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The patient should be normotensive patible and bioincompatible membranes is still a matter of debate buy cephalexin 250 mg with mastercard. The water permeability of a dialysis membrane is a function of Another aspect of the dialysis prescription is the composition membrane thickness and pore size and is indicated by its ultrafil- of the dialysate discount cephalexin 250mg visa. The concentrations of sodium, potassium, tration coefficient (KUf). During ultrafiltration additional solute calcium, and bicarbonate in the dialysate can be individualized removal occurs by solvent drag or convection. Because of such that ionic composition of the body is restored toward increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg) normal during the dialytic procedure. This topic is discussed in are associated with much higher clearances of average to high mol- detail in chapter 2. Because blood Although hemodialysis is effective in removing uremic toxins flow rates over 50 to 100 mL/min result in little or no further and provides adequate control of fluid and electrolyte abnor- increase in the clearance of these molecules, clearance is primarily malities, the procedure does not provide for the endocrine or membrane-limited. In contrast, clearance values for urea are not metabolic functions of the normal kidney. Therefore, the dialy- significantly greater with a high-flux membrane compared with a sis prescription often includes medications such as erythropoi- high-efficiency membrane because the blood flow rate, and not the etin and 1,25(OH)2 vitamin D. The dose of erythropoietin membrane, is the principal determinant of small solute clearance. Vitamin D therapy is often used in patients undergoing membrane is one in which minimal reaction occurs between the dialysis to help limit the severity of secondary hyperparathy- humoral and cellular components of blood as they come into roidism. Dosages usually range from 1 to 2 µg given intra- contact with the surface of the dialyzer. Trea t m e n t FIGURE 6-1 Diffusion Diffusional and convective flux in hem odialysis. Dialysis is a Blood Dialysate process whereby the composition of blood is altered by exposing it to dialysate through a semipermeable membrane. Solutes are transported Urea, 100 mg/dL Urea, 0 mg/dL across this membrane by either diffusional or convective flux. A, In diffusive solute transport, solutes cross the dialysis m em brane in a direction dictated by the concentration gradient established across the m em brane of the hem odialyzer. At a given tem perature, diffusive transport is directly proportional to both the solute concentration gradient across the membrane and the membrane surface area and inversely proportional to m em brane thickness. Bicarbonate, 20 mEq/L Bicarbonate, 35 mEq/L (Continued on next page) A Dialysis membrane The Dialysis Prescription and Urea M odeling 6. Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine) The rate of ultrafiltration is determ ined by the m agnitude of this pressure gradient. M ovem ent of water tends to drag solute across the m em brane, a process referred to as convective transport or sol- vent drag. The contribution of convective transport to total solute FIGURE 6-2 transport is only significant for average-to-high m olecular weight The com m on treatm ents for hem odynam ic instability of patients solutes because they tend to have a sm aller diffusive flux. It is im portant to begin by excluding reversible causes associated with hypotension because failure to recognize these abnorm alities can be lethal. Perhaps the m ost com m on rea- son for hem odynam ic instability is an inaccurate setting of the dry weight. O nce these conditions have been dealt with, the use of a high sodium dialysate, sodium m odeling, cool tem perature dialysis, and perhaps the adm inistration of m idodrine m ay be attem pted. All of these m aneuvers are effective in stabilizing blood pressure in dialysis patients. FIGURE 6-3 ACCEPTABLE M ETHODS TO M EASURE Acceptable m ethods to m easure hem odialysis adequacy as recom - HEM ODIALYSIS ADEQUACY* m ended in the Dialysis O utcom es Q uality Initiative (DO Q I) Clinical Practice Guidelines. These guidelines m ay change as new inform ation on the benefit of increasing the dialysis prescription becom es available. For the present, however, they should be con- •Formal urea kinetic modeling (Kt/V) using computational software sidered the m inim um targets. W hen prescribing the blood flow KoA 900 High-efficiency rate for a hem odialysis procedure the following m ust be considered: 300 dialyzer KoA 650 the relationship between the type of dialysis m em brane used, blood flow rate, and clearance rate of a given solute. For a sm all solute KoA 300 Conventional such as urea (m olecular weight, 60) initially a linear relationship 200 dialyzer exists between clearance and blood flow rates. Sm all solutes are therefore said to be flow-lim ited because their clearance is highly 100 flow-dependent. At higher blood flow rates, increases in clearance rates progressively decrease as the characteristics of the dialysis m em brane becom e the lim iting factor. The efficiency of a dialyzer 0 in rem oving urea can be described by a constant referred to as 0 100 200 300 400 KoA, which is determ ined by factors such as surface area, pore Blood flow rate, mL/min size, and m em brane thickness. Use of a high-efficiency m em brane (KoA >600 m L/m in) can result in further increases in urea clearance rates at high blood flow rates. In contrast, at low blood flow rates no significant difference exists in urea clearance between a conventional and a high-efficiency m em brane because blood flow, and not the m em brane, is the prim ary determ inant of clearance. FIGURE 6-5 2000 W ater perm eability of a m em brane and control of volum etric ultrafiltration in hem odialysis. The water perm eability of a dialysis 1800 m em brane can vary considerably and is a function of m em brane thickness and pore size.

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LY354740 has also been to the glycine site such as 5 500 mg cephalexin overnight delivery,7-dichlorokynurenic acid order 250mg cephalexin mastercard, shown to decrease withdrawal signs seen during naloxone- L689,560, ACEA 1021, and MDL 105,519 (104). Unfortunately, clinical develop- KA subunits (GluR5–GluR7 and KA-1–KA-2). Functional ment for many of these compounds was halted because of channels can be produced by homomeric expression of severe side effects, including psychotic-like symptoms. The GluR5 or GluR6 subunits, or by heteromeric expression of potential for these side effects has been a major deterrent for KA-1 or KA-2 with GluR5 or GluR6. KA sites are found using NMDA antagonists for the treatment of psychiatric in the hippocampus, cortex, and thalamus, whereas AMPA disorders. Although there are currently no drugs reported receptors are additionally localized in septal and cerebellar to be in development, preclinical studies have suggested that sites. Pharmacologic agents for blocking non-NMDA recep- selective antagonists of the strychnine-sensitive glycine site tors include the competitive antagonists CNQX, DNQX, can have anxiolytic properties with reduced side-effect po- and NBQX, and the noncompetitive antagonist GYKI tential relative to competitive and noncompetitive NMDA 52466. Recent Metabotropic glutamate receptors (mGluRs) mediate work has supported such a profile (112,113). Opposite effects to have anxiolytic actions in preclinical models. Thus, on cAMP may be mediated by either Gi or Gs stimulation. LY326325 was shown to have anxiolytic activity in the ele- Agonists include a conformationally restricted glutamate vated plus maze and in a conflict test (punished drinking) analogue, 1-aminocyclopentane-trans-1,3-dicarboxylic acid in rats (114), and CNQX injected directly into the peria- (trans-ACPD). Metabotropic receptors have been classified queductal gray produced anxiolytic effects on the elevated into three subgroups: group I (mGluR1, mGluR5), which plus maze (115). The antagonists CNQX and GYKI 52466 stimulate PI hydrolysis; and two groups that inhibit adenyl- were also able to block the anxiogenic responses produced ate cyclase, group II (mGluR2, mGluR3) and group III by bicuculline injected into the basolateral amygdala (116). Metabotropic receptors are widely distributed throughout the brain, in areas such as the hippo- campus, cerebellum, thalamus, olfactory bulb, and striatum, CCKB ANTAGONISTS though the precise distribution varies considerably between groups. In addition to the agonist trans-ACPD, other ago- Cholecystokinin (CCK) is a peptide found extensively both nists that are more specific for receptor subtypes include in the gut (where it was originally identified) and in the Chapter 68: Mechanism of Action of Anxiolytics 1003 brain (117). CCK exists in multiple forms, the most pre- depression and in the mechanism of action of antidepressant dominant of which is CCK octapeptide (CCK8) and, to a drugs. The role of cortico- lesser extent, CCK tetrapeptide (CCK4) (118). CCK is co- tropin-releasing factor in depression and anxiety disorders. J localized with a number of different neurotransmitters, in- Endocrinol 1999;160:1–12. CRF and restraint stress decrease ex- peptide Y, and VIP. CCK-like immunoreactivity has been ploratory behavior in hypophysectomized mice. Pharmacol Bio- demonstrated in anatomic regions that include the amyg- chem Behav 1989;34:517–519. Cerebrospinal fluid corti- dala, cerebral cortex, hippocampus, striatum, hypothala- cotropin-releasing hormone levels are elevated in monkeys with mus, and spinal cord (119). There are two subtypes of CCK patterns of brain activity associated with fearful temperament. The role of early adverse life accumbens, posterior hypothalamus, and area postrema. Ann NY Acad CCKB receptors are localized in cortex, olfactory bulb, nu- Sci 1997;821:194–207. Early postnatal experience alters hypo- A number of selective antagonists for the CCKB receptor thalamic corticotropin-releasing factor (CRF) mRNA, median have been synthesized, including LY288513 (Lilly), PD eminence CRF content and stress-induced release in adult rats. Griebel (34) reviewed the extensive literature on the effects 9. Corticotropin releasing factor receptors and their ligand family. Corticotropin-releas- that the results were contradictory and did not lead to a ing factor receptors: an overview. L-365,260 and CI-988 have been evalu- 1997;105:65–82. Localization of had significant anxiolytic effects (122–124). Autoradiographic locali- zation of CRF-1 and CRF-2 binding sites in adult rat brain. Many different neurotransmitter receptor systems have been Neuropsychopharmacology 1997;17:308–316. Autoradiographic and in situ shown to modulate anxiety and possess anxiolytic effects. J Comp Neurol 1999; control anatomic circuitry important in anxiety. Homologous by their side-effect profile than by their anxiolytic activity.

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Aggressive m anagem ent of risk factors is appropriate for all patients 750 mg cephalexin with mastercard, with or without IH D discount cephalexin 750 mg free shipping. In this study, 26 patients with insulin-dependent dia- 70 betes who were found to have over 75% stenoses in one or m ore 60 coronary arteries were random ly allocated to either m edical m an- 50 agem ent or a revascularization procedure before transplantation. These findings suggest that transplantation candidates (2) 10 who have diabetes should be screened for silent coronary artery 0 disease because revascularization decreases m orbidity and m ortality 0 3 6 9 12 15 18 21 24 after transplantation. The num bers in parentheses indicate the num - Follow-up, mo ber of patients being followed at that tim e. M yocardial perform ance has been shown to im prove in som e patients after renal transplanta- Signs and Yes tion. Thus, a low ejection fraction alone does not autom atically Exclude secondary symptoms of causes exclude patients from transplantation. O ccasionally, patients m ay be candidates for sim ultaneous heart and kidney transplantation. Patients m ust not undergo History of Yes Recent Yes surgery within 6 m onths of a stroke or transient ischem ic attack stroke or TIA? Asym ptom atic patients with a carotid bruit should be con- No No sidered for carotid ultrasonography because patients with severe Yes Refer to carotid disease m ay be candidates for prophylactic surgery. Consider carotid ultrasonography neurologist with autosom al dom inant polycystic kidney disease (ADPKD) and either a previous episode or a positive fam ily history of a ruptured No intracranial aneurysm m ust be screened with com puted tom ogra- High-risk Risk factor phy or m agnetic resonance im aging. No Proceed with evaluation Evaluation of Prospective Donors and Recipients 12. Peripheral vascular disease is com m only associated with coronary artery disease, cerebral vascular disease, or both. H owever, PVD itself m ay PVD unresponsive Yes Consider require intervention before transplantation to prevent infection and sepsis after transplan- to conservative invasive tation. In addition, som e patients m ay have aortoiliac disease severe enough to require management? Rarely, vascular disease is severe enough to m ake it difficult to find an artery suitable for the anastom osis of the allograft renal artery. Patients m ust be free of cognitive im pairm ents and able to give Psychosocial inform ed consent. M ost transplantation centers require patients with a history of alcohol evaluation or drug abuse to dem onstrate a period of supervised abstinence, generally 6 m onths or m ore. Sim ilarly, patients with a past history of m edication adherence poor enough to suspect that the im m unosuppressive regim en will be com prom ised m ay need to delay Free of limiting No transplantation until reasonable adherence can be dem onstrated. Yes History of limiting Yes Refer until medication resolved noncompliance? O besity 2 Yes increases the risks of surgery, and a weight reduction program BM I >35 kg/m before transplantation m ust be considered for very obese patients. O lder age is a relative contraindication to transplantation; however, No Consider weight it is difficult to precisely define an upper age lim it for all patients. H ypertension should be controlled before transplantation. Yes W hen control of hypertension is difficult, bilateral nephrectom y Age >65? No Proceed with evaluation 100 100 90 * * 90 * * * * 80 * * 70 80 60 50 70 40 Obese patients 60 30 * Nonobese patients 20 Obese patient grafts 10 50 Nonobese patient grafts 0 40 0 3 6 9 12 15 18 21 24 Age n t1/2 Time, mo 30 0–5 198 15. In this case-control study, 46 obese (body m ass index > 30 kg/m 2) recipients of cadav- 0 eric renal transplantation were com pared with nonobese controls 0 1 2 3 4 5 m atched for the following after transplantation: age, gender, dia- Years after transplantation betes, panel reactive antibody status, graft num ber, cardiovascular disease, date of transplantation, and im m unosuppression. Survival of patients and grafts was significantly less am ong obese patients FIGURE 12-19 com pared with controls (P < 0. Data from the following occurred m ore often in obese versus nonobese patients: United Network for Organ Sharing Scientific Registry indicate that delayed graft function, postoperative com plications, wound com - recipients over the age of 60 have slightly less allograft survival com- plications, and new-onset diabetes. No Proceed with FIGURE 12-21 evaluation Pancreas graft survival in recipients of pancreatic transplantation with simultaneous, no previous, and previous kidney transplantation. Survival rates of pancreatic grafts are best when pancreatic and FIGURE 12-20 kidney transplantations are perform ed at the sam e tim e. Patients with difficult to control the United N etwork for O rgan Sharing Scientific Registry. However, patients with diabetes who have a living donor are generally better off undergoing transplantation with the living donor kidney alone. Patients with symptomatic hyperparathyroidism or uncontrolled hypercalcem ia should be considered for parathy- roidectomy before transplantation. M edications that interfere with the metabolism of immunosuppressive agents such as cyclosporine should be substituted with appropriate alternatives, if possible, before transplantation.

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