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Trough drug concentrations (Cmin) represent those concentrations in plasma which occur immediately prior to a scheduled dose P viagra extra dosage 200mg with mastercard erectile dysfunction late 20s. The inter-dose excursion between Cmax and Cmin is a reflection of systemic drug exposure and in some instances order 120 mg viagra extra dosage impotence help, is associated with a “target” dosing strategy (e. Volume of distribution (apparent volume of distribution) represents a hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in the blood. The Exposure–Response Relationship Drug action results only when an exposure (both extent and duration of) occurs that is sufficient to translate a drug–receptor interaction into a physiologic response. Thus, the exposure–response relationship for a given drug represents an interface between pharmacokinetics and pharmacodynamics that can be conceptualized by simultaneous consideration of two profiles: (a) plasma concentration versus time (Figs. The pharmacokinetic-pharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. Following drug administration, the concentration (both in the plasma and by inference, also at the receptor) increases as does the effect; first in an apparent linear fashion (at low drug concentrations) followed by a nonlinear increase in effect to an asymptotic point which reflects the maximal effect (Emax) after which, further increases in drug concentration are not associated with an increase in the desired drug effect. For example, when plasma drug concentration versus effect data are plotted, a negative hysteresis often results which is a consequence of the delay between peak plasma concentrations and peak drug effect. When the dose of a given drug is escalated, the dose versus response curve shifts to the right. As with therapeutic effect, a toxic drug response has its own dose versus response curve. This is exemplified by the opiate analgesics where the concentration versus effect curve for analgesic effects and that for the respiratory depressant effects are different and modulated by two distinct receptors. A clinical example of this later situation is seen with the rapid onset of respiratory depression after dose escalation of opiates as tolerance develops to the analgesic effects. With few exceptions, it is rarely possible to measure drug concentrations at or near the receptor given that their primary location is in the tissue biophase, not in the plasma. In most instances, a change in a given surrogate measurement is examined in association with the plasma drug concentration versus time curve to assess pharmacodynamic properties. For drugs whose pharmacokinetic properties are best described by first-order (as opposed to zero- or mixed-order) processes, a semi-logarithmic plot of plasma drug concentration versus time data for an agent given by an extravascular route of administration (e. After the time where maximal plasma concentrations (Cmax) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting; the terminal portion of this segment of the plasma concentration versus time curve being representative of drug elimination from the body. By being able to characterize the pharmacokinetics of a specific drug, the clinician can use the data to individualize drug–dosing regimens so as to compensate for factors that can influence pharmacokinetics (e. For drugs where a therapeutic plasma concentration range and/or “target” systemic exposure (i. When linked with information regarding the pharmacodynamic behavior of a drug and the status of the patient (e. Panel B illustrates developmental differences in body composition which can influence the apparent volume of distribution for drugs. Panel C illustrates the ontogeny of factors pertaining to gastrointestinal physiologic function, one or more of which can influence either the rate and/or extent of drug absorption. Panel D illustrates the acquisition of renal function (both glomerular filtration rate and active tubular secretory capacity reflected by para-aminohippuric acid clearance, a validated biomarker) during development. Panel E illustrates the impact of development on aspects of the integumentary system which collectively, can modulate the systemic absorption of drugs applied to the skin. Developmental pharmacology—drug disposition, action and therapy in infants and children. Accumulated information supports that many of these changes are indeed predictable (4) and consequently, they can be used to inform the design of pediatric clinical trials through the use of modeling and simulation and also, to clinically individualize drug treatment for a given patient based on known or expected pharmacokinetic behavior of a given drug (5). An example of therapeutic utility of pharmacokinetic-based optimization of drug treatment has been recently illustrated in the provision of antiretroviral therapy in children (6). For the clinical application of such data, it is important for the clinician to have a conceptual understanding of how development influences both drug disposition and effect. In the following paragraphs, we provide a summary of developmental pharmacokinetics, much of which has been excerpted (with permission) from previous works (1,7,8) published by one of the co-authors (G. These publications can be referred to for reference to citations in the primary literature upon which the following summaries are based. Drug Absorption Absorption of drugs administered by extravascular routes occurs largely via passive diffusion. At certain anatomical sites where drug transport proteins are expressed, absorption can occur via active transport or facilitated diffusion. In addition to physiologic changes that occur during development, the concomitant presence of certain disease states (e. A summary of important factors that can influence drug absorption in neonates, infants, and children is provided in Table 82. Oral Absorption As is the case in adults, the majority of therapeutic drugs administered in the outpatient setting are given by the oral route. During development, maturational changes of gastric, intestinal, and biliary tract function (Fig. Given that most orally administered drugs have the physicochemical property of being either a weak acid or weak base, pH within the gastrointestinal tract can influence the amount of potentially absorbable drug (i. Gastric pH changes significantly throughout development with the highest values occurring during the neonatal period. In the fully mature neonate, the gastric pH ranges from 6 to 8 at birth and drops to 2 to 3 within a few hours of birth. However, after the first 24 hours of postnatal life, the gastric pH increases due to the immaturity of the parietal cells and gradually reaches expected adult values (e. As a result of these developmental differences, the bioavailability of acid-labile drugs (e. During development, one of the most important physiologic changes capable of altering the rate of drug absorption resides with gastrointestinal motility. By 6 to 8 months of age, gastrointestinal transit times may be shorter than those observed for older children and adults; a situation which can significantly influence both the rate and extent of bioavailability of drugs with limited water solubility (e. Finally, immature biliary function in neonates and young infants in the first few months of life has the potential for reducing the extent of oral bioavailability of lipophilic drugs which are dependent upon bile acids for their solubility in the small intestine (e. Developmental differences in the activity of intestinal drug-metabolizing enzymes (e. The clinical consequence of this observation of diminished expression in neonates and infants would be reduced presystemic clearance of substrates for these drug- metabolizing enzymes and higher circulating concentrations of the active compound in plasma (e. Conversely, if the medication is administered as a prodrug which is activated by these enzymes, we would expect reduced concentrations of the active compound in the plasma (e. While the patterns of ontogeny for these enzymes and transporters are not concordant, the majority appear to have adult expression within the first 6 to 12 months of postnatal life at which time, the influence of development on their activity as a determinant of bioavailability would be expected to be minimal (9,10). Extravascular Drug Absorption As is the case with oral drug absorption, development can influence the bioavailability of drugs administered by other extravascular routes (e. In the neonate, muscular blood flow is reduced in the first few days of life, as is the relative efficiency of muscular contractions. Furthermore, neonates and young infants have greatly reduced muscle mass (compared to older infants and children) an increased percentage of water per unit of muscle mass. Collectively, these developmental changes can produce variable and delayed rates of absorption of drugs given by the intramuscular route. In contrast, mucosal (rectal and buccal) and dermal permeability in the neonate and young infant is increased and thus, may result in enhanced absorption by these routes.

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Physiology Severe obstruction to pulmonary venous flow is present in this anomaly generic viagra extra dosage 200mg on-line food that causes erectile dysfunction. Because these patients can live a few days to a few weeks cheap 130mg viagra extra dosage otc erectile dysfunction after 80, some means of blood flow from the lungs must exist. One must assume that an exit, however restricted, is provided by the bronchopulmonary veins carrying blood from the lungs to the systemic venous system. A grade 1 to 2 soft systolic ejection murmur along the left sternal border is usual, although a murmur may be absent. The usual chest radiographic picture of severe pulmonary venous obstruction is present. Echocardiography Echocardiographic demonstration of atresia of the common pulmonary vein was reported in three of five infants with this anomaly. If the cardiac output is diminished, the Doppler flow in the aortic arch may be retrograde in systole. As a result of the pulmonary hypertension, a right-to-left shunt would be detected through the foramen ovale and ductus arteriosus by Doppler. Cardiac Catheterization Cardiac catheterization demonstrates severe pulmonary hypertension and marked systemic desaturation. Extracorporeal membrane oxygenation was an essential postoperative supportive measure in two of these patients (60). Prognosis Symptoms occur on the first day of life, and these patients follow a progressive downhill course to death within the first days of life when there is no surgical intervention. In few cases has surgery been performed, usually with no follow-up period, to know the long-term outcome. Cor triatriatum is an unusual congenital anomaly, but it is probably not as rare as some reports indicate. The variety of anatomic expressions of cor triatriatum defeats an attempt to define a unified embryogenesis for all of them. The theory that abnormal growth of the septum primum accounts for cor triatriatum is difficult to reconcile with the observations of most workers in this field. Some variants of cor triatriatum did not appear to be consistent with this theory, however. Other reports highlighted the embryogenetic complexities of this group of cardiac defects (63). So-called cor triatriatum dexter is usually a persistence of the right valve of the sinus venosus. Anatomy The number of variants of cor triatriatum demands an inclusive classification (Table 35. E: Decompressing vertical vein that descends below the diaphragm to connect to the systemic venous circulation via the hepatic or portal veins. F: “Partial” or subtotal cor triatriatum with normally draining left pulmonary veins; the right pulmonary veins communicate with the true left atrium via a stenotic orifice. G: Subtotal cor triatriatum of the right pulmonary veins along with partially anomalous venous return of the left pulmonary veins via the left innominate vein. Histologically, the anomalous membrane contains cardiac muscle fibers and is occasionally calcified. Right ventricular hypertrophy and dilation are found almost invariably, and right atrial hypertrophy and dilation are present in about 25% of cases (64). Distinction of this anomaly from stenosis of individual pulmonary vein(s) at the left atrial junction can be challenging. Microscopic Anatomy When cor triatriatum obstructs pulmonary venous flow, the lungs reflect varying degrees of pulmonary edema and intra-alveolar hemorrhage. There is medial hypertrophy of the pulmonary veins, and lymphatic channels are dilated. Pulmonary arterial lesions range from medial hypertrophy alone, to medial hypertrophy with intimal proliferation, to necrotizing arteriolitis. In the patient with subtotal cor triatriatum, the obstructive phenomenon affects only one lung. Reflex pulmonary arterial constriction in the affected lung will result in diminished flow through that lung; however, the remaining unobstructed lung is usually capable of accepting increased blood flow, and thus pulmonary arterial pressure is not elevated. Manifestations The following sections consider the features of only classic cor triatriatum. Clinical Features Most patients with classic cor triatriatum have onset of symptoms within the first few years of life. Nonetheless, some patients are asymptomatic until the second or third decade of life. Usually, the patients present with a history of breathlessness, frequent respiratory infections, and pneumonia. Signs of pulmonary hypertension, including loud pulmonary component of the second heart sound, right ventricular heave, and pulmonary systolic ejection click, are typical in patients with cor triatriatum. The usual cardiac murmur is a soft, blowing, systolic murmur along the left sternal border. Less often, a diastolic murmur is detected at the mitral area, or a continuous murmur is heard. Echocardiographic Features The advances in 2-D and Doppler echocardiography have simplified the noninvasive diagnosis of causes of pulmonary venous obstruction and increased its accuracy (see Fig. Imaging from the parasternal, apical, and subcostal windows allows assessment of the size of these cardiac chambers. The membrane in cor triatriatum usually is curvilinear and may have the appearance of a windsock. A supramitral stenosing ring is located on the atrial surface of the base of the mitral valve leaflets and is relatively immobile. The left atrial appendage and foramen ovale are located distal to the membrane of cor triatriatum, and the pulmonary veins insert into the proximal chamber. In contrast, the membrane in supravalvar stenosing mitral ring is usually adherent to the mitral valve, and has the left atrial appendage and foramen ovale located proximal to the membrane. Doppler interrogation of left atrial membranes may reveal disturbed diastolic flow profiles that may be best appreciated by color flow Doppler mapping. Electrocardiographic Features The typical finding is right ventricular hypertrophy. Broad, notched P waves are present in some cases, presumably as a consequence of the dilated pulmonary venous chamber, but are absent in others. Fine, diffuse, reticular pulmonary markings fan out from the pulmonary hilum to involve the lower lung fields. Prominent venous engorgement of the upper pulmonary veins results in the staghorn sign. The chest radiogram also reveals enlargement of the main pulmonary artery, right ventricular hypertrophy, and signs of “left atrial” enlargement, including posterior deviation of the barium-filled esophagus and a double density at the right cardiac border. Magnetic Resonance Imaging This is another noninvasive imaging modality that can delineate the left atrial membrane of cor triatriatum.

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More than 80% of stab wounds to the heart present with cardiac tamponade buy 150 mg viagra extra dosage otc impotence lipitor, whereas only 20% of gunshot wounds present in this fashion purchase viagra extra dosage cheap online herbal erectile dysfunction pills review. The retention of blood within the pericardial sac prevents rapid exsanguination, providing more time for the patient to reach medical care and receive life-saving cardiorrhaphy. However, if allowed to progress, hemopericardium can lead to fatal cardiac tamponade. Because of its thicker myocardial wall, stab wounds to the left ventricle that measure <1 cm will often spontaneously seal. Stab wounds to the right ventricular wall, however, usually result in cardiac tamponade because the thinner myocardial wall does not usually spontaneously seal. The thinness of atrial walls decreases the likelihood of spontaneous sealing; however, the low intrachamber pressures counterbalance this factor (41). As is the case with blunt cardiac trauma, the anatomic position of cardiac structures determines their likelihood of injury owing to penetrating trauma. In decreasing order of frequency, penetrating cardiac injuries involve the right ventricle, left ventricle, right atrium, and left atrium. For the same reason, the left anterior descending coronary artery is more frequently injured than the right coronary artery (42). These injuries most often occur during diagnostic procedures, invasive monitoring, or other therapeutic interventions (40). Other causes of penetrating injury to the heart include ice picks, nonbullet projectiles, swallowed sewing needles, and inward displacement of fractured ribs with chest trauma (44). Cardiac injury should be presumed to be present until proven otherwise in patients presenting with penetrating wounds of the precordium, neck, axilla, back, or upper abdomen. Beck triad is frequently absent in patients with cardiac tamponade, and determination of jugular venous distension is particularly difficult in young children because of their short necks. In addition, if there is hypovolemia owing to acute blood loss, increased central venous pressure may not be seen with cardiac tamponade (41). Penetrating injuries to the chest are frequently associated with intra-abdominal injury. Ten percent to thirty percent of patients with penetrating cardiac wounds also have intra-abdominal injury. This is important because mortality is greater for patients with penetrating cardiac injury associated with intra-abdominal injury than for those with cardiac injury alone (41). Approximately 60% to 80% of patients with penetrating cardiac wounds die prior to reaching a hospital. For those who arrive in the emergency department with vital signs, or for those who had vital signs at the scene and lost them en route to the hospital, resuscitative intervention must be immediate (45). Emergency department echocardiography is available at some trauma centers, which has decreased the time to diagnosis of penetrating cardiac injury and has improved survival. Pericardiocentesis can rule in, but not rule out, cardiac tamponade because of the high frequency of false- negative P. Performing a subxiphoid pericardial window has been recommended by some to diagnose hemopericardium in selected stable trauma patients. Initial emergency management of penetrating cardiac trauma is the same for children and adults, following the principles of (a) maintaining a patent airway with adequate oxygenation and ventilation, (b) preservation of adequate tissue perfusion through rapid intravenous or intraosseous administration of fluids and blood, and (c) control of hemorrhage (12). As with adults, children with a penetrating cardiac wound should receive emergency thoracotomy in the emergency department whenever they are too unstable to be transported to the operating room. Pericardiocentesis must be viewed as a temporizing measure until thoracotomy and definitive cardiorrhaphy can be performed. The purpose of emergency department thoracotomy is reversal of cardiac tamponade, control of hemorrhage, open chest cardiac massage, and temporary cross-clamping of the descending aorta to redistribute blood flow to the coronary and cerebral circulations (46). Indications for emergency department thoracotomy in patients with blunt chest trauma are controversial because reported survival rates for both pediatric and adult patients are 0% to 2% with this procedure (47). This is unfortunate, because the vast majority of trauma deaths in the pediatric age group are due to blunt injury. Electrical Injury The first human fatality caused by alternating current (250 V) was reported in 1879. Among all age groups, >1,000 people die each year in the United States because of electrocution on the work site or in the home, and 150 to 300 others die annually from lightning strikes. Damage to human tissue from electricity is related to the amount and duration of current that passes through it. The amount of current involved (and resulting tissue damage) is variable, because tissue resistance varies. Overall, bone provides the greatest resistance to current flow, followed in descending order by fat, tendons, skin, muscle, vasculature, and nerves (49). Skin resistance is the most important factor determining the probability of cardiac injury from electrocution. Skin resistance can vary dramatically, depending on skin thickness, vascularity, and, most important, moisture. Although the resistance of dry skin may be 100,000 Ω, that of moist skin may be as little as 1,000 Ω. This 100-fold change in skin resistance may mean the difference between a painful electrical shock and the conduction of enough current to cause cardiac dysrhythmia (49). Because the forearm flexors are stronger than the extensors, this may prevent the child from being able to let go of an electrical source that he or she has grasped. Additionally, the heart is more sensitive to alternating current than direct current. Cardiac dysrhythmias are more likely to occur from household current at 60 Hz than electrical current of higher frequency. The path of the electrical current through the body also is a determinant of the likelihood of cardiac dysrhythmia. Proposed mechanisms include direct myocardial muscle damage, coronary artery endarteritis, and coronary artery spasm. Myocardial ischemia, resulting from decreased coronary perfusion during electrically induced dysrhythmia, also has been proposed as a mechanism of cardiac damage. The only reported pathologic finding at autopsy is petechial hemorrhages in the myocardium (50). Sudden death owing to low-voltage (110 to 380 V) alternating current found in the household is usually secondary to ventricular fibrillation. This increased enzymatic activity is hypothesized to have been stimulated by the electrical injury. The effects of cardiopulmonary resuscitation, as well as direct current countershock during resuscitative attempts, also potentially confuse the picture (50). Lightning is responsible for more deaths in the United States than any other natural disaster. Lightning-related injuries are most common during the summer, when there is more thunderstorm activity. Only 20% to 30% of people struck by lightning die, and they are usually the ones who experience immediate cardiopulmonary arrest. Lightning-related injuries differ in a number of ways from injuries owing to man-made electricity. Lightning strikes involve brief, massive surges of unidirectional current with an associated shock wave.

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Some controversy exists as is evident from a letter to the editor responding to this study with many important questions about the true effect of the drug buy viagra extra dosage 200 mg mastercard impotence at age 70, selection bias purchase genuine viagra extra dosage online impotence natural treatments, and variable expressions of the disease (71). Other investigators used neuroendocrine parameters along with echocardiographic evaluation of left ventricular function to determine whether or not to treat (75,76). Improvement was temporary for some of the patients who worsened after normalizing. Clearly, ongoing prospective studies of whom to treat, which parameters should be used to indicate the need for treatment, serial assessment, and clear measurements of outcomes are necessary. Ventricular tachyarrhythmias are ominous and warrant treatment with an appropriate agent. Again, serial-controlled double-blind studies are necessary to answer these questions. A 10-year follow-up study of members of the study groups showed that 26/28 patients in the treated group were alive versus 19/29 in the placebo group and the Kaplan– Meier survival was significantly lower in the placebo group ( p = 0. The timing of initiation of heart failure care is debatable and often is accomplished when there are obvious signs or symptoms of decreased cardiac function. The mechanism is thought to be related to the antifibrotic effects of this class of medications in combination. Cardiac and skeletal muscle functions evaluated ex vivo remained at 80% of normal with this therapeutic regimen whereas those mice not treated had a decline to 40% of normal (79). Some have noted that eplerenone, another aldosterone antagonist that does not have the gynecomastia effects that are seen in teen boys taking spironolactone, may be a valid substitute. An adult trial in patients with congestive heart failure showed reduced risk of death and fewer hospitalizations in the cohort studied (80). Additionally, the drug has been used safely in a pediatric population with systemic hypertension (81). This demonstrated decreased decline in circumferential strain compared to placebo after 12 months of therapy, but the study was unable to determine long-term effects on cardiac function or event-free survival (82). As therapy initiation is debated, detection of early cardiac changes is also being evaluated further. Patients <10 years of age exhibited abnormal strain, and older boys had a further decline in strain analysis. Inherent risks exist with long-term access including infection; however, inotropic support is associated with a multitude of potential side effects, yet potential exacerbation of arrhythmias is paramount. Nonetheless, inotropic support may allow for more time at home or school and may provide symptomatic relief (83). Clinical trials have been done sporadically in this patient population to assess novel therapies. Idebenone was found to be safe and well tolerated, and its use was associated with a trend toward an increase in strain of the left ventricular inferolateral wall. Additionally, from a respiratory standpoint, there was a significant increase in peak expiratory flow (84,85). While therapies may prove promising in mdx mouse studies, the benefits may not translate to human studies. A wide range of prospects exists, which include growth-modulating agents that increase muscle regeneration and delay fibrosis, antisense oligonucleotides (2′-O-methyl phosphorothioate backbone or morpholinos) with the capacity to skip exons and agents designed to suppress or stop codon mutations, gene-therapy approaches include strategies to replace or repair genes or use surrogate genes to replace defective ones, and stem cell therapy, especially using mesoangioblasts. If these treatments do not improve the myocardium, it is incumbent upon the pediatric cardiology community to evaluate and employ the most effective cardiac therapies possible so that the hopes for skeletal muscle improvements are not encumbered by congestive heart failure. Another question is whether we should reevaluate our therapeutic attitudes toward this population in light of improved pulmonary care, greater longevity, and possible improvements in skeletal muscle from gene therapy or exon-skipping treatments. In recent years, there is precedent for using ventricular assist devices for destination therapy, P. Subtle echocardiographic findings were present in 36% of the entire group (38% Duchenne, 34% Becker). These studies imply the need for evaluation of proven female carriers, even if they are asymptomatic. In addition, the clinical disease varies from very mild to very severe, meaning that patients may lose ambulation shortly after age 15 years or remain ambulatory for many decades (76). Again, the cardiac manifestations do not necessarily correlate with skeletal muscle progression and can be present sooner or later than the skeletal problems (96,97). They can have supraventricular arrhythmias including atrial fibrillation/flutter and can have ventricular arrhythmias, especially toward end-stage myocardial dysfunction (98,99,100,101,102). Use of mechanical support devices while awaiting transplant is desirable if necessary (see Chapter 21). In addition to neurologic and cardiac sequelae, respiratory failure from muscle weakness is a prominent issue with these patients. Some data advocate early intervention with noninvasive positive-pressure ventilation at the first signs of nocturnal hypoventilation. Positive-pressure ventilation physiologically reduces left ventricular afterload and is used for symptomatic respiratory relief of congestive heart failure in adults and adolescents. Noninvasive positive-pressure ventilation, even for periods of time acutely, may induce favorable hemodynamic effects on the left ventricle. However, theoretically, this intervention may elicit long-term improved hemodynamics (111). Some have no skeletal muscle dystrophin abnormality but have abnormalities of the cardiac dystrophin (18,113,114,115). Other studies have shown a mild decrease in skeletal muscle dystrophin with normal distribution, but no dystrophin was found in heart muscle (116). Of note, female carriers can show heart failure that is slowly progressive and often fatal (22). Patients may complain of sleep disturbances and gastrointestinal problems, both constipation and diarrhea, before developing muscle weakness. Progressive facial muscle, temporalis, sternocleidomastoid, and limb weaknesses develop along with cataracts (98). The muscle weakness is unique among the common muscular dystrophies in that it affects the distal muscles to the same extent or more than proximal muscles. Patients also can have frontal baldness, diabetes, and frequently, infertility (118). When Steinert described the disease, he noted that patients often had a slow pulse rate (119). These findings worsen with time and will be found in 75% of patients with myotonic dystrophy (17,99,117,121,124). Cardiac syncope and sudden death have been reported, indicating that these patients would have benefited from pacemaker implantation (117). Some patients will have late ventricular dilation, severe congestive failure, and arrhythmias. Pacemaker implantation can be lifesaving, but late deaths have happened even in patients who have pacemakers (8,126,127,128,129,130,131,132,133,134,135,136).