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If blood glucose falls to <50 mg per dL or if the patient becomes symptomatic buy on line finasteride hair loss cure 4 sore, glucose infusion is resumed order 1mg finasteride overnight delivery hair loss in men xosbextliyi. Depending on the etiology of the hypoglycemia, parenteral glucose infusion may be required for many days and the use of additional drugs should be considered (see below). When recurrent severe hypoglycemia or volume management are problems, intensivists may wish to consider the addition of adjunctive therapies. Particularly when hypoglycemia is due to an insulinoma, nesidioblastosis, or other tumor, it may be necessary to supplement the glucose infusion with drugs that inhibit insulin secretion. Glucocorticoids Parenteral adrenocortical steroids can increase gluconeogenic substrates and inhibit insulin action in the periphery. This therapy is beneficial for patients whose hypoglycemia is in the context of adrenocortical insufficiency; one case report describes utility for hemangiopericytoma-associated hypoglycemia [110]. Octreotide (Sandostatin) Somatostatin is produced in pancreatic islet delta cells and inhibits insulin secretion. The long-acting analog octreotide can inhibit sulfonylurea-induced insulin secretion, and it has been used as supplemental therapy for insulinomas [220], oral agent-induced hypoglycemia [221–228], quinine-induced hypoglycemia in with the treatment of malaria [149], and reportedly in insulin glargine overdose where the mechanism of action is obscure [229]. Diazoxide (Hyperstat) Diazoxide is a benzothiadiazine non-diuretic antihypertensive agent that blocks the secretion of insulin from both normal and neoplastic β cells. To treat hypoglycemia, diazoxide is infused at a dose of 300 mg (1 to 3 mg per kg in children) in D W over 30 minutes every 4 hours, or as a5 constant infusion of 1 mg/kg/h. Glucagon is a useful drug for out-of-hospital treatment of hypoglycemia due to excess insulin of known diabetic patients. In the intensive care setting, however, there is seldom need to administer glucagon unless vascular access cannot be maintained. Rapamycin (Sirolimus) In one case report, rapamycin was effective in controlling intractable hypoglycemia in a patient with metastatic insulinoma [234]. The drug was thought to act both by reducing the malignant β cell proliferation and by inhibiting insulin production. In general, oral antidiabetic agents like sulfonylureas should be discontinued for seriously ill patients [236]. Several studies have demonstrated that hypoglycemia can be avoided while achieving glycemic control by using structured insulin orders and management algorithms [237,238]. Up to a third of patients admitted to an emergency department with severe hypoglycemia may experience recurrent hypoglycemia in the hospital [239]. After initial therapy with glucose, remember that only the symptoms and not the cause have been treated. Patients with sulfonylurea- or insulinoma-induced hypoglycemia may require aggressive treatment of hypoglycemia with parenteral glucose for many days. Mahmoodpoor A, Hamishehkar H, Beigmohammadi M, et al: Predisposing factors for hypoglycemia and its relation with mortality in critically ill patients undergoing insulin therapy in an intensive care unit. Giakoumidakis K, Eltheni R, Patelarou E, et al: Effects of intensive glycemic control on outcomes of cardiac surgery. Kagansky N, Levy S, Rimon E, et al: Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Garg R, Hurwitz S, Turchin A, et al: Hypoglycemia, with or without insulin therapy, is associated with increased mortality among hospitalized patients. Shimada R, Nakashima T, Nunoi K, et al: Arrhythmia during insulin- induced hypoglycemia in a diabetic patient. Lindstrom T, Jorfeldt L, Tegler L, et al: Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Arem R, Zoghbi W: Insulin overdose in eight patients: insulin pharmacokinetics and review of the literature. Matsumura M, Nakashima A, Tofuku Y: Electrolyte disorders following massive insulin overdose in a patient with type 2 diabetes. Hojlund K, Hansen T, Lajer M, et al: A novel syndrome of autosomal- dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Annane D, Cariou A, Maxime V, et al: Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. Furrer J, Hättenschwiler A, Komminoth P, et al: Carcinoid syndrome, acromegaly, and hypoglycemia due to an insulin-secreting neuroendocrine tumor of the liver. Otonkoski T, Ämmälä C, Huopio H, et al: A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Anlauf M, Wieben D, Perren A, et al: Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of b-cell changes. Klöppel G, Anlauf M, Raffel A, et al: Adult diffuse nesidioblastosis: genetically or environmentally induced? McLaughlin T, Peck M, Holst J, et al: Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. Koyama R, Nakanishi K, Kato M, et al: Hypoglycemia and hyperglycemia due to insulin antibodies against therapeutic human insulin: treatment with double filtration plasmapheresis and prednisolone. Varga J, Lopatin M, Boden G: Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus. Uchigata Y, Takayama-Hasumi S, Kawanishi K, et al: Inducement of antibody that mimics insulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain. Selinger S, Tsai J, Pulini M, et al: Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. Semakula C, Pambuccian S, Gruessner R, et al: Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide. Anaforoglu I, Simsek A, Turan T, et al: Hemangiopericytoma- associated hypoglycemia improved by glucocorticoid therapy: a case report. Korn E, Van Hoff J, Buckley P, et al: Secretion of a large molecular- weight form of insulin-like growth factor by a primary renal tumor. Kato A, Bando E, Shinozaki S, et al: Severe hypoglycemia and hypokalemia in association with liver metastases of gastric cancer. Ogiwara Y, Mori S, Iwama M, et al: Hypoglycemia due to ectopic secretion of insulin-like growth factor-I in a patient with an isolated sarcoidosis of the spleen. Aldhahi W, Armstrong J, Bouche C, et al: b-Cell insulin secretory response to oral hypoglycemic agents is blunted in humans in vivo during moderate hypoglycemia. Ben-Ami H, Nagachandran P, Mendelson A, et al: Drug-induced hypoglycemic coma in 102 diabetic patients. Bodmer M, Meier C, Krahenbuhl S, et al: Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Pijl H, Ohashi S, Matsuda M, et al: Bromocriptine—a novel approach to the treatment of type 2 diabetes. Takada M, Fujita S, Katayama Y, et al: the relationship between risk of hypoglycemia and use of cibenzoline and disopyramide. Kelesidis T, Canseco E: Quinolone-induced hypoglycemia: a life- threatening but potentially reversible side effect. Roustit M, Blondel E, Villier C, et al: Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in a diabetic patient. Strapazzon G, Nardin M, Zanon P, et al: Respiratory failure and spontaneous hypoglycemia during noninvasive rewarming from 24.

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Koivula I generic 5mg finasteride hair loss eyebrows, Hamalainen S order genuine finasteride on line hair loss graves disease, Jantunen E, et al: Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia. Rabensteiner J: Diagnostic and prognostic potential of presepsin in Emergency Department patients presenting with systemic inflammatory response syndrome [Letter]. Garnacho-Montero J, Gutierrez-Pizarraya A, Escoresca-Ortega A, et al: De-escalation of emperical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Shindo Y, Ito R, Kobayashi D, et al: Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia. Christ-Crain M, Stolz D, Bingisser R, et al: Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Muller L, Bobbia X, Toumi M, et al: Respiratory variations of inferior vena cava diameter predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use. Nunes T, Ladeira R, Bafi A, et al: Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation. Sanchez M, Jimenez-Lendinez M, Cidoncha M, et al: Comparison of fluid compartments and fluid responsiveness in septic and non-septic patients. Pierrakos C, Velissaris D, Scolletta S, et al: Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? Brandt S, Regueira T, Bracht H, et al: Effect of fluid resuscitation on mortality and organ function in experimental sepsis models. Rehberg S, Yamamoto Y, Sousse L, et al: Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. Alsous F, Khamiees M, DeGirolamo A, et al: Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Results of a meta-analysis and systematic review on the impact of fluid overload on morbidity and mortality. Scheingraber S, Rehm M, Sehmisch C, et al: Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Mohd Yunos N, Bellomo R, Hegarty C, et al: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. Young P, Bailey M, Beasley R, et al: Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit. Caironi P, Tognoni G, Masson S, et al: Albumin replacement in patients with severe sepsis or septic shock. Kremer H, Baron-Menguy C, Tesse A, et al: Human serum albumin improves endothelial dysfunction and survival during experimental endotoxemia: concentration-dependent properties. Avni T, Lador A, Lev S, et al: Vasopressors for the treatment of septic shock: systematic review and meta-analysis. De Baker D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis. Monnet X, Jabot J, Maizel J, et al: Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients. Abid O, Akca S, Haji-Michael P, et al: Strong vasopressor support may be futile in the intensive care unit patient with multiple organ failure. Vieillard-Baron A, Caille V, Charron C, et al: Actual incidence of global left ventricular hypokinesia in adult septic shock. Jardin F, Fourme T, Page B, et al: Persistent preload defect in severe sepsis despite fluid loading: a longitudinal echocardiographic study in patients with septic shock. Morelli A, Ertmer C, Westphal M, et al: Effect of heat rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock. Langenberg C, Wan L, Egi M, et al: Renal blood flow and function during recovery from experimental septic acute kidney injury. Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic therapy in critically ill patients. Saugel B, Ringmaier S, Holzapfel K, et al: Physical examination, central venous pressure, and chest radiography for the prediction of transpulmonary thermodilution-derived hemodynamic parameters in critically ill patients: a prospective trial. Boyer A, Vargas F, Coste F, et al: Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Bufalari A, Giustozzi G, Moggi L: Postoperative intraabdominal abscesses: percutaneous versus surgical treatment. Annane D, Bellissant E, Sebille V, et al: Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Chappell D, Jacob M, Hofmann-Kiefer K, et al: Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Volbeda M, Wetterslev J, Gluud C, et al: Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Modern scoring systems consider grade and severity and are intended to serve as predictors of outcome. All include clinical and laboratory data for six organs: respiratory, cardiovascular, hematologic, hepatic, renal, and central nervous system (Table 40. No single scoring system has been proven superior, but all predict mortality more accurately than they predict health care resource utilization [11,15]. It is likely that ongoing tissue hypoxia leads to activation of the acute inflammatory response, oxidative imbalance, structural rearrangement of cellular proteins, dysregulation of the immune system, activation of apoptotic pathways, cell death, and organ dysfunction [24]. Although the inflammatory response is an important component of normal recovery from injury and illness, organ failure appears to result from a loss of the balance between the pro- and anti-inflammatory cascades [25]. The proinflammatory response to a stimulus predominates initially, with increased release of proinflammatory mediators, increased capillary permeability, macrophage and neutrophil activation with tissue invasion and damage, disordered apoptosis, and microvascular thrombosis [26]. This initial response is normally tempered by the anti-inflammatory response, but immune regulation may become dysfunctional. During this period, the patient becomes susceptible to nosocomial pathogens, with a normally survivable event such as pneumonia representing a life-threatening “second hit” [27]. Clinicians should move briskly to optimize cardiorespiratory function, remove catabolic stressors, and provide nutrition while using antimicrobials selectively and avoiding blood product transfusion. Oxygen saturation in mixed venous blood has historically been an important, if not vital, resuscitation target (SvO -saturation in mixed venous blood2 obtained from a pulmonary artery catheter or ScvO -saturation in central2 venous blood obtained from a central venous catheter in superior vena cava). Subsequent studies of such “goal- directed therapy” have failed to show similar benefit but those investigations have been conducted in an era when the norm in resuscitation is much more advanced monitoring [39]. Antimicrobials should be used early and be targeted at a broad spectrum of likely organism, then tailored and de-escalated [15]. Although some European studies support parenteral and topical oropharyngeal antibiotics in reducing mortality, this is not widely accepted in the United States [42]. Arginine has been shown to be beneficial for surgical and trauma patients, but cannot be recommended for septic medical patients because of immunoinflammatory characteristics [53]. However, omega fatty acids do appear beneficial for shortening length of stay, ventilator days, and mortality among septic patients in some studies.

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Warfarin must not be initiated until the platelet count has returned to normal as it is procoagulant when first started discount 5mg finasteride with mastercard hair loss 3 months after giving birth, due to its effect on the production of naturally occurring anti- coagulants buy finasteride 5 mg low cost latest hair loss cure 2013, 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.

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Activation of sympathetic neurons increases the heart rate and force of contraction purchase genuine finasteride on line hair loss cure latisse, and activation of parasympathetic neurons reduces the heart rate and force of contraction (slightly) discount finasteride 1 mg with amex hair loss in men journal. Preganglionic neurons of the sympathetic system arise from thoracic and lumbar regions of the spinal cord, whereas the preganglionic neurons of the parasympathetic system arise from cranial nerves and the sacral region. When there is a sudden drop in blood pressure, the sympathetic system is activated, not the parasympathetic system. Neurotransmitters generally bind to membrane receptors on the postsynaptic effector cells and cause cellular effects. Receptors that are coupled to second messenger systems are known as metabotropic receptors. The receptors that directly activate ion channels are known as ionotropic receptors. Synthesis of acetylcholine Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy- dependent carrier system that cotransports sodium and can be inhibited by the drug hemicholinium. Release of acetylcholine When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage- sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of contents into the synaptic space. The postsynaptic cholinergic receptors on the surface of effector organs are divided into two classes: muscarinic and nicotinic (ure 4. Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells, as 148 mediated by second messenger molecules. Recycling of choline Choline may be recaptured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron. Muscarinic receptors Muscarinic receptors belong to the class of G-protein–coupled receptors (metabotropic receptors). By contrast, the muscarinic receptors show only a weak affinity for nicotine, an alkaloid found in tobacco and other plants (ure 4. There are five subclasses of muscarinic receptors; however, only M, M, and M receptors have been1 2 3 functionally characterized. Location of muscarinic receptors These receptors are found on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine 151 glands. Although all five subtypes are found on neurons, M receptors are also found on gastric parietal cells, M1 2 receptors on cardiac cells and smooth muscle, and M receptors on the bladder, exocrine glands, and smooth muscle. For example, when M or M receptors are activated, the receptor undergoes a conformational change and interacts with1 3 a G-protein that activates phospholipase C. Calcium can then interact 3 3 to stimulate or inhibit enzymes or to cause hyperpolarization, secretion, or contraction. In contrast, activation of the M subtype on the2 cardiac muscle stimulates a G-protein that inhibits adenylyl cyclase and increases K conductance. Muscarinic agonists Pilocarpine is a nonselective muscarinic agonist used to treat xerostomia and glaucoma. Attempts are currently underway to develop muscarinic agents that are directed against specific receptor subtypes. The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel (ionotropic receptor). Nicotine at low concentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor. The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. However, as a group, the direct-acting agonists show little specificity in their actions, which limits clinical usefulness. Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the cholinesterases. Nitric oxide then diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation via phosphodiesterase-3 inhibition. It lacks nicotinic actions (due to addition of the methyl group), but does have strong muscarinic activity. Actions Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. It also stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter muscles are relaxed. Therapeutic uses In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. Adverse effects Bethanechol can cause generalized cholinergic stimulation (ure 4. Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent. It can cause release of epinephrine from the adrenal medulla by its nicotinic action. The vision becomes fixed at some particular distance, making it impossible to focus (ure 4. Therapeutic uses Because of its high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used. Intraocular use provides miosis for eye surgery and lowers intraocular pressure in the treatment of glaucoma. Adverse effects With ophthalmologic use, few adverse effects occur due to lack of systemic penetration (quaternary amine). Actions Applied topically to the eye, pilocarpine produces rapid miosis, contraction of the ciliary muscle, and spasm of accommodation. Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. Therapeutic uses Pilocarpine is used to treat glaucoma and is the drug of choice for emergency lowering of intraocular pressure of both open-angle and angle-closure glaucoma. Pilocarpine is extremely effective in opening the trabecular meshwork around the Schlemm canal, causing an immediate drop in intraocular pressure because of the increased drainage of aqueous humor. The drug is beneficial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck. Sjögren syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine tablets and cevimeline, a cholinergic drug that also has the drawback of being nonspecific. Adverse effects Pilocarpine can cause blurred vision, night blindness, and brow ache. Poisoning with this agent is characterized by exaggeration of various parasympathetic effects, including profuse sweating (diaphoresis) and salivation. The effects are similar to those produced by consumption of mushrooms of the genus Inocybe, which contain muscarine. Parenteral atropine, at doses that can cross the blood–brain barrier, is administered to counteract the toxicity of pilocarpine. It is located both pre- and postsynaptically in the nerve terminal where it is membrane bound. It has a short duration of action of 10 to 20 minutes due to rapid renal elimination.