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In contrast to pentazocine and butorphanol buy discount sildalist 120 mg online, nalbuphine does not affect the heart or increase blood pressure sildalist 120mgmg for sale. A benefit of all three medications is that they exhibit a ceiling effect for respiratory depression trusted 120mgmg sildalist. It is used to manage moderate to severe acute and chronic pain 120mgmg sildalist with amex, including neuropathic pain associated with diabetic peripheral neuropathy. Because tapentadol does not produce active metabolites, dosing adjustment is not necessary in mild to moderate renal impairment. Administration of naloxone can only partially reverse tramadol toxicity and has been associated with an increased risk of seizures. As with other agents that bind the μ opioid receptor, tramadol has been associated with misuse and abuse. Antagonists the opioid antagonists bind with high affinity to opioid receptors, but they fail to activate the receptor-mediated response. Administration of opioid antagonists produces no profound effects in individuals not taking opioids. In opioid-dependent patients, antagonists rapidly reverse the effect of agonists, such as morphine or any full μ agonist, and precipitate the symptoms of opioid withdrawal. Naloxone can also be administered intramuscularly, subcutaneously, and intranasally, with a slightly longer onset of 2 to 5 minutes; however, little to no clinical effect is seen with oral naloxone due to extensive first-pass metabolism. Since naloxone has a half-life of 30 to 81 minutes, a patient who has been treated for an overdose and recovered may lapse back into respiratory depression, depending on the opioid ingested and dosage form of that opioid. It is imperative that prescribers counsel the patient and family members regarding the availability of these products, proper instructions for use, and the importance of calling emergency services in the case of overdose. For example, a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours, and the intramuscular formulation blocks the effect for 30 days. Naltrexone in combination with clonidine (and, sometimes, with buprenorphine) is used for rapid opioid detoxification. Naltrexone has been reported to cause hepatotoxicity and monitoring of hepatic function is recommended. A morphine overdose can be effectively treated with naloxone, and morphine is a phenanthrene. Naloxone antagonizes the opioid by displacing it from the receptor, but there are cases in which naloxone is not effective. Meperidine is a phenylpiperidine, not a phenanthrene, and the active metabolite, normeperidine, is not reversible by naloxone. In most cases of buprenorphine overdose, the dose of naloxone needs to be high and continuous due to the higher binding affinity to the mu receptor. Naloxone is effective for fentanyl overdoses; however, fentanyl is a phenylpiperidine, and not a phenanthrene. She reports that the pain has been uncontrolled with tramadol, and it is decided to start treatment with an opioid. It is very important to use a low dose and monitor closely for proper pain control and adverse effects. Meperidine should not be used for chronic pain, nor should it be used in a patient with renal insufficiency. The transdermal patch is not a good option, since her pain is considered acute and she is opioid naïve. Morphine is not the best choice due to the active metabolites that can accumulate in renal insufficiency. Buprenorphine has a much higher incidence of opioid-induced respiratory depression compared to other μ agonists. Buprenorphine has many dosage formulations, and all formulations can be prescribed for the treatment of pain or opioid dependence. Buprenorphine has a lower incidence of opioid-induced respiratory depression compared to the μ agonists due to the ceiling effect created by the partial μ agonist activity. Buprenorphine is available in many different dosage formulations, but these formulations are indicated for either pain management or medication-assisted treatment of opioid dependence, not both. Based on the mechanism of action, which opioid could be considered in this patient to treat both nociceptive and neuropathic pain? Tapentadol has a unique mechanism of action in comparison with the other choices given. Tapentadol has a dual mechanism of action (μ agonist and norepinephrine reuptake inhibition), which has been shown to effectively treat neuropathic pain associated with diabetic peripheral neuropathy. All other μ agonists could help manage neuropathic pain, but in some situations, higher doses of opioids are needed to achieve efficacy. Methadone is an excellent choice for analgesia in most patients because there are limited drug–drug interactions. The duration of analgesia for methadone is much shorter than the elimination half-life. The active metabolites of methadone accumulate in patients with renal dysfunction. The duration of analgesia is much shorter than the elimination half-life, leading to dangers of accumulation and increased potential for respiratory depression and death. The equianalgesic potency of methadone is extremely variable based on many factors, and only providers familiar with methadone should prescribe this agent. The drug interactions associated with methadone are numerous due to the multiple liver enzymes that metabolize the drug. Methadone does not have active metabolites, which makes it a treatment option in patients with renal dysfunction. Which of the following is a short-acting opioid and is the best choice for this patient’s breakthrough pain? Hydrocodone is a commonly used short-acting agent that is commercially available in combination with either acetaminophen or ibuprofen. Methadone should not routinely be used for breakthrough pain due to the unique pharmacokinetics and should be reserved for practitioners who have experience with this agent and understand the variables associated with this drug. Fentanyl is available in formulations for treatment of breakthrough pain for cancer treatment. Nalbuphine is a mixed agonist/antagonist analgesic that could precipitate withdrawal in patients who are currently taking a full μ agonist such as oxycodone. Which of the following opioids would have the lowest chance of drug interactions in this patient? The risk of respiratory depression is highest during an initial opioid initiation or following a dose increase. The incidence of nausea and sedation increases with long-term use of opioid therapy. Decreased testosterone levels are commonly seen with short-term use of opioid therapy. The risk of respiratory depression is highest when the opioid is first initiated or a dosage is raised (or sometimes a drug–drug interaction leads to higher opioid levels). Opioid-induced constipation can occur at any time during the therapy, and a patient does not develop a tolerance to this side effect. Side effects such as nausea and sedation commonly decrease after repeated dosing due to development of tolerance to these adverse effects. Chronic opioid exposure has been linked to decreased testosterone levels in males. He has been converted to oral morphine in anticipation of discharge from the hospital. A bowel regimen should be prescribed with the initiation of the opioid since constipation is very common and can occur at any time, and tolerance to this adverse effect does not occur. Docusate sodium is a stool softener that is ineffective in opioid-induced constipation when used as a single agent. Combination products that include both docusate and senna are commonly used and can be effective, mainly due to the actions of senna. Diphenhydramine can be used for urticaria that might occur with the initiation of an opioid, and methylphenidate has been used for opioid-induced sedation in certain situations, but these issues are not reported in this case. His pain has been fairly well controlled, and he remains active, reports satisfaction with his pain regimen, and denies any side effects. Which of the following options is the best treatment recommendation for him at this time? Taper off all opioids due to increased risk of opioid-induced respiratory depression. Prescribe naloxone nasal spray to have at home in case he experiences an opioid overdose. Prescribe oral naloxone tablets to have at home in case he experiences an opioid overdose. Since the pain is controlled and no side effects are reported, tapering off the opioids at this time is not the best answer. Because of the first-pass effect, naloxone is not clinically effective for management of an overdose when given orally. Offering the at-home naloxone nasal spray, along with proper education, might be lifesaving if an overdose occurs. Providing proper education to the patient and caregivers on the importance of having the naloxone nasal spray at home and of calling emergency services is critical in case of an overdose situation. The psychomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity. The hallucinogens produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord. Caffeine, the most widely consumed stimulant in the world, is found in highest concentration in certain coffee products (for example, espresso), but it is also present in tea, cola drinks, energy drinks, chocolate candy, and cocoa.

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Allopurinol is therefore used prophy- lactically to help prevent uric acid build up in patients either undergoing or about to undergo chemotherapy buy generic sildalist 120 mg, such as in this case order sildalist 120 mg free shipping. As part of the medical team on call generic sildalist 120 mg visa, the orthopaedics team have contacted you because her platelet count has been consist- ently dropping discount 120 mg sildalist, and they are now concerned that it is too low for her to continue with the heparin infusion that she is currently receiving for her metallic heart valve, which was started 6 days ago. During her admission she has been generally well, but had experienced a urinary tract infection, treated with gentamicin. The operation had gone smoothly without any significant bleeding and there was no haematoma at the wound site. Her past medical history included type 2 diabetes mellitus, on metformin and a metallic aortic valve for which she was normally on warfarin. She had been placed on a hepa- rin infusion pump on admission as her usual anticoagulation with warfarin had to be reversed prior to surgery. She was on candesartan, metformin, aspirin and warfarin, the aspirin also having been stopped on admission. Examination On examination, she was drowsy due to analgesia which was partly for her post-oper- ative pain, but also for some new left foot/calf pain. This patient has sustained a fractured neck of femur and during her admission to have this surgically corrected, has developed a significant thrombocytopenia. The normal blood count on admission with platelet count of 225 × 109/L is useful as it rules out pre-existing thrombocytopenia, and confirms this as a new development. The most common cause of thrombocytopenia in hospital patients is infection/ sepsis, which can result in quite a profound drop in platelet count. Another common cause of thrombocytopenia is drug therapy and it would therefore be useful to review the drug chart to rule out drugs that could cause this. First, it is generally accepted that when platelet counts drop below 50 × 109/L, the risk of therapeutic anticoagulation increases significantly, often outweighing the benefits gained. In this patient, the presence of a metallic heart valve and the significant consequences of it thrombosing – which could prove fatal – mean that the balance between risks and benefits is more difficult to achieve, but needs to be considered carefully. It usually occurs 5–14 days after initiating heparin, which relates to the time taken for the immune response to develop. However, in those with previous exposure to heparin, the development of thrombocytopenia can occur 24 hours after exposure due to preformed antibodies. No further heparin should be administered to the patient and this includes the use of small volumes of heparin to flush indwelling catheters. Warfarin must not be initiated until the platelet count has returned to normal as it is procoagulant when first started, due to its effect on the production of naturally occurring anti- coagulants, such as protein C. Her history is difficult to obtain, but you can ascertain that she has never had a stroke before and denies any risk factors for stroke, such as hypertension, hyper- cholesterolaemia, or previous vascular disease, but she does smoke 30 cigarettes a day and has done so for the past 30 years. Medication included mycophenolate mofetil, aspirin and warfarin, although this had recently been temporarily stopped in preparation for an upcoming colonoscopy. Examination Examination of the cardiovascular system was normal with no audible murmurs and a regular pulse with a rate of 76 bpm. The chest was clear to auscultation and the abdo- men was soft and non-tender with no spleen or liver palpable. Neurological examina- tion revealed increased tone, decreased power and hyper-reflexia in the right arm and leg. The presence of a lupus anticoagulant is not always pathological, but in some cases it can produce a procoagulant state resulting in arterial or venous thrombosis, such as this case. Antiphospholipid syndrome is an acquired autoimmune condition causing arterial or venous thromboses, or pregnancy complications and failure. It is characterized by the presence of auto-antibodies directed at negatively charged phospholipids, such as anticardiolipin antibodies, lupus anticoagulant, or anti-β2-glycoprotein I antibodies. The diagnostic criteria for the syndrome can be seen below and require the presence of at least one clinical and one laboratory feature to be present: • Clinical criteria – Vascular thrombosis – one or more episodes of arterial, venous or small vessel thrombosis – Pregnancy morbidity: c{One or more unexplained deaths of a morphologically normal foetus at or beyond the 10th week of gestation c{One or more preterm births of a morphologically normal neonate before the 34th week of gestation because of (1) eclampsia or severe pre- eclampsia or (2) recognized features of placental insufficiency c{Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomic or hormonal abnor- malities and paternal and maternal chromosomal abnormalities excluded. It is likely that this woman was already known to have antiphospholipid syndrome due to previous vascular thromboses which instigated her treatment with warfarin, as no other obvious indication for warfarin has been revealed. The current stroke Case 65: Middle-aged woman with right-sided weakness 309 may therefore have resulted from under-anticoagulation, while the warfarin was stopped pre-colonoscopy. Treatment of this patient’s acute stroke will require input from experts in stroke medicine and haematology, as therapeutic anticoagulation will be required at an earlier time point than that which is usually recommended in stroke. This increases the risk of haemorrhagic transformation, but there are some cases where the risk of further thrombosis is greater. He had been experiencing early satiety recently and feels that this may explain his recent weight loss. He denies any change in bowel habit or obvious blood loss, but does report easy bruising on minimal trauma. Apart from this, he has recently experienced recurrent chest infections that took three courses of antibiotics to clear. An occa- sional right basal crepitation was audible on his chest and cardiovascular examination was normal. His abdomen was soft and non-tender with a large mass palpable in the left upper quadrant extending down to the umbilicus, the top edge of which was not palpable. Very few conditions, other than chronic bone marrow pathologies, can present in this chronic manner, although haematinic deficiencies, such as B12 and folate, should be excluded initially. Chronic haemolytic anaemias may present in this manner, but would be unusual in the presence of leukopenia and thrombocytosis. Examination of the blood film might help with the diagnosis which in this case showed tear drop poikilocytes (red cells in the shape of tear drops), and immature red and white cells – the so-called ‘leukoerythroblastic blood picture’. Bone marrow investigations are the next step in diagnosis and would reveal the presence of fibrosis within the marrow, among other typical features. Myelofibrosis is a clonal myeloproliferative neoplasm which commonly develops in the sixth and seventh decades. It has occasionally been linked to ionizing radiation and benzene exposure, but is generally idiopathic. Proliferation of granulocyte and platelet precursors occurs within the bone marrow and results eventually in bone marrow fibrosis, which interferes with normal blood cell production. Due to reduced capacity for blood production within the marrow, other tissues within the body are taken over to produce it, including the spleen and liver. Treatment is generally with supportive measures that reduce symptoms, such as blood transfusion and analgesia. The only curative option is an allogeneic stem cell transplant, but the majority of people diagnosed with myelofibrosis are unsuitable for such intensive treatment. Life expectancy is very variable and depends on a number of factors, but can range from just 13 months median survival up to 93 months. Case 66: Middle-aged man with increasing tiredness 313 Differential diagnosis • Chronic myeloid leukaemia and other haematological malignancies such as lymphoma • Myelofibrosis • Infections • Inflammatory/autoimmune conditions • Metastatic malignancies Key points • Gradual onset of symptoms suggests a gradually progressive condition. He had been for a preoperative assess- ment for a hernia repair and, as part of the assessment, a full blood count had been performed which produced the results below. He is frustrated that his hernia operation has been postponed due to these results and is keen to find out what is wrong. Cardiovascular, respiratory and abdominal exami- nations were entirely normal, except for a reducible direct right inguinal hernia. This patient has polycythaemia – an increase in red cell mass – as indicated by the elevated haemoglobin and haematocrit. Polycythaemia may be ‘apparent’ due to a decreased plasma volume, giving the appearance of polycythaemia but with a nor- mal red cell mass; or it may be ‘true’ polycythaemia. Secondary polycythaemias may be due to increased erythropoietin production with or without hypoxia as a driving force. In patients with elevated platelet counts, such as here, drug treat- ments including hydroxycarbamide, interferon and anegralide can be used to reduce the platelet count. The polycythaemia itself is treated with regular venesection, ini- tially every few weeks, aiming to reduce the haematocrit to 0. Case 67: Elderly man with abnormal blood test results 317 Differential diagnosis Causes of secondary polycythaemia: • Chronic hypoxia (lung disease, heart disease, high altitude) • Long-term smoking • Abnormal haemoglobins • Increased erythropoietin production (renal tumours, other malignancies) Key points • Polycythaemia may be ‘true’ or ‘apparent’. The cellulitis had developed over the past few days and by now was bright red, painful and hot to touch. He had no known drug allergies and was on ramipril, diclofenac and sul- phasalazine, which had been started 10 weeks previously for his rheumatoid arthritis. He had obvious erythema over his left upper anterior thigh, along with a couple of small sub-centimetre tender lymph nodes in the left groin. This man has developed cellulitis compounded by profound neutropenia, making it difficult to treat, and producing constitutional symptoms. His pro- found neutropenia is occurring in the face of a normal platelet count, and near normal haemoglobin. A recent full blood count would be useful to determine the rapidity of neutrophil decline and to ensure it is a new phenomenon. There are many possible causes of neutropenia (see list below), but not many cause such an isolated low neutrophil count. The likely diagnosis here is therefore a drug-induced neutropenia/marrow failure secondary to sulphasalazine, which had only recently been started. Treatment in suspected drug-induced bone marrow failure/neutropenia is to imme- diately withdraw the suspected drug wherever possible. Antibiotic therapy will be required for the cellulitis and, in view of the neutropenia, an admission to a side room for intravenous antibiotics with broad-spectrum cover is imperative, in case other underlying infections are present. The neutropenia usually recovers within a few days to a few weeks, with the median time to neu- trophil recovery being 10 days. In cases where the diagnosis is unclear, or where neutrophil recovery is slow, a bone marrow examination may be required to rule out other underlying pathologies, such as aplastic anaemia, acute leukaemia or myelodysplastic syndromes. In younger patients, the possibility of inherited bone marrow failure syndromes (inherited aplastic anaemia) should be considered, although a pancytopenia would be more usual as an outcome, rather than just neutropenia.

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High-level fluoroquinolone resistance is primarily driven by chromosomal mutations within topoisomerases sildalist 120mgmg with visa, although decreased entry buy sildalist 120 mg visa, efflux systems cheap 120 mg sildalist with amex, and modifying enzymes play a role sildalist 120 mg with amex. Decreased accumulation Reduced intracellular concentration is linked to 1) a reduction in membrane permeability or 2) efflux pumps. Alterations in membrane permeability are mediated through a reduction in outer membrane porin proteins, thus limiting drug access to topoisomerases. Fluoroquinolone degradation An aminoglycoside acetyltransferase variant can acetylate fluoroquinolones, rendering them inactive. Absorption Fluoroquinolones are well absorbed after oral administration, with levofloxacin and moxifloxacin having a bioavailability that exceeds 90% (ure 31. Ingestion of fluoroquinolones with sucralfate, aluminum- or magnesium-containing antacids, or dietary supplements containing iron or zinc can reduce the absorption. Calcium and other divalent cations also interfere with the absorption of these agents (ure 31. Concentrations are high in bone, urine (except moxifloxacin), kidney, prostatic tissue (but not prostatic fluid), and lungs as compared to serum. Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms such as Listeria, Chlamydia, and Mycobacterium. Moxifloxacin is metabolized primarily by the liver, and while there is some renal excretion, no dose adjustment is required for renal impairment (see ure 31. Common adverse effects leading to discontinuation are nausea, vomiting, headache, and dizziness. Patients taking fluoroquinolones are at risk for phototoxicity resulting in exaggerated sunburn reactions. Arthropathy is uncommon, but arthralgia and arthritis are reported with fluoroquinolone use in pediatric patients. Use in the pediatric population should be limited to distinct clinical scenarios (for example, cystic fibrosis exacerbation). Hepatotoxicity or blood glucose disturbances (usually in diabetic patients receiving oral hypoglycemic agents or insulin) have been observed. Identification of any of these events should result in prompt removal of the agent. Serum concentrations of medications such as theophylline, tizanidine, warfarin, ropinirole, duloxetine, caffeine, sildenafil, and zolpidem may be increased (ure 31. Examples of clinically useful fluoroquinolones Due to increasing resistance and boxed warnings, fluoroquinolones should be used with caution in select circumstances. They may be considered in patients who do not tolerate other agents (for example, severe beta-lactam allergies) or as definitive therapy once susceptibilities are available. Ciprofloxacin is used in the treatment of traveler’s diarrhea, typhoid fever, and anthrax. It is a second-line agent for infections arising from intra-abdominal, lung, skin, or urine sources. Of note, high-dose therapy should be employed when treating Pseudomonas infections. It may be considered for mild-to-moderate intra- abdominal infections, but should be avoided if patients have fluoroquinolone exposure within previous three months, due to increasing B. Moxifloxacin may be considered as a second-line agent for management of drug-susceptible tuberculosis. Due to its spectrum of activity, it is an option for managing acute bacterial skin and skin structure infections. Humans use dietary folate to synthesize the critical folate derivative, tetrahydrofolic acid. By contrast, many bacteria are impermeable to folate derivatives, and rely on their ability to synthesize folate de novo (ure 31. Sulfonamides (sulfa drugs) are a family of antibiotics that inhibit de novo synthesis of folate. A second type of folate antagonist, trimethoprim, prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid. The combination of the sulfonamide sulfamethoxazole with trimethoprim (the generic name for the combination is cotrimoxazole) provides a synergistic effect. Sulfonamides Sulfa drugs were among the first antibiotics used in clinical practice. Today, they are seldom prescribed alone except in developing countries, where they are employed because of low cost and efficacy. Antibacterial spectrum Sulfa drugs have in vitro activity against gram-negative and gram-positive organisms. Common organisms include Enterobacteriaceae, Haemophilus influenzae, Streptococcus spp. Resistance Bacteria that obtain folate from their environment are naturally resistant to sulfa drugs. Acquired bacterial resistance to the sulfa drugs can arise from plasmid transfers or random mutations. Absorption Most sulfa drugs are well absorbed following oral administration (ure 31. It is not absorbed when administered orally or as a suppository and, therefore, is reserved for treatment of chronic inflammatory bowel diseases. Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators. Because of the risk of sensitization, sulfa drugs are not usually applied topically. Distribution Sulfa drugs are bound to serum albumin in circulation and widely distribute throughout body tissues. Sulfa drugs penetrate well into cerebrospinal fluid (even in the absence of inflammation) and cross the placental barrier to enter fetal tissues. The acetylated product is devoid of antimicrobial activity but retains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria (“stone formation”; see below) and potential damage to the kidney. Excretion Unchanged sulfa drug and metabolites are eliminated via glomerular filtration and secretion, requiring dose adjustments with renal impairment. Adequate hydration and alkalinization of urine can prevent the problem by reducing the concentration of drug and promoting its ionization. Hypersensitivity Hypersensitivity reactions, such as rashes, angioedema, or Stevens-Johnson syndrome, may occur. When patients report previous sulfa allergies, it is paramount to acquire a description of the reaction to direct appropriate therapy. Fatal reactions have been reported from associated agranulocytosis, aplastic anemia, and other blood dyscrasias. Kernicterus Bilirubin-associated brain damage (kernicterus) may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. Contraindications Due to the danger of kernicterus, sulfa drugs should be avoided in newborns and infants less than 2 months of age, as well as in pregnant women at term. Sulfonamides should not be given to patients receiving methenamine, since they can crystallize in the presence of formaldehyde produced by this agent. Mechanism of action Trimethoprim is a potent inhibitor of bacterial dihydrofolate reductase (see ure 31. Inhibition of this enzyme prevents the formation of the metabolically active form of folic acid, tetrahydrofolic acid, and thus, interferes with normal bacterial cell functions. Trimethoprim binds to bacterial dihydrofolate reductase more readily than it does to human dihydrofolate reductase, which accounts for the selective toxicity of the drug. Antibacterial spectrum the antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. Resistance Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity for trimethoprim. Because the drug is a weak base, higher concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal fluids. The drug is widely distributed into body tissues and fluids, including penetration into the cerebrospinal fluid. Trimethoprim undergoes some O-demethylation, but 60% to 80% is renally excreted unchanged. These effects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those with nutrient-poor diets. These blood disorders may be reversed by simultaneous administration of folinic acid (also known as leucovorin), which does not enter bacteria. Trimethoprim has a potassium-sparing effect and may cause hyperkalemia, especially at higher doses and when administered with other medication that causes hyperkalemia (for example, angiotensin converting enzyme inhibitors). The combination was selected because of the synergistic activity and the similarity in the half-lives of the two drugs. Mechanism of action the synergistic antimicrobial activity of cotrimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydrofolic acid. Antibacterial spectrum Cotrimoxazole has a broader spectrum of antibacterial action than the sulfa drugs alone (ure 31. Resistance Resistance to the trimethoprim–sulfamethoxazole combination is encountered less frequently than resistance to either of the drugs alone, because it requires bacterium to maintain simultaneous resistance to both drugs. Significant resistance has been documented in a number of clinically relevant organisms, including E.

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These changes become more widespread with erythema and telangiectasia spreading to the neck purchase 120mgmg sildalist amex, sun-exposed area of the chest and back in a shawl distribution 120 mg sildalist for sale, as well as to the scalp cheap 120 mg sildalist mastercard, elbows buy sildalist 120 mg free shipping, and knees. Gottron’s sign, which consists of scaly reddish papules over the knuckle, is considered pathognomonic of dermatomyositis. Hands may take on the appearance of mechanics’ hands with hyperpigmentation, scaling, fissuring of the fingertips, ragged cuticles, and enlarged proximal nail fold capillaries. Aggressive treatment at an early stage allows for better disease control with lower immunosuppression. Early treatment also reduces the development of disfiguring calcium deposition in the skin and muscle. Initial treatment of skin disease includes sunscreens with topical corticosteroids or calcineurin inhibitors, but resistant skin disease may require methotrexate or antimalarials. With appropriate and timely therapy, patients may become disease-free and off therapy within 2 to 4 years. Of note, patients should be surveyed for an occult visceral malignancy which is associated with dermatomyositis in up to 25% of adult cases. Poor prognostic factors include malignancy, older age, initiating therapy after 24 months of muscle weakness, extensive cutaneous lesions, dysphagia, and cardiac or pulmonary disease [137]. A discussion of myositis and systemic disease associated with dermatomyositis is detailed in Chapter 66. First, recipient tissue damage from conditioning regimens leads to inflammatory cytokines, this activates donor lymphocytes, and finally, alloreactive T cells expand into cytotoxic T cells [139]. Skin findings begin with painful or pruritic erythematous macules which can arise on the palms, soles, and ears, and evolve into a diffuse morbilliform eruption which is often folliculocentric. Histopathology of involved skin classically shows an interface dermatitis and apoptotic keratinocytes. The lichenoid variant is characterized by erythematous and violaceous papules and plaques, often distributed on flexural surfaces that resemble lichen planus. The sclerodermoid form presents with sclerotic, indurated white to yellow plaques that involve the dermis. The oral mucosa is often involved and may demonstrate redness and atrophy of mucosal surfaces, lacy white reticulations of buccal mucosa, and ulcerations. A furuncle represents an abscess associated with a hair follicle and a carbuncle is a collection of multiple furuncles. The clinical presentation consists of a small red papule that evolves into a tender, erythematous deep-seated nodule that may become fluctuant. The differential diagnosis includes an inflamed epidermal inclusion cyst, hidradenitis suppurativa, and arthropod bite. Infectious folliculitis is usually caused by staphylococci, Pseudomonas, or Malassezia furfur, whereas noninfectious folliculitis is the result of trauma to or occlusion of the pilosebaceous unit. The lesions may be pruritic and are most often found on the face, scalp, thighs, axillae, and inguinal area. Pseudomonal folliculitis may be more inflammatory and localized to a distribution that would be covered by a bathing suit. Pityrosporum folliculitis may be localized to the upper back and chest and be extremely pruritic [146]. Most cases will respond to appropriate topical and/or oral antibiotics (most commonly anti-staphylococcal). Pityrosporum folliculitis requires topical or oral antifungals and pseudomonal folliculitis is often self-limited, but may require fluoroquinolones in immunosuppressed patients. Peripheral Edema Peripheral edema, which is commonly seen among elderly and hospitalized patients, occurs when capillary hydrostatic pressure and filtration exceeds the lymphatic drainage rate. Common causes of edema include heart failure, renal failure, nephrotic syndrome, cirrhosis, venous thrombosis, or medications, particularly calcium channel blockers. Acute exacerbations of chronic edema may cause edema blisters which present as asymptomatic, noninflammatory tense vesicles and bullae with clear fluid, usually on the distal lower extremities. Edema blisters can be distinguished from other blistering disorders by clinical history and physical examination. If needed, a biopsy for routine histopathology and immunofluorescence may help exclude other blistering disorders. Acute peripheral edema may also produce local dermal edema, leading to induration of the skin and dimpling, known as peau d’orange. Risk factors include conditions that exacerbate lower extremity edema such as obesity, congestive heart failure, cirrhotic liver disease, and chronic renal insufficiency. Typically, there is reddish mottling and a yellowish or brown discoloration of the medial lower legs, corresponding to the location of major communicating veins. There may be an eczematous component as well that often results from contact sensitization to topical medicaments applied to the legs. There are often other signs of venous hypertension, including edema, varicose veins, and venous leg ulcers. Over years, the legs may develop lipodermatosclerosis, which occurs when adipose tissue becomes indurated and adherent to fascia, and lower legs take on the appearance of an inverted wine bottle. However, asteatotic eczema, contact dermatitis, and cellulitis may also be considered in the differential. Of note, bilateral cellulitis of the legs is extremely rare and is often confused with stasis dermatitis. Long-term management involves improving venous return through various measures such as leg elevation, elastic compression, and exercises to strengthen calf muscles. Secondary infection is not uncommon as the barrier function of the skin is lost with chronic stasis dermatitis. The presence of bacteria must be recognized as a secondary event to the stasis, and treatment with antibiotics in conjunction with topical steroids is routine. Pressure Ulcers Pressure ulcers are areas of ischemic soft tissue necrosis resulting from prolonged pressure, shearing force, or friction anywhere on the body. Sites that are most frequently involved include skin overlying bony prominences of the sacrum, ischial tuberosities, heels, greater trochanters, and lateral malleoli. Ulceration may occur as partial thickness skin loss, full thickness skin loss involving subcutaneous tissue, or full thickness skin loss extending to muscle, tendon, or bone. Treatment involves relief of pressure, which may be accomplished through frequent position changes and supportive surfaces such as air, liquid, or foam cushions. Local wound care includes cleansing with normal saline, debridement, and occlusive hydrocolloid dressings or foam dressings to optimize healing [149]. A recent randomized control trial showed improved pressure ulcer healing in malnourished patients given a nutritional formula enriched with arginine, zinc, and antioxidants [150]. The majority of pressure ulcers are superficial and heal by secondary intention, but operative repair is necessary for some cases. Psoriasis In its most common form (chronic plaque psoriasis), psoriasis presents as chronic well-demarcated erythematous plaques with adherent silvery scale, most commonly over the elbows, knees, and scalp. In guttate (raindrop-like) psoriasis, there are smaller psoriatic papules and plaques diffusely over the body, and this is often triggered by streptococcal infections. Sudden onset of sterile pustules that coalesce to form “lakes of pus” at the edges of psoriatic plaques associated with fever typifies the more generalized form of pustular psoriasis. These patients are itchy and also complain of chills from the extensive heat loss due to dilatation of cutaneous vessels. There is a recognized association of psoriasis, particularly severe disease, with increased risk of cardiovascular, cerebrovascular, and peripheral vascular disease [151,152]. Large pustules coalescing to form “lakes of pus” over an area of well- demarcated erythema of the palm. For erythrodermic psoriasis, cyclosporine and infliximab appear to be the fastest acting agents; however, their use is predicated on severity of presentation and patient comorbidities [153]. Atopic Dermatitis Atopic dermatitis is characterized by eczematous skin changes and typically involves flexor surfaces in adults, although any body area may be involved. The disease is most common among young children in whom the tendency for atopic dermatitis is to gradually improve with age; however, in a minority of patients, disease persists into or manifests in adulthood. In the most severe cases, eczematous dermatitis may evolve into erythroderma (see “Exfoliative Erythroderma” section). Other complications of this disease include secondary bacterial infection (impetigo) or herpetic infection, a condition known as eczema herpeticum. Treatment of atopic dermatitis includes topical corticosteroids, emollients, oral antihistamines, antibiotics as needed, and management of coexisting asthma and allergies. Contact Dermatitis Contact dermatitis occurs when direct contact with a substance triggers an inflammatory response in the skin. Irritant contact dermatitis, which accounts for 80% of contact cases, occurs when a chemical directly induces damage to the skin. Causes of allergic contact dermatitis in hospitalized patients include adhesives, topical medications, topical antibiotics, preservatives, fragrances, metals, and rubber components. Older adults have an impaired epidermal barrier and are more susceptible to both irritants and allergens. Patients with stasis dermatitis and lower extremity ulcerations are at increased risk of allergic contact dermatitis [154]. Acute contact dermatitis, whether irritant or allergic in nature, presents with pruritic papules and weepy vesicles on an erythematous base, initially localized to the area of contact. Chronic lesions are erythematous plaques of thickened skin with accentuated skin markings, scale, and occasionally fissuring. The differential diagnosis may vary depending on the location of the eruption, but generally includes atopic dermatitis, seborrheic dermatitis, stasis dermatitis, and tinea.

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In general cheap 120 mg sildalist visa, therapy is guided by the primary pathophysiologic mechanism underlying the hypotension (e buy sildalist 120 mg on line. The pace and aggressiveness of therapeutic intervention are guided by the presence or absence of clinical signs of hypoperfusion discount sildalist 120mg fast delivery. For example effective 120mgmg sildalist, holding vasodilators may be sufficient for the hypotensive patient without changes in mental status or urine output. In contrast, the acutely hypotensive patient with clinical shock needs rapid resuscitation with intravascular volume expansion and usually vasoactive therapy. To better understand the similarities and differences among these agents, a basic knowledge of adrenergic receptor distribution and function is helpful [1]. The adrenergic receptors that are most relevant to the management of hypotension are the α1, β1, and β2 receptors. The presence of α1 receptors has also been demonstrated in the myocardium, where stimulation appears to result in a positive inotropic effect with little change in heart rate. Stimulation of β2-adrenergic receptors causes relaxation of smooth muscle cells in bronchial, gastrointestinal, and uterine muscle, as well as vasodilation of skeletal muscle. Thus, at low doses of epinephrine, the vasodilatory effect of β2 receptors predominates, whereas at high doses, α1-mediated vasoconstriction overcomes the β2 effect and increases systemic vascular resistance. The overall clinical effects of vasoactive agents depend not only on the outcome of direct adrenergic receptor stimulation, but also on the reflex response of homeostatic forces. For example, stimulation of β1-adrenergic receptors by norepinephrine would be expected to cause an increase of heart rate; however, norepinephrine-mediated α1-adrenergic stimulation induces a reflex increase of vagal tone that cancels out its positive chronotropic effects. Commonly used drugs with vasopressor activity are dopamine, epinephrine, norepinephrine, phenylephrine, and ephedrine. Agents with positive inotropic activity that are useful for the treatment of hypotension include dobutamine, dopamine, epinephrine, and isoproterenol. When administered intravenously, the effects of dopamine are mediated by dose-dependent stimulation of dopaminergic and adrenergic receptors, and by stimulation of norepinephrine release from nerve terminals. At low doses (less than 5 μg/kg/min), dopamine predominantly stimulates dopaminergic receptors in renal, mesenteric, and coronary vessels with minimal adrenergic effects. In normal subjects, the so-called renal-dose dopamine augments renal blood flow, glomerular filtration rate, and natriuresis, with little effect on blood pressure. Low-dose dopamine has frequently been used by itself or in combination with other drugs as a renoprotective agent. Although mechanistic studies have demonstrated renal vasodilatory effects of dopamine among patients with heart failure [4], a randomized placebo-controlled trial in 360 patients with acute heart failure and renal dysfunction demonstrated no effect of low-dose dopamine on renal function or decongestion, and no difference in symptoms or clinical outcomes compared to placebo [5]. Moderate doses of dopamine (5 to 10 μg/kg/min) stimulate β1-adrenergic receptors in the myocardium, augmenting cardiac output by increasing contractility and, to a lesser extent, heart rate. At higher doses (greater than 10 μg/kg/min), α1-adrenergic receptor stimulation predominates, resulting in systemic arteriolar vasoconstriction. However, it should be remembered that there is a great deal of overlap in the dose-dependent effects of dopamine in critically ill patients [1,3]. In studies of fluid-resuscitated patients with septic shock, dopamine produced a mean increase in mean arterial pressure of approximately 25%, primarily owing to an increase of cardiac index and, to a lesser extent, systemic vascular resistance [3]. In the setting of hyperdynamic septic shock when excessive vasodilation is the primary source of hypotension, addition or substitution of a more potent α- adrenergic agonist such as norepinephrine may be more effective. Moreover, evidence of worsening splanchnic oxygen utilization with the use of high-dose dopamine has made it a less attractive agent. By itself or in combination with other agents, dopamine may be used at moderate doses for the management of patients with acute heart failure and hypotension. Dopamine may also be combined with dobutamine for added inotropic effects or used at low doses to augment diuresis [9], although the benefits of “renal-dose” dopamine remain unproven and other agents may be more effective for preserving renal function of critically ill patients [10]. For patients with symptomatic bradycardia unresponsive to atropine, particularly when associated with hypotension, dopamine can be effective while preparing for emergent transvenous temporary pacing [11]. The use of dopamine is associated with several adverse effects, including tachycardia, tachyarrhythmias, and excessive vasoconstriction. Although these effects are generally dose dependent, in individual patients there may be substantial overlap of receptor affinity such that even at low doses dopamine may result in toxicity [5]. For patients with ischemic heart disease, increased myocardial oxygen consumption coupled with some degree of coronary vasoconstriction with high-dose dopamine can result in myocardial ischemia. As with other positive inotropes, dopamine can increase flow to poorly oxygenated regions of the lung and cause shunting and hypoxemia. In addition, dopamine has been shown to depress minute ventilation of normoxic patients with heart failure [12]. When dopamine is used for patients with acute heart failure, increased venous tone and pulmonary arterial pressure may exacerbate pulmonary edema in the setting of already high cardiac filling pressures. There is mounting evidence that dopamine adversely effects splanchnic perfusion at doses usually required to treat septic shock. A small, randomized study of patients with sepsis using selective splanchnic and hepatic cannulation showed that infusion of dopamine was associated with a disproportionate increase of splanchnic oxygen delivery compared with oxygen extraction (65% vs. In contrast, norepinephrine produced better-matched increases in oxygen delivery and extraction (33% vs. Another study showed that among patients with septic shock randomly assigned to treatment with norepinephrine or dopamine, gastric intramucosal pH worsened significantly among patients treated with dopamine despite similar improvements in mean arterial pressure [14]. Thus, the use of dopamine for septic shock may be associated with splanchnic shunting, impairment of gastric mucosal oxygenation, and increased risk of gastrointestinal bleeding [3]. Epinephrine Epinephrine is an endogenous catecholamine that is a potent nonselective agonist of α- and β-adrenergic receptors. Stimulation of myocardial β1 and β2 receptors increases contractility and heart rate, resulting in a rise in cardiac output. Cardiac output is further augmented by an increase in venous return as a result of α1-mediated venoconstriction. Diastolic blood pressure and overall peripheral vascular resistance may actually decrease owing to vasodilation of skeletal muscle. With higher doses of epinephrine, stimulation of α-adrenergic receptors in precapillary resistance vessels of the skin, mucosa, and kidneys outweighs β2-mediated vasodilation in skeletal muscle, causing increased mean and systolic blood pressure [1]. Epinephrine plays a central role in cardiovascular resuscitation (see Chapter 14) and the management of anaphylaxis (see Chapter 69). Epinephrine is also used to reverse hypotension with or without bradycardia after cardiopulmonary bypass or cardiac transplantation [15]. Because of its adverse effects on splanchnic [16] and renal blood flow and potential for inducing myocardial ischemia and tachyarrhythmias, epinephrine has generally been regarded as a second- line agent in the management of septic shock [3,17]. However, a randomized trial showed no difference in efficacy or safety between epinephrine alone versus norepinephrine plus dobutamine for patients with septic shock [18]. For patients with symptomatic bradycardia and hypotension who have failed atropine or external pacing, epinephrine may be used to stabilize the patient while awaiting more definitive therapy (e. When used to treat hypotension, epinephrine is given as a continuous infusion starting at a low dose (0. Epinephrine should be avoided for patients taking β-adrenergic antagonists, because unopposed α-adrenergic vasoconstriction may cause severe hypertension and cerebral hemorrhage. Norepinephrine Norepinephrine is an endogenous catecholamine that is a potent β1- and α1-adrenergic agonist, with little β2 activity. The main cardiovascular effect of norepinephrine is dose-dependent arterial and venous vasoconstriction owing to α-adrenergic stimulation. The positive inotropic and chronotropic effects of β1 stimulation are generally counterbalanced by the increased afterload and reflex vagal activity induced by the elevated systemic vascular resistance. Thus, heart rate and cardiac output usually do not change significantly, although cardiac output may increase or decrease depending on vascular resistance, left ventricular function, and reflex responses [7]. Although traditionally reserved as a second-line agent or used in addition to other vasopressors in cases of severe distributive shock, norepinephrine has emerged as the agent of choice for the management of hypotension in hyperdynamic septic shock [18,20]. Although only 5 of 16 patients randomized to dopamine were able to achieve these endpoints, 15 of 16 patients randomized to norepinephrine were successfully treated with a mean dose of 1. Moreover, 10 of the 11 patients who remained hypotensive on high-dose dopamine improved with the addition of norepinephrine. A subsequent prospective, nonrandomized, observational study suggested that in adults with septic shock treated initially with high-dose dopamine or norepinephrine, the use of norepinephrine was associated with improved survival [22]. In a subgroup analysis of patients with cardiogenic shock (n = 280), dopamine was associated with an increased risk of death (p = 0. Meta- analyses of norepinephrine versus dopamine in the treatment of septic shock have also suggested that norepinephrine is associated with reduced mortality and less arrhythmic events [24]. In the setting of sepsis, norepinephrine improves renal blood flow and urine output [25], although large doses may be required to achieve these effects because of α-receptor downregulation [3]. A total of 1,044 patients were in septic shock, 280 were in cardiogenic shock, and 263 were in hypovolemic shock (From De Backer D, Biston P, Devriendt J, et al: Comparison of dopamine and norepinephrine in the treatment of shock. Norepinephrine can also cause necrosis and sloughing at the site of intravenous injection owing to drug extravasation. As previously discussed, the overall effect of norepinephrine on gut mucosal oxygenation of septic patients compares favorably with that of high-dose dopamine. Phenylephrine Phenylephrine is a synthetic sympathomimetic amine that selectively stimulates α1-adrenergic receptors. When administered intravenously, phenylephrine causes dose-dependent arterial vasoconstriction and increases peripheral vascular resistance. Phenylephrine, infused at 40 to 180 μg per minute, is commonly used for the management of anesthesia-induced hypotension [26,27] and hyperdynamic septic shock. Its rapid onset of action, short duration, and primary vascular effects make it an ideal agent for treating hemodynamically unstable patients in the intensive care setting. However, there are few data regarding its relative efficacy compared with older vasopressors such as norepinephrine and dopamine.