Richard Frothingham, MD

• Associate Professor of Medicine
• Assistant Professor in Molecular Genetics and Microbiology
• Member of the Duke Human Vaccine Institute

https://medicine.duke.edu/faculty/richard-frothingham-md

Exercise has been shown to improve body composition and reduce other cardiovascular risk factors associated with obesity (Zorba et al bacteria habitat purchase vantin discount. It is important to emphasize that aerobic exercise activities such as running antibiotic high vantin 100 mg on-line, walking antibiotic resistance news vantin 100 mg discount, and cycling are preferred to static forms of exercise in the management of hypertension antibiotic with sulfa proven 200mg vantin. Unfortunately antibiotic with anaerobic coverage 200mg vantin overnight delivery, weight loss is notoriously difficult and usually unsuccessful best antibiotics for sinus infection in adults buy cheap vantin 200mg, especially in the primary care setting. However, identifying a complication of obesity such as hypertension can perhaps provide the necessary motivation for patients and families to make the appropriate lifestyle changes. The role of diet in the treatment of hypertension has received a great deal of attention, most of which has focused on sodium. Once hypertension has been established, "salt sensitivity" becomes more common, and reduction in sodium intake may be of benefit (Cutler, 1999; Hanevold, 2013). Other dietary constituents that have been examined in patients with hypertension include potassium and calcium, both of which have been shown to have antihypertensive effects (Cutler, 1999; Mu et al. Therefore, a diet that is low in sodium and enriched in potassium and calcium may be even more effective than a diet that restricts sodium only. However, it has also been argued that the long-term consequences of untreated hypertension in an asymptomatic, hypertensive child or adolescent without underlying secondary hypertension or hypertensive target organ damage are completely unknown (Thompson et al. There is also a significant lack of data on the long-term effects of antihypertensive medications on the growth and development of children. Therefore, a definite indication for initiating pharmacologic therapy should be ascertained before medication is prescribed. Published results of the industrysponsored clinical trials (which have been summarized elsewhere [Ferguson & Flynn, 2013]) can be used to guide the prescribing of antihypertensive agents in children and adolescents who require pharmacologic treatment, thereby increasing the confidence of the practitioner who treats such children. The dosing recommendations contained in Table 16-9 incorporate data from many of these studies. No studies demonstrating a specific benefit of one class of antihypertensive agent over another are available for the pediatric age group; therefore, the choice of initial antihypertensive agent for use in children remains up to the preference of the individual practitioner. Diuretics and -adrenergic blockers, which were recommended as initial therapy in the First and Second Task Force Reports (Blumenthal et al. Consideration should be given to using specific classes of antihypertensive medications in hypertensive children with specific underlying or concurrent medical conditions (Ferguson & Flynn, 2013). Treatment goals recommended by the Fourth Report are less than 95th percentile for children with primary hypertension and less than 90th percentile for hypertensive children with secondary hypertension or hypertensive target organ damage (National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, 2004). However, further confirmatory studies are required before uric acid reduction can be advocated as a treatment of hypertension, especially given the known adverse risk profile of allopurinol (Yanik & Feig, 2013). Information on preparation of a stable extemporaneous suspension is available for these agents. It may also be appropriate to consider "stepdown" therapy in selected children and adolescents. The differential diagnosis of hypertension in neonates and older infants is wide ranging Tables 16-7 and 16-10). For a more comprehensive discussion, the reader is encouraged to consult other references (Dionne et al. Investigation of hypertensive infants should proceed in a similar fashion to the evaluation of older children with hypertension. As in older children, cuffs of proper size should be used in infants to avoid measurement error. Renal ultrasonography is particularly useful given the preponderance of renal causes Table 16-10). On the other hand, relatively well infants with mild hypertension may be treated with oral antihypertensive agents. Recommended doses for antihypertensive drugs in infants can be found in Table 16-11. A recent study demonstrated that antihypertensive agents of numerous classes have been employed in neonates (Blowey et al. Unfortunately, the legislative initiatives that have increased data on pediatric drug efficacy and safety have not extended to infants (Flynn, 2003). Thus, the choice of antihypertensive medications for use in neonates relies heavily on the experience of the individual practitioner. Acute Severe Hypertension the pathophysiology, management, and outcome of severe hypertension in children and adolescents have been reviewed in detail elsewhere (Flynn & Tullus, 2009; Singh et al. Many aspects are similar to hypertensive emergencies and urgencies in adults as reviewed in Chapter 8. Underlying conditions that may produce acute severe hypertension in a child or adolescent commonly include acute or chronic renal disease, solid organ transplantation, renal artery stenosis, and congenital renal diseases such as autosomal recessive polycystic kidney disease. Medication nonadherence in patients with established hypertension, the most common cause of acute severe hypertension in adults (Bender et al. Less severe symptoms may include nausea, vomiting, or unusual irritability; since these may be somewhat nonspecific, especially in younger children, a high degree of clinical suspicion must be maintained. Other intravenous agents that have found use in children with severe hypertension include sodium nitroprusside, esmolol, hydralazine, and fenoldopam (Singh et al. It should be noted that there is little clinical trial evidence available for these drugs in pediatric patients, so their use is largely based on expert opinion. Oral antihypertensive agents can be used in pediatric patients with acute severe hypertension who do not have life-threatening symptoms. The choice of oral antihypertensives for use in management of severe hypertension in pediatric patients is fairly limited. As in adults, short-acting nifedipine is no longer recommended (Flynn & Tullus, 2009). For recommended doses of both oral and intravenous drugs useful in the treatment of acute severe hypertension in children and adolescents, see Table 16-12. Prevalence of hypertension in junior high school-aged children: Effect of new recommendations in the 1996 Updated Task Force Report. Systemic hypertension in very low birth weight infants with bronchopulmonary dysplasia: Incidence and risk factors. Essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. Characteristics and management of patients presenting to the emergency department with hypertensive urgency. Childhood risk factors predict adult risk associated with subclinical cardiovascular disease: the Bogalusa Heart Study. Multidisciplinary therapy, reduces risk factors for metabolic syndrome in obese adolescents. Ability of blood pressure to predict left ventricular hypertrophy in children with primary hypertension. Indicators of fetal growth do not independently predict blood pressure in 8-year-old Australians: A prospective cohort study. Are pitfalls of oscillometric blood pressure measurements preventable in children Blood pressure and obesity among adolescents: a school-based population study in China. The predictive value of childhood blood pressure values for adult elevated blood pressure. Clustering of long-term trends in metabolic syndrome variables from childhood to adulthood in Blacks and Whites: the Bogalusa Heart Study. Tracking of blood pressure from childhood to adulthood: A systematic review and meta-analysis. The effects of reducing sodium and increasing potassium intake for control of hypertension and improving health. Sexual maturation and racial differences in blood pressure in girls: the National Heart, Lung, and Blood Institute Growth and Health Study. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study. Moderators of blood pressure development from childhood to adulthood: A 10-year longitudinal study. Echocardiographic evaluation of children with and without family history of essential hypertension. High blood pressure trends in children and adolescents in national surveys, 1963 to 2002. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. High risk blood pressure and obesity increase the risk for left ventricular hypertrophy in African-American adolescents. Dietary nutrients and blood pressure in urban minority adolescents at risk for hypertension. Unravelling the fetal origins hypothesis: Is there really an inverse association between birth weight and subsequent blood pressure Elevated blood pressure in adolescent boys predicts endothelial dysfunction: the cardiovascular risk in young Finns study. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Emergence of novel genetic effects on blood pressure and hemodynamics in adolescence: the Georgia Cardiovascular Twin Study. Left ventricular hypertrophy in adolescents with elevated blood pressure: Assessment by chest roentgenography, electrocardiography, and echocardiography. Effects of childhood primary hypertension on carotid intima media thickness: A matched controlled study. Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States. Fetal, infant, and childhood growth and adult blood pressure: A longitudinal study from birth to 22 years of age. Increased blood pressure reactivity in children of borderline hypertensive fathers. Childhood blood pressure as a predictor of arterial stiffness in young adults: the Bogalusa Heart Study. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. Left ventricular hypertrophy and arterial wall thickening in children with essential hypertension. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. Differentiation between primary and secondary hypertension in children using ambulatory blood pressure monitoring. Update: Ambulatory blood pressure monitoring in children and adolescents: A scientific statement from the American Heart Association. Birth weight and systolic, blood pressure in adolescence and adulthood: Meta-regression analysis of sex- and age-specific results from 20 Nordic studies. Analysis of longitudinal data from the Centers for Disease Control and Prevention Pediatric Nutrition Surveillance System. The effects of obesity, gender, and ethnic group on left ventricular hypertrophy and geometry in hypertensive children: A collaborative study of the International Pediatric Hypertension Association. Blood pressure and cardiac structure in children with a parental history of hypertension: the Odense Schoolchild Study. Longitudinal factor analysis reveals, a distinct clustering of cardiometabolic improvements during intensive, short-term dietary and exercise intervention in obese children and adolescents. Autonomic, abnormalities demonstrable in young normotensive subjects who are children of hypertensive parents. Clinical and research aspects of ambulatory blood pressure monitoring in children. Management of high blood pressure in children and adolescents: Recommendations of the European Society of Hypertension. Prevalence, persistence, and clinical significance of masked hypertension in youth. Long-term follow-up of cardiovascular risk factors after exercise training in obese children. Elevated plasma immunoreactive leptin levels preexist in healthy offspring of patients with essential hypertension. Athletic participation by children and adolescents who have systemic hypertension. Left ventricular hypertrophy in hypertensive adolescents: Analysis of risk by 2004 National High Blood Pressure Education Program Working Group staging criteria. Increased arterial stiffness in, children with a parental history of hypertension. Parental hypertension and cardiac alterations in normotensive children and adolescents. Reduction of blood pressure with calcium and potassium supplementation in children with salt sensitivity: A 2-year double-blinded placebo-controlled trial. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 task force report on high blood pressure in children and adolescents: A working group report from the National High Blood Pressure Education Program. Prevalence of hypertension in children after early repair of coarctation of the aorta: A cohort study using casual and 24 hour blood pressure measurement. Effect of breast feeding in infancy on blood pressure in later life: Systematic review and meta-analysis.

Hyperventilation syndrome and the assessment of treatment for functional cardiac symptoms bacteria 37 degrees celsius buy vantin online from canada. Characteristics of 100 consecutive patients presenting with orthostatic hypotension virus que causa llagas en la boca generic vantin 200 mg line. Systemic hypertension in antibiotics drug test purchase 200 mg vantin visa, low-gradient severe aortic stenosis with preserved ejection fraction antibiotic resistance uk purchase vantin with amex. Effects of normal blood pressure antibiotic levofloxacin purchase on line vantin, prehypertension bacteria quiz 100mg vantin amex, and hypertension on coronary microvascular function. Interaction between renal function and microalbuminuria for cardiovascular risk in hypertension: the nordic diltiazem study. Assessing the value of diagnostic tests: A framework for designing and evaluating trials. Evaluation and management of transient ischemic attack and minor cerebral infarction. Role of blood pressure in development of early retinopathy in adolescents with type 1 diabetes: Prospective cohort study. Urinary sodium and potassium profile of blacks and whites in relation to education in two different geographic urban areas. Antecedent hypertension and the effect of captopril on the risk of adverse cardiovascular outcomes after acute myocardial infarction with left ventricular systolic dysfunction: Insights from the Survival and Ventricular Enlargement trial. Racial variation in cardiovascular morbidity and mortality in essential hypertension. A 4-tiered classification of left ventricular hypertrophy based on left ventricular geometry: the Dallas heart study. Differences in left ventricular structure between black and white hypertensive adults: the Hypertension Genetic Epidemiology Network Study. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Tracking and prediction of arterial blood pressure from childhood to young adulthood in 868 patients with type 1 diabetes: A multicenter longitudinal survey in Germany and Austria. Exercise capacity and blood pressure associations with left ventricular mass in prehypertensive individuals. High-normal diastolic blood pressure is a risk for development of microalbuminuria in the general population: the Watari study. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Potassium and calcium intake, excretion, and homeostasis in blacks, and their relation to blood pressure. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. High blood pressure and headaches: Results from a meta-analysis of 94 randomised placebo controlled trials with 24000 participants. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. The unappreciated importance of blood pressure in recent and older atrial fibrillation trials. Cardiovascular disease risk in type 2 diabetes mellitus: Insights from mechanistic studies. Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in young adults. Prevalence of hypertensionattributed symptoms in routine clinical practice: A general practitioners-based study. Chronic kidney disease controversy: How expanding definitions are unnecessarily labelling many people as diseased. Pulsatile and steady 24-h blood pressure components as determinants of left ventricular mass in young and middle-aged essential hypertensives. Retinal vascular changes in prediabetes and prehypertension: New findings and their research and clinical implications. Prehypertension increases the risk for renal arteriosclerosis in autopsies: the Hisayama Study. Forecasting the future of stroke in the United States: A policy statement from the American Heart Association and American Stroke Association. Sodium retention in black and white female adolescents in response to salt intake. Role of elevated heart rate in the development of cardiovascular disease in hypertension. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Meta-analysis of cohort studies of baseline prehypertension and risk of coronary heart disease. Effects of normal, prehypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. Treatment of young subjects at high familial risk of future hypertension with an angiotensinreceptor blocker. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Effect of antecedent hypertension and follow-up blood pressure on outcomes after high-risk myocardial infarction. Prehypertension and black-white contrasts in cardiovascular risk in young adults: Bogalusa Heart Study. Stroke declines from third to fourth leading cause of death in the United States: Historical perspective and challenges ahead. Environmental and genetic factors of hypertension in a biracial Beduin population. A risk score for predicting near-term incidence of hypertension: the Framingham Heart Study. Relationship of left ventricular hypertrophy and diastolic function with cardiovascular and renal outcomes in African Americans with hypertensive chronic kidney disease. Carotid bruits as a prognostic indicator of cardiovascular death and myocardial infarction: A meta-analysis. Effects of systemic hypertension on arterial dynamics and left ventricular compliance in patients 70 years of age. Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events. Ambulatory blood pres, sure monitoring and postprandial hypotension in elderly persons with falls or syncopes. Pulse pressure and risk of Alzheimer disease in persons aged 75 years or older: A communitybased, longitudinal study. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: Relation to myocardial fibrosis. Isolated and borderline isolated systolic hypertension relative to long-term risk and type of stroke: A 20-year follow-up of the National Health and Nutrition Survey. Prevalence, predisposing factors, and prognostic importance of postural hypotension. Middle age cardiovascular risk factors and abdominal aortic aneurysm in older age. Factors influencing arterial stiffness in systolic hypertension in the elderly: Role of sodium and the reninangiotensin system. Prevalence of unrecognized abnormal glucose tolerance in patients attending a hospital hypertension clinic. A twin study of depression, symptoms, hypertension, and heart disease in middle-aged men. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. Relations of serum aldosterone to cardiac structure: Gender-related differences in the Framingham Heart Study. Asymptomatic left ven, tricular systolic dysfunction in essential hypertension: Prevalence, determinants and prognostic value. Regression of left ventricu, lar hypertrophy and prevention of stroke in hypertensive subjects. High blood pressure, and cerebral white matter lesion progression in the general population. Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Hypertensive target organ damage and the risk for vascular events and all-cause mortality in patients with vascular disease. Women exhibit a greater age-related increase in proximal aortic stiffness than men. Screening for future cardiovascular disease using age alone compared with multiple risk factors and age. Nonlinear relations of, blood pressure to cognitive function: the Baltimore Longitudinal Study of Aging. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Primary prevention of hypertension: Clinical and public health advisory from the National High Blood Pressure Education Program. Optimal blood pressure control for the prevention of atrial fibrillation [Abstract]. We will now turn to its treatment, examining the benefits and costs of therapy in this chapter and the use of nondrug and drug treatments in the two chapters that follow. In this chapter, three main questions are addressed: I First, what is the evidence that treatment is beneficial Lifestyle modifications, which will be examined in the next chapter, can be justified for everyone, hypertensive or not. To answer these questions, in this chapter, only data comparing active drug therapy against untreated or placebo-treated patients are considered. Reasons for this residual risk will be examined when evidence from trials of treatments is reviewed. Interrupting the Progress of Hypertension A 15- to 17-year longitudinal study of Welshmen (Miall & Chinn, 1973) and a 24-year follow-up of American aviators (Oberman et al. This conclusion is further supported by the results of the major placebo-controlled trials of antihypertensive therapy: Whereas 10% to 17% of those on placebo progressed beyond the threshold of diastolic pressure above 110 mm Hg, only a small handful of those on drug treatment did so (see Chapter 4, Tables 4-2 and 4-3). The kidney with renal artery stenosis is exposed to a lower pressure than is the contralateral kidney without stenosis. Arteriolar nephrosclerosis develops in the high-pressure nonstenotic kidney, occasionally to such a degree that hypertension can be relieved only by removal of the nonstenotic kidney, along with repair of the stenosis (Thal et al. The vessels exposed to the high pressure above the coarctation develop atherosclerosis to a much greater degree than do the vessels below the coarctation, where the pressure is low (Hollander et al. The low pressure within the pulmonary artery ordinarily protects these vessels from damage. When patients develop pulmonary hypertension secondary to mitral stenosis or certain types of congenital heart disease, both arteriosclerosis and arteriolar necrosis often develop within the pulmonary vessels (Heath & Edwards, 1958). Practitioners must be aware of the features, both good and bad, of both the performance and the presentation of clinical trials since they are the foundation of evidence-based medicine, i. Evidence from Animal Experiments Just as hypertension accelerates and worsens atherosclerosis in humans, animals that are made hypertensive develop more atherosclerosis than do normotensive animals fed the same high-cholesterol diet (Chobanian, 1990). In animals, the lesions caused by hypertension, including accelerated atherosclerosis, can be prevented by lowering the pressure with antihypertensive agents (Chobanian et al. Over the last six decades, since oral antihypertensive therapy has become available, protection with antihypertensive therapy has been demonstrated at progressively lower levels of pressure and, more recently, in the very elderly (Beckett et al. The benefits of individual drugs against placebo are so compelling as to preclude the performance of such trials, so attention has turned to trials contrasting a set of one or two drugs against another set of one or two. In particular, the financial sponsorship of clinical trials by drug marketers, although often essential for their performance, has been associated with selection of an inappropriate comparator and poorer quality of methods, selective reporting of outcomes, and more positive conclusions than seen in trials funded by nonprofit sources (Yank et al. Even if effectively treated, these damages may be irreversible, particularly if other risk factors are also not corrected. Too Short Duration of Treatment: the duration of the trials is usually less than 5 years. Patients Lost to Follow-Up: In some trials, as many as 25% of patients have been lost to follow-up before completion. In general, more high-risk patients are lost, weakening the evidence for benefit (Mancia, 2006). Treatment of these high-risk patients in the control groups will underestimate the real benefit of active therapy. Harm from Drugs: the drugs available and chosen for almost all the earlier trials in subjects younger than 60 years old were high doses of diuretics and adrenergic inhibitors, mostly nonselective -blockers. Noncompliance with Therapy: Patients assigned to active drug therapy may not have taken all of their medication and thereby have had less benefit. Although pill counts are usually performed, no truly accurate assessment of compliance is available. Data from clinical trials may overestimate the benefits of therapy as they are applied to the universe of hypertensives for the following reasons: Inclusion of Inappropriate End Points: To maximize the impact of therapy, multiple end points may be combined, some of questionable significance such as hospitalizations, which occur at the subjective discretion of the investigator (Lim et al. Lauer and Topol (2003) argue that only all-cause mortality should be the primary end point since it is objective, unbiased, and clinically relevant. As they note, "any end point that requires a measurement involving human judgment is inherently subject to bias. Better Compliance with Therapy: Patients enrolled in trials in which medications and all health care are free and follow-up is carefully monitored are likely to be more compliant with therapy than are patients in clinical practice.

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When available virus file scanner cheapest generic vantin uk, generic agents that are equally efficacious are more likely to be taken (Shrank et al virus blocker vantin 100 mg line. The prescription of two or more doses per day when long-acting once-a-day options are available (Egan et al antibiotic 777 buy 200 mg vantin fast delivery. The starting and usual doses are determined by trials in only a limited number of usually uncomplicated patients antibiotic used for urinary tract infection vantin 100 mg without a prescription. In the future antibiotic resistance evolves in bacteria when quizlet purchase vantin 100mg with visa, genetic typing may provide a way to maximize the response non prescription antibiotics for acne order vantin uk, but as of now, few have been reported to provide clinically useful data (Turner et al. Patient Involvement Involvement of the patient is helpful, not only in making initial decisions which are therefore more likely to be followed but also in monitoring the course of the disease. Moreover, as noted in Chapter 2, responses to therapy are more closely related to outof-office measurements than office readings. Intensity of Therapy the rapidity of reaching goal is now in question since too fast a course may cause intolerable symptoms, but too slow may expose high-risk patients to immediate dangers. Timing of Dosing the time of day to take one-a-day antihypertensive medications needs to be more carefully considered. Dealing with Side Effects Some medications are easier to take than others, but some patients cannot seem to take any. Such patients with nonspecific intolerance to multiple antihypertensive drugs almost always have underlying psychological morbidity, often manifested as recurrent hyperventilation, panic attacks, generalized anxiety, or depression (Davies et al. As noted before, the labeling of hypertension can induce adverse psychological effects (Spruill et al. Fortunately, the use of currently available drugs slows cognitive decline and may prevent dementia (Marpillat et al. They state: "Although the pharmaceutical industry and its analysts measure innovation in terms of new molecular entities as a stand-in for therapeutically superior medications, most have provided only minor clinical advantages over existing treatments. Since the mid-1990s, independent reviews have also concluded that about 85% to 90% of all new drugs provide few or no clinical advantages for patients. The number of hypertensive subjects taking antihypertensive drugs has progressively risen over the past 40 years. Aldosterone receptor blockers, though potassium sparers, are considered separately because of their additional effects. More importantly, chlorthalidone when used alone has been shown to reduce morbidity and mortality (Roush et al. As a consequence of these results, chlorthalidone will likely be used more frequently. The site of action determines their relative efficacy, as expressed in the maximal percentage of filtered sodium chloride excreted (Brater, 2000). Agents acting in the proximal tubule (site I) are seldom used to treat hypertension. Plasma and extracellular fluid volume are thereby shrunken, and cardiac output falls (Wilson & Freis, 1959). Humoral and intrarenal counterregulatory mechanisms rapidly reestablish the steady state so that sodium intake and excretion are balanced within 3 to 9 days in the presence of a decreased body fluid volume (Sica, 2004a). Metolazone Metolazone, a long-acting and more potent quinazoline thiazide derivative, maintains its effect in the presence of renal insufficiency (Paton & Kane, 1977). Nonthiazide Sulfonamide Diuretics Chlorthalidone Antihypertensive Efficacy When used alone, diuretics provide efficacy similar to that of other classes of drugs (Law et al. Blacks and the elderly respond better to diuretics than do nonblacks and younger patients (Brown et al. This potentiation depends on the contraction of fluid volume by the diuretic (Finnerty et al. Indapamide Indapamide (Lozol) is a chlorobenzene sulfonamide but has a methylindoline moiety, which may provide additional protective actions beyond its diuretic effect (Chillon & Baumbach, 2004). Duration of Action the durations of action listed in Table 7-3 relate to the diuretic effect; the full antihypertensive effect may not last beyond the diuretic effect. In hypertensives with good renal function, most of the antihypertensive effect will be obtained from such small doses, with less hypokalemia and other side effects. Protection Against Cardiovascular Events Diuretics protect against cardiovascular morbidity and mortality as well as any other class of drug (Cushman et al. Thiazides may also be coupled with loop diuretics in those with renal impairment, because they counter the distal nephron hypertrophy that occurs with loop diuretics alone (Brater, 2000). The combination of a thiazide with a loop diuretic usually increases sodium excretion but may induce hypokalemia, hyponatremia, and hypotension (Dussol et al. Logically, side effects occur with about the same frequency and severity with equipotent doses of all diuretics, and their occurrence will diminish with lower doses. Hypokalemia Resistance to Diuretics Resistance to the natriuretic and antihypertensive action of diuretics may occur for numerous reasons including these: Excessive dietary sodium intake. Because these drugs must be secreted into the renal tubules to work and because endogenous organic acids that build up in renal insufficiency compete with diuretics for transport into the proximal tubule, the renal response progressively falls with increasing renal damage. The mechanism for hypercholesterolemia remains in question, although it is shown as arising via hypokalemia. The major potential risks of potassium depletion are to increase the incidence of stroke (Levine & Coull, 2002) and ventricular arrhythmias causing sudden death (Grobbee & Hoes, 1995). PreVention of diuretic-induced hyPokalemia By lowering dietary sodium, increasing dietary potassium, and using the least amount of diuretic needed, potassium depletion may be avoided. Rarely, severe, symptomatic hyponatremia develops, usually soon after high doses of diuretics are started in thin elderly women who appear to have an expanded fluid volume from increased water intake in the face of a decreased ability to excrete free water (Mann, 2008). Hyperuricemia If prevention does not work, the potassium deficiency can be replaced with supplemental K+, usually given as the chloride. The problem may be compounded in diabetics who may be unable to move potassium rapidly into cells and in those with renal insufficiency who may have a limited ability to excrete potassium. Hypomagnesemia Serum uric acid levels are high in as many as 30% of untreated hypertensives and diuretics increase renal urate reabsorption, raising uric acid levels further, occasionally provoking gout (Choi et al. Moreover, Richard Johnson and others have provided evidence for a casual role of hyperuricemia in the pathogenesis of hypertension (Feig et al. Calcium Metabolism Alterations Some of the problems attributed to hypokalemia may be caused by hypomagnesemia but conventional doses of diuretics rarely induce magnesium deficiency (Wilcox, 1999). Clinical features include weakness, nausea, neuromuscular irritability, and the appearance of ventricular arrhythmias, which are resistant to treatment unless both hypomagnesemia and hypokalemia are corrected (Whang et al. Renal calcium reabsorption also is increased with chronic thiazide therapy, and urinary calcium excretion is decreased by 40% to 50% (Friedman & Bushinsky, 1999). By reducing renal calcium excretion, thiazides are used to treat patients with renal stones caused by hypercalcemia from increased calcium absorption (Quereda et al. The retention of calcium in bone offers protection from osteoporosis and fractures (Schoofs et al. However, loop diuretics, which increase urinary calcium excretion, are associated with an increased rate of hip bone loss in older men (Lim et al. In a review of data from 83 trials with thiazides, the rise in blood glucose was closely correlated with the fall in serum potassium (Zillich et al. As with all the adverse effects of diuretics, the impairment of glucose utilization that connotes insulin resistance is seen more with high doses (McHenry et al. It is likely that part of the increases in diabetes in diuretic-treated patients comes from the concomitant use of -blockers, the "conventional" therapy of older trials. Effect on Lipids of patients, and approximately the same percentage develops photosensitivity, which may be involved in the reported increase in lip cancer (Friedman et al. An increased relative risk of renal cell cancer has been reported with diuretic therapy (Corrao et al. Conclusion Strong controlled trial data document the benefits of diuretics in particular chlorthalidone, for the treatment of hypertension. These adverse effects are dose dependent and should be much less problematic with appropriately lower doses, doses that will provide most, if not all, of their antihypertensive effects. With low doses, thiazides have little effect on the blood lipid profile (Weir & Moser, 2000). However, higher doses may induce significant effects on fat distribution, which in turn may be associated with insulin resistance. After the 12 weeks on the diuretic, the subjects had increases in abdominal and hepatic fat, abnormal liver function test, insulin resistance, and increased C-reactive protein levels. Therefore, the loop diuretics are more potent and have a more rapid onset of action than do the thiazides. Their major use is in patients with renal insufficiency, in whom large enough doses can be given to achieve an effective luminal concentration (see Chapter 9). Other Side Effects Furosemide the maintenance of a slightly shrunken body fluid volume, which is critical for an antihypertensive action from diuretic therapy, is not met by the short duration of furosemide action (3 to 6 hours for an oral dose); during the remaining hours, sodium is retained, so that net fluid balance over 24 hours is left unaltered (Wilcox et al. If furosemide is used twice daily, the first dose should be given early in the morning and the second in the late afternoon, both to provide diuretic action at the time of sodium intake and to avoid nocturia. Fever and chills, blood dyscrasias, cholecystitis, pancreatitis, necrotizing vasculitis, acute interstitial nephritis, and noncardiogenic pulmonary edema have been seen rarely. The drug has been used as medical therapy for hyperaldosteronism in patients intolerant to aldosterone blockers and in patients with mutations of the genes regulating sodium channels that lead to the fullblown Liddle syndrome (see Chapter 11) or to a less severe prototype from the T594M polymorphism (Baker et al. Nausea, flatulence, and skin rash have been the most frequent side effects and hyperkalemia the most serious. Bumetanide, although 40 times more potent and 2 times more bioavailable than furosemide on a weight basis, is identical in its actions when given in an equivalent dose (Brater et al. Torsemide Torsemide differs from the other diuretics in that it is mainly eliminated by hepatic metabolism, with only 20% being excreted unchanged in the urine (Brater, 1993). In patients with chronic renal disease, 40 mg of torsemide once a day provided equal natriuresis and hypertensive effect as 40 mg of furosemide twice a day (Vasavada et al. Ethacrynic Acid Although structurally different from furosemide, ethacrynic acid also works primarily in the ascending limb of Henle loop and has an equal potency. It is used much less than is furosemide, mainly because of its greater propensity to cause permanent hearing loss with high doses. Since it does not contain a sulfonamide moiety, its main use has been in patients with sulfonamide sensitivity. Aldosterone Receptor Blockers the first of these, spironolactone, has long been available but little used in the U. Since then, a large body of experimental and clinical evidence has revealed a multiorgan profibrotic effect of aldosterone so that blocking the hormone has assumed an important place in clinical medicine. At the same time, the marketing of a more specific aldosterone blocker, eplerenone, has stimulated the use of these agents. Potassium-Sparing Agents Amiloride and triamterene act directly to inhibit sodium reabsorption by the epithelial sodium channels in the renal distal tubule, decreasing the net negative potential in the tubular lumen and thereby reducing potassium and hydrogen secretion and excretion, independent of aldosterone. Mode of Action the primary mineralocorticoid aldosterone causes hypertension when present in large excess, the syndrome of primary aldosteronism covered in Chapter 11. However, even "normal" amounts of aldosterone in the presence of the relatively high sodium intake of modern societies are now known to activate mineralocorticoid receptors in multiple organs including the brain, heart, kidney, and blood vessels (Schiffrin, 2006). Moreover, the incidence of hypertension over 4 years was 60% higher in those initially nonhypertensive subjects who were in the highest quartile of serum aldosterone (Vasan et al. Eplerenone in a twice higher dose has equivalence to spironolactone in blocking the mineralocorticoid receptor but a much lower blockade of androgen and progesterone receptors, explaining its fewer side effects (Funder, 2002). Subsequently, the drug was shown to reduce mortality in these subjects whether they had been hypertensive or not (Pitt et al. With appropriate monitoring, eplerenone is both safe and effective in patients with impaired renal function (Eschalier et al. The antibiotic trimethoprim is similar to the potassium-sparing agent amiloride and reduces potassium excretion by 40%. Therefore, hyperkalemia may occur if the antibiotic is given to patients on an aldosterone blocker (Antoniou et al. Antihypertensive Efficacy Spironolactone has been used alone to treat hypertension for many years, particularly in France (Jeunemaitre et al. More recently, it has been found to effectively control patients with refractory hypertension (Chapman et al. For these reasons, the use of aldosterone blockers will almost certainly expand to initial therapy, usually in combination with a diuretic, for more and more hypertensives. Central -Agonists Central -agents stimulate 2a-adrenergic receptors that are involved in depressor sympathoinhibitory mechanisms (Vongpatanasin et al.

Hypertension and Lactation Breast-feeding for at least 6 months is associated with a lower incidence of hypertension in both mother (Lupton et al virus 01 april 200 mg vantin with mastercard. All Risks in Perspective In a cohort study with data from all Danish women 15 to 49 years of age over the interval of 1995 to 2009 antimicrobial 220 purchase generic vantin from india, Lidegaard et al virus on macbook air buy 100mg vantin. We will turn next to hypertension in children and adolescents antibiotic drops for pink eye purchase 200mg vantin with mastercard, a rapidly growing problem treatment for uti vs kidney infection buy vantin 100mg with visa. Evaluating the role of bedrest on the prevention of hypertensive diseases of pregnancy and growth restriction antibiotics std purchase vantin 100mg overnight delivery. Oral estrogen therapy in, postmenopausal women is associated with loss of kidney function. Early-onset severe preeclampsia: Induction of labor vs elective cesarean delivery and neonatal outcomes. Drug treatment of hypertension during pregnancy: a critical review of adult guideline recommendations. Cortical blindness in severe preeclampsia: Computer tomography, magnetic resonance imaging, and single-photon-emission computed tomography findings. Ambulatory blood pressure monitoring for the early identification of hypertension in pregnancy. Prevalence, trends, and outcomes of chronic hypertension: A nationwide sample of delivery admissions. The relationship between pre-eclampsia and peripartum cardiomyopathy: A systematic review and meta-analysis. However, estrogen will continue to be used since nothing else will effectively prevent hot flushes (North American Menopause Society, 2012). In a prospective study of 1,000 postmenopausal and premenopausal untreated women followed for a median of 5. The maternal, cerebral circulation in pre-eclampsia: Investigations using Laplace transform analysis of Doppler waveforms. Potassium regulation and progesterone-aldosterone interrelationships in human pregnancy: A prospective study. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Preeclampsia is associated, with the presence of transcriptionally active placental fragments in the maternal lung. Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: A prospective study. Prospective study of oral contraceptives and hypertension among women in the United States. Calcium supplementation prevents endothelial cell activation: possible relevance to preeclampsia. Metabolic syndrome in postmenopausal women: the influence of oral or transdermal estradiol on inflammation and coagulation markers. Accuracy of mean arterial pressure and blood pressure measurements in predicting preeclampsia: Systematic review and meta-analysis. Cardiovascular and metabolic characteristics 40 years after hypertensive pregnancies: a longterm follow-up study of mothers. Effect of magnesium sulfate given for neuroprotection before preterm birth: A randomized controlled trial. Systematic review, and meta-analysis of preterm birth and later systolic blood pressure. Aldosterone, vascular endothelial growth factor, and preeclampsia: a mystery solved Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy. Clinical morbidities, trends, and demographics of eclampsia: A population-based study. Hypertensive disorders of pregnancy and cardiometabolic health in adolescent offspring. Vascular endothelial growth factor-A and aldosterone: Relevance to normal pregnancy and preeclampsia. Low-to-moderate alcohol consumption during pregnancy and child development-moving beyond observational studies. Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study. Reproducibility of the tolerance-hyperbaric test for diagnosing hypertension in pregnancy. Calcium supplementation during pregnancy for preventing hypertensive disorders is not associated with changes in platelet count, urate, and urinary protein: A randomized control trial. Association between maternal alcohol consumption in early pregnancy and pregnancy outcomes. Maternal cardiovascular impairment in pregnancies complicated by severe fetal growth restriction. Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. The 2012 hormone therapy position statement of: the North American Menopause Society. Impact of fetal programming, birth weight, and infant feeding on later hypertension. Comparison of 24-hour urinary protein and protein-to-creatinine ratio in women with preeclampsia. Light drinking versus abstinence in pregnancy-behavioural and cognitive outcomes in 7-year-old children: a longitudinal cohort study. Low sodium diet and pregnancy-induced hypertension: A multi-centre randomised controlled trial. Trends in pregnancy hospitalizations that included a stroke in the United States from 1994 to 2007: Reasons for concern Spiral artery remodeling and tropho, blast invasion in preeclampsia and fetal growtth restriction. Evidence of endothelial dysfunction in preeclampsia and risk of adverse pregnancy outcome. Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth restriction. C-type natriuretic peptide in complicated pregnancy: Increased secretion precedes adverse events. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. Uric acid is as important as proteinuria in identifying fetal risk in women with gestational hypertension. Prevention of pre-eclampsia with low-dose aspirin or vitamins C and E in women at high or low risk: a systematic review with meta-analysis. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia. Preeclampsia-eclampsia:, Clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. Intergenerational factors: a missing link for preeclampsia, fetal growth restriction, and cardiovascular disease Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review. Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study. Early and late preeclampsia: Two different maternal hemodynamic states in the latent phase of the disease. Blood pressure in 12-year-old children is associated with fatty acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort. New gestational phasespecific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. Soluble (pro)renin receptor and blood pressure during pregnancy: a prospective cohort study. Maternal caffeine consumption during pregnancy and the risk of miscarriage: A prospective cohort study. This chapter will describe the features of hypertension in children and adolescents and will also examine the increasingly strong evidence that the genesis of adult cardiovascular disease has its origins in childhood (Expert Panel, 2011). Initially, the thresholds used for defining hypertension in the young were the same as those used in adults. Unsurprisingly, hypertension was found to be exceedingly rare in young children but could affect up to 2% of adolescents Table 16-1). The impact of the childhood obesity epidemic on the prevalence of hypertension in the young can be seen in several recent studies from the Houston Screening Project (McNiece et al. In multiple publications, these investigators have demonstrated an increased prevalence of hypertension among obese children-as high as 4. According to this analysis, the prevalence of prehypertension has now reached 10% and the prevalence of hypertension nearly 4%. Similar findings have been seen in screening studies performed in other countries, including China (Cao et al. The significance of hypertension in the young is further underscored by the many studies documenting the occurrence of hypertensive target organ damage in children and adolescents. However, the strength of tracking appears to decrease with longer periods of follow-up (Chen & Wang 2008; Toschke et al. In view of the higher prevalence of hypertension in black adults than in white adults, comparisons of the tracking phenomenon in black and white children have been made (Lane & Gill, 2004). While longstanding hypertension has long been recognized as a risk factor for the development of cognitive impairment and even dementia in the elderly (Paglieri et al. In a recent follow-up study, hypertensive children were found to have decreased executive function that was associated with decreased cerebrovascular reactivity in response to hypercapnia (Ostrovskaya et al. Fewer pediatric data are available on the other major target organ effect of hypertension, namely renal damage. Taken together, these data indicate that over time, adult morbidity and mortality will be more tightly connected with childhood precursors and emphasize the need for early intervention (Expert Panel, 2011). The Critical Role of Obesity Obesity is growing at an alarming pace among children and adolescents in all developed societies, with-as in many other aberrant behaviors-the U. Unfortunately, adolescent obesity tracts closely with adult obesity (Kvaavik et al. Some factors are either genetic or environmental, but most have contributions of both. The pathophysiologic links between childhood obesity and the development of hypertension, including the crucial role of sympathetic nervous system activation, have recently been reviewed (Flynn, 2013). Whether there is more to breastfeeding than a reduced rate of excess weight gain (Grummer-Strawn & Mei, 2004) is uncertain, but slower early growth appears to be beneficial for longterm cardiovascular health (Singhal et al. Recently published studies have demonstrated that a large percentage of children and adolescents with primary hypertension have positive family histories of hypertension in a parent or grandparent (Flynn & Alderman, 2005; Robinson et al. Table 16-3 lists some of the differences reported among normotensive children with a positive family history versus those with a negative family history of hypertension. A relationship between birth weight and coronary heart disease and type 2 diabetes has also been noted (Barker et al. Proposed explanations for these findings include deficient maternal nutrition (Barker et al. Autopsy studies demonstrating a reduced number of nephrons in patients with primary hypertension (Keller et al. Those children who were small at birth but who have accelerated weight gain either very early after birth (Singhal et al. Obese adolescents also have heightened responsiveness to sodium intake (Rocchini et al.