By V. Hanson. Reinhardt College.

FIGURE 7-14 THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS The side effect profile of -adrenergic antagonists discount 20 mg tadalis sx overnight delivery. The side effect profile of beta- blockers is related to the specific blockade Side effects Mechanisms of 1 or 2 receptors tadalis sx 20mg cheap. This table lists the m ore com m on side effects and their pro- Bronchospasm Blockade of 2-adrenergic receptors; increased airway resistance posed m echanism (s) of action [6,9]. Bradycardia Blockade of atrial 1/ 2-adrenergic receptors; decrease in heart rate Congestive heart failure; decrease in Blockade of ventricular 1-adrenergic receptors exercise tolerance Claudication Blockade of peripheral vascular 2-adrenergic receptors Constipation, dyspepsia Blockade of gastrointestinal 1/ 2-adrenergic receptors; decreased motili- ty and relaxation of sphincter tone Central nervous system manifestations Blockade of CNS 1/ 2-adrenergic receptors (sleep disturbances, depression) Sexual dysfunction (impotence, Unknown decrease libido) Impaired glucose tolerance Impaired 2-adrenergic–mediated islet cell insulin secretion; increase hepatic glucose, and/or decrease insulin-stimulated glucose disposal Prolonged insulin-induced Block epinephrine-mediated counterregulatory mechanisms hypoglycemia Hepatocellular necrosis Labetalol only, idiosyncratic reaction W ithdrawal syndrome Acute overshoot in heart rate with increased myocardial oxygen demand Unstable angina due to increase in number and/or sensitivity of -adrenergic receptors Myocardial infarction during chronic blockade Dyslipidemia Increased -adrenergic tone; reduced lipoprotein lipase activity Increased total triglycerides Decreased high-density lipoproteins cholesterol Pharmacologic Treatment of Hypertension 7. Central 2-adrenergic agonists cross the blood-brain barrier 2 and stim ulate 2-adrenergic receptors in the vasom otor center of the brain stem [6,9]. The guanabenz net effect is a reduction in norepinephrine release. The central -adrenergic agonist clonidine 2 Stimulates Stimulates also binds to im idazole receptors in the brain; activation of these receptors inhibits central sym pathetic outflow. Central 2-adrenergic agonists m ay also stim ulate the peripheral 2- Central α2 I1-Imidazoline adrenergic receptors that m ediate vasoconstriction; this effect predom inates at high plasm a adrenoceptor receptor drug concentrations and may precipitate an increase in blood pressure. The usual physiologic effect is a decrease in peripheral resistance and slowing of the heart rate; however, output is either unchanged or m ildly decreased. Preservation of cardiovascular reflexes prevents postural hypotension. NTS RVLM Nucleus Rostral tractus ventrolateral solitarii medulla Inhibition of central sympathetic activity Blood pressure reduction CENTRAL 2-ADRENERGIC ANTAGONISTS Generic (trade) name First dose, mg Usual daily dose Maximum daily dose Duration of action -Methyldopa (G) (Aldomet) 250 250–1000 mg bid 3000 24–48 h Clonidine (G) (Catapres) 0. The antihypertensive effect results from is adm inistered transderm ally, therapeutic plasm a levels are achieved accumulation of 2-adrenergic receptors, displacing and competing with within 2 to 3 days. M ethyldopa is absorbed poorly Guanabenz, a guanidine derivative, is highly selective for central (<50% ); peak plasm a concentrations occur in 2 to 4 hours. It is absorbed well (>75% ); peak plasm a metabolized in the liver and excreted in the urine mainly as the inactive levels are reached in 2 to 5 hours. The plasma half-life of methyldopa (1 to 2 hours) hepatic metabolism; less than 2% is excreted unchanged in the urine. Clonidine, an im idazoline derivative, acts by stim ulating either Guanfacine is a phenylacetyl-guanidine derivative with a longer central 2-adrenergic receptors or imidazole receptors. It is absorbed well (>90% ); peak be administered orally or by a transdermal delivery system (TTS). The drug is W hen given orally, it is absorbed well (>75% ); peak plasm a con- primarily metabolized in the liver. Guanfacine and its m etabolites centrations occur in 3 to 5 hours. Clonidine is m etabolized m ainly are excreted prim arily by the kidneys; 24% to 37% is excreted as in the liver; fecal excretion ranges from 15% to 30% , and 40% to unchanged drug in the urine. The plasm a half-life (15 to 17 hours) 60% is excreted unchanged in the urine. In patients with renal is not prolonged in patients with renal insufficiency [6,9]. The side 2-ADRENERGIC AGONISTS effect profile of these agents is diverse [6,9]. Side effects Mechanisms Sedation/drowsiness Stimulation of 2-adrenergic receptors in the brain Xerostoniia (dry mouth) Centrally mediated inhibition of cholinergic transmission Gynecomastia in men, galactorrhea Reduced central dopaminergic inhibition in women of prolactin release (methyldopa only) Drug fever, hepatotoxicity, positive Long-term tissue toxicity Coombs test with or without (methyldopa only) hemolytic anemia Sexual dysfunction, depression, Stimulation of 2-adrenergic receptor decreased mental acuity in the brain “Overshoot hypertension” Acute excessive sympathetic discharge Restlessness in the face of chronic downregulation Insomnia of central 2-adrenergic receptors in Headache an inhibitory circuit during chronic Tremor treatment when treatment is stopped Anxiety Nausea and vomiting A feeling of impending doom Indicates blockade FIGURE 7-18 Brain stem Central and peripheral adrenergic neuronal blocking agents. Rauwolfia alkaloids act both within the central nervous system and in the peripheral sympathetic nervous system [6,9]. They effectively Preganglionic deplete stores of norepinephrine (N E) by com petitively inhibiting neuron the uptake of dopam ine by storage granules and by preventing the Ganglion incorporation of norepinephrine into the protective chrom affin granules; the free catecholam ines are destroyed by m onoam ine oxidase. The predom inant pharm acologic effect is a m arked Postganglionic decrease in peripheral resistance; heart rate and cardiac output adrenergic are either unchanged or m ildly decreased. NE nerve ending NE NE β1 α1 α2 Vascular smooth muscle cells Pharmacologic Treatment of Hypertension 7. Reserpine pressure is m axim ally lowered 2 to 3 weeks after beginning therapy. It is absorbed poorly Reserpine is metabolized by the liver; 60% of an oral dose is recovered (approxim ately 30% ); peak plasm a concentrations occur in 1 to 2 in the feces. Less than 1% is excreted in the urine as unchanged drug. Catecholam ine depletion begins within 1 hour of drug The plasm a half-life (12 to 16 days) is not prolonged in patients adm inistration and is m axim al in 24 hours.

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Increases in arterial pressure lead to natriuresis (called pressure natriuresis) order tadalis sx 20 mg with visa, which reduces blood volume purchase 20 mg tadalis sx free shipping. A decrease in blood volume reduces venous return to the heart and C H A P T ER cardiac output. Urinary volume excretion exceeds dietary intake until the blood volume decreases sufficiently to return the blood pressure to the set point. Disorders of sodium balance resulting from primary renal sodium retention lead only to modest volume expansion without edema because increases in M AP quickly return sodium excretion to baseline 2 2. Examples of these disorders include chronic renal failure (see Chapter 1). Disorders of sodium balance are disorders of and states of mineralocorticoid excess. This construct has a physiologic basis because a return to sodium balance is hypertension. Disorders of sodi- water balance and sodium balance can be controlled separately um balance that result from secondary renal sodium retention, and by distinct hormonal systems. It should be emphasized, as in congestive heart failure, lead to more profound volume however, that disorders of sodium balance frequently lead to or expansion owing to hypotension. In mild to moderates cases, are associated with disorders of water balance. This is evident volume expansion eventually returns the M AP to its set point; from Figure 2-24 in which hyponatremia is noted to be a sign the price of sodium balance in this case is edema. In more severe of either ECF volume expansion or contraction. Thus, the dis- cases, volume expansion never returns blood pressure to nor- tinction between disorders of sodium and water balance is use- mal, and renal sodium retention is unremitting. In still other sit- ful in constructing differential diagnoses; however, the close uations, such as nephrotic syndrome, volume expansion results interrelationships between factors that control sodium and from changes in both the renal set point and body volume dis- water balance should be kept in mind. In this case, the price of sodium balance may be both The figures herein describe characteristics of sodium home- edema and hypertension. In each of these cases, renal sodium ostasis in normal persons and also describe several of the regu- (and chloride) retention results from a discrepancy between the latory systems that are important participants in controlling existing M AP and the renal set point. Next, mechanisms of sodium transport The examples listed previously emphasize that disorders of along the nephron are presented, followed by examples of dis- sodium balance do not necessarily abrogate the ability to orders of sodium balance that illuminate current understanding achieve sodium balance. W hen balance is defined as the equa- of their pathophysiology. Recently, rapid progress has been tion of sodium intake and output, most patients with ECF made in unraveling mechanisms of renal volume homeostasis. Intracellular signaling m echanism s expense of expanded or contracted ECF volume. The failure to responsible for their effects have been characterized. The renal achieve sodium balance at normal ECF volumes characterizes transport proteins that mediate sodium reabsorption also have these disorders. The remaining challenges are to Frequently, distinguishing disorders of sodium balance from integrate this information into models that describe systemic disorders of water balance is useful. According to this scheme, dis- volume homeostasis and to determine how alterations in one or orders of water balance are disorders of body osmolality and usu- more of the well-characterized systems lead to volume expan- ally are manifested by alterations in serum sodium concentration sion or contraction. Normal Extracellular Fluid Volume Homeostasis FIGURE 2-1 Adult male Fluid volum es in typical adult m en and Extravascular Adult female wom en, given as percentages of body (15%) weight. In m en (A), total body water typi- ECF volume Extravascular cally is 60% of body weight (Total body (20%) (11%) ECF volume Plasma (5%) water = Extracellular fluid [ECF] volum e + (15%) Blood volume Plasma (4%) Intracellular fluid [ICF] volum e). The ECF (9%) RBC (4%) Blood volume RBC (3%) volum e com prises the plasm a volum e and (7%) the extravascular volum e. The ICF volum e ICF volume com prises the water inside erythrocytes ICF volume (40%) (35%) (RBCs) and inside other cells. The blood volum e com prises the plasm a volum e plus A B the RBC volum e. Thus, the RBC volum e is a unique com ponent of ICF volum e that contributes directly to cardiac output and blood pressure. Typically, water com prises a sm aller percentage of the body weight in a wom an (B) than in a m an; thus, when expressed as a percentage of body weight, fluid volum es are sm aller.

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Bergstrom J tadalis sx 20mg discount, Alvestrand A tadalis sx 20mg fast delivery, Bucht H, Guttierrez A: Progression of chronic angiotensin system : a key to understanding blood pressure regulation. Katholi RE, N afilan AJ, O paril S: Im portance of renal sym pathetic tone in the developm ent of DO CA-salt hypertension in the rat. Brazy PC, Stead W W , Fitzwilliam JF: Progression of renal insufficiency: H ypertension 1980, 2:266–273. JNC Committee: Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, M D: National Institutes of Health Publication; 1997. Kidney Int improvement in kidney function and causes cellular and ductopenic 1997; 51:244–252. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin- 12. N Engl J M ed duction in rats with renal m ass reduction. Rees DD, Palm er RM J, M oncada S: Role of endothelium -derived nitric enzym e inhibitor benazepril on the progression of chronic renal insuf- oxide in the regulation of blood pressure. Am J gression to end-stage renal failure in proteinuric, non-diabetic chronic Physiol 1991, 261:F1033–F1037. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzym e the renal response to L-arginine in hum an kidney transplant recipients. Pohl he major issues in approaching patients with renal artery steno- sis relate to the role of renal artery stenosis in the management Tof hypertension, ie, “renovascular hypertension,” and to the potential for vascular compromise of renal function, ie, “ischemic nephropathy. M uch discussion has focused on the pathophysiology of renovascular hyper- tension, the renin angiotensin system, diagnostic tests to detect pre- sumed renovascular hypertension, and the relative merits of surgical renal revascularization (SR), percutaneous transluminal renal angio- plasty (PTRA), and drug therapy in managing patients with renal artery stenosis and hypertension. H emodynamically significant renal artery stenosis, when bilateral or affecting the artery to a solitary func- tioning kidney, can also lead to a reduction in kidney function (ischemic nephropathy). This untoward observation may be reversed by interventive maneuvers, eg, surgical renal revascularization, PTRA, or renal artery stenting. The syndrome of “ischemic renal disease” or “ischemic nephropathy” now looms as an important clinical condi- tion and has attracted the fascination of nephrologists, vascular sur- geons, and interventional cardiologists and radiologists. The detection of renal artery stenosis in a patient with hyperten- sion usually evokes the assum ption that the hypertension is due to the renal artery stenosis. H owever, renal artery stenosis is not synony- m ous with “renovascular hypertension. The vast m ajority of patients with ASO -RAS who have hypertension have essential hypertension, not renovascular hyperten- sion. These hypertensive patients with ASO -RAS are rarely cured of their hypertension by interventive procedures that either bypass or 3 3. Thus, it is critical to distinguish chronic subcapsular hematoma, and unilateral ureteral obstruction between the anatom ic presence of renal artery stenosis, in may also be associated with hypertension that is relieved when which a stenotic lesion is present but not necessarily causing the affected kidney is removed. These clinical analogues of the hypertension, and the syndrom e of renovascular hypertension experimental Page kidney reflect the syndrome of renovascular in which significant arterial stenosis is present and sufficient to hypertension (RVHT), but without main renal artery stenosis. In the exam ples of RVH T without m ain renal artery stenosis. FIGURE 3-1 CLASSIFICATION OF RENAL Classification of renal artery disease. Two m ain types of renal arterial lesions form the ARTERY DISEASE anatom ic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO -RAD) is the most common cause of renal artery disease, accounting for 60% to 80% of all renal artery lesions. The fibrous dysplasias are the other m ajor category of renal artery disease, Disease Incidence, %* and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm and arteriovenous m alform ation are rarer types of renal artery disease.

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These allow an estimation of the absolute and analysis buy 20mg tadalis sx. The analytic framework chosen depends on the relative net social benefit of intervention 20 mg tadalis sx amex. This is calculated perspective of the analysis and the economic questions posed as the monetary value of the consequences of an intervention (19). Any health or social care intervention with a net social benefit greater than zero (i. Cost-Minimization Analysis In a cost-minimization analysis, the direct costs of two or KEY COMPONENTS OF AN ECONOMIC more health care interventions are compared. This form of EVALUATION analysis does not include a formal economic comparison of Perspective of Analysis the outcomes of health and social care. However, the evi- dence that patient outcomes do not differ between interven- Economic studies should consider all costs and outcomes tions must be clear and reliable. If such evidence is not that are a consequence of the illness (cost of illness) or the 1270 Neuropsychopharmacology: The Fifth Generation of Progress health or social care interventions evaluated (economic eval- Measurement and Valuation of Costs uation). For AD, these may include the costs of hospital An economic study should describe and quantify the re- care, community-based health care services, social welfare sources used to produce health and social care and support services, and care provided by voluntary agencies or family for the patients and their carers. People with AD and their families may also from data on the quantity and type of resources used (e. However, what number of hospital-based physician visits, number of hospi- constitutes a cost from one point of view may not be a cost tal admissions, number of days per admission) multiplied from another. For example, the costs of social care services or patient If the evaluation compares two or more interventions, care and family out-of-pocket expenses are a cost to society but must be taken to ensure that all relevant types of resource not to those responsible for provision or funding of hospital use and costs are identified. In contrast, social welfare payments are a cost vention, follow-up care and support for patients and carers, to the agency that pays them, but a benefit to the patients and management of side effects or adverse events. From the point of view of These aspects are termed the direct costs to produce of society, social welfare payments are both a cost and a benefit; health and social care. From a societal perspective, direct when added together, they cancel each other out, so they costs also include out-of-pocket expenses and the use of should not be included. These should be measured and valued about the viewpoint or perspective and therefore the range because they are potentially important inputs to the produc- of costs and consequences included. The time costs of volunteers and family mem- spective that reflects the costs and outcomes to society bers can be valued with average wage rates or the cost of should be adopted. At a minimum, the perspective of the equivalent services with a market price (e. Measurement and Valuation of Outcomes It is crucial that an economic study include the health- Time Frame of Analysis related consequences of morbidity and mortality. For AD, Economic studies should use a time frame that allows full these could be the number of years of life lost and the illness- measurement of the relevant costs and benefits. Compara- associated reductions in health status and quality of remain- tive economic evaluations should monitor resource use, ing years of life for both patients and informal carers. The first is to value the consequences in mone- tary terms as indirect or productivity costs and intangible Target Population and Comparators costs. The second is to combine data about length of life and morbidity to provide a single, nonmonetary measure The population considered in the analysis should be repre- of impact. The interventions compared should be relevant to the health and social care choices faced by decision makers. Unless 'do nothing' is Monetary Valuation a valid management strategy, comparison of a new interven- tion with placebo is not appropriate for an economic evalua- Indirect costs represent the value of changes in the amount tion. They are also called productivity or time costs (18,19). With AD, the ability to engage in the normal daily activities of life and leisure is reduced by Opportunity Cost impaired cognitive function and, in some cases, early death. The economic concept of cost is the value of a good or The physical and mental health of carers may also be af- service in terms of its best alternative use, or opportunity fected. Typically, these costs are valued in the same way as cost. Often, the market price or value of the resources used, the time costs of unpaid carers, by using market values of the such as the time of a health care professional, facilities, or time in full health lost, such as average wage rates. However, medicines, is a reasonable approximation of the opportunity indirect or productivity costs do not include the costs of cost or value to society of the services provided. Chapter 89: Cost-Effectiveness of Therapeutics for Alzheimer Disease 1271 Intangible costs represent the monetary value to individu- intervention; current treatment patterns; relevant compara- als and society of health and life per se.

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