Paul S. Pagel, MD, PhD

• Professor of Anesthesiology
• Director of Cardiac Anesthesia
• Medical College of Wisconsin
• Clement J. Zablocki Veterans Affairs Medical Center
• Milwaukee, Wisconsin

Insulin managing diabetes 700 order diabecon with mastercard, a hormone released after meals blood glucose range purchase diabecon 60 caps fast delivery, causes liver cells to polymerize glucose into glycogen to prepare for future periods of starvation blood sugar vision discount 60caps diabecon mastercard. Pathophysiology Disorders of the urea cycle involve enzymatic deficiencies that prevent detoxification of ammonia from protein catabolism into urea non sugar diabetes in dogs buy diabecon 60 caps on line. Therefore diabetes 59 order diabecon online pills, the finding that unites them all is hyperammonemia that worsens with high protein intake definition of diabetic foot ulcer cheap 60caps diabecon free shipping. Of note, all the other urea cycle disorders are inherited in an autosomal recessive fashion. The urea cycle occurs in the liver, and its primary function is conversion of the toxic ammonia into the benign urea. Hyperammonemia can cause altered mental status and neurologic changes, including the classic asterixis, a loss of flexor tone, leading to "flapping" of the hands with wrists extended. Because there is neurologic dysfunction due to liver pathology, this condition is referred to as hepatic encephalopathy. Fat cells, perceiving a state of starvation, induce lipolysis, which releases free fatty acids. Similarly, hepatocytes will upregulate gluconeogenesis and glycogenolysis, creating and releasing more glucose, respectively. Glucose-6phosphatase is not involved directly in synthesis or breakdown of glycogen. Pompe (type 2) Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, and systemic findings leading o early death. Cori (type 3) Debranching enzyme (-1,6glucosidase) Glycogen is excessively branched, owing to lack of debranching enzyme. McArdle (type 5) glycogen in muscle, but muscle cannot break it down painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Significa t hepatomegaly, mild hypoglycemia causing ketosis and growth retardation. Hers (type 6) Hepatic phosphorylase Normal, but in excess amounts, because glycogen can be synthesized but not degraded in Hers disease. Glucose can be polymerized into glycogen by specialized enzymes during the process known as glycogenesis. Distinct enzymes liberate glucose from glycogen in the process called glycogenolysis. Defects in either of these pathways are referred to as glycogen storage disorders. Glyceraldehyde-3phosphate Galactose pathway Converts galactose to substrate for glycolysis. Glucose-1-phosphate Cori cycle/anaerobic metabolism Cori cycle shuttles lactate from anaerobic metabolism in muscle to liver. Cytoplasm and mitochondria of kidney and liver, intestinal epithelium All substrates end up as pyruvate/ phosphoenolpyruvate conversion to glucose. Amino acids are extensively used in the synthesis of new proteins (eg, enzymes, hormones, growth factors) and can also be used as an energy source. To understand amino acids and their purpose in metabolism, it is always important to group them based on chemical properties and their role in medicine. Acidic Amino Acids Aspartic acid and glutamic acid contain an additional carboxylic acid group and are negatively charged at physiologic pH (7. An amino acid with a negative net charge can interact with metal cations in an enzyme. Remember that amino acids such as branched chain amino acids will have a net charge of 0. An amino acid consists of three main groups: (1) an amine group, (2) a functional side group, and (3) a carboxylic acid group. At physiologic pH, acidic amino acids are negatively charged, whereas basic amino acids, with the exception of histidine, have a net positive charge. Histidine titration Remember, amino acids are not stored; they are converted into glycogen or fat if they are not used. The chemotherapy drug L-asparaginase is used to lower plasma asparagine levels, thereby starving leukemia cells. Acceptor (usually -ketoglutarate, can be pyruvate, oxaloacetate) becomes a new amino acid. All other amino acids must be converted to glutamate by transamination prior to oxidative deamination. In this reaction, an -amino group is being transferred from donor amino acid to the acceptor keto acid. During this reaction, glutamate dehydrogenase catalyzes the removal of the -amino group leaving an -ketoglutarate carbon skeleton. Significan e Tyrosine is the precursor for catecholamines (eg, dopamine, adrenaline, noradrenaline), melanin, and thyroxine. Serine, Glycine, Cysteine Precursors Precursors for these amino acids are from glycolysis intermediates. To synthesize cysteine from serine, the essential amino acid methionine is required. Synthesis Serine: Mainly a three-step process from glycolytic intermediates in the cytosol. Deficiencies in either phenylalanine hydroxylase or its required cofactor tetrahydrobiopterin cause the disease phenylketonuria. B Serine (Ser) is mainly synthesized in a three-step process from the glycolytic intermediate 3-phosphoglycerate. Alternatively, serine can be formed from glycine (gly) by transfer of a hydromethyl carbon group. Significan e Glycine is a component of collagen and also in the antioxidant glutathione, along with glutamate and cysteine. The tetanus toxin produced by Clostridium tetani acts by inhibiting the release of glycine, thereby causing constant neurotransmitter release and producing generalized muscle spasms. Cysteine synthesis interruption can lead to a buildup of homocysteine in the urine known as homocystinuria (discussed later). Folate is recommended for women wishing to conceive, as it reduces the risk of spinal cord defects in fetuses. The regeneration of methionine requires homocysteine and the enzyme methionine synthase. Methionine synthase transfers a methyl group from 5-methyltetrahydrofolate, which forms tetrahydrofolate, to homocysteine, to form methionine. Alanine is synthesized from the glycolytic intermediate pyruvate by a one-step transamination. In the kidney, the enzyme glutaminase is used to regenerate glutamate and ammonia from glutamine. Arginine: Two-step synthesis from glutamate involving reduction and transamination to ornithine. Degradation continues in the small intestine to produce free amino acids, dipeptides, and tripeptides. These components are taken into epithelial cells via specific transporters and hydrolyzed into free amino acids. The concentration of amino acids inside the cell is greater than the concentration outside the cell; therefore, the transport of amino acids inside requires energy. At this branch point, either (3) proline can be formed in three steps or (4) ornithine can be formed in two and sent to the urea cycle, where it is metabolized to arginine. The four main transport systems are based on their amino acid side chain specificity (Table 2-23). Amino Acid Transport Deficiency Hartnup Disease this is a rare autosomal recessive defect in the intestinal and renal transporters for neutral amino acids. Urinalysis reveals the presence of renal stones that turn green when exposed to air. Treatment Management is targeted at replacing niacin and providing a high-protein diet with nicotinamide supplements. Cystinuria Autosomal recessive defect in kidney tubular reabsorption of the basic amino acids, such as cysteine, ornithine, lysine, and arginine-resulting in high levels of their excretion. Presentation Patients may present with bilateral flank pain, hematuria, and, in severe cases, pyelonephritis, all of which are symptoms of kidney stones. Treatment Management strives to eliminate precipitation and stone formation by increasing urine volume (high daily fluid ingestion) and urinary alkalization with citrate. They are either used for protein synthesis or transaminated to glutamate for rapid oxidative deamination and urea excretion. Patients with this disease are also at risk for urinary tract infections, pyelonephritis, and hydronephrosis due to stone obstruction. Methionine Derivative S-Adenosyl-l-methionine Main biosynthetic reaction methyl donor. When digested, protein is broken down into amino acids, most of which are converted to alanine and shuttled via the portal vein to the liver. The liver can use the amino acids for protein synthesis or lose the amino acids via entry to the urea cycle and excretion from the kidney. Populations who drink well water can be exposed to perchlorate, which competitively inhibits the sodiumdependent iodine transporter on the basolateral membrane. Iodide oxidized to iodine (I) and incorporated into the tyrosine side chains of 2 the thyroglobulin. Thyroglobulin, which is rich in tyrosine, is transported to the lumen, where its tyrosine residues are iodinated. The various forms of thyroid hormones ([T3], thyroxine [T4]) produced can then be released in a regulated manner. Vitiligo will have localized loss of pigmentation and is caused by autoimmune destruction of melanocytes. His past medical history is only significant for depression, for which he takes tranylcypromine regularly. Moments after taking duloxetine, he becomes agitated and has diaphoresis and an increased heart rate. Phenylalanine is absorbed in the intestine and converted to tyrosine in the liver. Synthesis reaction: Requires cofactors pyridoxine (vitamin B6), riboflavin (vitamin B2), and thiamine (vitamin B1). Serotonin is present in platelets and is released when they bind to a clot; this promotes local vasoconstriction. Serotonin is derived from tryptophan via hydroxylation and decarboxylation cells of the aromatic ring, followed by decarboxylation. Glycine Derivatives Heme Electron carrier in cytochromes and enzymes, O2 carrier in hemoglobin and myoglobin. Synthesis location: Mitochondria and cytosol of bone marrow erythroid cells (for hemoglobin), liver hepatocytes (for cytochromes). Eight-step reaction with first three and last three occurring in the mitochondria. Measurement of cardiac-specific creatine phosphokinase is important in the diagnosis of myocardial infarction. Creatine and creatine phosphate spontaneously cyclize, creating creatinine for excretion in urine. Urea Nontoxic disposable form of ammonia that is generated during amino acid turnover. In muscle, when energy demand is high, the high-energy phosphate can be removed and creatine phosphate is converted back to creatine. Nitric Oxide Positively regulates vessel dilation through smooth muscle relaxation. Two main steps are involved in this process: the removal of the -amino group, followed by salvage of the carbon skeleton. In the first route, glutamate undergoes oxidative deamination in the mitochondria, and the amino group is sent to the urea cycle for disposal. In the second route, the glutamate is transaminated a second time with a transfer of the -amino group to oxaloacetate to form aspartate. Alanine-Glucose Cycle As amino acids undergo catabolism, there is a net increase in the amount of ammonia produced. Alanine is then released into the bloodstream, where it is taken up by the liver and the process is reversed, resulting in glutamate being regenerated in the liver. The patient presents 3 weeks later with complaints of diarrhea and a general skin rash over his body. What should have been prescribed along with this medication to prevent these symptoms The first step in disposal is the transamination of amino acids to form a common pool of glutamate. Ketogenic amino acids are those that are broken down into the ketone body formers acetyl-CoA and acetoacetyl-CoA. Isoleucine, phenylalanine, tyrosine, threonine, and tryptophan are both ketogenic and glucogenic. Isoniazid inhibits the enzyme pyridoxine phosphokinase, which is used in many vitamin B6-dependent reactions, such as the conversion of tryptophan to niacin. Therefore, the patient should have been given vitamin B6 (pyridoxine) to prevent these symptoms. The lack of this enzyme causes a buildup of phenylalanine and an inability to produce tyrosine. Dihydrobiopterin reductase is used for the conversion of phenylalanine to tyrosine and also to dopa. Excess phenylalanine is converted into the phenylketones: phenylpyruvate, phenyllactate, and phenylacetate. Depending on the energy needs of the cell, these products can also be used to synthesize fat or glycogen.

Syndromes

• Difficulty moving one side of the face, known as facial nerve palsy
• Phenytoin: greater than 30 mcg/mL
• Ultrasound examination of the heart (echocardiography)
• Weakness of the muscles in the face (later in the disease)
• Developmental milestones record - 12 months
• Galactosemia
• With macular degeneration, the side vision is normal but the central vision is slowly lost
• Tonometry (if glaucoma is suspected)

While organochlorine pesticides are not used in this country diabetes vegetables generic 60caps diabecon with visa, they are manufactured for export blood glucose ketone trusted 60 caps diabecon. An acute high exposure to herbicide would be primarily irritation of skin and mucous membranes diabetes y alcohol consecuencias purchase diabecon cheap. The teacher is concerned because compared to her kindergarten classmates diabetes insipidus rash cheap diabecon 60 caps free shipping, she is hyperactive diabetes mellitus vessel degeneration order diabecon 60 caps line, restless diabetes medications flow chart quality 60 caps diabecon, and easily distracted. Recently the child has complained of abdominal pain and has had occasional constipation. About 3 years ago the parents moved into a 75-year-old house in the inner city and have been renovating it extensively. Within the past year, the parents separated and the father moved out of the house. Since the parents have been renovating this older home, it is likely that they have removed some of the older paint, generating lead-containing dust and paint chips. Small children may exhibit pica, which is the compulsive eating of nonfood items, and this can occur during times of stress, such as the separation of parents. If the parents have not cleaned up adequately after removing the paint, it is probable that the child has had the opportunity to consume substantial quantities of lead. There is evidence that at blood lead levels of about 10 g/dL, children are at risk for developmental impairment. Other tests that may be useful include examination for microcytic anemia and erythrocyte stippling and radiographic examination of the long bones for lead lines. Protocols are available for using the chelators depending upon the severity of symptoms. This chapter provides a conceptual framework for bioethical analysis, presents some cases that illustrate ethical problems, and delineates some guidelines for consideration. Bioethics is the study of ethical issues associated with providing health care or pursuing biomedical research. Most approaches to bioethics in the United States are secular in nature and presuppose no particular religious or theological perspective. Although the law is often a consideration in bioethical decision making, laws in themselves do not determine the morality of an action. Laws are supposed to reflect a societal consensus on issues and are established to set a minimum standard of behavior. Thus, while religion and law provide guidelines for acceptable actions, religious beliefs, and knowledge of the law are frequently insufficient to guide moral action, in the realm of health care. Solving problems that arise in the scientific and clinical contexts requires knowledge of ethical principles and the methodology for applying them. While bioethical analysis is multifactorial, four moral principles play key roles in establish- ing a basic framework. These principles were developed from a pluralistic, albeit North American, framework. Although not every problem will involve all four principles of bioethics, an understanding of the principles of autonomy, beneficence, nonmaleficence, and justice will build a solid framework for critical analysis. The principle of autonomy entails that persons should be treated as inherently valuable individuals with the moral right to make decisions about their own lives. The principle also entails that persons with diminished autonomy, such as those who are illiterate or retarded, deserve to have their interests protected. This obligation is founded on the principle that individuals are the appropriate decision makers for choices that do not harm others. As the primary moral principle quoted in medical codes and oaths, the principle of beneficence is fundamental to the practice of medicine and clinical research. For example, concerns about beneficence motivate physicians, pharmacologists, pharmacists, and clinical investigators, all of whom share the goal of conducting studies that will ultimately benefit society by producing or refining effective treatments. The principle of nonmaleficence asserts that professionals have an obligation to prevent harm or if harm is unavoidable, minimize that harm. Thus the principles of beneficence and nonmaleficence dictate that the overall goal of scientific advancement cannot trump the duty to protect human subjects of clinical research from harm. The principle of justice states that individuals should be given what they deserve, be that benefit or burden. Cases that are alike should be treated similarly, and relevant distinctions should be drawn consistently. The principle of justice does not specifically state what distinctions are fair or which criteria are reasonable; it simply requires that, once criteria are determined, they be applied fairly. Justice is important in many areas, such as recruitment of research subjects for pharmaceutical studies. For example, researchers must guard against distributing the burdens of participation disproportionately among populations that are poorly equipped to give informed consent, such as children or the mentally incompetent. The principles of autonomy, beneficence, nonmaleficence, and justice form a foundation for analysis of ethical quandaries. The guidelines further require that research on human subjects be conducted by qualified individuals and that most clinical research be reviewed by an independent committee, which is generally an institutional review board. Those guidelines define national policies for biomedical research, apply ethical standards to the circumstances often present in research in economically developing nations, and define mechanisms for ethical review of human subjects research. In drug studies, specific ethical concerns focus on balancing benefits and burdens to subjects, on the need for investigators to use noninvasive and minimally painful means of determining drug disposition, on minimizing the frequency of bodily fluid sampling, and on choosing study subjects who are representative of the target population whenever possible rather than exposing healthy volunteer subjects. Recently, attention has focused on the issue of international medical research, especially that done with patients in economically developing nations. Since such a study in an economically developed nation would probably not have a placebo arm, critics argue that this reflects a double standard for research. They assert that one standard for ethical research should prevail, regardless of the social and economic conditions of the subjects. Bioethicists and those directly involved in research are reconsidering whether subjects who are already suffering under impoverished conditions might suffer further exploitation at the hands of medical researchers. In 1948, in response to the atrocities perpetrated by Nazi experimentation, the Nuremberg Code was developed to set forth guidelines for the acceptable conduct of scientific research. In 1964 the World Medical Association adopted the Declaration of Helsinki, which specifically guides physicians in biomedical research. These documents specify basic moral guidelines ultimately founded on concerns for autonomy, beneficence, and justice. Enrollment in the study offered a benefit over and above the status quo, they assert, and did not deprive subjects of anything they could otherwise obtain. If the research relies on the continuation of undesirable social conditions, such as the general lack of prenatal care, critics assert that there is a fundamental obligation to improve those background conditions rather than take advantage of access to the perfect "laboratory. Even so, is that the role of pharmaceutical research or a broader social role that goes beyond what researchers should have to provide While it would be foolhardy to insist that the only ethically acceptable research is done on patients with full access to comprehensive health care, we do not want to make those who are already deprived and in poverty into "lab rats" who participate in research that ultimately benefits primarily those in the developed world. Clinical research can target the needs of those in economically developing nations and those who are medically underserved in the United States. Yet we must be cautious in the design and implementation of research studies to ensure that those who are the most vulnerable, whether locally or abroad, are offered the most protections and stand to gain proportionately from the studies in which they participate. Research must satisfy the needs of the population in which it is undertaken, and the products developed during the course of the research must subsequently be made reasonably available. Drug Research and Development Pharmacology, unlike some other basic science disciplines, has a unique status when it comes to potential conflicts of interest. The pharmaceutical industry combines a desire for discovery and development with profit-motivated marketing and sales goals. Although scientists and physicians share the desire for drug discovery and development and are motivated by the desire to contribute to scientific advancement and improved patient care, pharmaceutical companies are simultaneously under strong commercial pressures. In some cases, this financial support may compromise professional judgment in conducting, analyzing, or reporting research. For example, often a pharmaceutical company will contract with a private physician to recruit patients into a drug study. While this arrangement frequently offers patients access to treatment that might otherwise be unavailable, the potential conflict may ultimately result in lack of objectivity in study design, data interpretation, and dissemination of research results. For example, a 1986 study in the Journal of General Internal Medicine found a statistically significant relationship between drug company funding and outcomes favoring a new therapy. The doctor assumes a position of responsibility to the company while simultaneously maintaining the usual duties to protect and benefit his or her patients. Although disclosure to patients is important, patients are generally ill suited to assess how a potential conflict of interest actually affects their treatment. In addition to disclosure to patients, we need rigorous reporting requirements for those engaged in drug studies. The interrelationship between scientists, physicians, and researchers and the pharmaceutical industry has given rise to a variety of well-publicized cases raising concerns about conflicts of interest. The pharmaceutical industry depends on scientists and clinicians for research, development, and marketing. Conversely, the medical profession depends on research that is largely financed by the pharmaceutical industry. While this interdependence often benefits industry, research, and patient care, conflicts of interest may arise in two main areas: (1) drug research and development and (2) clinical education and product marketing. Clinical Education and Product Marketing the second area for ethical concern is clinical education and product marketing. As the gatekeepers for all prescription drugs, physicians have the power to determine which drugs will compete successfully in the marketplace, making doctors the logical targets for marketing efforts by pharmaceutical firms. In fact, pharmaceutical companies spend more than $11 billion each year on promotion and marketing. A voluntary code has recently been adopted by the Pharmaceutical Research and Manufacturers of America which establishes guidelines for relationships between the pharmaceutical industry and health care professionals. Ultimately, prescribing practices are the main source of concern, as physicians may be induced to prescribe some products rather than others based on factors other than therapeutic effectiveness or cost. Many drug companies have generous programs for providing their products free of charge to those who cannot afford them. The patient, as a health care consumer, is not in a position to assess the need for a certain drug or decide whether it is prescribed appropriately and sometimes cannot accurately determine whether it is therapeutically effective. Thus, the patient is entitled to be protected by the physician, whose primary role is that of patient advocate as dictated by the principles of beneficence and nonmaleficence. In addition to direct product advertising in medical journals and direct to consumer advertising in the popular media, pharmaceutical company sales representatives frequently visit physicians. Company representatives present "educational" information, provide meals, and may give gifts or incentives to the doctor. Although such visits may keep clinicians informed about current products, they may also precipitate conflicts of interest. Gifts of more than token value, trips to resort areas for "educational" programs with little scientific merit, and cash incentives for prescribing a drug or having it added to a hospital formulary all are cause for concern. The line between a gift and a bribe is not a sharp one, and clinicians and drug company employees should strive to avoid any impropriety. The American Medical Association has stated in its Current Opinions that gifts should primarily benefit patients and should not be of substantial value. While textbooks, modest meals, and educational or workrelated gifts, such as notepads or textbooks, may be appropriate, cash payments are not appropriate. A helpful criterion suggested by the American College of Physicians when considering the ethical appropriateness of a particular interaction between a physician and drug company is to ask whether one would be willing to have the arrangement generally known. If not, the action falls outside the realm of ethical acceptability and should be avoided. Medical students and residents are not exempt from the influence of drug companies. Many students and residents are offered gifts of educational books or equipment or are invited to attend company-sponsored events. Young professionals need to be extremely careful to avoid impropriety and should receive specific instruction about the ethically appropriate scope and limits of interactions with drug company representatives. While some industry-sponsored education provides a good opportunity for unbiased scientific exchange, such as when a drug company underwrites the cost of an educational program but places no restrictions on topics discussed or speakers chosen, too often "education" is a euphemism for marketing. To be considered legitimate, a conference or meeting must be primarily dedicated to scientific and educational activities, and the main incentive for bringing attendees together must be to further broad knowledge. While consultants who provide genuine services 8 Contemporary Bioethical Issues in Pharmacology and Pharmaceutical Research 77 may receive reasonable compensation and accept reimbursement for travel expenses, token consulting or advisory arrangements cannot be used to justify compensating physicians. Speakers at company-sponsored events who are drawn from the professional community should subject their presentation to the same level of scientific rigor as they would apply to a presentation at a professional meeting. In particular, they should refrain from allowing the pharmaceutical company to influence the data they present, the means of presenting it, or the outcomes drawn. When companies financially support conferences or lectures other than their own, the organizers of the conference should maintain control over the topics and speakers selected. If a speaker wishes to mention a specific product, he or she should be sure to avoid any appearance of impropriety by comparing it fairly and completely with competing products. Researchers and clinicians who are invited to conduct studies supported by drug companies and present their data at company-sponsored educational events should take special care to conduct the study meticulously, analyze the data rigorously, and present the data as objectively as possible. In addition, industry sponsorship should be noted in any publication reporting study results. Finally, both attendees and speakers should demand that financial sponsorship be revealed before registration and that financial relationships between speakers and the promoter be plainly stated. In short, to ensure objectivity and eliminate any appearance of conflict of interest, doctors should get their information primarily from professional peer-reviewed journals and not rely solely on material provided by drug companies. First, would it be embarrassing for the clinician if the public knew about the financial arrangement Arrangements that would cause embarrassment or lead others to suspect a conflict of interest should be avoided.

Purchase diabecon 60 caps online. Ketones and Diabetic Ketoacidosis | Knowing the Signs and Symptoms.

Opening of this K 15 Pharmacological Management of Chronic Heart Failure 155 priate neurohumoral activation by the kidney in response to perceived volume depletion from hemorrhage diabetesorg order 60caps diabecon amex. Mechanisms that result in vasoconstriction are normally compensatory in the short term for acute bleeding diabetes diet webmd cheap generic diabecon uk. Before diuretics were available diabetes mellitus zahlen 60caps diabecon with mastercard, rotating tourniquets were used to diminish venous return by ligating the lower extremities diabetes type 2 just diagnosed generic 60 caps diabecon overnight delivery. This procedure diminished the effective intravascular volume that would otherwise have accumulated in the lungs diabetes type 1 icd 9 purchase 60 caps diabecon overnight delivery. The availability of loop diuretics (particularly furosemide) has resulted in the virtual elimination of this practice diabete et miel buy diabecon 60caps fast delivery. Aldosterone enhances salt and water retention at the expense of enhanced renal K and H excretion. Spironolactone enhances diuresis by blocking sodium and water retention while retaining potassium. The likely concomitant use of the loop diuretic furosemide, which depletes K, dictates careful monitoring of serum potassium to avoid life-threatening rhythm disturbances. There is also evidence for the existence of mineralocorticoid receptors on cardiac myocytes. The resultant effect is delivery of more Na to the distal tubule and enhanced urinary loss of Na and water. Unfortunately, the resultant increase in urinary excretion of H and K can lead to arrhythmias. The rationale for their use is so compelling that placebo-controlled studies appear unethical. The use of the potassiumsparing diuretic spironolactone has been shown to improve survival and is discussed below. The concept of afterload reduction was developed for the treatment of mitral regurgitation. It was noted that a decrease in systemic vascular resistance, as reflected in lower arterial blood pressure, resulted in an increase in the percentage of blood that flowed from the left ventricle to the aorta as opposed to the left atrium (decreased regurgitant fraction). The decrease in backup of blood into the lungs provided considerable symptomatic relief from dyspnea, fatigue, and chest pain. There were fewer deaths among the patients on the combination of hydralazine and nitrates. Patients taking prazosin did not benefit, probably because chronic therapy with prazosin results in tachyphylaxis. The mechanisms of action of prazosin, hydralazine, and organic nitrates are discussed in more detail elsewhere. This study was conducted with patients who were not taking a -adrenoceptor blocking agent. It was recognized that the way to improve survival in heart failure was not by directly addressing the weakened heart pump but rather by reversing the inappropriate peripheral vasoconstriction that results from neurohumoral activation. Captopril (Capoten) was the original prototype product, and it was administered three times a day. Low flow to the kidney occurs when damage to the heart results in a low cardiac output. This increase in intracellular ionized free calcium causes vasoconstriction by vascular smooth muscle cells, aldosterone secretion by adrenal glomerulosa cells, increased central sympathetic outflow, and enhanced thirst. This system is activated as part of the normal host response to stressful injury, such as bleeding or trauma. The physiological rationale for not using -blockers in heart failure was certainly well founded. A rapid increase in heart rate does play an important role in the physiological response to acute hemorrhage. Thus, a decrease in heart rate, along with a depression in contractility produced by -blockers, would be expected to precipitate catastrophic decompensation; and this certainly can happen in the acute setting. Young people with asthma have highly reactive airways and can die within hours of a bronchospasm in response to an exposure to an external agent. This highly reversible dynamic condition contrasts sharply with the destruction of connective tissue in lung parenchyma and dead airway sacs that are not very reactive. It appears that norepinephrine levels are more than just markers of disease severity: norepinephrine is actually directly toxic to cardiac myocytes, at least in culture. The addition of either an - or -blocker confers partial protection from norepinephrine damage. This rationale favors the use of the combined nonselective - and -blocker carvedilol over the relatively selective 1-antagonist metoprolol. Thus, the 1-selectivity of metoprolol may not confer any advantage over the less specific -blocker carvedilol. It is clear from clinical trial data that -adrenoceptor blockers are not all the same. Use of some has produced improvements in survival, and others have produced no improvements at all. Speculation includes up-regulation of -adrenoceptors, improved G-protein coupling, altered regulation of nitric oxide, and so on. This has been observed repeatedly in acutely ill patients in the intensive care unit with the intravenous infusion of either -adrenergic agonists. However, the use of these drugs in appropriately selected patients is highly effective for symptomatic relief. A 40-year-old man goes to the emergency department because of an intractable cough for the past few days. No one else in his household has any cough, fever, upper respiratory infection, and so on. He was discharged with prescriptions for digitalis, furosemide, captopril, and carvedilol. He has been more active and has noted improvement in his dyspnea and fatigue that prompted his initial presentation 10 days ago. He appreciates all of the care that he received and apologizes for making a fuss over the cough. He states that his wife made him come in because she was concerned that it might be his heart. He states that the cough is different from the congested feeling he had 10 days ago. On examination, he was afebrile; his heart rate was 60 beats per minute; blood pressure, 100/60. Chest radiograph and electrocardiogram revealed no acute changes and no active disease. The physician was satisfied that he was hemodynamically stable and the cough was not resulting from worsening heart failure. A 67 year old woman has had fatigue and shortness of breath over the past few months. She has diabetes and hypertension for which she has been treated for 25 years with appropriate medications. On examination she was noted to be in acute respiratory distress with a respiratory rate of 24, a heart rate of 60, and blood pressure of 110/60. Heart revealed a third heart sound and a high pitched holosystolic murmur at the apex consistent with mitral regurgitation. The combination of hydralazine and nitrates has been shown to improve survival in patients of heart failure. All of the following statements about this combination are true except: (A) the combination serves to decrease both afterload and preload. Myocardial infarction is extremely unlikely in this patient based on the catheterization data showing normal coronary anatomy. Abrupt withdrawal of a -blocker may precipitate tachycardia and hypertension and should be avoided. This may be a reversible event or part of the inevitable decline of the disease process. This results in an increase in intracellular Ca and an enhanced myocardial contractibility. There is no definitive evidence that digitalis improves survival of patients in heart failure, but it clearly improves the symptoms of this condition. Prazosin has been shown not to be as effective as the combination of hydralazine and nitrates. Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. He is unable to walk more than 50 feet on flat ground before getting short of breath (dyspnea on exertion at 50 feet). His heart rate at rest is 85 beats per minute and his blood pressure while seated is 130/85. His neck veins are flat; carotid upstrokes are normal; lungs are clear; and heart examination reveals no murmurs, gallops, or rubs. Presently the choices are either the 1-selective adrenergic blocker, metoprolol, or the combined nonselective - and -adrenergic blocker carvedilol. The target heart rate at rest should be in the range of 50 to 60 beats per minute. The target blood pressure should be in the range of 90 to 110 systolic, or orthostatic symptoms of light-headedness develop. Cardiac arrhythmias may result in alterations in heart rate or rhythm and arise from alterations in impulse generation or conduction. The clinical implications of disordered cardiac activation range from asymptomatic palpitations to lethal arrhythmia. Pharmacological management of arrhythmias uses drugs that exert effects directly on cardiac cells by inhibiting the function of specific ion channels or by altering the autonomic input into the heart. Recent technological advances have lead to an increase in nondrug strategies, including transcatheter radiofrequency ablation, intraoperative cryoablation, implanted pacemakers, and defibrillation. Physicians caring for patients with arrhythmias therefore must understand and appreciate the benefits and risks provided by each therapeutic modality, what the indication for each is, and how these modalities may interact. This is accomplished while avoiding the omnipresent risk of side effects such as proarrhythmia. This chapter first provides a brief overview of the cellular events that underlie the cardiac action potential and lead to the formation and propagation of the 160 16 Antiarrhythmic Drugs 161 normal cardiac impulse. Basic mechanisms of arrhythmias are reviewed, and the pharmacology of specific antiarrhythmic agents is discussed. The characteristic action potential is the result of activation and inactivation of multiple ion channels, which allows the flow of charged ions across the sarcolemmal membrane. The ion channels are transmembrane proteins possessing two important features: an ion selective pore that allows the passage of a specific cation or anion and regulatory components that respond to chemical stimulation or changes in the transmembrane potential by opening or closing. The ions flow through open channels according to the electrochemical driving forces at any given moment. The normal resting [K]i is 140 mM, whereas the extracellular K concentration, [K]0, is 4 mM. The resting myocardial cell tends to be highly permeable to K and less so to Na and Ca; therefore, a net diffusion of K flows out of the cell, leaving behind negatively charged proteins. As a result, the interior of the cell becomes electronegative, and two opposing forces are established: a chemical force due to a concentration gradient and a counteracting electrostatic force established by the negatively charged ions within the cell. When the electrode tip penetrates the fiber, a resting membrane potential of 90 mV is recorded. The application of a subthreshold stimulus (#1) produces a depolarizing current that fails to result in excitation of the myocardial cell. Major transmembrane currents carried by specific ions entering the cell through selective ion channels are depicted to the right. The membrane potential at which this occurs may be calculated using the Nernst equation: Ex 61 log([x]i/[x]o) In this equation, x is the ion in question, [x]i is the concentration inside the cell, and [x]o is the concentration outside the cell. The contribution of other ionic species to the resting membrane potential is smaller because of the low transmembrane permeability at hyperpolarized resting membrane potentials. An examination of the relationship of [K]o] and [K]i] in the Nernst equation shows that an increase in the [K]o will result in a decrease in the membrane resting potential (less negative). Changes in the extracellular concentration of another ion (Na, Ca, Mg, Cl) may also modify the resting potential. To produce membrane depolarization, a current stimulus of sufficient intensity to exceed the outward K current must be applied to the cell. If the depolarizing stimulus raises the membrane potential above a threshold value, sodium channels within the sarcolemmal membrane change their conformation and open their ion-selective pore, allowing Na to enter the cell driven by the electrochemical gradient. The open sodium channels raise the membrane potential toward the equilibrium potential of sodium (65 mV) and set into motion the intricate and precisely coordinated series of ion channel openings and closings leading to the characteristic action potential. The action potential has been divided into five phases, rapid depolarization (phase 0), early repolarization (phase 1), plateau (phase 2), rapid repolarization (phase 3) and finally the resting phase in myocytes or slow diastolic depolarization (phase 4). The last is a property in cells with the potential for automaticity (defined later). The interval during which the myocyte cannot be stimulated is the absolute refractory period. After the myocyte returns to a hyperpolarized resting potential, the channels cycle through the inactivated state back to the rested or closed conformation and again are available to open in response to a stimulus of sufficient intensity.

Diseases

• Wernicke Korsakoff syndrome
• Inhalant abuse, haloalkanes
• MPO deficiency
• Sipple syndrome
• Chromosome 3, Trisomy 3q2
• Short rib syndrome Beemer type
• Delayed membranous cranial ossification
• Lipidosis with triglycerid storage disease
• Chromosome 13q-mosaicism