Jacob Hogue, M.D.

• Department of Pediatrics
• Madigan Army Medical Center
• Tacoma, Washington

Identifying High-Risk Patients Calcium salts are contraindicated for patients with hypercalcemia virus alive discount cefixime 100 mg buy, renal calculi antimicrobial stewardship program cefixime 100 mg buy fast delivery, and hypophosphatemia infection japanese movie proven 100 mg cefixime. Dosage Individual calcium salts differ with respect to percentage of elemental calcium virus - ruchki zippy purchase 100 mg cefixime mastercard. As a result antibiotic diarrhea treatment purchase cefixime us, the dose required to provide a specific amount of calcium differs among the salts. Preadministration Assessment Therapeutic Goal Reversal of clinical manifestations of hypocalcemia. Baseline Data Assess for signs and symptoms of hypocalcemia (tetany, convulsions, laryngospasm, spasm of other muscles). Identifying High-Risk Patients Parenteral calcium is contraindicated for patients with hypercalcemia or ventricular fibrillation. Drugs that contain phosphate, carbonate, sulfate, and tartrate groups can precipitate calcium; do not mix these drugs with parenteral calcium solutions. Calcium chloride may cause necrosis and sloughing if solutions become extravasated. Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Evaluate the patient for reductions in tetany, muscle spasm, laryngospasm, paresthesias, and other symptoms of severe hypocalcemia. Overdose can produce acute hypercalcemia, resulting in nausea, vomiting, weakness, lethargy, coma, and possibly death. Administration Advise patients to take oral calcium salts with a large glass of water; dosing with or after meals promotes absorption. Advise patients to avoid taking calcium with foods that can suppress calcium absorption. Ongoing Evaluation and Interventions Minimizing Adverse Effects Prolonged therapy can cause hypercalcemia. Inform patients about signs of hypercalcemia (nausea, vomiting, constipation, frequent urination, lethargy, and depression), and instruct them to notify the prescriber if these occur. Baseline Data the prescriber may order measurements of serum alkaline phosphatase, calcium, and phosphorus, as well as a 24-hour urinary hydroxyproline. Instruct patients using calcitonin-salmon nasal spray to prime the metered-dose pump by holding the bottle upright and depressing the two white sidearms toward the bottle 6 times, which should produce a faint initial spray. The drug is then administered by placing the nozzle in the nostril and depressing the pump handle. Teach patients how to inject calcitonin subQ, and instruct them to rotate sites of injection. Proper administration is needed to maximize absorption and minimize the risk of esophagitis. Accordingly, instruct patients to: Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Postmenopausal Osteoporosis. Monitor for reductions in bone pain, serum alkaline phosphatase levels, and 24-hour urinary hydroxyproline value. This applies to all oral bisphosphonates except Atelvia, a delayed-release brand of risedronate, which can and should be administered after eating. For patients receiving zoledronate, obtain a baseline value for creatinine clearance and assess for adequate hydration. Identifying High-Risk Patients Oral bisphosphonates are contraindicated for patients with esophageal disorders that can impede swallowing, and for patients who cannot sit or stand for at least 30 minutes (60 minutes with ibandronate). Oral bisphosphonates can cause severe esophagitis, sometimes resulting in ulceration. To minimize risk, instruct patients to (1) administer the drug in accord with the guidelines described previously, (2) avoid lying down after dosing, and (3) discontinue the drug and contact the prescriber if they experience symptoms of esophageal injury (difficulty in swallowing, pain upon swallowing, new or worsening heartburn). Avoid these drugs in patients with esophageal disorders that could impede swallowing and in patients who are unable to sit or stand for 30 minutes (60 minutes with ibandronate). Very rarely, long-term bisphosphonate therapy has been associated with atypical fractures of the femur. Identifying High-Risk Patients Raloxifene is contraindicated for use by patients who are pregnant or who have a history of venous thrombotic events. Ongoing Evaluation and Interventions Promoting Therapeutic Effects Advise women taking raloxifene for osteoporosis to ensure adequate intake of calcium and vitamin D. Rarely, bisphosphonates cause conjunctivitis, scleritis, blurred vision, eye pain, and other ocular problems. Intravenous zoledronate can damage the kidney, leading to acute renal failure and possibly death. Exercise caution in patients at increased risk (owing to advanced age, chronic renal impairment, dehydration, or use of diuretics or nephrotoxic drugs). Before dosing, ensure that hydration is adequate and that kidney function is adequate too (creatinine clearance above 35 mL/min). Monitor renal function by determining creatinine clearance at baseline, before each dose, and periodically after each infusion. Advise patients to raloxifene to patients with a history of venous thrombotic events. Advise patients to avoid extended periods of restricted activity, as can happen when traveling. Characteristic signs and symptoms are a sense of breathlessness and tightness in the chest, together with wheezing, dyspnea, and cough. However, despite these sobering statistics, with proper treatment, most patients can lead full lives with no limitations. Symptoms include chronic cough, excessive sputum production, wheezing, dyspnea, and poor exercise tolerance. In the most recent report by the Centers for Disease Control and Prevention, chronic lower respiratory diseases were listed as the third leading cause of death in the United States. Drug therapy does not slow disease progression, reduce hospitalizations, or prolong life. In addition, they promote infiltration and activation of inflammatory cells (eosinophils, leukocytes, macrophages). The end result is airway inflammation, characterized by edema, mucus plugging, and smooth muscle hypertrophy, all of which obstruct airflow. In about 50% of children with asthma and in some adults, airway inflammation results from an immune response to known allergens. In the remaining children and in most adults, the cause of airway inflammation is unknown-although as-yet unidentified allergens are suspected. Although this model may not apply completely to all asthma patients, it nonetheless provides a basis for understanding the drugs used for treatment. In most cases, both processes are caused by an exaggerated inflammatory reaction to cigarette smoke. Chronic bronchitis-defined by chronic cough and excessive sputum production-results from hypertrophy of mucus-secreting glands in the epithelium of the larger airways. Emphysema is defined as enlargement of the air space within the bronchioles and alveoli brought on by deterioration of the walls of these air spaces. That is, some patients may suffer primarily from chronic bronchitis, some primarily from emphysema, and some from both disease processes. As a result of the frequent and recurrent irritation and the subsequent response by various leukocytes and inflammatory mediators, pathologic changes result in the bronchial edema and increase in mucus secretion that characterize chronic bronchitis. Additionally, the continuous inflammation inhibits the production of protease inhibitors, which have a protective role in maintaining alveolar integrity. As a result of the inhibition, the protease enzymes break down elastin, resulting in the destruction of alveolar walls and the decrease in elastic recoil that characterize emphysema. In a small percentage of the population, emphysema results from a genetic alteration that results in alpha-1 antitrypsin deficiency. They fall into two main pharmacologic classes: antiinflammatory agents and bronchodilators. This route has three advantages: (1) therapeutic effects are enhanced by delivering drugs directly to their site of action, (2) systemic effects are minimized, and (3) relief of acute attacks is rapid. Four types of inhalation devices are employed: metered-dose inhalers, Respimats, dry-powder inhalers, and nebulizers. When 2 inhalations are needed, an interval of at least 1 minute should separate the first inhalation from the second. Accordingly, patients will need a demonstration, as well as written and verbal instruction. About 80% affects the oropharynx and is swallowed, and the remaining 10% is left in the device or exhaled. Some spacers contain a one-way valve that activates upon inhalation, obviating the need for good hand-breath coordination. Some spacers also contain an alarm whistle that sounds off when inhalation is too rapid, thus maximizing effective drug administration. They can also prevent bronchospasm that may occur with sudden intake of an inhaled drug. Note that, when a spacer is used, more medication reaches its site of action in the lungs, and less is deposited in the mouth and throat. Patient Care Concerns Inhaled glucocorticoids are the preferred long-term treatment for children of all ages, including infants. Face masks are recommended for the administration of inhaled glucocorticoids to children younger than 4 years. Montelukast is the only leukotriene modifier approved for children ages 1 to 5 years. Of the leukotriene modifiers, montelukast and zafirlukast are Pregnancy Risk Category B,a while zileuton is Risk Category C. Inhaled glucocorticoids are much safer for this population than systemic formulations. Nebulizers A nebulizer is a small machine used to convert a drug solution into a mist. The droplets in the mist are much finer than those produced by inhalers, resulting in less drug deposit on the oropharynx and increased delivery to the lung. Inhalation of the nebulized mist can be done through a face mask or through a mouthpiece held between the teeth. Because the mist produced by a nebulizer is inhaled with each breath, hand-breath coordination is not a concern. Nebulizers take several minutes to deliver the same amount of drug contained in 1 inhalation from an inhaler, but for some patients, a nebulizer may be more effective than an inhaler. Although nebulizers are usually used at home or in a clinic or hospital, these devices, which weigh less than 10 pounds, are sufficiently portable for use in other locations. Adverse reactions to inhaled glucocorticoids are generally minor, as are reactions to systemic glucocorticoids taken acutely. However, when systemic glucocorticoids are used long term, severe adverse effects are likely. Mechanism of Antiasthma Action Glucocorticoids reduce asthma symptoms by suppressing inflammation. Specific anti-inflammatory effects include: · Decreased synthesis and release of inflammatory mediators. There is also some evidence that glucocorticoids may increase the number of bronchial beta2 receptors, as well as their responsiveness to beta2 agonists. Because beneficial effects develop slowly, these drugs cannot be used to abort an ongoing attack. Glucocorticoids do not alter the natural course of asthma, even when used in young children. Inhaled glucocorticoids are first-line therapy for management of the inflammatory component of asthma. Inhaled glucocorticoids are very effective and are much safer than systemic glucocorticoids. Because of their potential for toxicity, these drugs are prescribed only when symptoms cannot be controlled with safer medications (inhaled glucocorticoids, inhaled beta2 agonists). Because the risk for toxicity increases with duration of use, treatment should be as brief as possible. These preparations are largely devoid of serious toxicity, even when used in high doses. The most common adverse effects are oropharyngeal candidiasis and dysphonia (hoarseness, speaking difficulty). To minimize these effects, patients should rinse the mouth with water and gargle after each administration. With long-term, high-dose therapy, some adrenal suppression may develop, although the degree of suppression is generally low. In contrast, with prolonged use of oral glucocorticoids, adrenal suppression can be profound. Glucocorticoids can slow growth in children and adolescents-but these drugs do not decrease adult height. Short-term studies have shown that inhaled glucocorticoids slow growth; however, long-term studies indicate that adult height, while delayed, is not reduced. Less is known regarding whether glucocorticoids suppress growth and development of the brain, lungs, and other organs, in part because having asthma alone can affect organ growth. Because the benefits of inhaled glucocorticoids tend to be much greater than the risks, current guidelines for asthma management recommend these drugs for children while monitoring for evidence of complications. Fortunately, the amount of loss is much lower than the amount caused by oral glucocorticoids. To minimize bone loss, patients should (1) use the lowest dose that controls symptoms, (2) ensure adequate intake of calcium and vitamin D, and (3) participate in weight-bearing exercise. There has been concern that prolonged therapy might increase the risk for cataracts and glaucoma. While this may be an issue of concern with continuous use of high-dose inhaled glucocorticoids, this problem is not associated with long-term use of low to medium doses of inhaled glucocorticoids.

If a patient taking these drugs were to ingest alcohol bacterial infection in stomach buy 100 mg cefixime with mastercard, a disulfiram-like reaction could occur antibiotic resistance powerpoint 100 mg cefixime order. Therapeutic Uses the therapeutic role of the cephalosporins is continually evolving as new agents are introduced and more experience is gained with older ones virus classification order cefixime line. The cephalosporins are broad-spectrum bactericidal drugs with a high therapeutic index antimicrobial 8536 cefixime 100 mg order amex. Cephalosporins can be useful alternatives for patients with mild penicillin allergy virus incubation period 100 mg cefixime for sale. The five generations of cephalosporins differ significantly in their applications. When a cephalosporin is indicated for a gram-positive infection, a first-generation drug should be used; these agents are the most active of the cephalosporins against gram-positive organisms and are less expensive than other cephalosporins. First-generation agents are frequently employed as alternatives to penicillins to treat infections caused by staphylococci or streptococci (except enterococci) in patients with penicillin allergy. However, it is important to note that cephalosporins should be given only to patients with a history of mild penicillin allergy-not those who have experienced a severe, immediate hypersensitivity reaction. The first-generation agents have been employed widely for prophylaxis against infection in surgical patients. First-generation agents are preferred to second- or third-generation cephalosporins for surgical prophylaxis because they are as effective as the newer drugs, are less expensive, and have a more narrow antimicrobial spectrum. Cefuroxime has been used with success against pneumonia caused by Haemophilus influenzae, Klebsiella, pneumococci, and staphylococci. Oral cefuroxime is useful for otitis, sinusitis, and respiratory tract infections. In contrast, the third-generation agents have qualities that make them the preferred therapy for several infections. The fourth- and fifth-generation agents are effective against resistant organisms. Nosocomial infections caused by gram-negative bacilli, which are often resistant to first- and second-generation cephalosporins (and most other commonly used antibiotics), are appropriate indications for the third-generation drugs. Two third-generation agents-ceftriaxone and cefotaxime-are drugs of choice for infections caused by Neisseria gonorrhoeae (gonorrhea), H. Cefepime is commonly used to treat healthcareand hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas. A prime rule of antimicrobial therapy is to match the drug with the bug: the drug should be active against known or suspected pathogens, but its spectrum should be no broader than required. When a cephalosporin is appropriate, we should select from among those drugs known to have good activity against the causative pathogen. The third- and fourth-generation agents, with their very broad antimicrobial spectra, should be avoided in situations where a narrower spectrum, first- or second-generation drug would suffice. For some infections, one cephalosporin may be decidedly more effective than all others and should be selected on this basis. For example, ceftazidime (a third-generation drug) is the most effective of all cephalosporins against P. In patients with normal renal function, the half-lives of the cephalosporins range from about 30 minutes to 9 hours (see Table 85. Because they require fewer doses per day, drugs with a long half-life are frequently preferred. Cephalosporins with the longest half-lives in each generation are as follows: first generation, cefazolin (1. Hence, for meningitis caused by susceptible organisms, these drugs are preferred over first- and second-generation agents. A trial is currently recruiting participants to evaluate the use of ceftaroline in this capacity. Most cephalosporins are eliminated by the kidneys; if dosage is not carefully adjusted, these drugs may accumulate to toxic levels in patients with renal impairment. Only one agent-ceftriaxone-is eliminated primarily by nonrenal routes, and hence can be used with relative safety in patients with kidney dysfunction. However, there are some differences between cephalosporins, and these differences may render one agent preferable to another for treating a specific infection in a specific host. The differences that do exist can be grouped into two main categories: antimicrobial spectrum and pharmacokinetics. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment. If oral cephalosporins produce nausea, administration with food can reduce the response. Intramuscular injection of cephalosporins is frequently painful; the patient should be forewarned. The injection site should be checked for induration, tenderness, and redness, and the prescriber should be informed if these occur. Drug Selection Eighteen cephalosporins are currently employed in the United States, and selection among them can be a challenge. Within each generation, the similarities among cephalosporins are more pronounced than the differences. To delay emergence of resistance, these drugs should be reserved for patients who cannot be treated with a more narrow-spectrum agent. As a result, imipenem may be of special use for treating mixed infections in which anaerobes, Staph. Imipenem is supplied in fixed-dose combinations with cilastatin, a compound that inhibits destruction of imipenem by renal enzymes. Preparations, Dosage, and Administration Imipenem is formulated in 1: 1 fixed-dose combinations with cilastatin. Antimicrobial Spectrum Imipenem is active against most bacterial pathogens, including organisms resistant to other antibiotics. The drug is highly active against gram-positive cocci and most gramnegative cocci and bacilli. In addition, imipenem is the most effective beta-lactam antibiotic for use against anaerobic bacteria. When employed alone, imipenem is inactivated by dipeptidase, an enzyme present in the kidneys. To increase urinary concentrations, imipenem is administered in combination with cilastatin, a dipeptidase inhibitor. When the combination is used, about 70% of imipenem is excreted unchanged in the urine. Hypersensitivity reactions (rashes, pruritus, drug fever) have occurred, and patients allergic to other beta-lactam antibiotics may be cross-allergic with imipenem. Fortunately, the incidence of cross-sensitivity with penicillins is low-only about 1%. Interaction With Valproate Imipenem can reduce blood levels of valproate, a drug used to control seizures (see Chapter 24). If no other antibiotic will suffice, supplemental antiseizure therapy should be considered. Therapeutic Use Because of its broad spectrum and low toxicity, imipenem is used widely. The drug is effective for serious infections caused by gram-positive cocci, gram-negative cocci, gram-negative bacilli, and anaerobic bacteria. This broad antimicrobial spectrum gives imipenem special utility for antimicrobial therapy of mixed infections. Cephalosporins are commonly used to treat bacterial infections in children, including otitis media and gonococcal and pneumococcal infections. Administration of telavancin during pregnancy should be avoided due to a risk for adverse developmental outcomes. Unlike most other drugs discussed here, vancomycin does not contain a beta-lactam ring. Mechanism of Action Like the beta-lactam antibiotics, vancomycin inhibits cell wall synthesis and thereby promotes bacterial lysis and death. Instead, it disrupts the cell wall by binding to molecules that serve as precursors for cell wall biosynthesis. Other susceptible organisms include streptococci, penicillin-resistant pneumococci, and C. The drug is also employed as an alternative to penicillins and cephalosporins to treat severe infections. Second, telavancin binds to the bacterial cell membrane and thereby disrupts membrane function. To delay the development of resistance, telavancin should be reserved for the treatment of vancomycin-resistant infections or for use as an alternative to linezolid [Zyvox], daptomycin [Cubicin], or tigecycline [Tygacil] in patients who cannot take these drugs. In patients with renal impairment, the half-life is prolonged and blood levels increase. In patients with moderate hepatic impairment, the kinetics of telavancin remain unchanged. As with vancomycin, rapid infusion can cause red man syndrome, characterized by flushing, rash, pruritus, urticaria, tachycardia, and hypotension. Kidney damage develops in 3% of patients, as indicated by increased serum creatinine, renal insufficiency, or even renal failure. To reduce risk, kidney function should be measured at baseline, every 72 hours during treatment, and at the end of treatment. If these tests indicate nephrotoxicity, switching to a different antibiotic should be considered. Risk is dose related and increased by concurrent use of other nephrotoxic drugs. To minimize risk, trough serum levels of vancomycin should be no greater than needed (see later in this chapter). If significant kidney damage develops, as indicated by a 50% increase in serum creatinine level, vancomycin dosage should be reduced. Risk is increased by prolonged treatment, renal impairment, and concurrent use of other ototoxic drugs. Rapid infusion of vancomycin can cause a constellation of disturbing effects-flushing, rash, pruritus, urticaria, tachycardia, and hypotension-known collectively as red man syndrome. These effects, which may result from the release of histamine, can usually be avoided by infusing vancomycin slowly (over 60 minutes or more). The reaction can be minimized by administering vancomycin in dilute solution and by changing the infusion site frequently. Rarely, vancomycin causes immune-mediated thrombocytopenia, a condition in which platelets are lost and spontaneous bleeding results. The underlying mechanism is the development of unusual antibodies that bind to platelets-but only if the platelets first bind with vancomycin (forming a vancomycin-platelet complex). The resulting antibody-vancomycin-platelet complexes are then removed from the circulation by macrophages. Accordingly, vancomycin is an alternative to penicillins in patients with penicillin allergy. Drug Interactions Telavancin should be used with caution in patients taking other drugs that can damage the kidneys. Clinically significant interactions involving cytochrome P450 enzymes have not been observed. Preparations, Dosage, and Administration Telavancin [Vibativ] is supplied as a powder (750 mg) for reconstitution as a concentrated solution (15 mg/mL), followed by dilution to a final concentration of 0. The usual dosage is 10 mg/kg once daily, infused over 60 minutes to reduce the risk of red man syndrome. In patients with renal impairment, as indicated by reduced creatinine clearance, dosage should be decreased. For systemic infection, vancomycin is administered by intermittent infusion over 60 minutes or longer. One recommended regimen consists of giving 500 mg in 100 mL of normal saline every 6 hours, using a retention enema. Aztreonam Chemistry Aztreonam [Azactam, Cayston] belongs to a class of beta-lactam antibiotics known as monobactams. These agents contain a beta-lactam ring, but the ring is not fused with a second ring. Therefore, like most beta-lactam antibiotics, the drug inhibits bacterial cell wall synthesis and thereby promotes cell lysis and death. Antimicrobial Spectrum and Therapeutic Use Aztreonam has a narrow antimicrobial spectrum, being active only against gram-negative aerobic bacteria. Aztreonam is highly resistant to beta-lactamases and therefore is active against many gram-negative aerobes that produce them. Telavancin Actions and Uses Telavancin [Vibativ] is the first representative of a new class of agents, the lipoglycoproteins, synthetic derivatives of vancomycin. As shown in the following table, oral metronidazole is recommended for a mild/moderate initial episode, and oral vancomycin is recommended for a severe initial episode. If the patient has complete ileus (absence of intestinal motility), rectal instillation of vancomycin may be added. If there is a second recurrence, the guidelines recommend a prolonged course of oral vancomycin in which the number of daily doses is gradually decreased. Promising options include the following: · Fidaxomicin [Dificid]-a narrow-spectrum macrolide antibiotic with high selectivity for C. Presumably, when the benign strain colonizes the bowel, it occupies the same niche that a virulent strain would occupy and thereby prevents the virulent strain from becoming established.

Accordingly antibiotics for uti while nursing generic cefixime 100 mg, patients using the drug must be warned about the risks of alcohol consumption in combination with a sulfonylurea antibiotics for acne azithromycin order cefixime cheap. A variety of drugs virus living cefixime 100 mg purchase without prescription, acting by diverse mechanisms antibiotics and xtc cheap cefixime 100 mg buy line, can intensify hypoglycemic responses to most sulfonylureas antibiotic resistance of bacterial biofilms cefixime 100 mg purchase mastercard. Included are nonsteroidal anti-inflammatory drugs, sulfonamide antibiotics, alcohol (used acutely in large amounts), and cimetidine. Caution must be exercised when a sulfonylurea is used in combination with these drugs. Beta blockers can diminish the benefits of sulfonylureas by suppressing insulin release. The main difference between the glinides and the sulfonylureas is their pharmacokinetic profile- the glinides are more short acting and are taken with each meal. In clinical trials, repaglinide was about as effective as glyburide and glipizide (second-generation sulfonylureas). Because repaglinide has the same mechanism as the sulfonylureas, patients who do not respond to sulfonylureas will not respond to this agent either. Blood levels peak within 1 hour of oral dosing and return to baseline about 4 hours later. Blood levels of insulin rise and fall in parallel with levels of repaglinide-and since levels of repaglinide rise and fall quickly, so do blood levels of insulin. In patients with liver dysfunction, metabolism of repaglinide may be slowed, and hence the risk of hypoglycemia may be increased. Because of possible hypoglycemia, it is imperative that patients eat no later than 30 minutes after taking the drug. Gemfibrozil [Lopid], a drug used to lower triglyceride levels, can inhibit the metabolism of repaglinide, thereby causing its level to rise. For patients who have not used another oral antidiabetic drug, the initial dosage is 0. Patients who have used another oral antidiabetic drug may take 1 or 2 mg before each meal. The pharmacology of nateglinide [Starlix] is nearly identical to that of repaglinide. Both drugs have the same indication: treatment of type 2 diabetes, either as monotherapy or combined with metformin or a glitazone. They also have the same mechanism of action (promotion of insulin release), the same major adverse effect (hypoglycemia), and perhaps the same major drug interaction (elevation of their blood level by gemfibrozil). Because the glinides and sulfonylureas have the same mechanism of action, nateglinide, like repaglinide, will not work in patients who have not responded to a sulfonylurea. Nateglinide undergoes extensive metabolism by cytochrome P450 enzymes, followed by rapid and complete excretion, primarily in the urine. For patients with A1C concentrations close to the target value, the initial dosage is lower: 60 mg 3 times a day taken 0 to 30 minutes before a meal. These drugs are not related chemically or functionally to sulfonylureas or biguanides. Soon after its approval, troglitazone was withdrawn, owing to a high incidence of severe liver damage that proved fatal in some patients. Due to this previous restriction, however, pioglitazone is the agent most commonly utilized in this class. Pioglitazone [Actos] reduces insulin resistance and may also decrease glucose production. As a result, cellular responses to insulin are increased, thereby promoting (mainly) increased glucose uptake by skeletal muscle and adipose cells, and (partly) decreased glucose production by the liver. Since pioglitazone enhances responses to insulin, insulin must be present for the drug to work. Pioglitazone is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The drug can be used as monotherapy, but is usually combined with metformin, a sulfonylurea, and/or supplemental insulin. Because insulin is required for pioglitazone to work, the drug is not effective in patients with type 1 diabetes. Food slows absorption (blood levels peak 3 to 4 hours after dosing), but does not reduce the extent of absorption. The half-lives of pioglitazone and its metabolites are 3 to 7 hours and 16 to 24 hours, respectively. The most common reactions are upper respiratory tract infection, headache, sinusitis, and myalgia. In these individuals, fluid retention is exacerbated when pioglitazone is used in combination with insulin therapy. Pioglitazone can cause ovulation in anovulatory premenopausal women, thereby posing a risk of unintended pregnancy. This effect has not been studied in clinical trials, and hence the incidence is unknown. Women should be informed about the potential for ovulation and educated about contraceptive options. Postmarketing data indicate an increased risk of bladder cancer, associated mainly with long-term, high-dose pioglitazone therapy. Package labeling warns against using pioglitazone in patients with active bladder cancer or with a history of bladder cancer. Among these are exercise, ensuring adequate intake of calcium and vitamin D, and, if indicated, the use of drugs for osteoporosis (see Chapter 75). However, although pioglitazone has been associated with rare cases of hepatic failure, a causal relationship has not been established. Patients should be informed about symptoms of liver injury (nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, jaundice) and instructed to notify the prescriber if these develop. The net effect appears to be either (1) a reduction in cardiovascular risk or, at worst, (2) no increase in cardiovascular risk. The initial dosage for monotherapy is 15 or 30 mg once a day, taken with or without food. The maximum dosage is 45 mg once a day for patients not using insulin, but only 30 mg once a day for patients who are using insulin. Rosiglitazone Rosiglitazone [Avandia] is used only rarely today even though restrictions on its use have been lifted. Rosiglitazone shares many of the same clinical and safety considerations with pioglitazone. Acarbose [Precose, Glucobay] is available in tablets (25, 50, and 100 mg) to be taken with the first bite of main meals. Depending on tolerability and postprandial blood glucose levels, the dosage may be increased at 4- to 8-week intervals. The maximum dosage is 50 mg 3 times a day (for patients under 60 kg) and 100 mg 3 times a day (for patients over 60 kg). Miglitol Miglitol [Glyset] is the second alpha-glucosidase inhibitor approved in the United States. Like acarbose, miglitol delays conversion of oligosaccharides and complex carbohydrates to glucose and other monosaccharides, and thereby reduces the postprandial rise in blood glucose. In clinical trials, the drug was especially effective among Latinos and African Americans. Hypoglycemia does not occur with miglitol monotherapy, but may occur if the drug is combined with insulin or a sulfonylurea. Alpha-Glucosidase Inhibitors the alpha-glucosidase inhibitors-acarbose and miglitol-act in the intestine to delay absorption of carbohydrates. Acarbose [Precose, Glucobay] delays absorption of dietary carbohydrates and thereby reduces the rise in blood glucose after a meal. To be absorbed, oligosaccharides and complex carbohydrates must be broken down to monosaccharides by alpha-glucosidase, an enzyme located on the brush border of cells that line the intestine. Acarbose inhibits this enzyme and thereby slows digestion of carbohydrates, which reduces the postprandial rise in blood glucose. In clinical trials, 24 weeks of therapy with acarbose alone reduced mean peak postprandial glucose levels by 57 mg/dL, compared with 71 mg/dL for tolbutamide (a sulfonylurea) alone and 85 mg/dL for acarbose plus tolbutamide. In addition to lowering glucose levels after meals, acarbose lowers A1C levels, indicating an overall improvement in glycemic control. Because acarbose acts locally in the intestine, lack of absorption is considered beneficial. In the gut, acarbose is converted to inactive products by bacteria and digestive enzymes. Acarbose frequently causes flatulence, cramps, abdominal distention, borborygmus (rumbling bowel sounds), and diarrhea. These responses result from bacterial fermentation of unabsorbed carbohydrates in the colon. Hypoglycemia does not occur with acarbose alone, but may develop when acarbose is combined with insulin or a sulfonylurea. When hypoglycemia develops, sucrose cannot be used for oral therapy because acarbose will impede its hydrolysis and thereby delay absorption. Accordingly, in patients taking acarbose, oral therapy of hypoglycemia must be accomplished with glucose itself. Asymptomatic elevation of plasma transaminases (which come from damaged liver cells) occurs in about 15% of patients. Liver function tests should be monitored every 3 months for the first year and periodically thereafter. However, for some patients, even this small improvement can be clinically meaningful. Sitagliptin [Januvia] enhances the actions of incretin hormones, endogenous compounds that (1) stimulate glucose-dependent release of insulin and (2) suppress postprandial release of glucagon (a hormone that increases glucose production by the liver). Sitagliptin is indicated for type 2 diabetes, either as monotherapy or combined with another antidiabetic drug. Like all the other agents for managing diabetes, sitagliptin should be used as an adjunct to diet and exercise. Sitagliptin undergoes rapid and nearly complete absorption, both in the presence and absence of food. In clinical trials, the most common side effects were upper respiratory tract infection, headache, and inflammation of the nasal passages and throat-at rates similar to those seen with placebo. There have been postmarketing reports of serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome. Nonetheless, if a hypersensitivity reaction is suspected, sitagliptin should be discontinued. Sitagliptin has few drug-drug interactions, which is one benefit of this class of medications. Because sitagliptin is eliminated primarily by renal excretion, dosages should be reduced in patients with renal impairment, as indicated by reduced creatinine clearance. Dosage should be reduced to 50 mg once daily (in moderate renal disease) and 25 mg once daily (in severe renal disease). Linagliptin is a substrate for P-glycoprotein, a transporter that promotes excretion of linagliptin and other drugs. Accordingly, the manufacturer recommends that linagliptin not be used with rifampin and other P-glycoprotein inducers. The absolute bioavailability of alogliptin is approximately 100% when administered orally. Alogliptin does not undergo extensive metabolism, with the majority of an oral dose excreted unchanged in the urine. Accordingly, this drug is dose-adjusted when used in people with renal impairment. Alogliptin has a terminal half-life of about 20 hours and thus can be administered once daily. The most common side effects reported in clinical trials included upper respiratory tract infection and nasopharyngitis. Again, like other agents in this class, hypersensitivity reactions and postmarketing reports of pancreatitis have been noted. Similar to saxagliptin, the label for alogliptin includes a warning related to a potential increased risk of heart failure. Again, similar to saxagliptin, there was a small increase in the number of patients requiring hospitalization for heart failure. Alogliptin is primarily excreted renally, yet no significant drug-drug interactions have been noted with other drugs excreted through the kidneys. Saxagliptin may be used as monotherapy or combined with other antidiabetic agents. In clinical trials, the most common adverse effects were upper respiratory infection, urinary tract infection, and headache. Saxagliptin can intensify hypoglycemia caused by a sulfonylurea, but causes little or no hypoglycemia when used alone. Like sitagliptin, saxagliptin has been associated with rare cases of pancreatitis and severe hypersensitivity reactions. The prescribing information for saxagliptin also recommends that the agent be used with caution in patients with a history of or increased risk for heart failure. This recommendation is in place because patients taking saxagliptin were found to have a small increase in risk of hospitalization for heart failure in a large cardiovascular outcomes study performed with saxagliptin. This mechanism of action has proven clinically useful in patients with type 2 diabetes in terms of improving glycemic control. While currently approved agents hold an indication for the management of type 2 diabetes only, these agents are being studied and used off-label in people with type 1 diabetes. Clinical studies of canagliflozin have shown benefits in terms of improved glycemic control and weight loss. In addition, canagliflozin has been shown to improve cardiovascular and renal outcomes in patients with a history of cardiovascular disease.

Several devices are available virus types order genuine cefixime, including CoaguChek and the ProTime Microcoagulation System antibiotics kill bacteria order cefixime with a visa. Home monitoring is more convenient than laboratory monitoring and gives patients a sense of empowerment bacteria in urine icd 9 order cefixime now. Long-term warfarin use (more than 12 months) may weaken bones and thereby increase the risk of fractures antibiotics for dogs cuts cefixime 100 mg buy on line. The CoaguChek meter costs about $1300 and the ProTime meter costs about $2700 to $3500 virus pro buy discount cefixime 100 mg on-line. Patients should be monitored closely for signs of bleeding (reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain, headache, and lumbar pain). Of note, compared with warfarin, the newer oral anticoagulants-apixaban, rivaroxaban, edoxaban, and dabigatran-pose a significantly lower risk of serious bleeds. Candidates for treatment must be carefully screened for risk factors (see Warnings and Contraindications). When a patient is incapable of accurate self-medication, a responsible individual must supervise treatment. Patients should be advised to make a record of each dose, rather than relying on memory. Patients anticipating elective procedures should discontinue warfarin several days before the appointment. If an emergency procedure must be performed, injection of vitamin K can help suppress bleeding. Warfarin is subject to a large number of clinically significant adverse interactions-perhaps more than any other drug. As a result of interactions, anticoagulant effects may be reduced to the point of permitting thrombosis, or they may be increased to the point of causing hemorrhage. Patients must be informed about the potential for hazardous interactions and instructed to avoid all drugs not specifically approved by the prescriber. As indicated, the interactants fall into three major categories: (1) drugs that increase anticoagulant effects, (2) drugs that promote bleeding, and (3) drugs that decrease anticoagulant effects. The major mechanisms by which anticoagulant effects can be increased are (1) displacement of warfarin from plasma albumin, (2) inhibition of the hepatic enzymes that degrade warfarin, and (3) decreased synthesis of clotting factors. The major mechanisms for decreasing anticoagulant effects are (1) acceleration of warfarin degradation through induction of hepatic drug-metabolizing enzymes, (2) increased synthesis of clotting factors, and (3) inhibition of warfarin absorption. The existence of an interaction between warfarin and another drug does not absolutely preclude using the combination. The interaction does mean, however, that the combination must be used with due caution. The potential for harm is greatest when an interacting drug is being added to or withdrawn from the regimen. The interaction of heparin with warfarin is obvious: Being an anticoagulant itself, heparin directly increases the bleeding tendencies brought on by warfarin. By blocking aggregation, aspirin can suppress formation of the platelet plug that initiates hemostasis. Therefore, when the antifibrin effects of warfarin are coupled with the antiplatelet and ulcerogenic effects of aspirin, the potential for hemorrhage is significant. Accordingly, patients should be warned specifically against using any product that contains aspirin, unless the provider has prescribed aspirin therapy. Like aspirin, other antiplatelet drugs can increase the risk of bleeding with warfarin. Women of childbearing age should be informed about the potential for teratogenesis and advised to postpone pregnancy. Unlike aspirin, which promotes bleeding by inhibiting platelet aggregation, acetaminophen is believed to inhibit warfarin degradation, thereby raising warfarin levels. At this time, the interaction between acetaminophen and warfarin has not been proven. Several drugs, including phenobarbital, carbamazepine, and rifampin, are powerful inducers of hepatic drug-metabolizing enzymes. As a result, these drugs can accelerate warfarin degradation, thereby decreasing anticoagulant effects. Accordingly, if one of these drugs is added to the regimen, warfarin dosage must be increased. Of equal importance, when an inducer is withdrawn, causing rates of drug metabolism to decline, a compensatory decrease in warfarin dosage must be made. We have long known that systemic miconazole (as well as other azole antifungal agents) can inhibit the metabolism of warfarin and can thereby cause warfarin levels to rise. Apparently, intravaginal miconazole can be absorbed in amounts sufficient to do the same. Because of this interaction, women taking warfarin should not use intravaginal miconazole. If the drugs must be used concurrently, anticoagulation should be monitored closely and warfarin dosage reduced as indicated. Like the azole antifungal agents, cimetidine (a drug for ulcers) and disulfiram (a drug for alcoholism) can inhibit warfarin metabolism and can thereby increase anticoagulant effects. Vitamin K increases clotting factor synthesis and can thereby decrease anticoagulant effects. Sulfonamide antibacterial drugs can displace warfarin from albumin and thereby increase anticoagulant effects. Case reports suggest that two other antiarthritic agents-glucosamine and chondroitin-may also potentiate warfarin action. Decreased synthesis of clotting factors Drugs that promote bleeding Inhibition of platelet aggregation Inhibition of clotting factors and/or thrombin Warnings and Contraindications Like heparin, warfarin is contraindicated for patients with severe thrombocytopenia or uncontrollable bleeding and for patients undergoing lumbar puncture, regional anesthesia, or surgery of the eye, brain, or spinal cord. In addition, warfarin is contraindicated in the presence of vitamin K deficiency, liver disease, and alcoholism-conditions that can disrupt hepatic synthesis of clotting factors. Promotion of ulcer formation Drugs that decrease the effects of warfarin Induction of drugmetabolizing enzymes Promotion of clotting factor synthesis Reduction of warfarin absorption Accordingly, these drugs. In fact, acetaminophen was routinely recommended as an aspirin substitute for patients who needed a mild analgesic. Now, however, it appears that Vitamin K1 for Warfarin Overdose the effects of warfarin overdose can be overcome with vitamin K1 (phytonadione). Intravenous vitamin K acts faster than oral vitamin K, but can cause severe anaphylactoid reactions, characterized by flushing, hypotension, and cardiovascular collapse. If vitamin K fails to control bleeding, levels of clotting factors can be raised quickly by infusing fresh whole blood, fresh-frozen plasma, or plasma concentrates of vitamin K­ dependent clotting factors. Like medicinal vitamin K, dietary vitamin K can reduce the anticoagulant effects of warfarin. Dietary sources include mayonnaise, canola oil, soybean oil, and green leafy vegetables. If vitamin K intake does increase, then warfarin dosage should be increased as well. Conversely, if vitamin K intake decreases, the warfarin dosage should decrease too. Contrasts Between Warfarin and Heparin Although heparin and warfarin are both anticoagulants, they differ in important ways (Table 52. Although both drugs decrease fibrin formation, they do so by different mechanisms: heparin inactivates thrombin and factor Xa, whereas warfarin inhibits synthesis of clotting factors. Heparin and warfarin differ with respect to time course of action: effects of heparin begin and fade rapidly, whereas effects of warfarin begin slowly but persist several days. Protamine is given to counteract heparin; vitamin K1 is given to counteract warfarin. Dosage requirements for warfarin vary widely among individuals, and hence dosage must be tailored to each patient. Preparations Warfarin sodium [Coumadin, Jantoven] is available in tablets (1, 2, 2. In addition, warfarin is available in a formulation for parenteral dosing, which is not commonly done. Direct Thrombin Inhibitors the anticoagulants discussed in this section work by direct inhibition of thrombin. Hence, they differ from the heparinlike anticoagulants, which inhibit thrombin indirectly (by enhancing the activity of antithrombin). Compared with warfarin-our oldest oral anticoagulant-dabigatran has five major advantages: rapid onset; no need to monitor anticoagulation; few drug-food interactions; lower risk of major bleeding; and, since responses are predictable, the same dose can be used for all patients, regardless of age or weight. The drug binds with and inhibits thrombin that is free in the blood, as well as thrombin that is bound to clots. At the lower dabigatran dose (110 mg twice daily), the incidence of bleeding with dabigatran was less than with warfarin, but protection against stroke was less too. By contrast, at the higher dose (150 mg twice daily), the incidence of bleeding with dabigatran Therapeutic Use Atrial Fibrillation. The half-life is 13 hours in patients with normal renal function (CrCl 50 mL/ min or higher), and it increases to 18 hours in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Compared with warfarin, dabigatran is safer, posing a much lower risk of hemorrhagic stroke and other major bleeds. Because dabigatran is not highly protein bound, dialysis can remove much of the drug (about 60% over 2 to 3 hours). For patients with normal renal function (CrCl 50 mL/min or higher), dosing should stop 1 or 2 days before surgery. For patients with renal impairment (CrCl below 50 mL/ min), dosing should stop 3 to 5 days before surgery. Symptoms of dyspepsia can be reduced by taking dabigatran with food and by using an acid-suppressing drug (proton pump inhibitor or histamine2 receptor blocker). Dabigatran is not metabolized by hepatic P450 enzymes, nor is it an inhibitor or inducer of these enzymes. Dabigatran etexilate is a substrate for intestinal P-glycoprotein, the transporter protein that can pump dabigatran and other drugs back into the intestine. Drugs that inhibit P-glycoprotein can increase dabigatran absorption and blood levels, and drugs that induce P-glycoprotein can decrease dabigatran absorption and blood levels. Combined use with a P-glycoprotein inducer appears to be safe, even though it might reduce beneficial effects somewhat. Dabigatran etexilate [Pradaxa] is available in three strengths: 75-, 110-, and 150-mg capsules. If the capsules are crushed, chewed, or opened, absorption will be increased by 75%, thereby posing a risk of bleeding. However, if the missed dose cannot be taken at least 6 hours before the next scheduled dose, the missed dose should be skipped. In patients with significant renal impairment (CrCl 15 to 30 mL/min), the dosage is 75 mg twice a day. For patients with greater renal impairment (CrCl below 15 mL/min), no dosing recommendation can be made. The drug is a synthetic 20­amino acid peptide that is chemically related to hirudin, an anticoagulant isolated from the saliva of leeches. Bivalirudin is given in combination with aspirin, clopidogrel, or prasugrel to prevent clot formation in patients undergoing coronary angioplasty. In one trial-the Hirulog Angioplasty Study-bivalirudin plus aspirin was compared with heparin plus aspirin. In a subgroup of patients-those with postinfarction angina-bivalirudin was significantly more effective than heparin. Other relatively common effects (incidence greater than 5%) include vomiting, abdominal pain, pelvic pain, anxiety, nervousness, insomnia, bradycardia, and fever. However, compared with heparin, bivalirudin causes fewer incidents of major bleeding (3. Coadministration of bivalirudin with heparin, warfarin, or thrombolytic drugs increases the risk of bleeding. Bivalirudin is eliminated primarily by renal excretion and partly by proteolytic cleavage. The half-life is short (25 minutes) in patients with normal renal function, but may be longer in patients with renal impairment. Bivalirudin is just as effective as heparin and has several advantages: It works independently of antithrombin, inhibits clot-bound thrombin as well as free thrombin, and causes less bleeding and fewer ischemic events. However, the drug has one disadvantage: Bivalirudin is more expensive than heparin. One single-use vial, good for a full course of treatment, costs about $1000, compared with $10 for an equivalent course of heparin. However, the manufacturer estimates that reductions in bleeding and ischemic complications would save, on average, $1000 per patient, which would offset the greater cost of bivalirudin. Bivalirudin works as well as heparin, is safer, and may be equally cost effective-and hence is considered an attractive alternative to heparin for use during angioplasty. Bivalirudin [Angiomax] is supplied as a lyophilized powder (250 mg) for reconstitution in sterile water. If necessary, bivalirudin may be infused for up to 20 additional hours at a rate of 0. Desirudin is completely absorbed following subQ injection, achieving peak plasma levels in 1 to 3 hours. In patients with normal renal function, the elimination half-life is 2 to 3 hours. By contrast, in those with severe renal impairment, the half-life is greatly prolonged (up to 12 hours). As with other anticoagulants, hemorrhage is the adverse effect of greatest concern. In clinical trials, the incidence of hemorrhage was 30% in the desirudin group, compared with 33% in the enoxaparin group and 20% in the heparin group. Less serious effects include wound secretion, injection-site mass, anemia, nausea, and deep thrombophlebitis.

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