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Effect of Rate of Infusion on Plasma Level Rate of infusion (1<0) does determine plasma level at steady state generic super p-force oral jelly 160 mg otc. If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled. Plotting dose against plasma concentration yields a straight line (linear kinetics). In some situations, it may be necessary to give a higher dose (loading dose) to more rapidly achieve effective blood levels. Effect of a Loading Dose on the Time Required to Achieve the Minimal Effective Plasma Concentration • Such loading doses are often one time only and (as shown in Figure I-1-14) are esti- mated to put into the body the amount of drug that should be there at a steady state. An important element concerning drug biodistribution is permeation, which is the ability to cross membranes, cellular and otherwise. Ionization affects permeation because unionized molecules are minimally water soluble but do cross biomembranes, a feat beyond the capacity of ionized molecules. Figure 1-1-2 illustrates the principles associated with ionization, and Table 1-1-1 summarizes the three basic modes of transport across a membrane: passive, facilitated, and active. Because absorption may not be 100% efficient, less than the entire dose administered may get into the circulation. Any orally administered hydrophilic drug will be absorbed first into the portal vein and sent directly to the liver, where it may be partially deactivated. The distribution of a drug into the various compartments of the body is dependent upon its permeation properties and its tendency to bind to plasma proteins. The placental and blood-brain barriers are of particular importance in considering distribution. The Vd is a kinetic parameter that correlates the dose given to the plasma level obtained: the greater the Vd value, the less the plasma concentration. As well as having the ability to cross the blood-brain barrier, lipophilic drugs have a tendency to be deposited in fat tissue. Because with each administration more lipophilic drug is absorbed into the fat, the duration of action of such a drug increases with the number of doses until the lipid stores are saturated. Biotransformation is the metabolic conversion of drugs, generally to less active compounds but sometimes to iso-active or more active forms. The transformations include hydroxylations and dealkylations, as well as the promotion of oxidation/reduction reactions. The conjugation may be glucuronidation, acetylation, sulfation, or addition of glutathione. I Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e. Renal clearance (C1 ) represents the volume of blood cleared by the kidney per unit time and is a R I constant for drugs with first-order elimination kinetics. The time to reach a I steady state is dependent only on the elimination half-life. It is independent of dose and frequency of , administration or rate of infusion (see Figures 1-1-12,-13, and -14). Agonist: A drug is called an agonist when binding to the receptor results in a response. Antagonist: A drug is called an antagonist when binding to the receptor is not associated with a response. The drug has an effect only by preventing an agonist from binding to the receptor. Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can Definitions reveal information about affinity, potency, and efficacy of these agonists. Affinity is inversely related to Parallel and Nonparallel D-R Curves the Kd of the drug. V Log Dose of Drug Efficacy: the maximal effect Log Dose of Drug an agonist can achieve at the highest practical concentration. Comparison of D-R,Curves for Two Drugs Acting Notice the analogy with the on the Same (left panel) and on Different Vmax used in enzyme kinetic (right panel) Receptors studies. When two drugs interact with the same receptor (same pharmacologic mechanism), the D-R curves will have parallel slopes. In terms of potency, drug A has greater potency than drug B, and X is more potent than Y. Full and Partial Agonists Full agonists produce a maximal response-they have maximal efficacy. Partial agonists are incapable of eliciting a maximal response and are less effectivethan full agonists. In Figure 1-2-2, drug B is a full agonist, and drugs A and C are partial agonists. Efficacy and Potency of Full and Partial Agonists Drug A is more potent than drug C, and drug B is more potent than drug C. However, no general comparisons can be made between drugs A and B in terms of potency because the former is a partial agonist and the latter is a full agonist.

In addition cheap 160mg super p-force oral jelly fast delivery, the brain uptake of many P-gp substrates increased by inhibiting P-gp activity or in Mdr1a(–/–) and Mdr1a/1b(–/–), but not Mdr1b(–/–), (195,198–200). Respiratory depression, an opioid central nervous system effect, produced by loperamide was induced by the simultaneous administration of quinidine to healthy volunteers (217). Cyclosporin A sig- 11 nificantly increased the brain concentration of C-verapamil (218). The concentration of etoposide in the cerebrospinal fluid in the Mdr1a/1b/Mrp1(–/–) mice was 10-fold greater than that in Mdr1a/1b(–/–) mice, while there was no significant difference in the plasma concentration (224). The efflux transport of E217bG from the brain was significantly delayed in Mrp1(–/–) mice (225), while there was no significant change in the elimination of E217bG from the cere- brospinal fluid (226). It turned out that the biliary excretion of amphipathic organic anions, such as glutathione conjugates, glucuronides, and relatively lipophilic nonconjugated organic anions, is mediated by primary active transport, and deficient in the mutant strains (228,230–232). In the small intestine, the Mrp2 expression is higher in the duodenum than that in the jejunum in rodent (234,238) and higher or similar to that in the ileum in human (204,206). Functional analysis was performed in vitro using Ussing chamber and everted sac (240). Furthermore, hepatic expression of Mrp3 was subjected to induction by bile duct ligation and the treatments of a-naphthylisothiocyanate, phenobarbital, or bilirubin in rats (249), while that of Mrp3 was unchanged by bile duct ligation in mice (245). Using Mrp3(–/–) mice, it was shown that Mrp3 is involved in the sinusoidal efflux of glucuronide conjugates of morphine, acetoa- minophen, and 4-methylumbelliferone in the liver (256–258). The membrane localization of Mrp4 is tissue dependent: sinusoidal membrane in the hepatocytes (261), brush border membrane of the renal tubules (262,263), luminal membrane of the brain capillaries (262), and basolateral membrane of the choroid epithelial cells (262). In addition, the concen- tration of topotecan in the cerebrospinal fluid was markedly increased in Mrp4(–/–) mice (262). In the kidney, the renal clearance of furosemide with regard to the plasma concentration was decreased, and the kidney concentrations of hydro- chlorothiazide, adefovir, and tenofovir were significantly increased in Mrp4(–/–) mice (267,268). Digoxin-Quinidine and Digoxin-Quinine Digoxin undergoes both biliary and urinary excretion in human (291). The drug- drug interactions between digoxin and quinidine or quinine (a stereoisomer of quinidine) are very well known (291). The degree of inhibition by quinidine and quinine of the biliary and urinary excretion of digoxin are different; quinine reduced the biliary excretion clearance of digoxin to 65% of the control value, while quinidine reduced both the biliary and renal clearance to 42% and 60%, respectively (Fig. In proportion to the reduction in total body clearance, coadministration of quinine and quinidine increases the plasma concentration of digoxin by 1. In addition to these agents, verapamil also has an inhibitory effect, but specifically on the biliary excretion (292), has only a slight inhibition of renal excretion (293). No inhibitory effect of quinine and quinidine was obtained in isolated human hepatocytes at a concentration of 50 mM (294), whereas stereoselective inhibition of quinine and quinidine has been observed in isolated rat hepatocytes (295). Quinine inhibits uptake into isolated hepatocytes at the concentration of 50 mM, while the effect of quinidine was minimal (at most a 20% reduction) Figure 7 Change in the biliary and renal clearance of digoxin caused by quinidine or quinine treatment. After a steady state concentration of quinine or quinidine was achieved by multiple oral administrations, the plasma concentration and biliary and urinary excretion of digoxin after oral administration were measured in healthy volunteers. On the basis of the animal (209,210) and clinical (216) observations, P-gp has been suggested to be the candidate transporter for the biliary and urinary excretion of digoxin. The role of P-gp in this drug-drug interaction has been examined using the Mdr1a(–/–) mice (297). Coadministration of quinidine caused a 73% increase in the plasma concentration of digoxin in normal mice, whereas it had little effect (20% increase) in the Mdr1a(–/–) mice at the same plasma concentration of quinidine (Fig. The drug-drug interaction between digoxin and quinidine has been also suggested in the intestinal absorption of digoxin in rats (298). These results indicate that digoxin undergoes active efflux in the small intestine (298). Indeed, the intestinal secretion of digoxin was significantly reduced in Mdr1a(–/–) and Mdr1a/1b(–/–) mice (209,210). Therefore, the interaction of quinidine and digoxin involving intestinal absorp- tion may be due to the inhibition of P-gp function. Fexofenadine-Itraconazole/Verapamil/Ritonavir Fexofenadine is mainly excreted into the bile and urine without metabolism. On the basis of in vivo study using Mdr1a and Mdr1a/1b(–/–) mice, it has been shown that P-gp limits intestinal absorption and brain penetration of fexofenadine, but makes only a limited contribution to the biliary and urinary excretion (212,302). Fur- thermore, inhibition of P-gp in the intestine allowed detection of saturable uptake of fexofenadine and inhibition by Oatp inhibitor in rats (88). Drug-drug interactions involving fexofenadine have been reported which includes not only interactions with concomitant drugs, but also those with fruit juices. Itraconazole and verapamil did not affect the renal clearance of fexofenadine, while the effect of ritonavir on the renal clearance was not examined. Considering the absence of the effect on the renal clearance, these interactions will include the inhibition of intestinal 170 Kusuhara and Sugiyama efflux and/or hepatobiliary transport. Since itraconazole [Ki * 2 mM (306,307)], verapamil [Ki * 8 mM (308)], and ritonavir [Ki * 4 and 12 mM (306,309)] are inhibitors of P-gp, it is possible that these drug-drug interactions involve inhi- bition of P-gp-mediated efflux in the small intestine. Cyclo- sporin A also increased the total area under the plasma concentration–time curve of repaglinide by 2. Rifampicin is a well-known drug causing induction of drug metabolizing enzymes and transporters by repeated adminis- tration, but it may also inhibit hepatic uptake process by a concomitant usage.

Bottom: “Boot” shaped heart and decreased pulmonary vascular markings in a cyanotic patient with tetralogy of Fallot purchase 160 mg super p-force oral jelly visa. This group of congenital lesions can be divided by physiological principles into those that induce a volume load on the heart (most commonly due to a left-to-right shunt but also due to atrioventricular valve regurgitation or to abnormalities of the myocardium itself-the cardiomyopathies) and those that induce a pressure load on the heart (subvalvar, valvar or great vessel stenoses). The chest X-ray is a useful tool for differentiating between these two major categories, since heart size and pulmonary vascular markings will usually both be increased in the left-to-right shunt lesions. Classification of acyanotic congenital heart defects based on physiologic perturbation. The common pathophysiologic denominator in this group of lesions is a communication between the left and right sides of the circulation and the shunting of fully oxygenated blood back into the lungs. Although pulmonary Fetal Circulation & Congenital Heart Disease - Daniel Bernstein, M. As pulmonary resistance drops over the first month of life, the left-to-right shunt increases, and so does the intensity of the murmur and the symptoms. The increased volume of blood in the lungs is quantitated by pediatric cardiologists as the pulmonary to systemic blood flow ratio or Qp:Qs. This increase in pulmonary blood flow decreases pulmonary compliance and increases the work of breathing. Fluid leaks into the interstitium or alveoli causing pulmonary edema and the common symptoms: tachypnea, chest retractions, nasal flaring, poor feeding and wheezing (Table 1). In order to maintain a left ventricular output which is now several times normal (although most of this output is ineffective, since it returns to the lungs) heart rate and stroke volume must increase, mediated by an increase in sympathetic stimulation. The increased work of breathing and the increase in circulating catecholamines lead to an elevation in total body oxygen requirements, taxing the oxygen delivery capability of the circulation. Thus, the common symptoms of tachycardia, sweating, irritability and failure to thrive. The combination of left-to-right shunt and valve regurgitation increases the volume load on the heart and usually leads to earlier presentation and more severe symptomatology. As opposed to the left-to-right shunts, the cardiomyopathies (see below) cause heart failure directly due to diminished cardiac muscle function, leading to increased atrial and ventricular filling pressures, and to pulmonary edema secondary to increased capillary pressure. The common pathophysiologic denominator of these lesions is that, unless the stenosis is severe, cardiac output is maintained, thus, in children, symptoms of heart failure are often not present. This compensation is accomplished by a marked increase in cardiac wall thickness (hypertrophy). If the ductus arteriosus is still open, the oxygen saturation may be Fetal Circulation & Congenital Heart Disease - Daniel Bernstein, M. Coarctation of the aorta may present solely with a systolic murmur and with diminished pulses in the lower compared with the upper extremities. Thus, it is important to always palpate both the femoral and either the brachial or radial pulses simultaneously during a routine screening examination of any infant or child. A coarctation may be localized to the area of the descending aorta immediately opposite the ductus arteriosus (juxtaductal coarctation). In these patients, in the first few days or weeks of life the ductus arteriosus may remain partially patent and will serve as a conduit for blood flow to partially bypass the obstruction at the level of the coarctation. In more severe forms, coarctation involves hypoplasia of the transverse aortic arch, in which case it presents with a more significant obstruction to blood flow and usually causes heart failure and signs of poor perfusion in the neonatal period. This group of congenital heart lesions can be divided by physiological principles into those associated with decreased pulmonary blood flow (e. The chest X-ray is again an important primary initial diagnostic tool for differentiating between these two major categories. There are two basic pathophysiologic elements which underlie all of these lesions: First, is an obstruction to pulmonary blood flow at some level (tricuspid valve, sub- pulmonary muscle bundles, pulmonary valve, main or branch pulmonary arteries). It is important to remember that even with severe pulmonic stenosis, systemic desaturation will not occur unless there is right-to-left shunting at some level. Classification of cyanotic congenital heart lesions based on physiologic perturbation. In these lesions, the degree of clinical cyanosis will depend on the degree of obstruction to pulmonary blood flow. If the obstruction is mild, cyanosis may not be present at rest, but only with stress (these hypercyanotic episodes are known as "Tet spells"). If the obstruction is severe, pulmonary flow may be totally dependent on the patency of the ductus arteriosus. These infants present with profound cyanosis in the newborn period and require pharmacologic manipulation (prostaglandin E1) to maintain ductal patency until surgical intervention. Unlike the previous group of lesions, pulmonary blood flow is more than adequate in this group, yet because of the defect only a small portion of this oxygenated blood can enter the systemic circulation. Deoxygenated blood from the body returns to the right side of the heart and is pumped directly back to the body again. Oxygenated blood from the lungs returns to the left side of the heart and is pumped back into the lungs. If not for the persistence of fetal pathways such as the foramen ovale and ductus arteriosus, this lesion would not be compatible with life. These pathways allow for some degree of both left-to-right and right-to-left mixing of oxygenated and deoxygenated blood until surgical intervention can occur.

We can mention that he de- signed the frst hydroelectric power plant in Niagara Falls in 1895 order 160 mg super p-force oral jelly otc. Electrons were emitted and Nikola Tesla accelerated by the electrical feld in his “Tesla coil”. Tesla managed to obtain images of the human body with this radiation – the shadowgraphs. He also sent some of his images to Roentgen shortly after Roentgen published his discov- ery. Tesla gave Roentgen full credit for the fnding and never attempted to proclaim priority. In the magazine “Electrical Review” for 1896 some X-ray observations by Tesla were pub- lished. He described some clinical benefts of x-rays – for example; determination of for- eign body position and detection of lung diseases. Furthermore, during the next 50 years x-ray pictures and fuoroscopy played an important role in the treatment of tuberculosis. In the period before streptomycin (1947) the only treatment was pneumothorax – an attempt to let the lung rest by accumulation of air in the pleural cavity – and the lung more or less collapsed. We can note that no dosimetry was carried out at the time – and the doses now quoted are very much speculations (see page 210). The idea was to introduce elements that could absorb ef- fciently the x-rays and thus enhance the contrast. The main absorption mechanism is the photoelectric effect – which varies consider- ably with the atomic number (approximately as Z4). In a complex mixture of elements like that found in the organs of a patient, the degree of attenuation varies with the average of the atomic number of all the atoms involved. If two organs have similar densities and similar average atomic numbers, it is not possible to distinguish them on a radiograph, because no natural contrast exists. For example, it is not possible to identify blood vessels within an organ, or to demonstrate the internal structure of the kidney, without artifcially altering the electron density and absorption. In the period from 1931 until it was stopped2 2 – 10 million patients worldwide have been treated with Thorotrast. In 1910 barium sulfate was introduced as contrast agent for gastrointestinal diagnosis. In 1924 the frst imaging of the gallbladder, bile duct and blood vessels took place. This tube was superior to other tubes at the time because of; 1) its high vacuum and 2) a heated flament as the source for electrons. He was able to show that a narrow catheter could be advanced from a vein in the arm into the right atrium of the heart, a distance of almost two-thirds of a meter. Obviously, this constituted a remarkable advance – and could be visual- ized by contrast compounds. This opened the way for angiography which al- lowed the routine imaging of blood vessels and the heart. In connection to this “break-through” in medical im- aging we have to mention the forerunner of the tech- nique called “planigraphy”. In 1948 Marius Kolsrud at the University of Oslo pre- sented a master thesis with the title; Godfrey Hounsfeld Allan Cormack Røntgen-skikt-avbildning. Kolsrud made equipment that made it possible to take x-ray pictures of a single plane in the object. Consequently, structures in the focal plane appear sharper, while structures in other planes appear blurred. It is thus possible to select different focal planes which contain the structures of interest. This method was used for chest x-ray pictures in connection with tuberculo- sis for a number of years. This technique uses x-ray fuo- roscopy to guide the compression of plaques and minimize the dangerous constriction of the heart vessels. The signal from the x-ray system is con- verted to a digital picture which can then be enhanced for clearer diagnosis Andreas Gruentzig and stored digitally for future review. The physical basis for an x-ray picture The x-ray picture is a shadow picture of the part of the body that is between the x-ray tube and the flm. Only the x-ray photons that penetrate the object and reach the flm can give a signal or blacken- ing of the flm. To see into the body we must have “something” that can penetrate the body – come out again – and give information.

From this equation discount super p-force oral jelly 160 mg on-line, it is evident that heat can be completely converted into work only if the heat is rejected into a reservoir at absolute zero temperature. Although objects can be cooled to within a very small fraction of absolute zero, absolute zero cannot be attained. In fact, the first law could lead us to the erroneous conclusion that animals should be able to function without a source of external energy. The body takes in energy that is in the chemical bonds of the food molecules and converts it to heat. If the weight and the temperature of the body remain constant and if the body performs no external work, the energy input to the body equals exactly the heat energy leaving the body. We may suppose that if the heat outflow could be stopped—by good insulation, for example—the body could survive without food. The need for energy is made apparent by examining the functioning of the body in the light of the Second Law of Thermodynamics. A single protein molecule in the body may consist of a million atoms bound together in an ordered sequence. Their specialized functions within the body depend on a specific structure and location. We know from the Second Law of Thermodynamics that such a highly ordered system, left to itself, tends to become disordered, and once it is disordered, it ceases to function. For example, the blood circulating in veins and arteries is subject to friction, which changes kinetic energy to heat and slows the flow of blood. The concentration of minerals inside a cell differs from that in the surrounding environment. Finally, cells that die must be replaced, and if the animal is growing, new tissue must be manufactured. For such replacement and growth, new proteins and other cell constituents must be put together from smaller, relatively more random subcomponents. Thus, the process of life consists of building and maintaining ordered structures. The situation is somewhat analogous to a pillar made of small, slippery, uneven blocks that tend to slide out of the structure. The work necessary to maintain the ordered structures in the body is obtained from the chemical energy in food. Except for the energy utilized in external work done by the muscles, all the energy provided by food is ulti- mately converted into heat by friction and other dissipative processes in the body. Once the temperature of the body is at the desired level, all the heat generated by the body must leave through the various cooling mechanisms of the body (see Chapter 11). The heat must be dissipated because, unlike heat engines (such as the turbine or the steam engine), the body does not have the ability to obtain work from heat energy. Even if the body did have mechanisms for using heat to perform work, the amount of work it could obtain in this way would be small. The temperature differences in the body are small—not more than about 7 C◦ between the interior and the exterior. With the interior temperature T at 310 K (37◦C) and the exterior 1 temperature T1 at 303 K, the efficiency of heat conversion to work would be (from Eq. Of all the various forms of energy, the body can utilize only the chemical binding energy of the molecules which constitute food. The body does not have a mechanism to convert the other forms of energy into work. A person could bask in the sun indefinitely, receiving large quantities of radiant energy, and yet die of starvation. As animals use chemical energy, so plants utilize solar radiation to provide the energy for the ordering processes necessary for life. The organic materials produced in the life cycle of plants provide food energy for herbivorous animals, which in turn are food for the carnivorous animals that eat them. Since living systems create order out of relative disorder (for example, by synthesizing large complex molecules out of randomly arranged subunits), it may appear at first glance that they violate the Second Law of Thermodynam- ics, but this is not the case. To ascertain that the second law is valid, we must examine the whole process of life, which includes not only the living unit but also the energy that it consumes and the by-products that it rejects. To begin with, the food that is consumed by an animal contains a considerable degree of order. The atoms in the food molecules are not randomly arranged but are ordered in specific patterns. When the chemical energy in the molecular bindings of the food is released, the ordered structures are broken down. The eliminated waste products are considerably more disordered than the food taken in. The ordered chemical energy is converted by the body into disor- dered heat energy. The amount of disorder in a system can be expressed quantitatively by means of a concept called entropy.