By F. Elber. West Virginia University. 2019.
An enhancement of asynchronous evoked EPSPs oocyte expression system purchase 1mg propecia overnight delivery hair loss 2, this receptor shows rapid desensi- via 5-HT2A receptors would provide a possible synaptic tization and is blocked by 5-HT3 antagonists (e order 5mg propecia overnight delivery hair loss young women. Its sequence homology with contrast propecia 1 mg generic hair loss cure queentet, 5-HT itself does not promote the late component the nicotinic acetylcholine receptor (27%) and the 1 sub- of electrically evoked release except during the washout phase, unit of the GABAA receptor (22%) indicates that this 5- presumably because of opposing actions at 5-HT1 or other HT3-receptor clone is a member of the ligand-gated ion non-5-HT2A receptors (132). Typically, members of this superfam- posed location of various 5-HT-receptor subtypes and their ily are comprised of multiple subunits; however, only one interactions with other neurotransmitter receptors within 5-HT3-receptor subunit and an alternatively spliced variant cortical circuitry. Chapter 2: Serotonin 23 In hippocampus slices, 5-HT has been reported to in- the ability of these cells to respond to excitatory inputs with crease spontaneous GABAergic IPSPs, most likely through robust spike activity. A similar 5-HT3 receptor-mediated induction of The circadian rhythm in mammals is set by a pacemaker IPSCs has been reported in the neocortex (117). Whole- located primarily in the suprachiasmatic nucleus of the hy- cell patch-clamp recordings have confirmed a direct 5-HT3 pothalamus. This pacemaker activity can be maintained in receptor-mediated excitatory effect on hippocampal in- hypothalamic slices, in which suprachiasmatic neurons dis- terneurons independent of G-protein activation (139). Administration though fast, rapidly inactivating excitation has generally be- of 5-HT appears to produce a phase shift in this activity come accepted as characteristic of 5-HT3 receptors, (150) by acting on a receptor that may be of the 5-HT7 nondesensitizing responses have also been reported. This shift is mediated by stimulation of ade- sal root ganglion cells, a relatively rapid but noninactivating nylate cyclase because it is mimicked by increasing intracel- depolarizing response has been described that has a 5-HT3 lular cyclic adenosine monophosphate (cAMP) and blocked pharmacologic profile (140). In neurons of nucleus tractus by inhibiting protein kinase A (151). However, the precise solitarius brain slices, a postsynaptic depolarizing response mechanism by which 5-HT7 receptors act is not presently to 5-HT3 agonists has been observed that is not rapidly known because it is unclear whether suprachiasmatic neu- desensitizing (141). In addition to these postsynaptic effects, rons themselves express the 5-HT7 receptors (144). Further- a 5-HT receptor-mediated increase in Ca2 influx has more, the effect of 5-HT on the membrane properties of 3 been described in a subpopulation of striatal nerve terminals these cells has not been examined. Another electrophysiologic effect that may be mediated The first known protein G -coupleds 5-HT receptor, the 5- through 5-HT receptors that are positively coupled to ade- HT4 receptor, was identified on the basis of pharmacologic nylate cyclase is the enhancement of the hyperpolarizing- and biochemical criteria (e. The Ih channels, responses to adenylyl cyclase) (9). Subsequently, a receptor which are homologous to cyclic nucleotide-gated channels with matching pharmacologic and other properties was in specialized sensory neurons, are positively modulated by cloned and found to be expressed in various regions of the cAMP (153,154). An increase in Ih tends to prevent exces- brain (143). Two other 5-HT receptors positively coupled sive hyperpolarization and increase neuronal excitability. Because their pharma- a number of regions of the brain, including the thalamus cology differed from that of the previously described 5-HT4 (155), prepositus hypoglossi (156), substantia nigra zona site, they were designated as 5-HT6 and 5-HT7 receptors compacta (157), and hippocampus (158), 5-HT has been (144–146). At this time, electrophysiologic studies are avail- shown to enhance Ih through a cAMP-dependent mecha- able only for the 5-HT4 and 5-HT7 receptors and are de- nism. Results of a pharmacologic analysis with multiple scribed below. Recently, the first drug with selectivity Binding studies using a selective 5-HT4 ligand indicate that toward the 5-HT7 receptor was shown to block activation 5-HT4 receptors are present in several discrete regions of of adenylyl cyclase by 5-HT agonists in guinea pig hippo- the mammalian brain, including the striatum, substantia campus (33). The increasing availability of such selective nigra, olfactory tubercle, and hippocampus (147). Because drugs should greatly enhance the electrophysiologic evalua- these regions also express 5-HT4-receptor mRNA, it appears tion of G -coupleds 5-HT receptors. The best studied of these regions is the hippocampus, in which both biochemical and electro- INTRACELLULAR SIGNAL TRANSDUCTION physiologic studies have provided a detailed picture of the PATHWAYS actions of 5-HT at 5-HT4 receptors. Electrophysiologic Multiple Signaling Pathways: G Proteins studies show that 5-HT4 receptors mediate an inhibition and Second Messengers of a calcium-activated potassium current that is responsible for the generation of a slow after-hyperpolarization in hip- Multiple intracellular signaling pathways constitute a com- pocampal pyramidal cells of the CA1 region (74,148,149). Inhibition of adenylate cyclase 24 Neuropsychopharmacology: The Fifth Generation of Progress was the first intracellular pathway to be described for campal homogenates suggests that both the 5-HT4 and 5- Gi/o protein-coupled receptors, such as the 5-HT1A recep- HT7 receptors are involved in cAMP formation (adenylate tor. However, it is now clear that these receptors regulate cyclase isoform unknown) in the hippocampus (164). Inter- multiple signaling pathways and effector molecules (Fig. Although all these signals are sensitive to pertussis G11,G14, and G15/16) activate phospholipase C in a pertussis toxin, so that Gi/o proteins are implicated, they may be toxin-insensitive manner. Activation of phospholipase C mediated by distinct G protein complexes. For example, was the first signal transduction mechanism identified for coupling to GIRK channels is mediated by subunits the 5-HT2-receptor family and is essentially universal. This released from Gi (and possibly Go) proteins, whereas inhibi- probably reflects the wide distribution of G and the 2 q/11 tion of Ca channels is mediated by subunits released functional redundancy of these two G proteins. The profile of signaling molecules varies HT receptor has been shown to couple in a pertussis 2C from cell to cell, offering diverse signaling possibilities and toxin-sensitive manner to G in Xenopus oocytes (e. In con- receptor activation of phospholipase C is cell-type depen- trast, recent evidence suggests that phospholipase C activa- dent; this signal is mediated by G protein subunits and tion in a native setting (choroid plexus) is mediated entirely thus requires the presence of a -regulated phospholipase by G coupling (167). The subunits, generated by dissociation of to G with subsequent cytoskeletal rearrangement has been 13 the heterotrimeric Gi protein, also activate the type 2 iso- recently described in a transfected cell line (168). This activation is conditional, evidence suggests that 5-HT2A and 5-HT2C receptors cou- dependent on the coactivation by G s (i. Phospholipase A2 is a well-characterized inde- ing actions of G i and G do not offset each other. The pendent signal transduction pathway that leads to arachi- answer may lie in the details. In addition to the large family donic acid, with subsequent prostaglandin and leukotriene of G proteins (21 subunits, 5 subunits, and 11 sub- formation (169). Most of these in vascular smooth muscle and is also thought to be inde- molecules are found in the central nervous system. The G pendent of phospholipase C activation (170,171). The 5- protein that contributes activation of type 2 adenylate HT2Areceptor increases phospholipase D activity via a small cyclase is G i1 or G i2 heterotrimer (160), whereas all three G-protein ARF (adenosine diphosphate ribosylation factor) G i subunits ( i3 i2 i1) have the ability to inhibit pathway, with protein kinase C activation being the princi- adenylate cyclase types 5 and 6 (161). This type brain-derived neurotrophic factor expression in hippocam- of interaction has been shown to occur in brain, in which pus (173,174). In addition, a 5-HT2A receptor-mediated G -linkedi receptors enhance -adrenergic responses (162); increase in transforming growth factor- 1, secondary to a similar interaction may take place in cells that coexpress a 5-HT receptor family member with one of the 5-HT protein kinase C activation, has been described (175). The 1A receptors (5-HT , 5-HT , or 5-HT ) linked to activation 5-HT2A and 5-HT2C receptors elicit region-specific in- 4 6 7 of adenylate cyclase. Extensive, complex cross-talk between the 5-HT2A ond messenger pathways defined in brain, the 5-HT recep- and 5-HT2B receptor and the 5-HT1B/D receptor has been 4 tor was one of the last 5-HT receptors to be cloned (143). In transfected cells, the 5-HT6 receptor couples tion (177).
When given to a to the brain too gradually and without the transient but group of smokers not trying to quit permanently buy propecia from india hair loss x chromosome, bupropion rewarding brief surges in brain nicotine levels from puffing decreased some withdrawal symptoms but had no effect on on a cigarette (5 cheap generic propecia canada hair loss 10 months after baby,19) buy propecia 1 mg lowest price hair loss 12776 dixie highway. Nicotine nasal sprays or inhalers more craving (86). Bupropion was a more cost-effective therapeu- closely approximate smoking in this respect, but only par- tic agent for tobacco addiction than NRT (68). An inhaled nicotine aerosol would, in princi- Other Therapies With and Without Utility ple, be an ideal substitute nicotine delivery system, but de- spite many attempts, a practical inhaled aerosol system pro- Clonidine shares some pharmacologic effects of bupropion viding the control over dose offered by a tobacco cigarette and tricyclic antidepressants. The Cochrane review of six has not been brought to market. Non–Nicotine Replacement Sensory stimulants mimic mouth and airway sensory re- Pharmacotherapies sponses to smoking that become associated with the phar- The consequences of neuroadaptive changes in brain func- macologic effects of nicotine and thus become reinforcers. Pharmacotherapies mimicking nico- toms over the short term (71). Pharma- nists could be useful to aid in smoking cessation (22). Nicotinic receptor antagonism offers creases desire to smoke (38). Although treatment with anxiolytics naltrexone on ad libitum smoking over brief periods in a did not improve outcome, antidepressants, bupropion, and laboratory were inconsistent, but some smokers smoked less. The mecha- A clinical trial compared naltrexone, 50 mg daily for 12 nisms by which antidepressant drugs benefit smoking cessa- weeks, or placebo, with or without transdermal nicotine tion are yet to be determined. Only transdermal nicotine increased abstinence rates. Transdermal FUTURE RESEARCH nicotine reduced craving and cigarette smoking in smokers who did not quit. Another As nicotinic cholinergic receptor subtype–specific agonists 4-week trial of naltrexone or placebo found no difference and antagonists are developed, more specific treatments for in smoking 6 months later (93). Thus, the clinical trial data nicotine addiction in subtypes of smokers should result (49). A nicotine antagonist mecamylamine has been in- Adolescent smoking initiation rates remain high (49). Mecamylamine started before quitting and is perhaps increasing (57). Although we understand much about nicotine addiction (2), we still do not know smoking and continued afterwards appeared useful in two enough to prevent people from becoming addicted or how studies (94). Combined use of mecamylamine and nicotine best to treat highly dependent tobacco users (77). Antibodies have been induced by immuniza- phrenia (43), and other drug dependence is important. Study of hormonal and psychosocial mechanisms will help Immunized animals had reduced brain nicotine concentra- us to understand gender differences in nicotine addiction tions and reduced behavioral and cardiovascular effects after (99). Longitudinal studies of children of mothers who intravenous nicotine (68). Whether immunization alters the smoke, with better measures of smoke exposure in utero reinforcing effects of nicotine remains to be determined. Although no longer marketed in the United States, lobeline is available elsewhere. No clinical trials had more CONCLUSION than a 6-month follow-up. The drug was judged unproven by the Cochrane review (75,91). Research since the early 1980s has expanded our under- ACTH has been suggested to aid smoking cessation, standing of nicotine addiction. Now the challenge is to based on the notion that nicotine increases ACTH and cor- translate knowledge of the biology of nicotine addiction tisol release and that during nicotine withdrawal, there may into pharmacotherapies and other therapeutics addressing be a state of hypoadrenocorticism. Uncontrolled trials with individual differences in addicted smokers. To do so will small numbers of smokers given a few ACTH injections require the development of new drugs, better understanding during the first week after quitting reported high quit rates of existing ones, and wisdom needed to match optimal ther- or decreased smoking, but without controlled clinical trials, apies to individual smokers. Much the same could be said ACTH must still be considered unproven (71). Silver acetate has long been available as an over-the-coun- ter smoking deterrent in the form of chewing gum, lozenges, ACKNOWLEDGMENTS and spray. A reaction with cigarette smoke produces an unpleasant metallic taste, the basis for this aversive therapy. Preparation of this manuscript was supported in part by US Several clinical trials reported short-term efficacy, particu- Public Health Service grant nos. DA02277, DA12393, and larly in less addicted smokers (71). Whenever the urge to DA00053 from the National Institute on Drug Abuse, Na- smoke is great, it is easy to stop silver acetate use, so it tional Institutes of Health. REFERENCES The effectiveness of other aversion therapies, acupunc- 1. Adolescent nicotine ture, hypnotherapy, and exercise was at best considered un- exposure causes persistent upregulation of nicotinic cholinergic certain (75,91). Chapter 107: Therapeutics for Nicotine Addiction 1541 2. A clinical practice guide- the role of specific genetic factors in cigarette smoking. Health line for treating tobacco use and dependence: a US Public Health Psychol 1999;18:14–20. Smoking withdrawal bacco smoking increases the density of ( )-[3H]nicotine binding dynamics in unaided quitters. Department of Health and Human Services, Public Health Ser- 25. The health consequences of smoking: nicotine addiction: a report on (3H)nicotine binding in human postmortem brain. Pharmacokinetics and metabolism of brain nicotinic receptors are altered by chronic nicotine and mec- nicotine and related alkaloids. Psychopharmacol- and in relation to neuroleptic medication. Hippocampal synaptic of nicotine dependence in adolescents. Tobacco Control 2000;9: transmission enhanced by low concentrations of nicotine. Physiological diversity of nicotinic ace- subcutaneous nicotine improves information processing in non- tylcholine receptors expressed by vertebrate neurons. A common genetic defect and drug use in eight- to sixteen-year-old twins: the Virginia in nicotine metabolism decreases risk for dependence and lowers Twin Study of Adolescent Behavioral Development.
International Clinical Trials Registry Platform (ICTRP) Geneva order genuine propecia on line hair loss cure news 2013, World Health Organization buy propecia hair loss in men 80, 2012 order propecia 1mg with mastercard hair loss in men makeup. World report on knowledge for better health − strengthening health systems. Sound choices: enhancing capacity for evidence-informed health policy. Disease control priorities in developing countries, 2nd ed. Research on implementation of interventions in tuberculosis control in low- and middle-income countries: a systematic review. Implementing new health interventions in developing countries: why do we lose a decade or more? Human Resources for Health Development Journal, 2000,4:106-110.. Assessing country-level eforts to link research to action. Bulletin of the World Health Organization, 2006,84:620-628. How can we increase translation of research into practice? Making an impact: a preferred framework and indicators to measure returns on investment in health research. The use of research evidence in public health decision making processes: systematic review. Translating research to practice: putting “what works” to work. Burlington, MA, Jones & Bartlett Learning, 2011:309–334. Contribution mapping: a method for mapping the contribution of research to enhance its impact. Efective implementation of research into practice: an overview of systematic reviews of the health literature. Applying difusion of innovation theory to intervention development. Implementation research evidence uptake and use for policy-making. SUPPORT Tools for evidence-informed health Policymaking (STP). Health Research Policy and Systems, 2009,7:Suppl 1:I1. Guidance for evidence-informed policies about health systems: assessing how much confdence to place in the research evidence. Guidance for evidence-informed policies about health systems: rationale for and chal- lenges of guidance development. Making health policy (Understanding public health), 2nd ed. Strategy on health policy and systems research: changing mindsets. Blueprints for informed policy decisions: a review of laws and policies requiring routine evaluation. Oslo, Kunnskapssenteret (Norwegian Knowledge Centre for the Health Services), 2012. The impact of universal coverage schemes in the developing world: a review of the existing evidence. Health research − essential link to equity in development. Research and development to meet health needs in developing countries: strengthening global fnancing and coordina- tion. Report of the consultative expert working group on research and development: fnancing and coordination. Health policy/systems research, realizing the initiative − a background document to an international consul- tative meeting at Lejondal, Sweden April 10–12. Global strategy and plan of action on public health, innovation and intellectual property. Strengthening mechanisms to prioritize, coordinate, fnance, and execute R&D to meet health needs in developing countries. The portal for rare diseases and orphan drugs (web site). Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans. The New England Journal of Medicine, 2011,364:2293-2304. Development of a group A meningococcal conjugate vaccine, MenAfriVac(TM). National health research system mapping in 10 Eastern Mediterranean countries. National health research systems in Pacifc island countries. Manila, World Health Organization Regional Ofce for the Western Pacifc, 2009. A new pathway for the regulation and governance of health research. Key points Drawing on previous chapters, Chapter 5 highlights the dominant themes of the report, and proposes a set of actions to guide the conduct of research and to support research for universal health coverage. Tere are a number of important considerations regarding the conduct of research with a focus on national health research systems. For instance: ■ Research is not merely an essential tool for improving health services; it is also a source of inspiration for public health. The people who do the research are the foremost asset in the research enterprise and should be in the front line of capacity-strengthening. Still greater effort is needed to translate evidence into policy and practice. Actions to support research nationally and internationally include: ■ monitoring (e. Te strategy aims to cultivate the highest quality research in order to deliver the greatest health benefts to the maximum number of people. Chapter 1 identifed two kinds of questions about research for univer- sal health coverage. Te frst set of questions is about improving health and well-being – how to advance towards universal coverage, and how improved coverage protects and improves health. Te second set of questions is about measurement – of the indicators that can be used as measures of the coverage of essential health services and fnancial risk protection in any setting.
The severe hyperglycem ia of N KH buy propecia 1 mg on-line hair loss cure 7th, Volume depletion Mild/moderate Severe often coupled with hypernatrem ia purchase propecia 5 mg on-line hair loss prevention mens health, increases serum osm olality buy cheap propecia 5mg on-line hair loss lyme disease, Renal failure (most com- Mild, inconstant Always present monly of prerenal nature) thereby causing the characteristic functional abnorm alities of the Severe neurologic Rare Frequent central nervous system. Depression of the sensorium , som no- abnormalities (coma in 25–50%) lence, obtundation, and com a, are prom inent m anifestations of Subsequent therapy with Always Not always N KH. The degree of obtundation correlates with the severity of insulin serum hypertonicity. Glucose < 800 mg/dL > 800 mg/dL Ketone bodies ≥ 2 + in 1:1 dilution <2+ in 1:1 dilution Effective osmolality < 340 mOsm/kg > 340 mOsm/kg pH Decreased Normal [HCO– ] Decreased Normal + 3 [Na ] Normal or low Normal or high [K+] Variable Variable M ANAGEM ENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEM IA Insulin Fluid Administration Potassium repletion Alkali 1. Add 100 U of regular insulin to 1 L of normal saline (0. Shock present: Normal saline and plasma if urinary output is at least total CO2 < 5 mmol/L; in hyper- expanders (ie,albumin, low molecular 30–60 mL/h and plasma [K+] chloremic acidosis, add NaHCO3 3. Give double rate of infusion if the blood glucose level does not decrease in a 2-h interval (expected decrease weight dextran) at maximal possible rate < 5 mEq/L. Give SQ dose (10–30 U) of regular insulin when ketosis is corrected and the blood glucose level decreases to glucose level decreases to 250 mg/dL. CO2— carbon dioxide; IV— intravenous; K+— potassium ion; NaCl— sodium chloride; NaHCO3— sodium bicarbonate; SQ— subcutaneous. FIGURE 6-24 Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) NKH, in which ketoacidosis is generally absent. Administration of insulin is the cornerstone of manage- deficit is generally severe in patients with NKH, many of whom have ment for both DKA and NKH. Replacement of the prevailing water, preexisting heart disease and are relatively old, safe fluid replacement sodium, and potassium deficits is also required. Alkali are adminis- may require monitoring of central venous pressure, pulmonary capil- tered only under certain circumstances in DKA and virtually never in lary wedge pressure, or both [1,17,18]. These disorders are character- Plasma bicarbonate 14–18 mEq/L Variable, may be 15–20 mEq/L ized by norm al anion gap (hyperchlorem ic) ion concentration < 10 mEq/L m etabolic acidosis. The defects responsible Plasma chloride Increased Increased Increased for im paired acidification give rise to three ion concentration distinct syndrom es known as proxim al RTA Plasma potassium Mildly decreased Mildly to Mildly to severely increased (type 2), classic distal RTA (type 1), and ion concentration severely decreased hyperkalem ic distal RTA (type 4). Plasma anion gap Normal Normal Normal Glomerular filtration rate Normal or Normal or Normal to slightly decreased slightly decreased moderately decreased Urine pH during acidosis ≤5. Excluding the case of carbonic anhydrase Sporadic Genetically transmitted Medullary cystic disease inhibitors, the nature of the acidification defect responsible for bicarbonate (H CO ) wastage rem ains unknown. K+— potassium Cystinosis Hyperparathyroidism ion; CA— carbonic anhydrase. Causes of proxim al renal tubular Pyruvate carboxylate deficiency acidosis (RTA) (type 2). An idiopathic form and cystinosis are the Metachromatic leukodystrophy m ost com m on causes of proxim al RTA in children. In adults, m ul- Methylmalonic acidemia tiple m yelom a and carbonic anhydrase inhibitors (eg, acetazo- Conditions associated with chronic hypocalcemia lam ide) are the m ajor causes. Ifosfam ide is an increasingly and secondary hyperparathyroidism com m on cause of the disorder in both age groups. Vitamin D deficiency or resistance Vitamin D dependence 6. Potential cellular defects underlying classic Sickle cell anemia Cyclamate distal RTA include a faulty luminal hydrogen ion–adenosine triphos- Marfan syndrome Balkan nephropathy phatase (H+ pump failure or secretory defect), an abnormality in the Carbonic anhydrase I deficiency basolateral bicarbonate ion–chloride ion exchanger, inadequacy of or alteration Tubulointerstitial diseases carbonic anhydrase activity, or an increase in the luminal membrane Osteopetrosis with carbonic Chronic pyelonephritis permeability for hydrogen ions (backleak of protons or permeability anhydrase II deficiency Obstructive uropathy defect). M ost of the causes of classic distal RTA likely reflect a secre- Medullary cystic disease Renal transplantation tory defect, whereas amphotericin B is the only established cause of a Neuroaxonal dystrophy Leprosy permeability defect. The hereditary form is the most common cause Hyperoxaluria of this disorder in children. This syndrom e represents the m ost II, or abnorm al aldosterone synthesis. Aldosterone resistance can com m on type of RTA encountered in adults. The characteristic reflect the following: blockade of the m ineralocorticoid receptor; hyperchlorem ic m etabolic acidosis in the com pany of hyperkalem ia destruction of the target cells in the collecting tubule (tubulointer- em erges as a consequence of generalized dysfunction of the collect- stitial nephropathies); interference with the sodium channel of the ing tubule, including dim inished sodium reabsorption and im paired principal cell, thereby decreasing the lum en-negative potential dif- hydrogen ion and potassium secretion. The resultant hyperkalem ia ference and thus the secretion of potassium and hydrogen ions causes im paired am m onium excretion that is an im portant contri- (voltage-m ediated defect); inhibition of the basolateral sodium ion, bution to the generation of the m etabolic acidosis. The causes of potassium ion–adenosine triphosphatase; and enhanced chloride this syndrom e are broadly classified into disorders resulting in ion perm eability in the collecting tubule, with consequent shunting aldosterone deficiency and those that im pose resistance to the of the transepithelial potential difference. Aldosterone deficiency can arise from com bined aldosterone deficiency and resistance. W henever possible, cause- specific m easures should be at the center of treatm ent of m etabolic acidosis. In the presence of severe acidem ia, such m easures should be supplem ented by judicious adm inistration of sodium bicarbon- Alkali therapy for severe ate. The goal of alkali therapy is to return the blood pH to a safer Cause-specific measures acidemia (blood pH<7. Anticipated benefits and potential risks of alkali therapy are depicted here. Benefits Risks • Prevents or reverses acidemia- • Hypernatremia/ related hemodynamic compromise. The mm Hg resultant alkalem ia dam pens alveolar ventilation and leads to the 40 50 secondary hypercapnia characteristic of the disorder. Available observations in hum ans suggest a roughly linear relationship between the steady-state increase in bicarbonate concentration 40 and the associated increm ent in the arterial carbon dioxide ten- 30 sion (PaCO 2). Although data are lim ited, the slope of the steady- - state PaCO 2 versus [H CO 3] relationship has been estim ated as 30 about a 0. The value of this slope is virtually identical to Normal that in dogs that has been derived from rigorously controlled 20 observations. Em piric observations in hum ans have been used for construction of 95% confidence intervals for graded 10 degrees of m etabolic alkalosis represented by the area in color in 10 the acid-base tem plate. The black ellipse near the center of the figure indicates the norm al range for the acid-base param eters. Assum ing a steady state is present, values falling within the area in color are consistent with but not diagnostic of sim ple 6. Acid-base values falling outside the area in Arterial blood pH color denote the presence of a m ixed acid-base disturbance. Two Alkali gain Calcium supplements Enteral crucial questions m ust be answered when Absorbable alkali + evaluating the pathogenesis of a case of Nonabsorbable alkali plus K exchange resins m etabolic alkalosis. Answering this question addresses the pathophysiologic events that m aintain Vomiting the m etabolic alkalosis. Gastric H+ loss Suction Villous adenoma Intestinal Congenital chloridorrhea Chloruretic diuretics Renal Inherited transport defects Mineralocorticoid excess + Posthypercapnia H shift + K depletion Reduced GFR Mode of perpetuation? Increased – renal acidification Cl responsive defect Cl–resistant defect FIGURE 6-32 Baseline Vomiting Maintenance Correction Changes in plasm a anionic pattern and body electrolyte balance Low NaCl and KCl intake High NaCl and KCl intake 45 during developm ent, m aintenance, and correction of m etabolic alkalosis induced by vom iting. Loss of hydrochloric acid from the 40 stom ach as a result of vom iting (or gastric drainage) generates the 35 hypochlorem ic hyperbicarbonatem ia characteristic of this disorder. During the generation phase, renal sodium and potassium excre- 30 tion increases, yielding the deficits depicted here. Renal potassium 25 losses continue in the early days of the m aintenance phase.