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Lancet 360: ple index for prediction of cardiac risk of major noncar- 187–195 500 mg zithromax with amex infection of the bone, 2002 diac surgery generic zithromax 500mg line antibiotic kidney failure. N Engl J Med 325:1621–1629, 1991 travenous unfractionated heparin in the initial treatment of Collaborative Group on Hormonal Factors in Breast Cancer: pulmonary embolism. Arch Intern stroke, and venous thrombosis in apparently healthy Med 166:391–397, 2006 men. Professor Department of Integrated Biology and Pharmacology and Graduate School of Biomedical Sciences Assistant Dean for Education Programs University of Texas Medical School at Houston Houston, Texas David S. Associate Professor Department of Integrated Biology and Pharmacology and Graduate School of Biomedical Sciences University of Texas Medical School at Houston Houston, Texas With special contributions by Medina Kushen, M. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner. The publisher is not responsible (as a matter of product liability, negligence or otherwise) for any injury resulting from any material contained herein. This publication contains information relating to general principles of medical care which should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages and precautions. Printed in the United States of America Library of Congress Cataloging-in-Publication Data Rosenfeld, Gary C. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. If you have comments or suggestions regarding this Lippincott Williams & Wilkins title, please contact us at the appropriate customer service number listed below, or send correspondence to book_comments@lww. If possible, please remember to include your mailing address, phone number, and a reference to the book title and author in your message. To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301) 824-7390. Preface to the Fifth Edition This concise review of medical pharmacology is designed for medical students, dental stu- dents, and others in the health care professions. This book presents condensed and succinct descriptions of relevant and current Board-driven information pertaining to phar- macology without the usual associated details. It is not meant to be a substitute for the comprehensive presentation of information and difficult concepts found in standard phar- macology texts. Other chapters discuss autocoids, ergots, anti-inflammatory and immunosuppressive agents, drugs used to treat anemias and disorders of hemostasis, infectious diseases, cancer, and toxicology. Each chapter includes a presentation of specific drugs with a discussion of their gen- eral properties, mechanism of action, pharmacologic effects, therapeutic uses, and adverse effects. A drug list, tables, and figures summarize essential drug information included in all chapters. This examination serves as a self-assessment tool to help students determine their fund of knowledge and diagnose any weaknesses in pharmacology. Nondiuretic Inhibitors of Tubular Transport 66 Review Test 68 vii viii Contents 4. Drug Poisoning 319 Review Test 321 Comprehensive Examination 324 Index 341 General Principles of chapter 1 Drug Action I. Drug effects are produced by altering the normal functions of cells and tissues in the body via one of four general mechanisms: 1. Interaction with receptors, naturally occurring target macromolecules that mediate the effects of endogenous physiologic substances such as neurotransmitters and hormones a. Figure 1-1 illustrates the four major classes of drug–receptor interactions, using specific examples of endogenous ligands. Figure 1-1A illustrates acetylcholine interacting with a nicotinic receptor that is a nonspecific Na+/K+ transmembrane ion channel. Interaction of a molecule of acetylcholine with each subunit of the channel produces a conforma- tional change that permits the passage of Na+ and K+. Other channels that are targets for various drugs include specific Ca2+ and K+ channels.

Use of clindamycin is limited to alternative therapy for abscesses associated with infections caused by anaerobes generic zithromax 500mg line antibiotic weight gain, such as B purchase zithromax 500 mg without prescription antimicrobial qualities of silver. It is used in dental patients with valvular heart dis- ease for prophylaxis of endocarditis. Potential severe pseudomembranous colitis occurs as a result of superinfection by resistant clostridia. Sulfonamides: sulfadoxine/pyrimethamine (Fansidar), sulfisoxazole, sulfadiazine, silver sulfa- diazine (Silvadene), sulfasalazine (Azaline, Azulfidine), trimethoprim (Proloprim), and trime- thoprim/sulfamethoxazole (Bactrim, Septra) a. Spectrum and therapeutic uses (1) Sulfonamides inhibit both gram-negative and gram-positive organisms. The combination is used in the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum. Adverse effects (1) Sulfonamides produce hypersensitivity reactions (rashes, fever, eosinophilia) in approx- imately 3% of individuals receiving oral doses. It is used in combination with other drugs for the treatment of most atypical mycobacteria, including M. Adverse effects of rifampin include nausea and vomiting, dermatitis, and red-orange discol- oration of feces, urine, tears, and sweat. Rifampin induces liver microsomal enzymes and enhances the metabolism of other drugs such as anticoagulants, contraceptives, and corticosteroids. Fluoroquinolones (1) These agents, ciprofloxacin (Cipro), norfloxacin (Noroxin), ofloxacin (Floxin), levoflox- acin (Levaquin), moxifloxacin (Avelox), lomefloxacin (Maxaquin), and gemifloxacin (Factive), are fluorinated analogs of nalidixic acid (NegGram), which is now used infrequently. Moxifloxacin and gemifloxacin have even greater activity against gram-positive organisms. These agents are useful against urinary tract infections and against infections caused by Chapter 11 Drugs Used in Treatment of Infectious Diseases 265 N. Cartilage toxic- ity has been reported, and thus these agents should not be used in children and young adults. Polymyxin is a cationic basic polypeptide that acts as a detergent to disrupt the cell membrane functions of gram-negative bacteria (bactericidal). Polymyxin has substantial nephrotoxicity and neurotoxicity and is therefore only for ophthal- mic, otic, or topical use. Polymyxin B often is applied as a topical ointment in mixture with bacitracin or neomycin, or both (Neosporin). Metronidazole, a prodrug, is bactericidal against most anaerobic bacteria, as well as other organisms, including anaerobic protozoal parasites. Daptomycin (Cubicin) is a very powerful cyclic lipopeptide bactericidal agent that has a spec- trum of activity similar to vancomycin. Myelosuppression and pseudomembranous colitis can occur with the use of this agent. The streptogranins bind the 50S ribosomal subunit and are bactericidal for most organisms. Trimethoprim/sulfamethoxazole, ampicillin, or third-generation cephalosporin Erythromycin Legionella spp. Hepa- totoxicity with jaundice is observed in up to 3% of individuals over age 35. High serum concentrations of this agent may result in peripheral neuropathy; slow acetylators are more susceptible. Structure and mechanism of action (1) Rifampin is a semisynthetic derivative of the antibiotic rifamycin. Resistance, a change in affinity of the polymerase, develops rapidly when the drug is used alone. It enters enterohepatic circulation and induces hepatic mi- crosomes to decrease the half-lives of other drugs, such as anticonvulsants. Structure and mechanism of action (1) Ethambutol inhibits arabinosyl transferases involved in cell wall biosynthesis. Ethambutol is administered orally in combination with isoniazid to avoid development of resistance. Pyrazinamide is inactive at neutral pH, but it inhibits tubercle bacilli in the acidic (pH 5) phagosomes of macrophages. Hepatotoxicity is the major adverse effect, with occasional jaundice and (rarely) death. Pyr- azinamide inhibits urate excretion and can precipitate acute episodes of gout.

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Site 2 is the ascending limb of the loop of Henle discount zithromax 100mg free shipping klebsiella antibiotic resistance mechanism, site of action of the loop diuretics cheap 100mg zithromax overnight delivery infection zombie movies. These agents are often used in combination with a potassium-sparing diuretic to manage mild cardiac edema, cirrhotic or nephrotic edema, and edema produced by hormone imbal- ances. Thiazide diuretics should be used cautiously in the presence of renal or hepatic diseases such as cirrhosis, and they should be used only as an an- cillary treatment in nephrotic syndrome. Thiazide diuretics produce electrolyte imbalances such as hypokalemia, hyponatremia, and hypochloremic alkalosis. The molecular targets of + thiazide and loop diuretics are trans- K membrane cotransporter channels, whereas the molecular target of amilor- ide is a specific Na+channel. These agents often elevate serum urate, presumably as a result of competition for the or- ganic acid carrier (which also eliminates uric acid). Thiazide diuretics can cause hyperglycemia (especially in patients with diabetes), hypertri- glyceridemia, hypercholesterolemia, and hypersensitivity reactions. Because of the high capacity for NaCl reabsorption in this segment, agents active at this site markedly increase water and electrolyte excretion and are referred to as high-ceiling diuretics. Loop diuretics cause increased renal prostaglandin production, which accounts for some of their activity c. These agents reduce reabsorption of Cl– and Na+; they increase K+, magnesium (Mg2+), and Ca2+ excretion. Prototype drugs include furosemide and its derivatives piretanide and bume- tanide, as well as ethacrynic acid and torsemide. These agents are used to treat hypertension, especially in individuals with diminished renal function. These drugs are often effective in producing diuresis in patients responding maximally to other types of diuretics. Loop diuretics produce hypotension and volume depletion, as well as hypokalemia, because + + of enhanced secretion of K. Mg wasting can also occur; therapy is often instituted gradually to minimize electro- lyte imbalances and volume depletion. Loop diuretics can cause dose-related ototoxicity, more often in individuals with renal impairment. These agents should be administered cautiously in the presence of renal disease or with use of other ototoxic agents such as aminoglycosides. Potassium-sparing diuretics reduce Na reabsorption and reduce K secretion in the distal part of the nephron (collecting tubule). These are not potent diuretics when used alone; they are primarily used in combination with other diuretics. Antagonists of the mineralocorticoid (aldosterone) receptor include eplerenone, which is highly receptor selective, and spironolactone, which binds to other nuclear receptors such as the androgen receptor. These agents inhibit the action of aldosterone by competitively bind- ing to the mineralocorticoid receptor and preventing subsequent cellular events + + + that regulate K and H secretion and Na reabsorption. They are also used to induce diuresis in clinical situations associated with hyperaldosteronism, such as in adrenal hyperplasia and in the presence of aldosterone-producing adenomas when surgery is not feasible. Spironolactone is associated with gynecomastia and can also cause menstrual abnormalities in women. They are available in combination products contain- ing thiazide or loop diuretics (e. Amiloride and triamterene produce hyperkale- mia, the most common adverse effect, and ventricular arrhythmias. Use of these drugs is contraindicated in the presence of diminished renal function. Carbonic anhydrase inhibitors inhibit carbonic anhydrase in all parts of the body. Carbonic anhydrase inhibitors are sometimes used as adjuvants for the treatment of seizure disorder, but the development of tolerance limits their use. These agents may be used to produce a desired alkalinization of urine to enhance renal secretion of uric acid and cysteine.

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It is possible to use human tissue for the demon- stration of drug resistance in an in vitro preparation order zithromax 100mg without a prescription infection under eye, providing a unique tool in the search for novel discount zithromax 500 mg online antibiotics for acne cause weight gain, more efficient anticonvulsants. Another mechanism underlying drug resistance in epilepsy may be the same as in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic substances by actively exporting the offending compounds. Use-dependent blockade of the fast Na current in dentate granule cells by carbamazepine is lost in hippocampi resected from patients with carbamazepine-resistant temporal-lobe epilepsy, although this finding does not extend to lamotrigine, which has a pharmacologic action similar to that of carbamazepine. Whether these changes result in reduced sensitivity to antiepileptic drugs that Universal Free E-Book Store Personalized Management of Epilepsy 433 act on the receptor is unknown. The hypothesis cannot account for the observation that patients often have epilepsy that is resistant to multiple drugs with different modes of action, although it cannot be ruled out that alteration in drug targets may play a contributory role. Once a patient’s epilepsy is recognized to be drug resistant, a personalized treat- ment plan should be formulated to limit any cognitive deterioration or psychosocial dysfunction. Conditions commonly associated with treatment-resistant epilepsy, such as anxiety, depression, and cognitive and memory disturbances, should be rec- ognized and treated. Surgery is considered as an option in drug-resistant epilepsy and the decision to offer surgical treatment requires an individualized risk-benefit assessment. Several surgical procedures can be performed, depending on the indication (Kwan et al. Corpus callosotomy is usually performed in children with clinically significant learning disabilities and severe generalized epilepsy. In hemispherectomy an extensively diseased and epileptogenic cerebral hemi- sphere is removed or functionally disconnected. An Algorithm for Personalized Management of Epilepsy Several stratification approaches to address the therapeutic challenges in epilepsy, take into consideration several investigations including pharmacogenomic and pharmacogenetic studies (Walker et al. An algorithm used by the author for personalized management of epilepsy is shown in Fig. Future drugs may be designed specifically according to the electrophysiological dysfunction as personalized medicines for epilepsy. Several new drugs are in development but there is still need for better drugs and strategies to overcome drug resistance. The knowl- edge that multidrug transporters are increased in epileptogenic areas opens potential new avenues for therapeutic intervention. Drugs can be developed to inhibit or bypass overexpressed transporters or implantable devices can be used to deliver high concentrations of drugs directly into the epileptogenic brain parenchyma. However, there is a lack of good correspon- dence between results from different laboratories, and more recent findings are awaiting attempts at confirmation. Different neuroimaging techniques may provide combined measurements that may become these biomarkers. Personalized Management of Migraine Migraine is a paroxysmal neurological disorder affecting up to 12 % of males and 24 % of females in the general population. Improvements in prophylactic treatment of migraine patients are desirable because the drugs currently available are not effec- tive in all patients, allow recurrence of the headache in a high percentage of patients and sometimes have severe adverse side effects. Genes involved in neurological, vascular, and hormonal pathways have been implicated in predisposing individuals to migraine. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. Pharmacogenomics of Migraine The development of International Hap Map project could provide a powerful tool for identification of the candidate genes in this complex disease and pharmacoge- nomics research could be the promise for individualized treatments and prevention of adverse drug response (Piane et al. The pathophysiology of migraine is not well understood, and although some gene mutations have been associated with special forms of migraine, genetic influ- ences on common migraine at the population level were previously unknown. These two genes are not associated with more common migraine syndromes and are not the most common hemiplegic migraine genes. However, the work on migraine can also have implications for the increasing number of additional neurological episodic dis- orders with the common denominator of channelopathy. Individualization of Use of Triptans for Migraine With a large number of triptans now available, it may be possible to match indi- vidual patient needs with the specific characteristics of the individual triptans to optimize therapeutic benefit. Pharmacogenetics provides the possibility of tailoring the therapeutic approach to individual patients, in order to maximize treatment effi- cacy while minimizing the potential for unwanted side-effects (Buzzi 2008 ). Pain relief by triptans is significantly modulated by a common genetic variant − G protein beta3 (Schürks et al. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications.

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Rather zithromax 250 mg without prescription virus wars, prevention should be reinforced as treatment progresses discount zithromax 100 mg on-line treatment for uti in goats, modifications being incorporated should these become necessary. It demands the creation of a partnership in which both the child and the parent are key players, though the relative role and prominence of each will differ with the age of the child. In the case of young children, parents are (or, at least, should be) responsible for food choices and oral hygiene, though the latter responsibility is not infrequently abdicated before the child has sufficient manual dexterity to brush adequately alone. As the child approaches the teenage years (and particularly when he or she enters secondary schooling), parental control inevitably decreases. Any discussion of the proposed treatment plan should, therefore, include an agreement as to what is required of the child and/or parent as well as what will be offered by various members of the dental team (including professionals complementary to dentistry). In this process, no attempt is made to render the cavities caries free; rather, minimal tissue is removed without local anaesthesia, allowing placement of an appropriate temporary dressing. The inclusion of such a phase in a holistic treatment plan reduces the overall bacterial load and slows caries progression, renders the child less likely to present with pain and sepsis, and buys time for the implementation of preventive measures and for the child to be acclimatised to treatment. However, one word of caution is offered: it is essential that the parent understands the purpose of stabilization and that what have been provided are not permanent restorations. Otherwise, it is possible that they will perceive that treatment is failing to progress. For example, in a scenario in which a child has not responded to acclimatization and has either refused stabilization or accepted this only with extreme difficulty, the dentist may be entirely justified in considering extractions. This will allow the child and his or her family to enjoy a period where no active treatment is required and in which prevention can be established (always provided, of course, they return for continuing care). The following are general rules of thumb: • small, simple restorations should be completed first; • maxillary teeth should be treated before mandibular ones (since it is usually easier to administer local anaesthesia in the upper jaw); • posterior teeth should be treated before anteriors (this usually ensures that the patient returns for treatment); • quadrant dentistry should be practised wherever possible (this reduces the number of visits to a minimum) but only if the time in chair is not excessive for a very young patient; • endodontic treatment should follow completion of simple restorative treatment; • extractions should be the last items of operative care (at this stage, patient co- operation can more reliably be assured) unless the patient presents with an acute problem mid-treatment. The determination of a recall schedule tailored to the needs of the individual child is an essential part of the treatment-planning process. It is generally accepted that children should receive a dental assessment more frequently than adults since • there is evidence that the rate of progression of dental caries can be more rapid in children than in adults; • the rate of progression of caries and erosive tooth wear is faster in primary than in permanent teeth; • periodic assessment of orofacial growth and the developing occlusion is required. In the latter context, there is considerable merit in ensuring that recall examinations coincide with particular milestones in dental development, for example, around 6, 9, and 12 years. Generally speaking, recall intervals of no more than 12 months offer the dentist the opportunity to deliver and reinforce preventive advice during the crucial period when a child is establishing the basis for their future dental health. This requires an assessment of disease levels as well as risk of/from dental disease. It is sufficient to emphasize here that, in this context, a comprehensive approach must be taken. Providing treatment under general anaesthesia for a child who has been shown to be unable to cope with operative dental care under local anaesthesia (with or without the support of conscious sedation) will do absolutely nothing to improve his or her future co-operation. Key Point The practice of extracting only the most grossly carious or symptomatic teeth (and assuming that other carious teeth can be restored under local anaesthetic at a later stage) predisposes to a high rate of repeat general anaesthesia and should be discouraged. The orthodontic implications of any proposed treatment should always be considered. This is particularly so when the loss of one or more permanent units is to be included in the treatment plan. In such cases, the latter should ideally be drawn up in consultation with a specialist in orthodontics. Treatment under general anaesthesia, irrespective of whether this includes restorative treatment or is limited to extractions, should be followed with an appropriate preventive programme. Failure to provide this almost inevitably leads to the child undergoing further treatment (usually extractions) under general anaesthesia. In creating this, appropriate specialist input to treatment planning should be sought where indicated. At the simplest level, an orthodontic opinion should be obtained before committing a child to multiple visits to restore first permanent molars of poor prognosis. However, it is in the treatment planning of complex cases (such as those presenting with generalized defects of enamel or dentine formation, hypodontia, or clefts of lip and palate) that interdisciplinary specialist input is essential. For example, such input may result in • the retention of anterior roots to maintain alveolar bone in preparation for future implants; • the use of preformed metal crowns to maintain clinical crown height in preparation for definitive crowns; • the use of direct/laboratory-formed composite veneers in preparation for porcelain veneers when growth (and any orthodontic treatment) is complete.

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