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A reduced serum iron con of that present in its nucleated precursors in the bone marrow 35 Postgraduate Haematology necessary to prepare red cells free of white cells (which have much higher levels of ferritin) weight loss doctors near me discount astralean. Percentage of hypochromic red cells As iron supply to the erythron diminishes weight loss 20 000 steps discount astralean 40 mcg fast delivery, the new red cells produced are increasingly hypochromic weight loss yoga biggest loser buy astralean 40 mcg low price. Assessment of the haemoglobin content of individual red cells weight loss pills fda approved order discount astralean, which is possible using some automated cell counters weight loss routine astralean 40 mcg with visa, allows measurement of the percentage of hypochromic cells weight loss 9 year old generic astralean 40 mcg on line. Values rising to above 6% may help in the early identi cation of impaired iron supply in patients with chronic renal failure who are receiving treatment with (a) recombinant erythropoietin, when associated in ammatory dis ease means that other measures of iron status can be misleading. Iron de ciency anaemia Sequence of events Depletion of iron stores When the body is in a state of negative iron balance, the rst event is depletion of body stores, which are mobilized for haemoglobin production. Iron absorption is increased when stores are reduced, before anaemia develops and even when the serum iron level is (b) still normal, although the serum ferritin will have already fallen. This leads to the development of iron-de cient erythropoiesis and increasing concentrations of serum transferrin receptor and red cell protoporphyrin. In general, red cell ferritin levels re ect the iron supply to de ciency, and siderotic granules are entirely absent from these the erythroid marrow and tend to vary inversely with red cell cells when iron de ciency anaemia is established. Despite some advantages over serum blasts have a ragged, vacuolated cytoplasm and relatively pyknotic ferritin as a measure of storage iron. The bone marrow macrophages show a total absence of of ferritin from damaged liver cells) the assay of red cell ferritin iron, except where very rapid blood loss outstrips the ability to has seen little routine application. Another 200 mg of iron is lost with the placenta and with badly tting dentures), glossitis (hair thinning) and pharyngeal the bleeding at delivery. Partial villous atrophy, with throughout pregnancy and increased requirements are partly minor degrees of malabsorption of xylose and fat, reversible by offset by amenorrhoea, this may not be suf cient to meet the iron therapy, has been described in infants suffering from iron resultant net maternal outlay of over 600 mg iron. There is a higher incidence of atrophic gastritis and histamine-fast achlorhydria in iron Blood loss de cient patients than in control subjects, and acid secretion may increase with iron therapy in some of these patients. Gastric Blood loss is the most common cause of iron de ciency in atrophy may also predispose to iron de ciency. The Iron-dependent enzymes in the tissues are usually better pre loss is usually from the genital tract in women or from the gas served than other iron-containing compounds. The most common cause on a de ciency, however, these enzymes are not inviolate and their world basis is infestation with hookworm, in which anaemia is levels may fall. This may be partly responsible for the general tis related to the degree of infestation. Self-induced haemorrhage may iron de ciency anaemia may have impaired mental develop occur as an unusual form of Munchausen syndrome. Chronic ment and function, and that this de cit may not be completely intravascular haemolysis, such as that in paroxysmal nocturnal restored by iron therapy. There is recent evidence that pre haemoglobinuria or mechanical haemolytic anaemia, may be a mature labour is more frequent in mothers with iron de ciency serious source of urinary iron loss. It remains controversial whether impaired work performance seen in adults results from the anaemia or from Malabsorption depletion of mitochondrial iron-containing enzymes. It is also unclear to what extent some of the other tissue effects of iron Malabsorption may be the primary cause of iron de ciency de ciency can occur even in the absence of anaemia. Dietary iron is poorly absorbed in gluten-induced enteropathy, in both children and adults, although patients with Causes of iron de ciency (Table 3. Diet Defective intake of iron is rarely the sole or major cause of iron Management of iron de ciency de ciency in adults in Western communities. The diet may con tain insuf cient or poorly available iron as a result of poverty, Management entails (i) identi cation and treatment of the religious tenets or food faddism. Increased physiological iron requirements Oral therapy Iron de ciency is common in infancy, when demands for growth In most patients, body stores of iron can be restored by oral iron may be greater than dietary supplies. Iron is equally well absorbed from several simple fer turity, infections and delay in mixed feeding. It is also frequent rous iron salts, and, as ferrous sulphate is the cheapest, this is the 37 Postgraduate Haematology Table 3. Dietary Especially vegetarian diet drug of rst choice; 200 mg of ferrous sulphate contains 67 mg disease, such as in ammatory bowel disease, is present. Where smaller doses are required, 300 mg of ferrous glu occasionally necessary in gluten-induced enteropathy and when conate provides 36 mg of iron. The side-effects when oral iron cannot keep pace with continuing haemorrhage of oral iron, such as nausea, epigastric pain, diarrhoea and con. If iron causes gastrointestinal symptoms, these can usually recombinant erythropoietin are also likely to require parenteral be ameliorated by reducing the dose, or taking the iron with iron therapy. In this situation, the demand for iron by the food, but this also reduces the amount absorbed. Increased of the iron is carried past the duodenum to sites of poor absorp red cell loss at dialysis contributes to iron needs and oral iron tion. Iron reduces absorption of tetracyclines (and vice versa) therapy is usually inadequate to prevent an impaired response to and of cipro oxacin. This will be slower when the dose tolerated is less than up by macrophages of the reticuloendothelial system, from which 100 mg per day, but this is seldom of clinical importance. Iron de cit of iron in circulating haemoglobin and in stores (shown sorbitol (Jectofer) is given deep (to avoid skin staining) by by a rise in serum ferritin to normal). Iron dextran (CosmoFer) is given intra patient not taking it, although there may be continued haemor venously by slow injection or infusion. It is important to reassess the diagnosis plex, Venofer, is given by slow intravenous infusion or as other causes of microcytic anaemia include many of the injection and is now considered to be the safest form. In patients receiving erythropoietin treatment treated with iron before haemoglobin studies, bone marrow in chronic renal failure, smaller intravenous doses of Venofer examination or other tests have revealed the correct diagnosis. With iron sorbitol, some tion, renal or hepatic failure, an underlying malignant disease or low-molecular-weight iron is released into the circulation and any other cause of anaemia in addition to iron de ciency. Parenteral iron should not be used if there is a history of allergy as anaphylaxis occasionally occurs. For iron Parenteral iron therapy dextran, a test dose should therefore be given slowly, followed by this is usually unnecessary, but it may be given if subjects genu close medical supervision of the rest of the infusion. Flushing, inely cannot tolerate oral iron, particularly if gastrointestinal nausea, urticaria, shivering, general aches and pains, dyspnoea 38 Iron metabolism, iron de ciency and disorders of haem synthesis Table 3. Photosensitive skin lesions (P) are seen when the level of the enzyme defect in the haem synthetic pathway leads to the accumulation of formed porphyrins. High-level blood transfusions to reactions, including arthralgia, fever and lymphadenopathy, are suppress erythropoiesis (combined with iron chelation therapy) well described and can persist for several days. An exacerbation have been used to reduce porphyrin production suf ciently to of rheumatoid arthritis may also be precipitated. Pathological alterations in haem synthesis Erythropoietic protoporphyria this is the most common erythropoietic porphyria and is usually caused by an autosomal dominant inherited de ciency Porphyrias of ferrochelatase, which results in increased free (not Zn) pro these are a group of inherited or acquired diseases, each toporphyrin concentrations in bone marrow, red cells, plasma characterized by a partial defect in one of the enzymes of haem and bile. This leaks from cells and is excreted of haem synthesis accumulate, the disorders being classi ed in the bile and faeces. Molecular analysis of the ferrochelatase by whether the effects are predominantly in the liver or the gene has revealed a variety of missense, nonsense and slicing erythron (Table 3. A full discussion of these disorders is mutations as well as deletions and insertions. The onset of beyond the scope of this chapter, but those with a particular the disease is usually in childhood. There is little haemolysis, but Congenital erythropoietic porphyria a mild hypochromic anaemia may occur, and accumulation this is a very rare autosomal recessive disorder that is due to of protoporphyrins can occasionally lead to severe liver disease. Large amounts of porphyrinogens accumulate, this may increase the amount of free protoporphyrin. There is a marked increase in porphyrins in liver, plasma, urine Sideroblastic anaemia and faeces. In the urine, uroporphyrin and heptacarboxyl por phyrin predominate with lesser amounts of coproporphyrin and the sideroblastic anaemias comprise a group of refractory penta and hexacarboxylporphyrin. It is precipitated in middle or hypochromic cells in the peripheral blood, with an excess of iron later life, more often in men than women, by factors such as liver in the bone marrow, many of the developing erythroblasts con disease, alcohol excess or oestrogen therapy. A modest increase taining iron granules arranged in a ring around the nucleus in liver iron is a common feature. In southern Europe, where C282Y is much less com the marrow are classi ed in Table 3. Removal of the iron by repeated phlebotomy is standard treatment, usually leading to remission. Lead poisoning Chronic ingestion of lead in humans causes an anaemia that is usually normochromic or slightly hypochromic. Red cell lifespan is shortened and there is a mild rise in reticulocytes, but jaundice is rare. Siderotic granules, and occasionally Cabot rings, are found in circulating red cells. The bone marrow shows increased sideroblasts, in some patients with ring sideroblasts. Haemolysis, probably due to the blocking of sulphydryl groups, with consequent denaturation of structural proteins, and damage to mitochondria with defective haemoglobin production due to Figure 3. Erythroblasts showing inhibition of the enzymes of haem synthesis, are the major factors. Siderocyte Mature red cell containing one or more siderotic granules (Pappenheimer bodies) Normal sideroblast Nucleated red cell containing one or more siderotic granules, granules few, dif cult to see, randomly distributed in the cytoplasm, reduced proportion of sideroblasts in iron de ciency and anaemia of chronic disorders Abnormal sideroblasts Cytoplasmic iron deposits (ferritin aggregates): increased granulation, granules larger and more numerous than normal, easily visible and randomly distributed, proportion of sideroblasts usually parallels the percentage saturation of transferrin. The bone marrow shows erythroid hyperplasia and the erythroblasts tend to be microcytic with a X-linked sideroblastic anaemia vacuolated cytoplasm. There are many (> 15%) ringed sidero In most reported families, inheritance has followed an X-linked blasts. All have enlargement of the facial bones may result from the erythroid been single-base substitutions. They are found with severe iron overload even when the anaemia is relatively scattered over the seven exons (out of 11) encoding the C mild, but the rate of iron loading is accelerated if red cell trans terminal, catalytically active part of the protein. Iron loading, however, aggravates the affecting the promoter have also been shown to cause disease. All haemopoietic is associated with early-onset, non-progressive cerebellar ataxia. The extent to which onset in some patients suggests that the degree of lyonization different tissues are affected depends to some extent on this may change with age. Iron loading may also aggravate the defect proportion and detection often requires the study of different in haem synthesis in both males and females with sideroblastic tissues. The roblasts in varying numbers are typically present and onset is response is usually partial. Some patients require only small usually in childhood, although some symptoms may be present doses (less than 10 mg per day) to maintain a higher haemo in infancy. Pyridoxine therapy is almost always ineffective in primary There are still a substantial number of cases of inherited side acquired sideroblastic anaemias. Some secondary sideroblastic roblastic anaemias in which the exact underlying genetic defect anaemias may, however, be completely reversed by pyridoxine remains obscure. This has been described in alcoholism, haemolytic inheritance and often show a macrocytic or dimorphic picture. Primary acquired sideroblastic anaemia (refractory Other forms of treatment anaemia with ring sideroblasts) Folic acid may bene t patients with secondary anaemia. For this is a form of myelodysplasia (refractory anaemia with ring refractory patients, the anaemia may remain stable and, if the sideroblasts), and arises as a clonal disorder of haemopoiesis.

Include training with use of log roll technique for supine to sit to minimize flexion as well as rotation along the spine weight loss medication xenical purchase astralean 40 mcg online. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures weight loss zumba discount 40 mcg astralean amex. Incidence of clinically diagnosed vertebral fractures: A population based study in Rochester weight loss kit purchase astralean 40 mcg amex, Minnesota weight loss 4 pills doctors select 40 mcg astralean, 1985-1989 weight loss meme astralean 40 mcg with visa. Vertebral compression fractures: Pain reduction and improvement in functional mobility after percutaneous polymethylmethacrylate vertebroplasty retrospective report of 245 cases weight loss pills guaranteed to work purchase astralean overnight. Current concepts review: Painful osteoporotic vertebral fracture: pathogenesis, evaluation, and roles of vertebroplasty and kyphoplasty in its management. Preliminary outcomes and efficacy of the first 360 consecutive kyphoplasties for the treatment of painful osteoporotic vertebral compression fractures. Subsequent Vertebral Fracture after Vertebroplasty: Incidence and Analysis of Risk Factors. Neck Rotation Sit on a chair or on the edge of the bed required exercise Gently turn your head to look over your. Lateral / Side Flexion Tilt your head to lower your ear down towards your shoulder Use your hand to gently pull your head further to the side Feel a stretch on the opposite side Hold for. Chin Retraction Sit on a chair or on the edge of the bed Pull your chin in towards you keeping your neck and back straight (make a double chin) Hold the end position and feel a good stretch in your neck for. Deep neck flexion Lie on your back with a thin pillow to support your head or do it in sitting Nod your head downwards so your chin comes towards your chest Hold for seconds Repetitions 6. Scapula Setting Sit on a chair or on the edge of the bed Place your fingers on your shoulders Roll your shoulders back Glide your shoulder blades down and together at the back Hold this posture for. Seconds Repetitions You can progress this by lying on your tummy with your arms by your side, palms facing up and lifting them off the bed. Scalene Stretch Sit on a chair or on the edge of the bed Place your right hand on your left shoulder Tilt your head to the right, bringing your right ear to your right shoulder (make sure the shoulder is kept still). Pectoralis Stretch Lie on your back with a rolled up towel placed lengthways under your back Slowly bring your arms out to the side into a Y shape Hold stretch for. The predisposing factors are malnutrition, environmental conditions and poor living standards. Musculoskeletal tuberculosis arises from haematogenous seeding of the bacilli soon after the initial pulmonary infection. The clinical symptoms are insidious onset, pain, swelling of the joint and limited range of movements. Surgical intervention is indicated in patients with abscess formation, intractable pain, neurological deficit, spine instability, kyphosis, and unsatisfactory response to chemotherapy. It is the most common single agent causing death in young adults and causes 4 two million deaths each year around the world. Some developing countries in Africa and Asia and some new states of the former Soviet Union have 6 experienced dramatic increases in the number of pulmonary tuberculosis cases. Therefore, an increase in the incidence and prevalence of joint and bone tuberculosis can also be suspected. Tuberculosis of bones and joints accounts for approximately 10% to 15% of all 7 extrapulmonary forms of tuberculosis. The following phrases were used for searching the articles: bone and joint tuberculosis, bone tuberculosis, joint tuberculosis. Some websites specializing in issues related to bone and joint tuberculosis were also searched. Bacteriology Several species of mycobacteria other than Mycobacterium tuberculosis or M. These are atypical mycobacteria which have been reported in lesions of the synovial sheath. The following factors are considered in the transmission of atypical mycobacteria: trauma, local steroid injection, surgical trauma, diabetes mellitus, immunosuppressive drugs in organ transplantation, and acquired 8 immunodeficiency syndrome. It has a slow growth rate, therefore, several weeks may be required for colonies to be identified. Pathophysiology Musculoskeletal tuberculosis arises from haematogenous seeding of the bacilli soon after the initial pulmonary infection. Osteoarticular tuberculosis usually starts as osteomyelitis in the growth plates of bones, where the blood supply is best, and then spreads locally into the 12 13 joint spaces. Joints can become infected by activation of dormant lymphatic or blood stream areas of 14 morbidity. The joint synovium responds to the mycobacteria by developing an inflammatory reaction, followed by formation of granulation tissue. The pannus of granulation tissue formed then begins to erode and 15 destroy cartilage and eventually bone, leading to demineralization. If allowed to 15 progress without treatment, however, abscesses may develop in the surrounding tissue. Since space-occupying exudates with extensive disruption of vascular supply do not occur, sequestration of bone is rare. Therefore, bone destruction without sequestra and with 16 minimal new bone formation characterizes the active phase of tuberculous osteomyelitis. It causes osteonecrosis characterized by loss of the exracellular matrix of vertebral bone and collapse 19 of the vertebrae. The anterior portions of two or more contiguous vertebrae are involved owing to 21 haematogenous spread through one arteria intervertebralis feeding two adjacent vertebrae. The spinal cord may become involved either by compression by bony elements and/or expanding abscess; or direct involvement of cord and leptomeninges by granulation 22 tissue. Neurological deficits are usually more symmetrical and more gradual in onset than 23 those resulting from other pathologies. Clinical features 2,5 Bone and joint tuberculosis is encountered in any age group. The most common location in childhood is spine, accounting for 60% to 70% of cases. The most frequently 2 involved joints are the weight-bearing joints such as hip, knee, shoulders, or elbow. The clinical symptoms are insidious onset, pain, swelling of the joint and limited range of 26 13 movement. In some cases, sinuses are the sole presentation, which could be misdiagnosed as pyogenic infection or 27 diabetic foot. Joint deformity may develop and granulomatous process eventually causes a 14 boggy or doughy feeling to the joint and periarticular structures. Localized pain may precede other symptoms of inflammation or radiographic changes by weeks or even 14 months. When diagnosis is late, joint contractures and limited functional improvement after treatment are more likely to occur, especially if bone and articular cartilage are 28 destroyed. Locally, there is stiffness, painful restricted joint movements in all directions and severe spasm of the surrounding muscles. If the lesion has been present for a sufficiently long time, a cold abscess occurs in the soft tissues, penetrating through the inter-muscular planes. A deformity, in the spine can be present as kyphosis along with local 8 tenderness. Diagnosis Diagnosis is by a high index of clinical suspicion, positive Mantoux test, radiological features, fine needle aspiration biopsy, aspiration of purulent material or synovial fluid for bacteriological examination, and biopsy for histopathological examination. Nevertheless, the gold standard for the diagnosis of osseous tuberculosis is culture of mycobacteria from bone tissue or synovial fluid. If negative 30 early, the tuberculin skin test should be repeated after 6 weeks of arthritis. In one case 32 series, the rate of false-negative results of Mantoux test was 14%. For this reason a positive Mantoux test result can be helpful in confirming a diagnosis of tuberculosis, but a negative result cannot exclude it. Radiographic changes in the joint are absent or non-specific in the early stages of disease, but soft-tissue swelling with little periosteal reaction, osteopenia, narrowing of the joint space (a late finding) and subchondral erosions of both sides of the joint suggest 33 tuberculosis. Chest radiographs may show evidence of pulmonary disease in 50% of patients with 36 osteoarticular tuberculosis, but active pulmonary disease is present in less than 1 in 5. By fine needle aspiration biopsy, granulamatous reaction, with or without caseation necrosis, was found in 73%. Positive Ziehl-Neelsen staining for acid-fast 4 bacilli requires at least 10 acid-fast bacilli per milliliter of specimen and does not 38 differentiate between tuberculous and non-tuberculous mycobacteria. Operative specimens, including purulent material or synovial fluid, of patients with osteoarticular tuberculosis revealed positive mycobacteria on direct smear in 27%, and on 27 culture in 63%. Culture of synovial fluid often gives positive results but synovial biopsy may be required to grow the organism. Mycobacteria might be identified from sinus-track culture whereas operative culture, histopathological and clinical examination could fail to 27 confirm the diagnosis of tuberculosis. Tuberculous bone infection should be suspected if there is no growth of any pyogenic bacteria or if there is growth of Staphylococcus epidermidis alone on routine aerobic and 39 anaerobic sinus-track specimen cultures. On a very rare occasion, mycobacteria and pyogenic bacteria were isolated concomitantly from operative specimen of spinal 40 tuberculosis. Therefore, isolation of pyogenic bacteria from operative or sinus specimen does not exclude the possibility of tuberculosis. Biopsy of the bony lesion, synovium or soft tissue masses may be required to clear up 41 14 diagnostic confusion. It is of significant value in cases where the organisms have not been seen on smear or culture, but caseating granulomas will be demonstrated on histological examination. Therefore, histological investigations must be performed in cases in which microbiologic tests give negative results in order to confidently exclude tuberculosis as a cause of chronic arthritis. It is therefore 29,24 unclear whether the suspicious cases represent false-positive or true-positive results. The cornerstone of treatment is multi-drug anti-tubercular chemotherapy and active or assisted non-weight bearing 45 exercises of the involved joint throughout the period of healing. The goals of treatment are to contain and eradicate the infection, relieve pain, and preserve and restore bone and joint 46 47 function. The Joint Tuberculosis Committee of the British Thoracic Society recommendation is ambulatory chemotherapy in disease of thoracic and lumbar spine. They recommend six-month regimen comprising rifampicin, isoniazid, pyrazinamide, and ethambutol for the initial two months followed by rifampicin and isoniazid for further four months. They also advice, that surgery plus chemotherapy may be required for the few 49 patients with evidence of spinal cord compression or instability. A study in Saudi Arabia that involved 110 patients who were treated at Riyadh Armed Forces for tuberculous spondylitis; the authors mentioned the advantages of surgical treatment in comparison to non-surgical treatment. These include relief of pain, early ambulation and early recovery from neurological deficit, less angle of kyphosis and short hospital stay. They recommended radical surgery for patients with neurologic deficit, 50 abscess, kyphosis or intractable pain. On the other hand, in Iranian prospective study involving 63 patients with bone and joint tuberculosis; all patients were treated by 51 chemotherapeutic agents whereas no patient needed surgical procedure. Medical Research Councils in Hong-Kong, Korea and India reported that overall outcome was the same for 52-54 both medical and surgical treatment of spine tuberculosis. There are few studies that define the optimal duration of treatment of skeletal tuberculosis, some investigators favor a prolong course of therapy to optimize post-treatment function. Others prefer that the nature of the few number of bacilli in the lesion make 6-month treatment course appropriate. Treatment should not be delayed waiting for culture results because experience suggests that delay in treatment may result in 31 less than optimal outcome. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. Use of polymerase chain reaction to diagnose tuberculous arthritis from joint tissues and synovial fluid. Diagnosis of tuberculosis of bone and soft tissue by fine-needle aspiration biopsy. Concomitant spine infection with Mycobacterium tuberculosis and pyogenic bacteria: case report. Case report: insidious destruction of the hip by Mycobacterium tuberculosis and why early diagnosis is critical. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations. A controlled trial of anterior spinal fusion and debridement in surgical management of tuberculosis of spine in patients on standard chemotherapy. We aim to reduce uncertainty and anxiety by providing clear, concise, accurate and helpful information and by answering commonly asked questions. Any medical information is evidence-based and accounts for current best practice guidelines and standards of care. It focuses on Chiari malformations in adults, describing what a Chiari malformation is, associated conditions, possible treatments including surgery, and how lifestyle can be afected. Chiari malformations afect each person diferently and your doctor or consultant will be in the best position to ofer advice and information to meet your individual needs. Sources of further support and information are listed in the Useful contacts section (see page 35).

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With the discovery of the angiogenic/antiangiogenic proteins weight loss pills nyc order astralean 40 mcg without a prescription, it may be possible to predict those who will develop preeclampsia before the onset of symptoms weight loss pills history generic 40 mcg astralean free shipping. While once considered absolutely contraindi cated weight loss 50 purchase astralean 40 mcg without a prescription, spinal anesthesia has proven to be a reliable technique with 192 out a higher incidence of hypotension weight loss pills at walgreens order cheapest astralean and astralean. Its inci dence depends on the severity of the disease and the presence or absence of placental abruption weight loss in elderly order genuine astralean online. A platelet count should therefore be checked prior to neuraxial analgesia/anesthesia in a parturient with preeclampsia weight loss 30 day challenge purchase astralean master card. If the patient receives general anesthesia for cesarean delivery, extreme care must be used in the dosing of non-depolarizing neu romuscular blockers. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Spinal versus epidural anesthesia for cesarean delivery in severe preeclampsia: a prospective, ran domized multicenter study. Shoulder DystociaShoulder Dystocia De nition Gentle downward traction on the fetal head by the obstetrician fails to result in delivery of the shoulders. The most common etiology is impaction of the anterior shoulder above the pubic bone. Pathophysiology During a normal delivery, the fetal head and shoulders rotate to allow for its descent and passage through the maternal pelvis. If the shoulder should rotate into the anterior-posterior diameter before entering the pelvis, the shoulders may become impacted on the pelvic bone. The obstetrician must be prepared to perform several maneuvers to relieve this impaction or must return the fetal head into the pelvis and perform an urgent cesarean delivery. Subsequent Management Following delivery, the infant should be resuscitated by a neonatal resuscitation team. The record should include the times of delivery of the head and shoulders, the arrival times of team members, and maneuvers used for the delivery. Training, especially simulation-based training, has been demonstrated to improve the management of shoulder dystocia. Special Considerations Shoulder dystocia requires an immediate and coordinated response from the entire team. The anesthesia provider must be prepared to 194 provide analgesia if an epidural catheter is present and to provide anesthesia if urgent cesarean delivery is required. Improving resident competency in the management of shoulder dystocia with simulation train ing. Total/High Spinal AnesthesiaTotal/High Spinal Anesthesia De nition Extensive spread of local anesthetic within the intrathecal space caused by an excessive volume of local anesthesia or high rostral spread. A total or high spinal may occur when a hyperbaric solution is used and the patient is placed in Trendelenburg position, or when a hypobaric solution is used and the patient is in a head-up position. Levels higher than T1 cause bradycardia due to blockade of the cardiac accelerator bers. Administer vasopressors (ephedrine or epinephrine) to treat hypotension; bradycardia may occur if the level of the block extends beyond T1, making phenlyephrine relatively contraindicated. Cardiac arrest during neuraxial anesthesia: frequency and predisposing factors associated with survival. Umbilical Cord ProlapseUmbilical Cord Prolapse De nition 197 the umbilical cord descends in advance of the fetal presenting part during labor, protruding into or through the cervix in the vast major ity of cases. Presentation Umbilical cord prolapse typically presents with persistent fetal bra dycardia or severe variable decelerations in the setting of ruptured membranes. The umbilical cord becomes limp after repeated compression and can more easily prolapse. Fetal acidosis increases the stiffness of the umbilical cord, which then leads to decreased adaptability and predisposes to cord prolapse. While these two postulated mechanisms are contradictory, both require ruptured membranes and a fetus who is not engaged in the pelvis prior to rupture of the membranes. If the parturient does not have an epidural catheter in place, con sider general anesthesia using rapid-sequence induction. The currently accepted man agement for umbilical cord prolapse is emergency cesarean delivery. Uterine dehiscence is an incomplete disruption of the uterine wall, usually with serosa overlying the defect in the uterine muscle. Presentation Uterine rupture usually occurs in parturients who have a uterine scar, although it may occur in an unscarred (no previous surgery) uterus. Pathophysiology In women with an unscarred uterus, uterine rupture is due to uterine anomalies or connective tissue disease. In parturients with a previous cesarean section, the risk of uterine rupture with a prior low trans verse scar is approximately 1%. While it gener ally occurs during labor with uterine contractions, it can occur before the onset of labor. Ultrasound may be used, but generally the obstetrician will proceed with urgent cesarean delivery if uterine rupture is suspected. Subsequent Management the presence of uterine rupture does not necessitate gravid hys terectomy. Usually the uterus can be repaired, but any subsequent pregnancy must be managed with elective cesarean delivery. If gravid hysterectomy is performed, close attention to adequate uid and blood resuscitation is mandatory. Special Considerations Despite the low incidence of uterine rupture during attempted vagi nal birth after cesarean delivery, the number of women attempting a trial of labor has decreased. American College of Obstetricians and Gynecologists guidelines state that an obstetrician and anesthesia provider must be immediately available when a parturient attempts a vaginal birth after cesarean delivery. Wagner Anaphylaxis 204 Asthma, Status Asthmaticus 206 Burns 209 Drowning and Near Drowning 212 Epiglottitis 215 Inhaled Foreign Body 217 Major Trauma 219 Neonatal Resuscitation 223 Pediatric Basic Life Support 227 Pediatric Advanced Life Support 230 203 Stridor 234 AnaphylaxisAnaphylaxis De nition Acute, potentially life threatening, type I hypersensitivity reaction to a speci c antigen with multisystemic manifestations resulting from rapid release of in ammatory mediators. Exposure triggers the produc tion and release of multiple in ammatory and vasoactive mediators, including histamine, prostaglandins, leukotrienes, cytokines, heparin, tryptase, and platelet-activating factor. Increased vascular perme ability causes transudation of uid into the skin and viscera, causing hypovolemia and shock. Arterial vasodilation produces decreased systemic vascular resistance and tissue hypoperfusion. If the patient is hemodynamically stable, increasing inhaled anesthetic concentration will also treat bronchospasm. If there is any question of a latex allergy, treat the child in a latex-free environment. Prophylactic medications to prevent ana phylaxis are not recommended because they may mask a true reac tion and delay immediate diagnosis and treatment. Follow-up with an allergy specialist is important to reduce the incidence of future anaphylactic reactions. Overdosing epi nephrine can lead to severe hypertension, supraventricular tachy cardia, or ventricular dysrhythmias. Respiratory abnormalities are the predominant nding with anaphylaxis in children, in contrast with adults where cardiovascular instability is more commonly seen. Asthma, Status AsthmaticusAsthma, Status Asthmaticus De nition Reversible airway obstruction caused by bronchial smooth muscle constriction, mucosal edema, airway in ammation, and secretions. Pathophysiology Acute asthma is caused by the local release of various chemical medi ators, immune mechanisms that lead to degranulation of bronchial mast cells and overactivity of the parasympathetic nervous system. Prevention Medical management and minimizing exposure to triggers can reduce the incidence of acute attacks. Children with chronic asthma are treated with daily inhaled corticosteroids (such as uticasone) and long-acting bronchodilators (salmeterol), along with leukotriene inhibitors (such as montelukast) and cromolyn sodium, as needed. First-degree burns are limited to the epithelium, 209 second-degree burns involve the dermis, and third-degree burns are full-thickness. Rapid sequence induction with succinylcholine is appropriate within the rst 24 hours after a burn (succinylcholine is contraindicated after 24 hours and for a prolonged period thereafter due to a profound hyperkalemic response). Slow inhalation induction with sevo urane and beroptic intubation for children with compromised airway. Cuffed endotracheal tubes (with little or no cuff in ation) do not need replacement as edema decreases (if continued postoperative intubation is planned). Scalding caused by reaching for hot liquids is the most common burn injury in children. Prevention Children are admitted and present to the operating room with this injury. Most common indications for surgical intervention in burn patients include wound debridement, skin grafting, and correction of contractures. Children with burn injuries rapidly develop tolerance to most opioids and sedatives and eventually require higher doses. Burn patients also demonstrate marked resistance to nondepolarizing muscle relaxants. Pulmonary complications are a major contributing factor or cause of death in patients with major burn injuries. Near drowning is suffocation while submerged with recovery for at least some period of time. Pulmonary injury, particularly intrapulmonary shunt ing of blood through poorly ventilated areas, is the primary pathophys iologic process. Loss of surfactant due to denaturation (fresh water) or washout (salt water) also occurs. Alveolar injury and pulmonary edema cause hypoxemia due to intrapulmonary shunting and ventilation-per fusion mismatch. EpiglottitisEpiglottitis De nition Sudden onset in ammatory edema of supraglottic structures, includ ing the arytenoids, aryepiglottic folds, and epiglottis, causing swelling and stiffening that can rapidly lead to complete airway obstruction.

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Antim icrobial spectrum Chloramphenicol weight loss help for women buy cheapest astralean, a broad-spectrum antibiotic weight loss pills trial offers discount astralean 40 mcg on-line, is active not only against bacteria but also against other microorganisms weight loss names cheap astralean 40 mcg amex, such as rickettsiae weight loss pills bodybuilding cheap 40 mcg astralean with mastercard. The drug is either bactericidal or (more commonly) bacteriostatic weight loss drugs purchase discount astralean line, depending on the organism weight loss 4 fat fighting ingredients order astralean from india. Resistance Resistance is conferred by the presence of an R factor that codes for an acetyl coenzyme A transferase. Another mechanism for resistance is associated with an inability of the antibiotic to penetrate the organism. Pharm acokinetics Chloramphenicol may be administered either intravenously or orally (Figure 32. It is completely absorbed via the oral route because of its lipophilic nature, and is widely distributed throughout the body. Excretion of the drug depends on its conversion in the liver to a glucuronide, which is then secreted by the renal tubule. Only about 10 percent of the parent compound is excreted by glomerular filtration. Adverse effects the clinical use of chloramphenicol is limited to life-threatening infections because of the serious adverse effects associated with its administration. In addition to gastrointestinal upsets, overgrowth of Candida albicans may appear on mucous membranes. Anemias: Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase. Other types of anemia occurring as a side effect of chloramphenicol include reversible anemia, which is apparently dose-related and occurs concomitantly with therapy, and aplastic anemia, which although rare is idiosyncratic and usually fatal. Gray baby syndrome: this adverse effect occurs in neonates if the dosage regimen of chloramphenicol is not properly adjusted. Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped renal function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes. This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term a gray babya), and death. Adults who have received very high doses of the drug can also exhibit this toxicity. Interactions: Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases and, thus, blocks the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating their concentrations and potentiating their effects (Figure 32. Clindamycin is employed primarily in the treatment of infections caused by anaerobic bacteria, such as Bacteroides fragilis, which often causes abdominal infections associated with trauma. However, it is also significantly active against nonenterococcal, gram-positive cocci. Resistance mechanisms are the same as those for erythromycin, and cross resistance has been described. Adequate levels of clindamycin are not achieved in the brain, even when meninges are inflamed. The drug is excreted into the bile or urine by glomerular filtration, but therapeutically effective levels of the parent drug are not achieved in the urine (Figure 32. Accumulation has been reported in patients with either severely compromised renal function or hepatic failure. In addition to skin rashes, the most serious adverse effect is potentially fatal pseudomembranous colitis caused by overgrowth of C. Oral administration of either metronidazole or vancomycin is usually effective in controlling this serious problem. Mechanism of action Each component of this combination drug binds to a separate site on the 50S bacterial ribosome, forming a stable ternary complex. In some cases, the enzymatic modification can change the action from bactericidal to bacteriostatic. Antibacterial spectrum the combination drug is active primarily against gram-positive cocci, including those resistant to other antibiotics (for example, methicillin-resistant staphylococci). Pharm acokinetics Quinupristin/dalfopristin is injected intravenously in a 5 percent dextrose solution (the drug is incompatible with a saline medium). The products are less active than the parent in the case of quinupristin and are equally active in the case of dalfopristin. Most of the parent drugs and metabolites are cleared through the liver and eliminated via the bile into the feces (Figure 32. Venous irritation: this commonly occurs when quinupristin/dalfopristin is administered through a peripheral rather than a central line. Arthralgia and myalgia: these have been reported when higher levels of the drugs are employed. Hyperbilirubinemia: Total bilirubin is elevated in about 25 percent of patients, resulting from a competition with the antibiotic for excretion. A drug interaction with digoxin appears to occur by the same mechanism as that caused by erythromycin. Mechanism of action the drug inhibits bacterial protein synthesis by inhibiting the formation of the 70S initiation complex. Linezolid binds to a site on the 50S subunit near the interface with the 30S subunit (Figure 32. Resistance Decreased binding to the target site confers resistance on the organism. Antibacterial spectrum the antibacterial action of linezolid is directed primarily against gram-positive organisms, such as staphylococci, streptococci, and enterococci, as well as Corynebacterium species and Listeria monocytogenes (Figure 32. However, its main clinical use is against the resistant organisms mentioned above. Like other agents that interfere with bacterial protein synthesis, linezolid is bacteriostatic. The drug is widely distributed throughout the body, having a volume of distribution of 40 to 50 liters. Two metabolites that are oxidation products have been identified, one of which has antimicrobial activity. Adverse effects Linezolid is well-tolerated, with some reports of gastrointestinal upset, nausea, and diarrhea, as well as headaches and rash. Thrombocytopenia was found to occur in about 2 percent of patients who were on the drug for longer than 2 weeks. Although no reports have appeared that linezolid inhibits monoamine oxidase activity, patients are cautioned not to consume large quantities of tyramine-containing foods. Reversible enhancement of the pressor effects of pseudoephedrine was shown to occur. Which antibiotic would you select to effectively treat an infection due to Bacteroides fragilis She developed a urinary tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Which of the following adverse effects was a risk to the fetus when the woman was on gentamicin You want to limit the risk of drug interactions in this woman, who is receiving five other medications. Fluoroquinolones Introduction of the first fluorinated quinolone, norfloxacin, was rapidly followed by development of other members of this group, such as ciprofloxacin, which has had wide clinical application. Newer fluorinated quinolones offer greater potency, a broader spectrum of antimicrobial activity, greater in vitro efficacy against resistant organisms, and in some cases, a better safety profile than older quinolones and other antibiotics. Compared to ciprofloxacin, the new compounds are more active against gram-positive organisms, yet retain favor able activity against gram-negative microorganisms. It seems likely that the number of drugs in this class of antibiotics will increase due to its wide antibacterial spectrum, favorable pharmacokinetic properties, and relative lack of adverse reactions. Unfortunately, their overuse has already led to the emergence of resistant strains, resulting in limitations to their clinical usefulness. The fluoroquinolones and other antibiotics discussed in this chapter are listed in Figure 33. Mechanism of action the fluoroquinolones enter the bacterium by passive diffusion through water-filled protein channels (porins) in the outer membrane. Like aminoglycosides, the quinolones exhibit concentration-dependent bacterial killing. Bactericidal activity becomes more pronounced as the serum drug concentration increases to approximately 30-fold the minimum inhibitory concentration. In general, they are effective against gram-negative organisms such as the Enterobacteriaceae, Pseudomonas species, Haemophilus influenzae, Moraxella catarrhalis, Legionellaceae, chlamydia, and mycobacteria (except for Mycobacterium avium-intracellulare complex). The newer agents (for example, levofloxacin and moxifloxacin) also have good activity against some gram-positive organisms, such as Streptococcus pneumoniae. It has become common practice to classify the fluoroquinolones into a generations,a based on their antimicrobial targets (Figure 33. The nonfluorinated quinolone nalidixic acid is considered to be first generation, with a narrow spectrum of susceptible organisms usually confined to the urinary tract. Ciprofloxacin and norfloxacin are assigned to the second generation because of their activity against aerobic gram-negative and atypical bacteria. In addition, these fluoroquinolones exhibit significant intracellular penetration, allowing therapy for infections in which a bacterium spends part or all of its life cycle inside a host cell (for example, chlamydia, mycoplasma, and legionella). Levofloxacin is classified as third generation because of its increased activity against gram-positive bacteria. Lastly, the fourth generation includes only moxifloxacin because of its activity against anaerobic as well as gram-positive organisms. Ciprofloxacin: this is the most frequently used fluoroquinolone in the United States (Figure 33. Ciprofloxacin is also particularly useful in treating infections caused by many Enterobacteriaceae and other gram-negative bacilli. Ciprofloxacin is also the drug of choice for prophylaxis and treatment of anthrax. It is the most potent of the fluoroquinolones for Pseudomonas aeruginosa infections and, therefore, is used in the treatment of pseudomonal infections associated with cystic fibrosis. The drug is also used as an alternative to more toxic drugs, such as the aminoglycosides. It may act synergistically with I lactams and is also of benefit in treating resistant tuberculosis. Additionally, due to its broad spectrum of activity, levofloxacin is utilized in a wide P. Resistance When the fluoroquinolones were first introduced, there was optimism that resistance would not develop. Decreased accumulation: Reduced intracellular concentration of the drugs in the bacterial cell is linked to two mechanisms. One involves a decreased number of porin proteins in the outer membrane of the resistant cell, thereby impairing access of the drugs to the intracellular topoisomerases. The other mechanism is associated with an energy-dependent efflux system in the cell membrane. Absorption: Only 35 to 70 percent of orally administered norfloxacin is absorbed, compared with 85 to 95 percent of the other fluoroquinolones (Figure 33. Intravenous preparations of ciprofloxacin, levofloxacin, and ofloxacin are available. Ingestion of the fluoroquinolones with sucralfate, antacids containing aluminum or magnesium, or dietary supplements containing iron or zinc can interfere with the absorption of these antibacterial drugs. Calcium and other divalent cations have also been shown to interfere with the absorption of these agents (Figure 33. The fluoroquinolones with the longest half-lives (levofloxacin and moxifloxacin) permit once-daily dosing. Levels are high in bone, urine, kidney, and prostatic tissue (but not prostatic fluid), and concentrations in the lung exceed those in serum. Penetration into cerebrospinal fluid is low except for ofloxacin, for which concentrations can be as high as 90 percent of those in the serum. The fluoroquinolones also accumulate in macrophages and polymorphonuclear leukocytes, thus being effective against intracellular organisms such as Legionella pneumophila. Toxicities similar to those for nalidixic acid have been reported for the fluoroquinolones (Figure 33. Gastrointestinal: the most common adverse effects of the fluoroquinolones are nausea, vomiting, and diarrhea, which occur in three to six percent of patients. Phototoxicity: Patients taking fluoroquinolones are advised to avoid excessive sunlight and to apply sunscreens. Thus, it is advisable that the drug should be discontinued at the first sign of phototoxicity. Connective tissue problems: Fluoroquinolones should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age, because articular cartilage erosion (arthropathy) occurs in immature experimental animals. Drug interactions: the effect of antacids and cations on the absorption of these agents was considered above. Ciprofloxacin and ofloxacin can increase the serum levels of theophylline by inhibiting its metabolism (Figure 33. This is not the case with the third and fourth-generation fluoroquinolones, which may raise the serum levels of warfarin, caffeine, and cyclosporine. To synthesize the critical folate derivative, tetrahydrofolic acid, humans must first obtain preformed folate in the form of folic acid as a vitamin from the diet. In contrast, many bacteria are impermeable to folic acid and other folates and, therefore, must rely on their ability to synthesize folate de novo. The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit this de novo synthesis of folate. Thus, both sulfonamides and trimethoprim interfere with the ability of an infecting bacterium to divide. Compounding the sulfonamide sulfamethoxazole with trimethoprim (the generic name for the combination is cotrimoxazole) provides a synergistic combination that is used as effective treatment of a variety of bacterial infections. Sulfonamides the sulfa drugs are seldom prescribed alone except in developing countries, where they are still employed because of their low cost and their efficacy in certain bacterial infections, such as trachoma and those of the urinary tract.

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The drug should not be used in pregnancy weight loss 3 weeks order 40 mcg astralean, and it should be used with caution in patients with hepatic weight loss 4 pills reviews purchase 40 mcg astralean with visa, renal weight loss pills ephedra order astralean 40 mcg overnight delivery, or cardiovascular disease weight loss yellow pill buy generic astralean 40 mcg on-line. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase (see Figure 41 weight loss retreat proven astralean 40 mcg. When xanthine oxidase is inhibited weight loss pills 153 buy astralean 40 mcg amex, the circulating purine derivatives (xanthine and hypoxanthine) are more soluble and, therefore, are less likely to precipitate. Therapeutic uses: Allopurinol is effective in the treatment of primary hyperuricemia of gout and hyperuricemia secondary to other conditions, such as that associated with certain malignancies (those in which large amounts of purines are produced, particularly after treatment with chemotherapeutic agents) or in renal disease. This agent is the drug of choice in those with a history of kidney stones or if the creatinine clearance is less than 50 mL/day. The primary metabolite is alloxanthine (oxypurinol), which is also a xanthine oxidase inhibitor with a half-life of 15 to 18 hours; the half-life of allopurinol is 2 hours. Thus, effective inhibition of xanthine oxidase can be maintained with once-daily dosage. Hypersensitivity reactions, especially skin rashes, are the most common adverse reactions, occurring in approximately three percent of patients. The reactions may occur even after months or years of chronic administration, and allopurinol therapy should be discontinued. Allopurinol interferes with the metabolism of the anticancer agent 6-mercaptopurine and the immunosuppressant azathioprine, requiring a reduction in dosage of these drugs. Uricosuric agents: Probenecid and sulfinpyrazone the uricosuric drugs are weak organic acids that promote renal clearance of uric acid by inhibiting the urate-anion exchanger in the proximal tubule that mediates urate reabsorption. Probenecid blocks the tubular secretion of penicillin and is sometimes used to increase levels of the antibiotic. These agents are appropriate for patients who have a creatinine clearance of less than 60 mL/min, undersecrete uric acid (<700 mg/day), and do not have a history of kidney stones. Overview Prostaglandins, histamine, and serotonin belong to a group of compounds called autacoids. These heterogeneous substances have widely differing structures and pharmacologic activities. They all have the common feature of being formed by the tissues on which they act; thus, they function as local hormones. Prostaglandins Prostaglandins are unsaturated fatty acid derivatives that act on the tissues in which they are synthesized and are 1 rapidly metabolized to inactive products at the site of action. Abortion: Several of the prostaglandins find use as abortifacients (agents causing abortions). Women can self-administer this regimen with complete abortion rates exceeding 95 percent. The overall case-fatality rate for abortion is less than one death per 100,000 procedures. Infection, hemorrhage, and retained tissue are among the more common complications. Peptic ulcers: Misoprostol is sometimes used to inhibit the secretion of gastric acid and to enhance mucosal resistance to injury in patients with gastric ulcer who are chronically taking nonsteroidal anti-inflammatory agents. Proton-pump inhibitors, such as omeprazole, and H2 antihistamines also reduce the risk of gastric ulcer and are better tolerated than misoprostol, which induces intestinal disorders. Histamine Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Histamine has no clinical applications, but agents that interfere with the action of histamine (antihistamines) have important therapeutic applications. Location: Histamine occurs in practically all tissues, but it is unevenly distributed, with high amounts found in lung, skin, and the gastrointestinal tract (sites where the a insidea of the body meets the a outsidea). Histamine also occurs as a component of venoms and in secretions from insect stings. In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. Release of histamine: the release of histamine may be the primary response to some stimuli, but most often, histamine is just one of several chemical mediators released. Stimuli causing the release of histamine from tissues include the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs. H3 and H4 receptors are expressed in only a few cell types, and their roles in drug action are unclear. For example, the H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability (Figure 42. Histamine promotes vasodilation by causing vascular 3 endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation. The two most common histamine receptors exert their effects by different second-messenger pathways. Antiallergic activities of H1 antihistamines, such as inhibition of the release of mediators from mast cells and basophils, involves stimulation of the intracellular activity of the polyphosphatidylinositol pathway. Role in allergy and anaphylaxis the symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings. Role of mediators: Symptoms associated with allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include histamine, serotonin, leukotrienes, and the eosinophil chemotactic factor of anaphylaxis. In some cases, these cause a localized allergic reaction, producing, for example, actions on the skin or respiratory tract. Under other conditions, these mediators may cause a full-blown anaphylactic response. It is thought that the difference between these two situations results from differences in the sites from which mediators are released and in their rates of release. For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for inactivation to be efficient, a full-blown anaphylactic reaction occurs. H Antihistamines1 the term antihistamine, without a modifying adjective, refers to the classic H1-receptor blockers. These compounds do not influence the formation or release of histamine; rather, they block the receptor-mediated response of a target tissue. The older first-generation drugs are still widely used because they are effective and inexpensive. However, most of these blockers have additional effects unrelated to their blocking of H1 receptors; these effects probably reflect binding of the H1 antagonists to cholinergic, adrenergic, or serotonin receptors (Figure 42. For example, antihistamines are the drugs of choice in controlling the symptoms of allergic rhinitis and urticaria, because histamine is the principal mediator. However, the H1-receptor blockers are ineffective in treating bronchial asthma, because histamine is only one of several mediators of that condition. Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and muscarinic receptors. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs where wakefulness is critical. Pharm acokinetics H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours. The average plasma half-life is 4 to 6 hours except for meclizine, which has a half-life of 12 to 24 hours. All first generation H1 antihistamines and some second-generation H1 antihistamines, such as desloratadine and loratadine, are metabolized by the hepatic P. The duration of action for many oral H1 antihistamines is at least 24 hours, facilitating once-daily dosing. They are most effective when used prophylactically before allergen exposure rather than as needed. The extent of interaction with these receptors and, as a result, the nature of the side effects vary with the structure of the drug. Furthermore, the incidence and severity of adverse reactions for a given drug varies between individual subjects. Other central actions include tinnitus, fatigue, dizziness, lassitude (a sense of weariness), uncoordination, blurred vision, and tremors. Dry mouth: Oral antihistamines also exert weak anticholinergic effects, leading not only to a drying of the nasal passage but also to a tendency to dry the oral cavity. In addition, the first-generation antihistamines (diphenhydramine and others) have considerable anticholinergic (antimuscarinic) actions. Overdoses: Although the margin of safety of H1-receptor blockers is relatively high and chronic toxicity is rare, acute poisoning is relatively common, especially in young children. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system. Histamine H2-Receptor Blockers Histamine H2-receptor blockers have little, if any, affinity for H1 receptors. Although antagonists of the histamine H2 receptor (H2 antagonists) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. Drugs Used to Treat Migraine Headache It has been estimated that 18 million women and 6 million men in the United States suffer from severe migraine headaches. For example, migraines present as a pulsatile, throbbing pain; cluster headaches, as excruciating, sharp, steady pain; and tension-type headaches, as dull pain, with a persistent, tightening feeling in the head. Patients with severe migraine headaches report one to five attacks per month of moderate to severe pain, usually unilateral. The headaches affect patients for a major part of their lives and result in considerable health costs. The first, migraine without aura (previously called common migraine), is a severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours. These headaches are often aggravated by physical activity and are accompanied by nausea, vomiting, photophobia (hypersensitivity to light), and phonophobia (hypersensitivity to sound). In the second type, migraine with aura (previously called classic migraine), the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, and/or cause speech or motor disturbances. In the 15 percent of migraine patients whose headache is preceded by an aura, the aura itself allows diagnosis. For both types of migraines, women are three-fold more likely than men to experience either type of migraine. Biologic basis of migraine headaches the first manifestation of migraine with aura is a spreading depression of neuronal activity accompanied by reduced blood flow in the most posterior part of the cerebral hemisphere. This hypoperfusion gradually spreads forward over the surface of the cortex to other contiguous areas of the brain. The hypoperfusion persists throughout the aura and well into the headache phase, after which hyperperfusion occurs. However, the pain of both types of migraine may be due to extracranial and intracranial arterial dilation. Sym ptom atic treatm ent of acute m igraine Acute treatments can be classified as nonspecific (symptomatic) or migraine specific. Nonspecific treatment includes analgesics, such as nonsteroidal anti-inflammatory drugs, and antiemetics, such as prochlorperazine, to control vomiting. Opioids are reserved as rescue medication when other treatments of a severe migraine attack are not successful. These agents rapidly and effectively abort or markedly reduce the severity of migraine headaches in about 70 percent of patients. The triptans are serotonin agonists, acting at a subgroup of serotonin receptors found on small, peripheral nerves that innervate the intracranial vasculature. The nausea that occurs with dihydroergotamine and the vasoconstriction caused by ergotamine (see below) are much less pronounced with the triptans, particularly rizatriptan and zolmitriptan. The drug has a short duration of action, with an elimination half-life of 2 hours. Headache commonly recurs within 24 to 48 hours after a single dose of drug, but in most patients, a second dose is effective in aborting the headache. Rizatriptan and eletriptan are modestly more effective than sumatriptan, the prototype drug, whereas naratriptan and almotriptan are better tolerated.

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