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First-order processes asymptotically approach completion buy cheap depakote 500 mg on-line medications bad for your liver, because a constant fraction of the drug buy 500mg depakote overnight delivery medicine zyprexa, not an absolute amount cheap depakote 500mg line treatment nail fungus, is removed per unit of time. However, after five half-lives, the process will be almost 97% complete (Table 11-4). For practical purposes, this is essentially 100%, and therefore there is a negligible amount of drug remaining in the body. Volume of Distribution The volume of distribution quantifies the extent of drug distribution. The physiologic factor that governs the extent of drug distribution is the overall capacity of tissues versus the capacity of blood for that drug. Overall tissue capacity for uptake of a drug is in turn a function of the total mass of the tissues into which a drug distributes and their average affinity for the drug. In compartmental pharmacokinetic models, drugs are envisaged as distributing into one or more “boxes,” or compartments. Rather, they are hypothetical entities that permit analysis of drug distribution and elimination and description of the drug concentration versus time profile. The volume of distribution is an “apparent” volume because it represents the size of these hypothetical boxes, or compartments, that are necessary to explain the concentration of drug in a reference compartment, usually called the central or plasma compartment. The volume of distribution, V ,d relates the total amount of drug present to the concentration observed in the central compartment: If a drug is extensively distributed, then the concentration will be lower relative to the amount of drug present, which equates to a larger volume of distribution. For example, if a total of 10 mg of drug is present and the concentration is 2 mg/L, then the apparent volume of distribution is 5 L. On the other hand, if the concentration was 4 mg/L, then the volume of distribution would be 2. Simply stated, the apparent volume of distribution is a numeric index of the extent of drug distribution that does not have any relationship to the actual volume of any tissue or group of tissues. It may be as small as plasma volume, or, if overall tissue uptake is extensive, the apparent volume of 670 distribution may greatly exceed the actual total volume of the body. In general, lipophilic drugs have larger volumes of distribution than hydrophilic drugs. Because the volume of distribution is a mathematical construct to model the distribution of a drug in the body, the volume of distribution cannot provide any information regarding the actual tissue concentration in any specific real organ in the body. However, this simple mathematical construct provides a useful summary description of the behavior of the drug in the body. In fact, the loading dose of drug required to achieve a target plasma concentration can be easily calculated by rearranging Equation 11-6 as follows: Table 11-4 Half-lives and Corresponding Percentage of Drug Removed Based on this equation, it is clear that an increase in the volume of distribution means that a larger loading dose will be required to “fill up the box” and achieve the same concentration. Therefore, any change in state because of changes in physiologic and pathologic conditions can alter the volume of distribution, necessitating therapeutic adjustments. Total Drug (Elimination) Clearance Elimination clearance (drug clearance) is the theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time. Total drug clearance can be calculated with pharmacokinetic models of blood concentration versus time data. Drug clearance is often corrected for weight or body surface area, in which case the units are mL/min/kg or mL/min/m ,2 respectively. This results in a smaller area under the concentration versus time curve, which equates to greater clearance (Fig. Nonetheless, estimation of drug clearance with these models has made important contributions to clinical pharmacology. In particular, these models have provided a great deal of clinically useful information regarding altered drug elimination in various pathologic conditions. Elimination Half-Life Although the elimination clearance is the pharmacokinetic parameter that best describes the physiologic process of drug elimination (i. The elimination half- life is the time during which the amount of drug in the body decreases by 50%. Although this parameter appears to be a simple summary of the physiology of drug elimination, it is actually a complex parameter, influenced by the distribution and the elimination of the drug, as follows: Figure 11-4 The plasma concentration (y-axis) versus time (x-axis) curve for two drugs which only differ in their elimination clearance. Notice that the areas under the curves are different, signifying that the drug that has the smaller area under the curve is more rapidly eliminated from the body than the drug that has the slower elimination clearance. For example, the elimination half-life of thiopental is prolonged in the elderly; however, the elimination clearance is unchanged and the volume of distribution is increased. Therefore, elderly patients need dosing strategies that31 accommodate for the change in the distribution of the drug rather than a decreased metabolism of the drug. In contrast, in patients with renal insufficiency, the increase in the elimination half-life of pancuronium is due to a simple decrease in renal elimination of the drug, and the volume of distribution is unchanged. In patients with hepatic disease, the elimination half-life of drugs metabolized or excreted by the liver is often increased because of decreased clearance, and, possibly, increased volume of distribution caused by ascites and altered protein binding. Therefore, when hepatic drug clearance is reduced, repeated bolus dosing or continuous infusion of such drugs as benzodiazepines, opioids, and barbiturates may result in excessive accumulation of drug as well as excessive and prolonged pharmacologic effects. Since recovery from small doses of drugs such as thiopental and fentanyl is largely the result of redistribution, recovery from conservative doses will be minimally affected by reductions in elimination clearance. In 673 patients with renal failure, similar concerns apply to the administration of drugs excreted by the kidneys. It is almost always better to underestimate a patient’s dose requirement, observe the response, and give additional drug if necessary. Nonlinear Pharmacokinetics The physiologic and compartmental models thus far discussed are based on the assumption that drug distribution and elimination are first-order processes. Therefore, their parameters, such as clearance and elimination half- life, are independent of the dose or concentration of the drug. Elimination of drugs involves interactions with either enzymes catalyzing biotransformation reactions or carrier proteins for transmembrane transport. If sufficient drug is present, the capacity of the drug-eliminating systems can be exceeded.

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Metoprolol Metoprolol is relatively selective for β -adrenoceptors but has no intrinsic1 sympathetic or membrane stabilization activity discount depakote 500mg amex treatment keloid scars. Like propranolol buy depakote 250 mg online keratin intensive treatment, oral metoprolol is rapidly absorbed trusted depakote 500mg medicine vocabulary, but the drug does undergo first-pass hepatic metabolism by cytochrome P450 2D6 that limits its initial availability. Metoprolol’s half-life of 3 to 4 hours allows twice-per-day dosing in patients with normal metabolism, but an extended release form is also available that allows once-daily administration. The half- life of metoprolol is doubled in patients who are poor cytochrome P450 2D6 metabolizers; these individuals are approximately fivefold more likely to develop adverse side effects after oral metoprolol administration. The drug has a longer half-life (6 to 9 hours) than metoprolol that facilitates a daily 840 dosing regimen. The liver does not metabolize atenolol, most of which is excreted in its original form by the kidney. As a result, the dose of atenolol must be reduced in patients with moderate to severe renal insufficiency. The lack of first-pass hepatic metabolism reduces variability in plasma atenolol concentrations between patients after oral administration. The chemical structure of esmolol1 is very similar to that of propranolol and metoprolol, but esmolol contains an additional methylester group that facilitates the drug’s rapid metabolism via hydrolysis by red blood cell esterases, resulting in an elimination half-life of approximately 9 minutes. The quick onset and rapid metabolism of esmolol makes the drug very useful for the treatment of acute tachycardia and hypertension during surgery. Esmolol is most often administered as an intravenous bolus, which causes almost immediate dose-related decreases in heart rate and myocardial contractility; arterial pressure most often falls as a result of these direct negative chronotropic and inotropic effects. Esmolol is often used to attenuate the sympathetic nervous system response to laryngoscopy, endotracheal intubation, or surgical stimulation, particularly in patients with known or suspected coronary artery disease who may be at risk for acute myocardial ischemia. Esmolol is also useful for rapid control of heart rate in patients with supraventricular tachyarrhythmias (e. Finally, esmolol effectively blunts the sympathetically mediated tachycardia and hypertension that occur shortly after the onset of seizure activity during electroconvulsive therapy. Because esmolol does not appreciably block β -adrenoceptors due to its relative β -2 1 selectivity, hypotension is more commonly observed after administration of this drug compared with other nonselective β-blockers. Labetalol Labetalol is composed of four stereoisomers that inhibit α- and β- adrenoceptors to varying degrees. The net effect of this mixture is a drug that selectively inhibits α -adrenoceptors while1 simultaneously blocking β - and β -adrenoceptors in a nonselective manner. Blockade of the α -adrenoceptor causes arteriolar1 841 vasodilation and decreases arterial pressure through a reduction in systemic vascular resistance. This property makes the drug very useful for the treatment of perioperative hypertension. Despite its nonselective β-blocking properties, labetalol is also a partial β -adrenoceptor agonist; this latter2 characteristic also contributes to vasodilation. Labetalol-induced inhibition of β -adrenoceptors decreases heart rate and myocardial contractility. Stroke1 volume and cardiac output are essentially unchanged as a result of the combined actions of labetalol on α - and β -adrenoceptors. Unlike other1 2 vasodilators, labetalol produces vasodilation without triggering baroreceptor reflex tachycardia because the drug blocks anticipated increases in heart rate mediated through β -adrenoceptors. This latter action is beneficial for the1 treatment of hypertension in the setting of acute myocardial ischemia. Labetalol is also useful for controlling arterial pressure without producing tachycardia in patients with hypertensive emergencies and those with acute aortic dissection. Labetalol has been shown to attenuate the sympathetic nervous system response to laryngoscopy and endotracheal intubation, although the drug’s relatively long elimination half-life (approximately 6 hours) limits its utility in this setting. Carvedilol Carvedilol is another third-generation β-blocker that inhibits β -, β -, and α -1 2 1 adrenoceptors. Carvedilol exerts important antioxidant and anti-inflammatory effects: the drug not only suppresses production of reactive oxygen species, but it also is a scavenger of these free radical intermediates. The antioxidant and anti-inflammatory actions of carvedilol inhibit the uptake of deleterious reduced low-density lipoproteins into coronary vascular endothelium and protect myocardium against ischemia- reperfusion injury, in part by attenuating recruitment, chemotaxis, and activation of cytotoxic neutrophils. The phosphodiesterase inhibitors currently in clinical use are somewhat isoenzyme-selective at lower doses, but this selectivity is lost when higher doses of these medications are used. This positive lusitropic effect serves to improve diastolic function in many patients with heart failure. Milrinone is 15- to 20-fold more potent than the chemically similar compound inamrinone. Levosimendan is used extensively in Europe for short-term treatment of heart failure123 and for inotropic support in patients undergoing cardiac surgery. Levosimendan exerts its positive inotropic and vasodilator actions through three major mechanisms. This action prolongs the interaction between actin and myosin filaments and enhances the rate and extent of myocyte contraction to increase myocardial contractility. The Ca2+-dependence of levosimendan–TnC binding prevents relaxation abnormalities that would otherwise be expected to occur. The modest reductions in arterial pressure observed with levosimendan are similar to those produced by milrinone and usually respond to volume administration. Digitalis glycosides are naturally occurring substances found in several plant species including “foxglove” (Digitalis purpurea). The most commonly prescribed digitalis glycosides are digoxin and digitoxin, but a number of related compounds are also used clinically. As a result, administration of+ + K is capable of reversing digitalis toxicity resulting from hypokalemia.

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It is well known that the sine qua non of opioid intoxication is a terminal lethal apnea purchase depakote cheap treatment 4 pimples. Patient characteristics purchase 250mg depakote with amex medicine education, which increase the risk of21 3940 sedation and respiratory depression depakote 250 mg overnight delivery medications known to cause pancreatitis, are listed in Table 55-9. Recommendations, which can decrease the risk of opioid-related respiratory depression, include the liberal use of opioid-sparing multimodal pharmacotherapy, regional anesthesia techniques, and the continuous monitoring of patient ventilation with pulse oximetry and capnography, particularly in the high-risk individual. See Table 55-4 for recommendations for multimodal therapy for some commonly performed surgeries. A more comprehensive discussion of this topic is beyond the scope of this chapter and the reader is referred to the excellent review by Javaheri and Randerath. Finally, opioid analgesics22 have profound immunomodulatory effects, which include inhibition of cellular and humoral immune functions, depressed natural killer cell activity, promotion of angiogenesis, and inhibition of apoptosis. Such effects can be beneficial or deleterious depending upon the clinical situation. Although the plasma half-life of the drug is approximately 2 hours its analgesic duration of action is closer to 4 to 5 3942 hours. Morphine undergoes hepatic glucuronidation to morphine-6- glucuronide and morphine-3-glucuronide, both of which are cleared by the kidney. Morphine-6-glucuronide is an active metabolite of morphine and is thought to be responsible for most of the analgesia associated with chronic dosing of the drug. Morphine-3-glucuronide, on the other hand, is considered to be devoid of analgesic activity. With chronic dosing these metabolites can accumulate and can be particularly problematic in patients with renal failure. Dosing adjustment is therefore necessary and monitoring of side effects is important. Morphine-6-glucuronide contributes to side effects such as drowsiness, nausea and vomiting, coma, and respiratory depression. Morphine-3-glucuronide, on the other hand, is thought to cause agitation, myoclonus, delirium, and hyperalgesia. Hydromorphone is a semisynthetic opioid that has four to six times the potency of morphine. Whereas the oral bioavailability of the drug is reported to be 20% to 50%, its bioavailability via the subcutaneous route is 78%, making it the ideal drug for long-term subcutaneous administration in the opioid- tolerant patient. The active metabolites are dihydromorphine and dihydroisomorphine and the inactive metabolite is hydromorphone-3-glucuronide. Although hydromorphone has traditionally been the preferred opioid for patients with acute pain and impaired kidney function, evidence suggests that hydromorphone-3-glucuronide can accumulate in those with renal failure and may contribute to side effects such as neuroexcitation and cognitive impairment. Opioid-related side effects such as nausea, vomiting, sedation, cognitive impairment, and pruritus are reported to be less intense with hydromorphone vis-à-vis morphine. In fact, the incidence of pruritus following neuraxial administration of hydromorphone is reported to be approximately 5% versus the 11% to 77% range reported for neuraxial morphine. In the United States, codeine is available for oral, subcutaneous, and intramuscular administration. In poor metabolizers and ultrarapid metabolizers codeine is contraindicated because of lack of efficacy in the former and the potential for toxicity in the latter (Table 55-10). Please refer to the section Strategies for Acute Pain Management for further details. Fentanyl, a synthetic opioid chemically related to the phenylpiperidines, is a relatively selective μ receptor agonist, which is considered to have 80 times the potency of morphine following intravenous administration. It is extensively metabolized in the liver to norfentanyl and other inactive metabolites, which are excreted in the urine and bile. The drug is available for intravenous, subcutaneous, transdermal, transmucosal, and neuraxial administration. The 3944 transdermal administration of fentanyl using iontophoresis (Ionsys, The Medicine Company) is a novel on-demand drug delivery system that does not require venous access. Ionsys is designed to deliver a 40-μg dose of fentanyl over a 10-minute period of time following activation of the dose button and is strictly intended for inpatient use only. Sufentanil, alfentanil, and remifentanil are analogues of fentanyl that have analgesic effects similar to those of morphine and the other μ receptor agonists. Sufentanil has approximately 1,000 times the potency of morphine and is primarily used in the operating room either intravenously or neuraxially. Like fentanyl, sufentanil is very lipophilic, and although their28 pharmacokinetic and pharmacodynamic profiles are similar, sufentanil has a smaller volume of distribution and shorter elimination half-life. The high28 intrinsic potency of sufentanil makes it an excellent choice for epidural analgesia in the opioid-dependent patient. Remifentanil is rapidly degraded by tissue and plasma esterases, which accounts for its incredibly short terminal elimination half-life of 10 to 20 minutes. One disadvantage, however, is that discontinuation of a remifentanil infusion results in rapid loss of analgesia. The drug is recommended for the short-term management of acute pain only and has absolutely no role in the management of chronic pain. The drug is biotransformed by the liver to normeperidine, a potentially neurotoxic metabolite, which has a 12- to 16-hour half-life. Repetitive dosing of meperidine can cause accumulation of normeperidine, which may precipitate tremulousness, myoclonus, and seizures. It is therefore recommended that the total daily intravenous dose in an otherwise healthy adult without renal or central nervous system disease should not exceed 600 mg/day and should not be administered for longer than 48 hours.

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Treatment starts with correcting any predisposing disease (hypoglycemia purchase depakote online from canada symptoms high blood pressure, polycythemia) and improving poor tissue oxygenation buy depakote 250mg otc treatment for shingles. However purchase depakote 250 mg online medicine cabinet home depot, the goals are to achieve a PaO2 of 60 to 100 mmHg and maintain normocapnia. Pulmonary arterial pressure changes in human newborn infants from birth to 3 days of age. Additional vasodilator therapy with prostacyclin (epoprostenol), phosphodiesterase inhibitors (sildenafil), and endothelin receptor antagonists (bosentan) has enjoyed varying levels of success beyond the neonatal period, into infancy. Success in treatment, and survival, varies directly with correction the underlying cause. Use of dobutamine in a normotensive patient may provide inotropy and decreased systemic vascular resistance, which could increase right-to-left shunting and offload the right ventricle. Therapy is now often guided with13 2936 the use of point-of-care echocardiography as its availability continues to grow and technology improves. Preoperative assessment of the echocardiogram14 by the pediatric anesthesiologist may help predict what problems may be encountered in the operative environment. Interference with the normal maternal placental circulation in the third trimester may cause fetal hypoxia. Fetal hypoxia can result in an increase in the amount of muscle in the blood vessels of the distal respiratory units. The fetus breathes in utero so the meconium mixed with amniotic fluid enters the pulmonary system. Meconium aspiration can be a marker of chronic fetal hypoxia in the third trimester. This condition is different from the meconium aspiration that occurs during delivery. Meconium at birth is thick and tenacious, and mechanically obstructs the tracheobronchial system. Meconium aspiration syndrome leads to varying degrees of respiratory failure, which can be fatal in spite of all treatment modalities. Current recommendations for intubation and suctioning for newborns at delivery with frank meconium aspiration or meconium staining (approximately 10% of newborns) emphasize a conservative approach. If meconium is present and the newborn is depressed, the trachea should be intubated and meconium and other aspirated material suctioned from beneath the glottis. If there is bradycardia, administer positive pressure ventilation and consider suctioning again later once the neonate is stabilized. In utero, the kidneys receive only about 3% of the cardiac output, whereas they will receive about 25% of cardiac output in adulthood. The systemic arterial pressure increases and the renal vascular resistance decreases, and the kidneys now receive a progressively increased part of the cardiac output. Part of the improvement in renal function is the establishment of gradients in the medullary interstitium that promotes resorption of sodium. This maturation continues in the normal, full-term neonate and the kidneys are approximately 60% mature by 1 month of age. Urine output is low in the first 24 hours, but increases to an expected level of at least 1 to 2 mL/kg/hr. Urine output, after the first day of life, of less than 1 mL/kg/hr should be considered indicative of either hypovolemia or decreased renal function from another cause. Despite rapid maturation of renal function and increased capacity of the neonatal kidneys, they still have limitations. From an anesthetic standpoint, the half-life of medications excreted by means of glomerular filtration will be prolonged. The relative inability to conserve water means that neonates,19 especially in the first week of life, tolerate fluid restriction poorly. In addition, the inability to excrete large amounts of water means the newborn tolerates fluid overload poorly. The newborn kidney is better able to conserve sodium than excrete sodium, making hypernatremia a risk if excess sodium is administered. However, because of the lack of tonicity in the medullary interstitium shortly after birth, there will be some obligate sodium loss in the first days of life. Sodium loss improves as the countercurrent multiplier is developed in the interstitium. This dramatic shift is beneficial to the child, especially in increasing the mobility of reserves in the face of dehydration. Thus, an infant or child is better situated to maintain intravascular volume in these situations than a neonate. The plasma water is usually about 5% of body weight and the related blood volume, assuming a hematocrit of 45%, is about 8% of body weight in infants and children. The water content is slightly higher in neonates and may approach 10% of body weight in preterm neonates. The interstitial fluid, usually about 15% of body weight, can demonstrate large increases in disease states such as liver failure, heart failure, renal failure, and other causes fluid retention, such as pleural effusions or ascites. Any condition that decreases oncotic pressure, such as loss of albumin in liver failure, promotes the loss of fluid into the interstitial fluid. On the other hand, raised hydrostatic pressures, such as seen in heart failure, can result in fluid leaving the plasma and accumulating in the interstitial space. Conditions that result in translocation of fluid from the plasma to the interstitial spaces, whether because of decreased oncotic pressure or increased hydrostatic pressure, are of significant consequence to the neonate. Loss of fluid from the plasma volume compromises the intravascular volume, potentially decreasing the perfusion of vital organs and systems.

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