflow penile erection. Inso-called salvage therapy in men who do not respond to jected intracavernosally, forskolin has been of limited intracorporeal injections of other agents. Headache is a common side effect, as are flushing Other herbal remedies or so-called natural products and rhinitis. More serious side effects include definite or purportedly can enhance male sexual activity. Natural prosexual agents of herbal origin include Epidemicum sagthatum, Tribulas terrestris, and Murira puama. Their use in folk medicine Trazodone in China and other countries is likely due to their sexual Trazodone (Apothecon) is also classified as an antidestimulating properties and their aphrodisiac effects. Drug Interactions Trazodone may cause priapism and enhance libido, and it prolongs nocturnal erections. It can more affected by aging and disease processes than are be used alone or in combination with yohimbine. However, it may be an operly man (see Chapter 6) influence the frequency of aption for selected patients, particularly those with perpearance of adverse reactions between several coadformance anxiety or low libido. For example, the concomitant use of sildenafil and nitroglycerin is contraindicated by cardiovascular complications. Also, Other Agents the use of testosterone in the presence of androgenMany other drugs and herbals exhibit varying degrees dependent tumors may promote tumor growth. Some have Sildenafil has other minor adverse effects, such as undergone limited clinical trials, while others are assoheadache, nasal congestion, and flushing. Generally, these agents clinically significant drug interactions between sildenafil are not particularly effective and are not widely used and apomorphine. Other drugs can either inis not unique and would likely be present with other crease or decrease serum levels of sildenafil. The resultant difect can be exacerbated by other vasodilatory drugs and minished first-pass metabolism and increased bioavailby the simultaneous ingestion of ethanol. Sildenafil scribed as does not appear to inhibit other forms of the en(A) Selective inhibitor of phosphodiesterase type 5 zyme. Sildenafil has no actions on either serotonin (B) Selective serotonin uptake inhibitor receptors or -adrenoceptors. Apomorphine is an older drug with dopamine re(D) -Adrenoceptor blocking agent ceptor agonist properties. The other choices are agents that possess (C) Actions are mediated only centrally erectogenic properties. The only time testosterone is indicated for the (D) Alcohol treatment of erectile dysfunction is if the cause is 4. All of the following classes of agents may produce clearly related to hypogonadism. Pharmacology of erectile function and (E) -Adrenoceptor blocking agents dysfunction. Drug-related erectile dystreatment of erectile dysfunction in which of the function. He states that he has a family history of diabetes Whether or not there is a vasculogenic problem mellitus but is not receiving any insulin or oral hypofrom the diabetes mellitus cannot be determined. He is married and has fathered two the blood glucose is elevated, and a workup for dichildren, aged 12 and 15. Based on this medical history and the hormone levels, what treatment would you initiate? The hormones T4 and T3 are iodineerate to maintain circulating thyroid hormone levels. Every tissue in acts to regulate the concentration of thyroid hormones the body is affected in some way by thyroid hormones, in the blood by controlling their synthesis and secretion and almost all cells appear to require constant optimal by the thyroid gland. It is Thyroid hormones exert a wide variety of physiointrinsic to the thyroid gland and acts to ensure that an logical actions through genomic and nongenomic mechadequate supply of iodide is extracted from the blood anisms and influence the metabolism of proteins, carand made available for thyroid hormone synthesis debohydrates, and lipids; cell morphology; membrane spite variations in dietary iodine intake. Relatively constant circulating pothyroidism resulting from dietary iodine deficiency. In concentrations of T4 and T3 are required for normal iodine-replete areas of the world, most thyroid disorgrowth and development and the proper functioning of ders are the result of autoimmune disease. The sympthe neural, reproductive, cardiovascular, gastrointestitoms manifested in hypothyroid and hyperthyroid nal, and hematopoietic systems. Unlike most other horstates are largely independent of any underlying disormones, whose circulating concentrations vary widely in der of the thyroid gland itself; they are a function of the response to external and internal stimuli, the circulating degree of hormone deficiency or excess. Selenium in the form of selenocysteine is a required Two competing pathways are involved in the clearance of component for three enzymes that remove iodide from I from the blood: renal filtration into urine and thyroidal thyroid hormones. The renal clearance rate for I (30–50 mL/minute) pathway by which T4 and T3 are cleared from the sysvaries only with the glomerular filtration rate. After secretion by the thyroid gland, T may be the thyroidal I clearance rate is autoregulated to main4 deiodinated to yield either T or the physiologically intain an absolute thyroidal I uptake rate of approximately 3 active reverse T (3,3,5 -triiodothyronine, or rT). To accomplish this, the thyroidal I 3 3 3 and rT3 are further deiodinated to form less active clearance rate may vary (3 to 100 mL/minute) depending metabolites. Selenium, like iodine, is deficient in many on the concentration of I in the blood. Thyroid follicular cells also remove iodide (I) the cell against both a concentration gradient and a negfrom the blood and concentrate it within the follicular ative potential (Fig. Within the follicles, some of the tyrosyl residues licular cell membrane, an iodide pump actively transports of Tg are iodinated, and a few specific pairs of iodotyrosyl residues may be coupled to form T4 and T3. Thus, T4,T,3 and iodine (in the form of iodinated tyrosyl residues) are found within the peptide structure of the Tg that is stored in the follicular lumen. Extracellular Follicular Cell Follicular Lumen the secretion of T4 and T3 requires the uptake of folFluid licular contents across the follicular cell apical membrane, the enzymatic release of T4 and T3 from peptide -50 mV -10 mV Ilinkage within Tg, and the transport of T4 and T3 across the follicular cell basal membrane to the blood. Iodine is naturally K+ Tg present in water and soil, although some soils contain very low amounts. These endocytotic vesicles miof I within the follicle may be as high as 250 times that grate from the follicular cell apical membrane toward of the blood. The lysosomes eventually fuse the thyroidal mechanism used for concentrating with the endocytotic vesicles to form lysoendosomes. However, none of these aniodothyronines (T4 and T3), and other free amino acids. The ability the basal plasma membrane into the pertechnetate and of the thyroid gland to concentrate radioactive pertecheventually into the circulation. The perchlorate and thiocyanate discharge the T4 and T3 that are released from the thyroid tests make use of the ability of these anions to inhibit I gland are firmly but reversibly bound to several plasma transport to test for defects in the incorporation of I proteins. The amount of T4 or Coupling of Iodotyrosines T3 entering the cells and the ultimate physiological reto Form Iodothyronines sponse are directly related to the plasma concentrations of free T4 and free T3. Nevertheless, it carries about 70% of the circulating T4 and T3 by virtue of Storage of Thyroid Hormones its high affinity for the two hormones. Transthyretin, forand Iodine in Colloid merly known as thyroxine-binding prealbumin, binds only about 10 to 15% of the hormones. In normal humans on an iodine-sufficient diet, Tg makes up approximately 30% of the mass of the thyroid gland and represents a 2to 3-month supply of hormone. Thyroid Hormone Plasma Concentrations and Various Kinetic Parameters Secretion of Thyroid Hormones the secretion of T4 and T3 is a relatively complex T4 T3 process because T4 and T3 are stored in the peptide Plasma concentration structure of Tg within the follicular lumen and therefore Total 7. Three deiodinase isoenzymes, encoded on three distinct genes, catalyze the reductive deiodination. The essential trace element selenium therefore plays an important role in thyroid hormone economy. Circulating T4 odeiodination of T4 to yield T3 produces a more active and T3 are also bound by high-density lipoproteins metabolite. Up to 80% of the circulating T3 originates from the thyroid hormone transport proteins are not esdeiodination of T4. Rather, they participate in (D1) activity in the liver, where most of the T3 formed is the maintenance of a steady supply of free hormone to exported into the circulation. Because of the presence of the binding proteins in to yield T3 is catalyzed by another deiodinase (D2). It the plasma, the size of the circulating thyroid hormone appears that D2 catalyzes T3 from T4 for local cellular pool is quite large, and both T4 and T3 have very long demands independent of circulating T3. The total amount of zyme involved in the reductive deiodination of T4,T,3 thyroid hormone bound to plasma proteins is about three and other iodothyronines is D3. The sole action of this times that secreted and degraded in the course of a single enzyme is the removal of iodide from the inner ring of day. This changes in rates of thyroid gland secretion or hormone arrangement allows for control of thyroid hormone acmetabolic clearance on plasma concentrations of free tion at the cellular level. Sodium iodide symporter H2O2 generation activity Thyroglobulin synthesis I conductance of the apical Cellular Uptake and Intracellular membrane Binding of T3 to Nuclear Thyroid Thyroperoxidase synthesis Hormone Receptors Hormone synthesis Endocytosis and hydrolysis Free T4 and T3 can enter cells by carrier-mediated facilof colloid itated diffusion or active transport. After gaining access Hormone secretion Type 1 deiodinase activity to the cell interior, T4 may undergo 5 -monodeiodinaHypertrophy tion to yield T3.

The initial rapid rise in insulin that follows a rise in glucose is termed the first phase of insulin Insulin is usually administered subcutaneously pain treatment for endometriosis order elavil 75 mg on-line. Insulin acts in stages pain treatment center of greater washington justin wasserman buy discount elavil 50 mg online, with the initial events related to receptor tyrosine kinase activity pain medication for uti discount 10 mg elavil with amex. The final stage includes the glucose transport molecules themselves quad pain treatment elavil 50 mg with amex, enzymes for glycogen and lipid synthesis pain medication for dogs advil order generic elavil on-line, and proteins involved in the hormone’s action on gene expression and cell growth arch pain treatment running discount elavil 10mg overnight delivery. Intramuscular injecand by the reductive cleavage of the insulin disulfide tions of insulin are used less often because absorption is bonds by glutathione–insulin transhydrogenase. Being a polypeptide hormone, insulin is kidney, insulin that undergoes glomerular filtration is alreadily inactivated if administered orally. In emergenmost completely reabsorbed and metabolized within the cies, such as severe diabetic ketoacidosis, insulin can be proximal convoluted tubules of the nephron. Clinical studies are examining the efficacy and safety of inhaled insulin, which may be promising for some patients. Hepatic insulinases destroy Diabetes mellitus affects approximately 5 to 8% of the approximately 50% of circulating insulin, with the repopulation. A large number of individuals are asymptomainder degraded by circulating proteases. The reonly a relatively small amount of the total endogenous cent rise in obesity in the United States accounts for insulin secreted ever reaches the peripheral tissues. Although insulin treatof insulin, the liver and kidney are the principal sites of ment has greatly increased the life expectancy of the dihormone uptake and degradation. Hyperglycemia is a common end point for all predispositions to the development of the diabetic state. Predisposing factors appear to include certain identified in humans, including a defective binding of inmajor histocompatibility complex haplotypes and ausulin to a receptor and a blunting of insulin signal transtoantibodies to various islet cell antigens. Conditions associated with elevated insulin levsion of the autoimmune response is characterized by els (hyperinsulinism), such as obesity, may be the result lymphocytic infiltration and destruction of the pancreof down-regulation in the number of insulin receptors, atic cells resulting in insulin deficiency. The extent to which receptor regulation is, a diabetic state that is most effectively managed by inactually participates in adjustments to changing physiosulin therapy. Physiological or psychological stress also can low-density lipoprotein cholesterol). Gestational diabetes als have demonstrated that the risk of developing mellitus is a condition that develops during the second chronic complications of diabetes is reduced by achievtrimester of pregnancy; the cause may be rises in human ing good glycemic control. This can be accomplished by placental lactogen and other hormones that contribute a combination of diet, exercise, and rational pharmacoto insulin resistance. This condition usually resolves durlogical therapy directly targeted to optimize diabetes ing the postpartum period. Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes. Treatment regiThere are only two major sources of blood glucose: exmens that have proved effective include a calorieogenous, or the ingestion of dietary carbohydrate, and restricted diet in combination with exogenous insulin or endogenous, which is contributed by hepatic and renal oral hypoglycemic drugs. In diabetics, exogenous and endogenous glutoms of diabetes, insulin remains universally important cose is not used effectively, and it accumulates in the in therapeutic management. Protein catabotends from the totally asymptomatic individual to one lism and the rate of nitrogen excretion are increased with life-threatening ketoacidosis, therapeutic managewhen blood insulin falls to low levels; stimulation of hement must be highly individualized. Many diabetof ketone bodies, such as acetoacetic acid, -hydroxybuics aim to achieve an average blood glucose below 150 tyric acid, and acetone. Unstable or ketoacidosisnous substances, and ketone bodies promote osmotic prone diabetics are difficult to maintain with a single diuresis that can result in dehydration, electrolyte abdose of either intermediateor long-acting insulin; they normalities, and acid–base disturbances. Diabetic keusually require multiple injections of combinations of toacidosis is the end result of insulin deficiency in unshort-, intermediate-, and/or long-acting insulin prepacontrolled type I diabetes. Both diabetic ketoacidoCommercially available insulins differ in their onset of sis and hyperosmolar coma are medical emergencies action, maximal activity, and duration of action (Table that require prompt insulin administration and intra67. Short-acting or regular insulins (Humulin R, Novolin Augment Enhance Delay Carbohydrate R) take 30 minutes to begin to exert their effect but Insulin Supply Insulin Action Absorption have a longer duration of action than does either lispro Sulfonylureas Biguanides -Glucosidase inhibitors insulin or insulin aspart. Typically, regular insulin is adMeglitinides Thiazolidineministered several minutes before a meal; it has a more Insulins diones gradual onset of action and is designed to control postprandial hyperglycemia. Regular insulin is primarily used to supplement intermediateand long-acting insulins derived from beef and pork. Some insulins have sulin preparations; however, it is also the preparation of been modified through genetic engineering to produce choice for glucose management during surgery, trauma, insulin analogues, derivatives that possess novel pharshock, or diabetic ketoacidosis. Regular insulin can be macokinetic properties (lispro, insulin aspart, and ingiven intravenously when emergency diabetes managesulin glargine). Prompt tors such as injection volume, injection site, and blood insulin zinc suspension (Semilente) is also a fast-acting flow at the site of administration. Rapid-acting and short-acting insulins are often amino acid modifications that promote rapid entry into administered two to three times a day or more. They begin to insulins are also employed in sliding scale insulin regiexert their effects as early as 5 to 10 minutes after adminmens, which supplement a person’s glucose control istration. Lispro insulin, the first insulin analogue to be apbased on blood glucose monitoring equipment. Conjugation of the insulin has a similar affinity for the insulin receptor, but it cannot molecule with either zinc or protamine or both will conform stable hexamers or dimers in subcutaneous tissue, vert the normally rapidly absorbed parenterally adminwhich promotes its rapid uptake and absorption. However, at physitrol diabetes in a variety of situations except during ological and pharmacological levels, the metabolic efemergencies. Both lispro insulin acting insulin preparations are usually given once or and insulin aspart have relatively fast onsets and short twice a day. Allergic reactions due to the use of zinc in the mixture than is found in isophane insulin susanimal-derived insulins has subsided since the use of repension. Over time, repeated subcutaneous injections of suspension except that it does not contain protamine. The introduction of two positive triphosphatase) with its resultant redistribution of K to arginine residues at the carboxy terminus of the -chain the intracellular compartment. A second modification of insulin, glargine, inInsulin Regimens volves the substitution of a charge-neutral glycine for a negatively charged asparagine at the amino terminal the rational design of insulin regimens involves estiend of the -chain; this prevents deamidation and mates and consideration of the patient’s diet, lifestyle, dimerization and enhances stability at physiological pH. Hence, it is not possible to provide a cookbook site of injection mimics the basal secretion of insulin approach for designing all diabetes regimens. Absorption of insulin glargine comusually less insulin resistance in type I diabetics, and it mences within a few hours of injection, and there is usuis possible to estimate metabolic needs of insulin based ally little or no peak or trough in the levels of insulin on the type I diabetic patient’s weight (typically 0. Other considerations, such as work it is necessary to maintain its acidic pH prior to injecschedule and mealtimes, are important in determining tion, insulin glargine must not be mixed with any other the way the insulin is divided proportionally to cover form of insulin during injection. Although there is quite a bit of variation, most diabetics have about half to two-thirds of their insulin as a long-acting Adverse Reactions to Insulin Therapy preparation, and the rest is usually delivered as a rapidthe most common side effect associated with insulin or short-acting insulin. In many cases, diabetics product is 75/25 insulin, which contains 75% protamine are aware that hypoglycemia is developing, and prompt lispro and 25% lispro insulin. While these combination glucose or intramuscular glucagon is required to reverse products may be convenient for some patients and can the hypoglycemia. Some is due to increased caloric storage of arately mixing their rapidor short-acting insulin with glucose by insulin, and some is due to renal sodium rean intermediateor long-acting insulin to arrive at a ratention resulting in fluid retention and edema. The pumps Other complications arising from insulin therapy are provide a basal rate of insulin between meals and can uncommon. Sometimes, diabetics treated with exogebe manually adjusted to facilitate glycemic control at 67 Insulin and Oral Drugs for Diabetes Mellitus 771 mealtimes. Rapid and short-acting insulins are typically were derivatives of the antibacterial sulfonamides. Pumps are usually worn 2 to 3 Although their structural similarities to the sulfondays before the tubing and needle are changed. In the presence of viable pancreatic -cells, sulfective treatment of diabetes mellitus. Some milder fonylureas enhance the release of endogenous insulin, forms of diabetes mellitus that do not respond to diet thereby reducing blood glucose levels. At higher doses, management or weight loss and exercise can be treated these drugs also decrease hepatic glucose production, with oral hypoglycemic agents. The success of oral hyand the second-generation sulfonylureas may possess poglycemic drug therapy is usually based on a restoraadditional extrapancreatic effects that increase insulin tion of normal blood glucose levels and the absence of sensitivity, though the clinical significance of these pharglycosuria. These mechanisms are was used interchangeably with sulfonylureas, but more summarized in Table 67. These classes of drugs are not generally used to the sulfonylureas, possibly because of the insulin rein type I diabetes. Less common adverse rethe -cell triggers insulin granule fusion to the -cell actions include muscular weakness, ataxia, dizziness, membrane and insulin release. Sulfonylureas are readily absorbed from the gastrointestinal tract following oral administration but undergo varying degrees and rates of metabolism in the liver First-Generation Sulfonylureas and/or kidney; some metabolites possess intrinsic hythe first-generation sulfonylureas are not frequently poglycemic activity. Thus, the biological half-lives of the used in the modern management of diabetes mellitus sulfonylureas vary greatly, and a comparison of the because of their relatively low specificity of action, dedrug half-life with the observed duration of action does lay in time of onset, occasional long duration of action, not always show a good correlation. They also tend to have their metabolites are excreted either renally or in the more adverse drug interactions than the second-generfeces. They are occasionally used in patients who have achieved previous adequate control Clinical Uses with these agents. Similarly, several drugs, a low to intermediate dose is given initially and weeks may be required to eliminate the drug after disthen gradually increased until the dosage results in norcontinuation of therapy. Once the maximum recommended dosage particularly when taken with alcohol, and can also cause for a particular sulfonylurea is reached, further increashyponatremia. This effect has been employed to treat ing the dose will not improve glycemic control. The most common adverse effect associated with sulTolazamide (Tolinase) is an orally effective hypofonylurea administration is hypoglycemia, which may glycemic drug that causes less water retention than do be provoked by inadequate calorie intake. Collectively, sulfonylureas also tend to compound that may be useful in patients who are prone cause weight gain, which is undesirable in individuals to hypoglycemia. Like repaglinide, it is approved for both monotherapy and the second-generation sulfonylureas display a higher in combination with metformin. Nateglinide is taken specificity and affinity for the sulfonylurea receptor three times a day before meals and achieves peak and more predictable pharmacokinetics in terms of plasma levels within an hour. Nateglinide administratime of onset and duration of action, and they have tion results in plasma insulin levels that peak within 2 fewer side effects. Nateglinide is also exert mild diuretic effects on the kidney and are metabolized by the liver and excreted by the kidney. Glyburide (DiaBeta, Micronase, Glynase), also known as glibenclamide, is approximately 150 times as potent as tolbutamide on a molar basis and twice as potent as Biguanides glipizide (discussed later). Glyburide is completely meBiguanides are a group of oral hypoglycemic agents tabolized in the liver to two weakly active metabolites that are chemically and pharmacologically distinct from before excretion in the urine. Metformin does not affrom 5 to 9 hours depending on the frequency of multifect insulin secretion but requires the presence of inple dosing. The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose upMeglitinides take. When used as monotherapy, metformin rarely Though structurally unrelated to sulfonylureas, the causes hypoglycemia. The incapable of stimulating insulin secretion in nutrientUnited Kingdom Prospective Diabetes Study demonstarved -cells, but in the presence of glucose, they strated a marked reduction in cardiovascular comordemonstrate hypoglycemic effects by augmenting the bidities and diabetic complications in metforminrelease of insulin. Insulin ing, anorexia, metallic taste, abdominal discomfort, and levels transiently rise postprandially after repaglinide diarrhea) occur in up to 20% of individuals taking metadministration but generally return to baseline by the formin; this can be minimized by starting at a low dose next meal. Although repaglinide does not appear to ofand slowly titrating the dose upward with food. Like fer any advantage over the sulfonylureas, it may be phenformin, metformin can cause lactic acidosis, but its helpful in patients with a known allergy to sulfa drugs. Glucovance is a combination of metformin and in conjunction with metformin, sulfonylureas, and and glyburide that may be helpful for diabetics who reinsulin. Metwhether this has any clinical significance or persists in formin is usually given two to three times a day at mealthe long term. The original prototype of this class of drugs, troglitazone (Rezulin), was taken off the U. Thiazolidinediones (sometimes termed glitazones) are Consequently, frequent monitoring of liver transamia novel class of drugs that were initially identified for nases is recommended for rosiglitazone and pioglitatheir insulin-sensitizing properties. They all act to dezone, and these drugs should be stopped if transamicrease insulin resistance and enhance insulin action in nases rise to more than two to three times the upper target tissues. There is often a other nuclear receptors to modulate the expression of modest amount of weight gain that is independent of insulin-sensitive genes. In laboratory animals, thiazoThiazolidinediones are readily absorbed from the lidinediones at high doses are associated with ultrastrucgastrointestinal tract following oral administration and tural histopathological changes in cardiac tissue; thereare rapidly metabolized by the liver. Plasma elimination fore, thiazolidinedione use is contraindicated in patients half-life is 2 to 3 hours for rosiglitazone (Avandia) and with significant heart failure. Safety in pregnancy is not estabthirds of conjugated metabolites appear in the urine lished. The biological effect of Hypoglycemia is rare with thiazolidinedione monothese drugs takes several weeks to develop, although therapy; however, these drugs may potentiate the hypopatients may see some benefit within a few days to a glycemic effects of concurrent sulfonylurea or insulin week. If a thiazolidinedione is to be added to a diaof the thiazolidinediones takes a while to develop. For betic’s regimen, the sulfonylurea or insulin dosage that reason, upward adjustments in dosage are made should be decreased to compensate for any enhanced gradually to avoid hypoglycemia. Improvements in -Glucosidase Inhibitors diabetic control are variable, ranging from a 1% reduction in hemoglobin A1c when used as monotherapy to the -glucosidase inhibitors primarily act to decrease greater reductions (2% reduction in hemoglobin A1c) postprandial hyperglycemia by slowing the rate at which when used in combinations with other agents, such as carbohydrates are absorbed from the gastrointestinal sulfonylureas or metformin. They act by competitively inhibiting -glucosiRosiglitazone is approved for use as monotherapy dases, a group of enzymes in the intestinal brush border and in conjunction with metformin, though it is someepithelial cells that includes glycoamylase, sucrase, maltimes combined with a sulfonylurea or insulin. The prolongation of the intestinal ally taken once or twice a day with or without food. To be effective, -glucosidase inhibitors must it is unclear whether this effect has any clinical signifibe taken before or with meals.

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