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By G. Felipe. Southwest Baptist University.

There is conflicting data as to whether or not proton pump inhibitors and H blockers increase the risk of pneumonia [2 7–9] discount cleocin gel 20 gm fast delivery. Upper Gastrointestinal Defenses Gastrointestinal mechanisms normally work in a coordinated buy generic cleocin gel 20 gm online, synchronized fashion order cleocin gel 20 gm fast delivery. The teeth break up large food particles, and the tongue propels fluid and masticated food into the hypopharynx. Because the hypopharyngeal muscles prepare to move food into the esophagus, the epiglottis covers the laryngeal inlet and the vocal cords close and the upper esophageal sphincter (cricopharyngeus muscle) relaxes. Even in the absence of known trauma or a neurologic insult that could affect the swallowing cascade, some of the previously mentioned defenses may become impaired in a variety of situations, leading to silent aspiration. Aging can result in progressive loss of cough and swallowing reflexes resulting in aspiration pneumonia. The vocal cords close much more slowly after the age of 50 years and may not close at all during sleep or with sedation irrespective of age. Furthermore, the cough response to airway irritation is decreased during sleep compared to the waking state. It has been estimated that half of all healthy adults aspirate oropharyngeal secretions during sleep [3]. The risk of aspirating fluid and food is increased when the normal swallowing and upper gastrointestinal mechanisms fail to work in a coordinated, synchronized manner. Edentulous or neurologically impaired patients may not adequately masticate food resulting in higher aspiration risk. Aspiration also may occur when the bolus cannot readily be cleared from the pharynx owing to neuromuscular disorders of any cause [10]. Structural abnormalities such as Zenker’s diverticulum place a patient at risk of aspiration because the diverticulum may empty “late” after the swallowing effort is completed, at the time when the vocal cords are abducted. Although mucociliary clearance removes the larger particles from the larger airways, additional defense mechanisms are needed to clear the smaller particles [12]. This is accomplished in respiratory bronchioles and alveoli primarily by the alveolar macrophages, aided by neutrophils [13]. Recent studies, utilizing newer, molecular biology, noncultural techniques, have revealed that the lungs have their own respiratory biome and may not be sterile as previously thought [14]. The respiratory filtration system and mucociliary clearance may become overwhelmed with large-volume fluid and food aspiration or with large amounts of inhaled infectious agents. Respiratory defenses may also become ineffective in the following settings: inhalational or systemic general anesthesia, endotracheal intubation, endotracheal suctioning, hypercapnia and hyperoxia, smoking, asthma, chronic bronchitis, cystic fibrosis and bronchiectasis, and respiratory infections with viruses and atypical organisms. In the absence of mucociliary clearance, the airways can still be cleared of excessive secretions and foreign bodies if the patient has an effective cough. An effective cough generates a column of expired air moving quickly through the bronchi, thus dislodging mucus and debris from the bronchial mucosa and propelling it out of the lungs [14]. However, cough is not a primary defense mechanism and only provides clearance when mucociliary clearance is inefficient or overwhelmed. Thus, cough may be ineffective in patients with severe asthma, chronic obstructive pulmonary disease, respiratory neuromuscular disorders, painful incisions, or in those receiving excessive sedation and analgesia with antitussive effects [14]. When the mechanical airway defenses are overwhelmed, alveolar macrophages represent the initial phagocytic response. Neutrophils are critical for the eradication of bacterial agents, and, therefore any impairment in their function would be detrimental [13]. Aspirated bacteria cause infectious pneumonia when the alveolar phagocytes become impaired, such as in alcoholism, pH less than 7. Immunologic defenses such as complement, innate immunity proteins, and immunoglobulins augment the nonimmunologic mechanisms. Patients with hereditary and acquired immunologic abnormalities, such as immunoglobulin G and complement deficiencies, are susceptible to frequent and often severe bacterial pneumonias. The presence of an endotracheal tube or a tracheostomy tube poses a high risk for aspiration and its consequences. Translaryngeal Intubation Clearly, no one would feed a patient with an oral or a nasal endotracheal tube in place, given the obvious mechanical barrier and distortion of the swallowing structures. What is often less intuitive is that dysphagia may persist for a variable time after the endotracheal tube has been removed. Factors that increase the likelihood of dysphagia after extubation include intubation >48 hours; laryngeal edema; and ulceration, erythema, and immobility of the vocal cords. Should aspiration occur, ciliary clearance and other respiratory defenses might not respond appropriately because of the physical insult of the endotracheal tube. Aspiration Risk After Tracheostomy Patients with a tracheostomy tube, with or without dependence on mechanical ventilation, are also at high risk for aspiration. The most commonly identified reasons for swallowing dysfunction for the patient with a tracheostomy tube are incomplete backward folding of the epiglottis, not allowing the glottis to rise and tilt forward with swallowing, pharyngeal retention, penetration, and aspiration [15]. The application of a speaking valve can restore subglottic air pressure and reduce aspiration and penetration [20]. In addition, the presence of a nasogastric feeding tube is associated with gram-negative bacterial contamination of the oropharynx, which, when aspirated, can result in infection of the lower airways [22]. Varying the size of the enteral feeding catheters and adjusting the location of the distal tip have been used in an attempt to minimize aspiration. Small-bore feeding tubes appear to provide no added benefit with respect to reflux events, even when advanced to the postpylorus position [24]. Patients with long-standing swallowing defects or on prolonged mechanical ventilation may be candidates for percutaneous gastrostomy or jejunostomy tubes; however, even percutaneous enteral feeding tubes alter lower esophageal tone and can allow reflux. In fact, patients fed by gastrostomy tubes have the same incidence of pneumonia as those fed by nasogastric tubes [25,26]. Furthermore, although a percutaneous jejunostomy tube may minimize the large-volume aspiration events, it is a misconception that it prevents aspiration or decreases its incidence relative to a percutaneous gastrostomy tube [27]. In fact, one study showed that the absence of monitoring gastric residual volume was noninferior to residual gastric volume monitoring in terms of ventilator-associated pneumonia prevention. Additionally, there was less prokinetic drug use and improved nutrition in the nonmonitored group [28,29]. Although signs of wheezing, shortness of breath, cyanosis, and hypoxia may be present, aspiration may also be completely asymptomatic. There is also a misconception that aspiration must be witnessed before it can be assumed to have occurred because many aspiration events are silent [30]. In addition to taking a history, performing a physical examination and observing the patient drink 3 ounces of water when appropriate can uncover a swallowing problem. Although the bedside evaluation is not sensitive, a pharyngeal problem may be evident by watching the patient cough, sputter, and tilt his or her neck and head in an unnatural posture when drinking the water. An absent gag reflex is not a useful predictor of aspiration because many healthy individuals who do not have a gag reflex can swallow normally [31]. Modified Barium Swallow/Video Fluoroscopy Although observing patients can be useful when there is obvious difficulty during swallowing, aspiration is often silent in the critically ill patient. Because of this, a negative bedside examination should be confirmed by a more objective method to evaluate aspiration for high-risk patients. It defines the pharyngeal anatomy with swallowing of a radiopaque contrast material, and the swallowed bolus is followed in “real time” under fluoroscopy.

Unchanged drug and metabolites are excreted predominantly through the bile into the feces 20gm cleocin gel visa. Adverse effects Adverse effects caused by tamoxifen include hot flashes purchase cleocin gel cheap online, nausea buy cheap cleocin gel 20 gm on line, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue). This agent binds to and causes estrogen receptor down- regulation on tumors and other targets. This agent reduces the risk of estrogen receptor–positive invasive breast cancer in postmenopausal women. Aromatase inhibitors the aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. These agents are considered first-line drugs for the treatment of breast cancer in postmenopausal women. They are orally active and cause almost a total suppression of estrogen synthesis. Both drugs are extensively metabolized in the liver, and metabolites and parent drug are excreted primarily in the urine. Because the metabolites are excreted in urine, doses of the drug must be adjusted in patients with renal failure. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy with regression of tumor and relief of bone pain. These drugs have some benefit in premenopausal women with advanced breast cancer and have largely replaced estrogens in therapy for prostate cancer. Leuprolide is available as 1) a subcutaneous daily injection, 2) a subcutaneous depot injection, or 3) an intramuscular depot injection to treat metastatic carcinoma of the prostate. Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected intramuscularly. Levels of androgen in prostate cancer patients may initially rise, but then fall to castration levels. The adverse effects of these drugs, including impotence, hot flashes, and tumor flare, are minimal compared to those experienced with estrogen treatment. They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate (see ure 35. The potency, pharmacokinetics, patterns of distribution, and dose-limiting toxicities differ significantly (ure 35. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. Carboplatin is used when patients cannot be vigorously hydrated, as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. Mechanism of action the mechanism of action for these agents is similar to that of the alkylating agents. In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses chloride in the low-chloride milieu. Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable to the actions of these drugs in the G and S phases. Cisplatin and carboplatin can also be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other organs. Adverse effects Severe nausea and vomiting occurs in most patients after administration of cisplatin and may continue for as long as 5 days. The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. Other toxicities include ototoxicity with high-frequency hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic. Oxaliplatin has a distinct adverse effect of cold-induced peripheral neuropathy that usually resolves within 72 hours of administration. These agents may cause hypersensitivity reactions ranging from skin rashes to anaphylaxis. Camptothecins Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. Topotecan is used in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small cell lung cancer. Adverse effects Bone marrow suppression, particularly neutropenia, is the dose-limiting toxicity for topotecan. Acute 1359 and delayed diarrhea with irinotecan may be severe and require treatment with atropine during the infusion or high doses of loperamide in the days following the infusion. Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma. Tyrosine Kinase Inhibitors the tyrosine kinases are a family of enzymes that are involved in several important processes within a cell, including signal transduction and cell division. Immunotherapy Immunotherapy with intravenous immune checkpoint inhibitors is a rapidly evolving option for cancer treatment. By blocking these molecules, the immune system is better able to attack the tumor and cause destruction. The adverse reaction profiles of these agents consist of potentially severe and even fatal immune-mediated adverse events. This is because turning off the immune checkpoints allows attack of the tumor, but can also lead to unchecked autoimmune response to normal tissues. Adverse events include diarrhea, colitis, pneumonitis, hepatitis, nephritis, neurotoxicity, dermatologic toxicity in the form of severe skin rashes, and endocrinopathies such as hypo- or hyperthyroidism. Patients should be closely monitored for the potential development of signs and symptoms of toxicity and promptly treated with corticosteroids if necessary. Hepatotoxicity may occur, and patients should be closely monitored for hypertension, hypokalemia, and fluid retention. Joint and muscle discomfort, hot flushes, and diarrhea are common adverse effects with this agent. Their exact mechanism of action is not clear, but they possess antimyeloma properties including antiangiogenic, immune-modulation, anti-inflammatory and antiproliferative effects. These agents are often combined with dexamethasone or other chemotherapeutic agents. Adverse effects include thromboembolism, myelosuppression, fatigue, rash, and constipation. However, severe birth defects were prevalent in children born to mothers who used thalidomide. Because of their structurally similarities to thalidomide, lenalidomide and pomalidomide are contraindicated in pregnancy. These agents work by inhibiting proteasomes, which in turn prevents the degradation of proapoptotic factors, thus leading to a promotion in programmed cell death (apoptosis). Malignant cells readily depend on suppression of the apoptotic pathway; therefore, proteasome inhibition works well in multiple myeloma.

Insulin and C-peptide are normally co-secreted by the pancreas in equimolar quantities order cleocin gel us, but C-peptide is not present in insulin for injection discount cleocin gel generic. Absence of C-peptide in a patient with unexplained fasting hypoglycemia strengthens the possibility of surreptitious insulin use buy cheap cleocin gel 20 gm line. Nesidioblastosis (nonmalignant islet cell hyperplasia) is a rare form of nonmalignant islet cell adenomatosis that leads to insulin- mediated hypoglycemia. Among infants, nesidioblastosis is typically characterized by islet hyperplasia, β cell hypertrophy, and increased β cell mass. Special cases of hyperinsulinemic hypoglycemia of infancy include Costello syndrome [70] and the Beckwith–Wiedemann syndrome, which is due to defects in pancreatic β cell potassium channels [71]. Whether these cases represent nesidioblastosis [75,77], “dumping syndrome,” or a reactive process leading to or unmasking a defect in β cell function [78] is unclear, perhaps in part because the pathologic diagnosis of nesidioblastosis is difficult [74]. The initial approach to patients with post-gastric bypass hypoglycemia should focus on avoidance of high carbohydrate content meals. Should that fail, other treatment options include diazoxide, streptozocin, calcium channel blockade [79], α-glucosidase inhibition [79], octreotide (discussed below), percutaneous gastrostomy into the remnant stomach [80], as well as partial pancreatectomy [77]. Autoimmune hypoglycemia can result from autoantibodies directed against insulin itself or autoantibodies directed against the insulin receptor [81]. Both can occur in either insulin-treated [82] or nondiabetic individuals, and both types of autoantibody can be found in the same patient [83]. Serum insulin concentrations typically are extremely high, usually higher than those produced by insulinomas. It is assumed that for these cases, glucose administration causes an excessive insulin response because the antibodies buffer most of the insulin secreted [85]. Endogenous antibodies that bind to and activate the insulin receptor can also cause hypoglycemia [86]. Some, but not all, cases are associated with other autoimmune disorders [87–89], and a few have occurred among patients with myeloma [90]. Previous exposure to exogenous insulin is not necessary, but some patients may have an abnormal insulin molecule [91]. The natural history of this syndrome is that the anti-receptor antibodies disappear and the syndrome resolves over months to years [38]. Hypoglycemia after pancreas and islet transplantation can occur [93], but it is generally not a significant clinical problem [94,95]. Certain tumors not of pancreatic islet origin are associated with fasting hypoglycemia clinically indistinguishable from that caused by islet cell neoplasms. Whereas insulinomas are typically quite small, non-pancreatic neoplasms associated with hypoglycemia tend to be large mesenchymal tumors. Non-islet cell neoplasms associated with hypoglycemia include gastrointestinal stromal cell tumors [108], hemangiopericytoma [109–111], hepatoma [112,113], uterine tumors [114], renal tumors [115], mesenteric sarcomas [116], colorectal cancer [117], gastric cancer [118], adrenocortical carcinoma, Hodgkin’s lymphoma [119], poorly differentiated thyroid cancer [120], somatostatinoma [121], phyllodes tumor [122], and leukemia [123]. Multiple myeloma may also cause hypoglycemia via an antibody- mediated mechanism described below [89]. As noted above, this can be done by obtaining simultaneous insulin and glucose measurements during hypoglycemia. Hypoglycemia due to Non-Insulin Hypoglycemic Agents Pharmaceuticals other than insulin that are used to treat type 2 diabetes fall into two classes. When given as monotherapy they do not cause hypoglycemia, but they can amplify the glucose-lower activity of insulin and the oral hypoglycemic agents. As discussed below, many drugs not used for the treatment of diabetes can also amplify the glucose-lowering activity of oral hypoglycemic agents, and a complete medication history can be critical for the diagnosis of hypoglycemia. Sulfonylureas reduce serum glucose by increasing insulin secretion, which also inhibits inhibiting glycogenolysis and gluconeogenesis, enhancing the response of target tissues to the effects of insulin [127]. Three “second-generation” sulfonylureas are in use in the United States, glipizide, glyburide, and glimepiride (Table 138. Severe hypoglycemia is not common with appropriate administration of these drugs [128], but it can be observed in several contexts [129]. In all age groups the condition is most often observed in the context of decreased carbohydrate intake. Maternal treatment of diabetes with glyburide can lead to postpartum hypoglycemia of their neonates [130]. Among patients between the ages of 11 and 30 years, a substantial number of hypoglycemic comas is due to sulfonylurea agents [51]. Among patients with type 2 diabetes older than 60 years, sulfonylurea-induced hypoglycemia is a frequent complication [129,131]. Metabolites of sulfonylureas are excreted in urine with one exception; 50% of glyburide metabolites is excreted in the bile. Accordingly, sulfonylurea-induced hypoglycemia is often observed among older individuals in the setting of acute or chronic starvation superimposed on mild to moderate liver or renal failure. The half-life of some sulfonylureas is >24 hours and the duration of action is often even longer (Table 138. Patients with sulfonylurea-induced hypoglycemia should therefore be hospitalized after initial resuscitation with glucose. Sulfonylurea drugs circulate bound to proteins, and drugs of several classes can displace sulfonylureas and enhance their hypoglycemic effect (Table 138. Repaglinide (Prandin) and nateglinide (Starlix), like the sulfonylureas, increase endogenous insulin secretion but do so by a different mechanism. Biguanides, when given as monotherapy, induce hypoglycemia much less frequently than do sulfonylureas [133,134], probably by inhibiting gluconeogenesis. It is also available in combination with the oral hypoglycemic agents glyburide (Glucovance), glipizide (Metaglip), and repaglinide (Prandimet); overdosage with these combination drugs can cause severe hypoglycemia. Acarbose (Precose) and miglitol (Glyset) are α-glucosidase inhibitors that inhibit the digestion of complex carbohydrates; they have not been reported to cause hypoglycemia when used as monotherapy. Patients treated with insulin or sulfonylureas in addition to acarbose who experience hypoglycemia may not respond to the oral administration of complex sugars, but should respond to monomeric glucose. Exenatide (Byetta), dulaglutide (Trulicity), albiglutide (Tanzeum), lixisenatide (Lyxumia), and liraglutide (Victoza) are injectable mimetics of gut incretins [135,136]. When given as monotherapy they rarely cause hypoglycemia but the risk increases with concurrent sulfonylurea use. They inhibit the degradation of endogenous gut incretins and have glucose- lowering effects and hypoglycemia risks similar to those of the gut incretins. Drugs in this class include sitagliptin (Januvia), linagliptin (Tradjenta), alogliptin (Nesina), and saxagliptin (Onglyza). It is targeted at controlling post-meal hyperglycemia in diabetic patients who are also taking insulin. They reduce blood glucose by reducing reabsorption of glucose by the kidney and as monotherapy do not cause hypoglycemia [6]. All are available in combination with metformin or a gliptin and these combination products can sometimes cause hypoglycemia. Bromocriptine is an oral dopamine agonist that is used in the treatment of pituitary tumors and Parkinson’s disease. Severe hypoglycemia can result from inadvertent substitution of an oral hypoglycemic agent for a different medication.

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