Because they are particularly toxic to hematopoietic tissues bipolar depression cant get out of bed buy genuine escitalopram, they may induce leukopenia (especially neutropenia) anxiety cat escitalopram 10 mg low price, thrombocytopenia anxiety ecards best escitalopram 20mg, and anemia. Azathioprine warrants special mention because it is used solely as an immunosuppressant. Azathioprine is a prodrug that yields 6-mercaptopurine on intracellular exposure to glutathione and other nucleophilic reactants. Although the pharmacologic features of azathioprine are essentially identical to those of 6-mercaptopurine (see Chapter 36), azathioprine is believed to be a more selective immunosuppressant. This advantage may stem from an enhanced uptake or metabolic activation of azathioprine in T cells. Mycophenolate mofetil is an ester that is rapidly hydrolyzed to mycophenolic acid, the active form of the drug. Mycophenolate is an inhibitor of inosine monophosphate dehydrogenase, an important enzyme in purine synthesis. Because lymphocytes depend more on the de novo synthesis of purines than other cells, which can reclaim purines by the salvage pathway, mycophenolate is a more selective immunosuppressant than other cytotoxic agents. Cytotoxic Drugs Cytotoxic drugs are of two classes: the first kills lymphocytes, and the second interferes with the proliferative stage of the immune response. They include the alkylating agents such as cyclophosphamide and phenylalanine mustard. The general pharmacologic characteristics of most of these drugs are discussed in Chapter 36. Although it is an alkylating agent, cyclophosphamide is inactive Slow-Acting, Disease-Modifying Antirheumatic Drugs One potential immunosuppressive strategy involves the inhibition of selected aspects of antigen processing within the endolysosome or by the proteasome. It has been suggested that these weak bases may impair endolysosomal acidification. Gold compounds-gold sodium thiomalate, aurothioglucose, and auranofin-function in part by inhibiting transcription activation. As a result, not only are various lymphocyte functions diminished, but also the induction of immune function in nonhematopoietic cells is impaired. Cytokine Therapy the concept of therapeutics based on the administration of hormones is not new. As more is learned about the activities of immune-induced factors, referred to as cytokines, new therapies to increase or decrease immunologic activities will be developed. Currently, over a dozen cytokines have been approved for human use, and others are in clinical trials. In the following discussion, cytokines and soluble cytokine receptors are reviewed in accordance with their principal biologic activities (see Table 35-1). Hematopoietic growth factors the hematopoietic growth factors include colony-stimulating factors, such as granulocyte colony-stimulating factor, granulocyte/ macrophage colony-stimulating factor, monocyte/macrophage colonystimulating factor, stem cell factor, erythropoietin, and a number of interleukins. Although it is beyond the scope of this chapter to discuss these growth factors, they are used clinically in the treatment of various hematopoietic deficiencies, including neutropenia, anemia, and thrombocytopenia, and they are reviewed in Chapter 25. Much of this survival is attributable to decreased inflammation, rather than to specific immunosuppression. The cytokine has been given the nonproprietary name of aldesleukin and has been marketed for the treatment of metastatic renal cell carcinoma (see Chapter 36).
The reasons for this may include better blood pressure control during the nighttime hours with the longer acting diuretic depression symptoms dysthymia order escitalopram 5 mg with visa. For a complete discussion of diuretics used in the treatment of hypertension papa roach anxiety order escitalopram with a mastercard, see Chapter 22 depression in men purchase escitalopram 10mg with visa. General Aims of Antihypertensive Drug Therapy Treatment of essential hypertension consists of therapy aimed at reducing the blood pressure into the normal range. As shown in Figure 23-2, many factors play a role in the determination of blood pressure, and consequently pharmacologic agents with diverse mechanisms of action can be used singly or in combination to treat essential hypertension. Renin catalyzes the conversion of angiotensinogen, a glycoprotein found in the blood, to angiotensin I, a decapeptide with little cardiovascular activity. Angiotensin peptides stimulate thirst and the secretion of aldosterone and antidiuretic hormone; the resultant increase in extracellular fluid and electrolytes augments the direct pressor effects. Patients with essential hypertension can be divided into three groups according to their renin-Na+ index. Approximately 15% of patients have renin concentrations higher than normal, 25% have renin concentrations lower than normal, and the remaining 60% exhibit normal renin titers. African American and elderly individuals tend to have a higher incidence of low-renin hypertension. The percentage of hypertensive patients with normal renin activity may be misleading because renin release is ordinarily depressed as the result of increased blood pressure. Undesired reflex actions can also occur in which diuretics and direct-acting vasodilators stimulate renin release. Captopril, the first drug of this class to be developed, was specifically designed to disrupt the renin-angiotensin pathway. Longer acting variants, including enalapril, lisinopril and fosinopril, are more commonly used for routine therapy. They may also act to maintain the lowered blood pressure by elevating bradykinin (a potent vasodilator) concentrations in the blood. Angiotensin expressed in the liver is cleaved by renin from the kidney to release angiotensin I in plasma. Salt and water retention is not induced, and orthostatic hypotension and tachycardia are not problems. Because food in the gastrointestinal tract significantly reduces the absorption of captopril, the drug should be taken 1 hour before meals. Approximately 40% of captopril is metabolized in the liver, and most of the metabolites and the parent drug are excreted by the kidney. Lisinopril is less well absorbed than captopril, resulting in peak plasma concentrations after approximately 7 hours. Its absorption is not influenced by food, and it has a longer duration of effect than captopril. Based on the mechanism of action, expected adverse events include hyperkalemia and hypotension. Aliskiren administration produces hyperreninemia owing to a compensatory increase in renin release. Similar to other inhibitors of the renin-angiotensin system, aliskiren is contraindicated in patients with bilateral renal artery stenosis and during pregnancy. Aliskiren has a poor bioavailability and is greater than 90% excreted unchanged in the feces, so minimal drug metabolism interactions are expected from this drug. Enalaprilat is not absorbed from the gastrointestinal tract but is effective after intravenous administration; it has been marketed for such use in patients unable to take drugs orally.
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Motor neurons: have axons intermediate in diameter between and motor neurons; innervate extrafusal and intrafusal muscle fibers D mood disorder case study buy 20 mg escitalopram with amex. Golgi tendon organs: encapsulated structures attached in series with the large mood disorder in children discount 10mg escitalopram fast delivery, collagenous fibers of tendons at the insertions of muscles and along the fascial covering of muscles; group 1b afferents terminate in small bundles within the capsule; when muscle contraction occurs depression diagnosis definition generic escitalopram 20 mg line, shortening of the contractile part of the muscle results in lengthening of the noncontractile region where the tendon organs are located, resulting in vigorous firing of the Golgi tendon organs; their afferents project to the spinal cord, where they polysynaptically inhibit the motor neurons innervating the agonist muscle and facilitate motor neurons of the antagonist muscle; central action of the Golgi tendon organs is responsible for the "clasp knife" phenomenon in spasticity. Basal ganglia: function is to control and regulate activities of the motor and premotor cortical areas so that voluntary movements can be performed smoothly; consists of five subcortical nuclei 1. Caudate: derived from the telencephalon; three parts: head, body, and tail (ending near the amygdala); along with the putamen, is the major input nuclei of the basal ganglia. Putamen: derived from the telencephalon; means "shell"; putamen + globus pallidus = lentiform nucleus 3. Cerebellum: three primary functions: maintenance of posture, maintenance of muscle tone, and coordination of voluntary motor activity 1. Afferent tract: ventral spinocerebellar portion of the rostral spinocerebellar tract, and trigeminocerebellar projections ii. Afferent tract: pontocerebellar fibers-crossed fibers from the pontine nuclei that project to the neocerebellum c. Others: fibers from the vestibular nerve and nuclei, reticulocerebellar fibers, some fibers from the rostral spinocerebellar 2. Molecular layer: outer layer underlying the pia; contains stellate cells, basket cells, and dendritic arbor of the Purkinje cells ii. Granule layer: inner layer overlying the white matter; contains granule cells, Golgi cells, and cerebellar glomeruli (which consist of a mossy fiber rosette, granule cell dendrites, and a Golgi cell axon) b. Granule cells: excite (by way of glutamate) Purkinje, basket, stellate, and Golgi cells through parallel fibers; excited by mossy fibers and inhibited by Golgi cells iii. Mossy fibers: the afferent excitatory fibers of the spinocerebellar, pontocerebellar, and vestibulocerebellar tracts; terminate as mossy fiber rosettes on granule cell dendrites; excite granule cells v. General afferent fibers: have their cells of origin in the cranial and spinal dorsal root ganglia a. General efferent fibers: arise in cells in the spinal cord, brainstem, and autonomic ganglia; innervate all musculature of the body except the branchiomeric muscles a. Trigeminal ganglion: semilunar or gasserian; contains pseudounipolar ganglion cells; three divisions: a. Ophthalmic nerve (V1): lies in the wall of the cavernous sinus; enters through the superior orbital fissure; also mediates the afferent limb of the corneal reflex b. Maxillary nerve (V2): lies in the wall of the cavernous sinus; exits the skull through the foramen rotundum c. First-order neurons: located in the trigeminal ganglion; gives rise to axons that descend in the spinal trigeminal tract and synapse with second-order neurons in the spinal trigeminal nucleus ii. Hair cells of the organ of Corti: innervated by the peripheral processes of bipolar cells of the spiral ganglion; stimulated by vibrations of the basilar membrane i. Inner hair cells: chief sensory elements; synapse with the dendrites of myelinated neurons whose axons comprise 90% of the cochlear nerve ii. Outer hair cells: synapse with the dendrites of unmyelinated neurons whose axons comprise 10% of the cochlear nerve; they reduce the threshold of the inner hair cells. Bipolar cells of the spiral (cochlear) ganglion: project peripherally to the hair cells of the organ of Corti; project centrally as the cochlear nerve to the cochlear nuclei c. Cochlear nuclei: receive input from the cochlear nerve and project to the contralateral superior olivary nucleus and lateral lemniscus.
The lost vitamin is quickly rebound by intrinsic factor in the small intestine and reabsorbed mood disorder unipolar safe 10 mg escitalopram. Because this enterohepatic circulation is so efficient depression yahoo answers order escitalopram mastercard, very little new vitamin B12 is required in the diet each day bipolar depression treatment resistant order escitalopram 5 mg mastercard. As long as the ability of the body to transport cobalamin across the intestinal wall and reabsorb the bile-secreted cobalamin remains intact, a diet completely devoid of vitamin B12 may not produce clinical symptoms for many years. Pathophysiologic characteristics Vitamin B12 deficiency can be difficult to diagnose. If there is a concurrent iron deficiency anemia, the combination of microcytic and macrocytic anemias may result in relatively normal-sized cells. The peripheral blood smear is abnormal, showing anisocytosis and poikilocytosis, along with the characteristic macro-ovalocytes. Serum vitamin B12 concentrations, normally 150 to 350 pg/mL, are less than 100 pg/mL. It is rare to see an individual with dietary vitamin B12 insufficiency, especially in first-world nations. Only the strictest of vegans who eat no animal and dairy products whatsoever may show dietary insufficiency. Even then, small amounts of vitamin B12 may be available in the diet from microorganisms of legumes or exogenous application of cobalamins to grain and cereal products. As previously mentioned, dietary deficiency may take decades to become clinically evident. In these patients, the transport proteins are defective, so that not only is the primary absorptive capacity decreased or lost, but also the ability of the body to recycle enterohepatic cobalamin is impaired. Luminal stasis may allow significant enteric bacterial overgrowth, leading to blind loop syndrome; the vitamin is "stolen" by the bacteria and is unavailable to the host. Other conditions such as surgical resection, carcinoma, Crohn disease, and other inflammatory bowel disorders may similarly induce a vitamin B12 deficiency. As the disease progresses, it becomes increasingly self-perpetuating because the enterocytes become defective and further lose their ability to absorb cobalamin. Pancreatic disease also decreases the absorption of vitamin B12 in the small intestine. Longterm exposure to nitrous oxide has been shown in pigs and humans to result in megaloblastic anemia by inhibiting methionine synthase activity. The nitrous oxide irreversibly oxidizes the exposed cobalt atom, and in so doing it permanently inactivates the enzyme. Vitamin B12 Nutrition and physiologic characteristics Vitamin B12 is a generic term for cyanocobalamin and hydroxocobalamin, two stable forms of cobalamin. The cobalamins are composed of a nearly planar macrocyclic corrin ring (similar to porphyrin) covalently linked to a trivalent cobalt atom by four coordination bonds in a manner similar to iron binding in heme. The sole natural and commercial source of cobalamin is synthesis by microorganisms. Many animals can use vitamin B12 produced by their own enteric bacteria, but because microbial synthesis in humans is limited to the large intestine (a site too distal for effective absorption) humans must derive their vitamin B12 exogenously.