By M. Hengley. Brooks Institute. 2019.

It is important to note that P-gp inhibition by a compound for the efflux of any of these ligands does not directly correlate with the ability of P-gp to efflux the compound of interest (177) buy 5 mg vasotec amex. Such is the case with paclitaxel purchase vasotec 10mg amex, which is con- sidered to be an excellent P-gp substrate but a poor inhibitor as determined by the dye-efflux method buy generic vasotec 5mg line. The converse is seen with progesterone, which is a good inhibitor of P-gp-mediated efflux and yet is a poor substrate. Furthermore, the false negatives due to poor permeability noted for transport assays can also produce false negatives in these interaction assays. Membrane vesicles are typically formed from intact cells and require some skill for their preparation. Given this relative limitation, the use of membrane vesicles as a rapid screen for P-gp efflux activity has not been extensive and has proven a better tool for studying the microscopic aspects of P-gp-mediated efflux. Additionally, these vesicles have been used to study microscopic aspects of P-gp-mediated efflux, such as the relationship of P-gp function to the membrane fluidity (137). In the intestinal segment study, the intestine is removed and either mounted in a diffusion apparatus (Ussing chamber) or everted to make an everted sac (234,414–416). The transport characteristics of verapamil were determined for each region of the intestine as well as the colon with this model system. The duodenum and jejunum showed the most P-gp activity followed by lower activity in the colon and, surprisingly, none in the ileum (416). Polarized transport of quinidine due to P-gp efflux was demonstrated by using intestinal segments mounted in Ussing chambers (414). Further studies using everted sacs showed that P-gp inhibition by quinidine caused an altered drug absorption of digoxin and explained the interaction seen with coadministration of these agents (234). Metabolism and P-gp-mediated efflux of the macrolide antibiotic tacrolimus were studied in perfusion studies and in everted sacs (415). It was shown that inhibiting P-gp with miconazole (a P-gp inhibitor) greatly increased the amount of tacrolimus in the tissue (415). The results of these experiments provided evidence that P-gp is active in limiting tissue exposure to drugs and also that the intestinal metabolism of certain compounds can be significant. P-gp, expressed in these in vitro systems, is thought to function normally (analogous to function seen in in vivo systems) even though the former lacks glycosylation at N-terminal. Despite the normal functional activity of P-gp, researchers found it difficult to use P-gp expressed in E. To solve this problem, Beja and Bibi developed a method to express P-gp in ‘‘leaky’’ E. The results of these assays may be significantly different than those obtained in studies performed with 400 Troutman et al. A membrane product pre- pared from baculovirus infected insect cells containing this activity is now commercially available from Gentest Corp. By determination of inorganic phosphate liberated in the reaction containing a P-gp preparation and a test compound, in the presence and absence of vanadate, one can determine if the test compound is a substrate/inhibitor of P-gp (123,422). In Situ and In Vivo Models Whereas in vitro models are the tool of choice to identify P-gp substrates and to specifically study molecular aspects of P-gp-mediated efflux activity, extrapolation of these data to predict relevance in vivo can sometimes be difficult. Indeed, P-gp-mediated efflux activity is often one of a multitude of parameters that ultimately combine to confer substrate disposition; these exact relationships between key parameters are complex and remain to be resolved. For these reasons, models with greater complexity, more specifically those in which more key factors are present such as in situ and in vivo models, are essential to gain insight into the overall relevance of P-gp efflux for substrate disposition. The following section summarizes the respective strengths and weaknesses of in situ and in vivo models currently used to study P-gp efflux. In Situ Studies and Models Some efforts have been made to determine the effect P-gp has on its substrates by use of in situ perfusion methods, including intestinal perfusion, liver perfu- sion, kidney perfusion, and brain perfusion. These experiments allow the researcher to study the transport of compounds in a physiologically relevant environment in which the integrity of the organ is preserved with regards to cell polarity and representation of all cell types seen in the organ. Furthermore, the reduction in complexity of in situ models versus in vivo studies facilitates the conduct of complex studies and allows more definitive conclusions to be made regarding the role P-gp may play in disposition. In situ intestinal perfusion studies are typically done with live animals in which a perfusion loop has been inserted into the intestine (233,424). Depending on the experimental protocol, the system can offer a relatively unbiased view of The Role of P-Glycoprotein in Drug Disposition 401 intestinal transport with respect to normal expression of transporters in healthy animals. One limitation of this protocol is that the disappearance rather than the appearance of a compound is often determined (appearance can be determined by collection of blood in the vessels perfusing the section of intestine studied, a process requiring significant surgical skill). Estimates of the polarity of transport imparted by P-gp are difficult to assess and typically can only be determined by using an inhibitor or antibody to P-gp. Often the animal is anesthetized, and the anesthetizing agent can further affect the results (altered membrane fluidity, possible inhibitory effects on P-gp-mediated efflux activity) (187). Using the intact intestine adds more levels of complexity that can further confound studies meant to elucidate the role of transporters, which act on the cellular level. However, this complexity can be a strength to the role P-gp plays in concert with other key factors that influence absorption and can be studied in parallel. It is possible that results will differ for intestinal region and also due to the presence of Peyer’s patches that have different physiological roles from enterocytes (414,416). Furthermore, these studies suffer from an interspecies variability (rats are typically the test subjects). Despite certain disadvantages, if these studies are con- ducted with appropriate controls involving known P-gp substrates, it can provide valuable insights on how to correlate the effectofP-gpobservedincellulartransport studies to that expressed in the absorption of drugs in vivo. By measuring the intestinal absorption from small intestine of rat in situ, Saitoh et al. Compared with prednisolone and hydrocortisone, meth- ylprednisolone absorption was significantly retarded in jejunum and ileum by an intestinal efflux system. In the presence of verapamil and quinidine, the attenua- tion in the absorption of methylprednisolone was reversed, suggesting that P-gp is responsible for the unique features of methylprednisolone absorption. This study provides a good example of the usefulness of an intestinal perfusion experiment in further determining the regional differences in intestinal drug absorption modu- lated by P-gp that would otherwise be difficult to deduce in experiments per- formed with cell culture models or performed with whole animal systems. The isolated perfused rat liver has been extensively used because of the minimal surgical manipulation needed due to its size and because the organ is less than 25 g, the perfusate used can be hemoglobin-free while ensuring ade- quate oxygen delivery at the flow rates used in these experiments (425). The isolated perfused liver system provides an excellent model for studying the hep- atobiliary disposition of compounds without confounding influences that may be seen in vivo, such as influences on hepatic metabolism and additional metabolism or excretion by other organs of clearance (270,425). The isolated perfused rat liver can be used to study biochemical regulation of hepatic metabolism, synthetic function of liver, and mechanism of bile formation and secretion (270). In a similar study on the hepatic elimination of other P-gp substrates, including vincristine and daunorubicin, it was reported that canalicular P-gp plays a significant role in the biliary secretion of these com- pounds (428,429). Because of the kidney’s involvement in the excretion of hydrophilic compounds and because most of the substrates of P-gp are hydrophobic com- pounds that are likely to be cleared mainly by biliary excretion or intestinal secretion, comparably fewer studies have been performed with the isolated perfused kidney. The isolated perfused rat kidney model was used to demonstrate that digoxin is actively secreted by P-gp located on the luminal membrane of renal tubular epithelial cells and that clinically important interactions with qui- nidine and verapamil are caused by the inhibition of P-gp activity in the kidney (332). One major advantage this technique has over an in vivo experiment involves the perfusion fluid used in the experiment. The composition of the solution can be controlled with respect to test compounds, plasma proteins, nutrients, and met- abolic cofactors (432). However, the use of a perfusate solution can also be a disadvantage as it may not be possible to provide all the necessary nutrients or metabolic cofactors that would be present in vivo and, thus, may lead to incorrect conclusions (430). The major disadvantages of the model with respect to in vitro models include the lack of control of the extracellular fluid concentration for studies of drug efflux from the brain and a greater complexity that the brain matrix provides.

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The second basic principle istokeep the goal of treatment clearly in mind and to tailor the aggressiveness of one’s therapyaccordingly purchase vasotec 10mg on-line. If one is treating an arrhythmiatoprevent death or permanent in- jury cheap vasotec 10 mg on line, for instance cheap vasotec 10mg on-line, a relatively aggressive approach may be appropri- ate and necessary. In theory, if the object istospare life and limb, one should err on the side of efficacy, perhaps willingly accepting the risk of certain drug toxicities. Inpractice, however, as we will see in Chapters 11 and 12, there are relatively fewinstances today where oneought to rely primarily on antiarrhythmic drugs to treat arrhythmias that threaten life and limb. In these cases, one generally shoulduse a stepwise strategy, beginning with milder, less risky forms of treatment, and carefully reassessing the risk-to-benefit ratio before each potential escalation of therapy. All too oftenphysicians pursue the treatment of relatively insignificant arrhythmias with Ninja-like intensity, an error that can result in unnecessary injury or death. The final basic principle of using antiarrhythmic drugs is that, if one feels compelled to expose a patient to the risk of the drugs, one should also feel compelled to take every reasonable precaution to reduce the risks. For instance, given the almost universal risk of proarrhythmia, one should oftenconsider placing patients on a cardiacmonitor while antiarrhythmic drugs are being initiated be- cause, although proarrhythmia can occuranytime during the course of treatment, a significant proportion of these events occur during the first 3 or 4days of drug usage. The accompanying tables summarize the factors that should be consideredinchoosing antiarrhythmic drugs for patients with and withoutsignificant underlying cardiacdisease. Pro- cainamide, for instance, shouldnot be usedinpatients with systemic lupus erythematosus; quinidine shouldnot be usedinpatients with chronic colitis;patients with severe lung disease (in whommild drug-inducedpulmonary toxicity goes a long way) ideally shouldnot receive amiodarone;patients with a history of heart failure should not receive drugs with negative inotropic effects. Beyond these obvious individual considerations, the presenceor absenceofunderlying heart disease is the most important variable in choosing an antiarrhythmic drug,because heart disease predisposes patients to reentrant circuits and, therefore, to proarrhythmia. Amiodarone rises in rank because of its relatively low risk of producing proarrhythmia. Sotalol and dofetilide carry a moderate risk of torsades de pointes for all patients. Amiodarone carries a substantial risk of significantend-organ toxicity for all patients, thoughonly a rela- tively small risk of proarrhythmia. The drug of choice in treating both atrial and ventricular tach- yarrhythmias dependson the presence or absenceofunderlying cardiacdisease. For ventricular arrhythmias, the primary con- siderationinpatients without underlying heart disease (i. As soon as one moves beyond these two classes of drugs, onebeginsaccepting asubstantial risk of proarrhythmia or other significant toxicity. On the other hand, for patients with underlying heart disease who require therapy for ven- tricular arrhythmias, efficacy(which here includes avoiding proar- rhythmia) is often the primary consideration. Thus, amiodarone is often the first drug considereddespite its potential for causing long-term end-organ toxicity. To summarize, whenit comes to using antiarrhythmic drugs, there are no pretty choices. If this is not possible, one must proceedwith the goals of treatment clearly in mind and take every precaution to avoid producing more problems than are caused by the arrhythmias being treated. Such maneuvers include Valsalva, carotid massage, ocular massage, and dunking one’s face in ice water. Antitachycardia pacing techniques are also highly effective in termi- nating supraventricular arrhythmias, butsincesomany less invasive options are available, pacing is rarely usedunless an atrial pacemaker is already in place. Prior to the 1990s, pharmacologic therapy was the only viable option for most patients. Given that choice, many patients quite reasonably opted for no therapy at all and accepted the fact that they would have to make periodic pilgrimages to emergency rooms to terminate acute episodes. With thistechnique, critical components of the reentrant path- ways responsible for a patient’s arrhythmia can be mappedinthe electrophysiology catheterization laboratory and cauterized (usually with radiofrequencyenergy) directly through the electrophysiology catheter. Therefore, treatmentaimed at maintain- ing sinus rhythmis inherently difficult and relatively risky. Often, it is more appropriate to accepta“lesser” therapeutic goal—that is, to allow the underlying arrhythmiatopersist while controlling the ventricular rate. The treat- ment of these arrhythmias, therefore, should include a systematic search for a primary cause. Arrhythmias caused by systemic processes (electrolyte distur- bances, hyperthyroidism, pulmonary disease, and use of alcohol or stimulant drugs) often improve or disappear once the systemic pro- cess isaddressed. Arrhythmias associatedwith underlying heart dis- ease, on the other hand, oftenpersist evenwhen therapy of heart disease isoptimized. Consequences Atrial fibrillation and atrial flutter have three major consequences that must be takeninto considerationwhenplanning therapy: loss of the atrial kick, the rapid heart rate itself, and the risk of throm- boembolism (Table 11. Loss of atrial kick The function of atrial contractionis to boost diastolic pressure within the ventricles just before ventricular systole begins. The atrial kick isvitally important in patients whose ventri- cles are noncompliant(i. Thus, patients with poor ventricular compliance de- velop severe symptomsalmost immediately if atrial fibrillation oc- curs; atrial kick isvital in these patients. On the other hand, patients with dilatedcardiomyopathies have enlarged, “baggy” ventricles that are significantly more compliant thannormal. These patients tend to have relatively little change in their baselinesymptoms with the onset of atrial fibrillation,and they often Treatmentofsupraventricular tachyarrhythmias 143 are unable to perceive any difference, at least acutely, between sinus rhythm and atrial fibrillation. Patients with normal ventricular compliancetend to experience intermediate symptoms with the onset of atrial fibrillation. These patients canusually pinpoint the timeofonset of atrial fibrillation,but in most cases, theirsymp- toms are limited to palpitationsand a mild-to-moderate sensation of breathlessness. The transient decrease in stroke volume resulting from the loss of the atrial kick is partially compensated by an increase in sympathetic tone, which di- rectly increases the heart rate and frequently also causes a sensation of anxiety. Thus, it is not unusual for a patient with acute atrial fibrillation or atrial flutter to present with very rapid heart rates and to experience extreme palpitations. Ingeneral, however, sympathetic tone drops within afew hours, and the heart rate slowstomore reasonable levels. If heart rates remain elevatedchronically—for a period of weeks or months—a tachycardiomyopathy may develop. Tachycardiomy- opathy refers to the ventricular dysfunction resulting from a per- sistently elevated heart rate. Although relatively uncommon,this conditionis indistinguishable from other formsofdilatedcardiomy- opathy. Fortunately, tachycardiomyopathy is largely reversible if the rapid heart rate is brought under control. In any case, the rapid heart rates accompanying atrial fibrillation and atrial flutter have signifi- cance beyond merely producing palpitations. Thromboembolism Perhaps the major hemodynamic consequenceofatrial fibrillation (and to a lesser extent, atrial flutter) is the risk of thromboembolism.

It does not have a substantial effect on nonvascular smooth musculature or cardiac tissues vasotec 5mg otc. Homeostatic circulatory reflexes remain natural buy vasotec 5 mg mastercard, and the resulting hypotension activates car- diovascular reflexes generic 5 mg vasotec with mastercard, which are expressed as an increase of heart work, power, and volume of cardiac output. The hypotensive effect is caused by peripheral vasodilation resulting from a direct effect on both arterial and venous vessels. Side effects also appear very quickly; however, they last for a very short time because of their extremely short half-life. Sodium nitroprusside is biotransformed to cyanide and thiocyanate, which upon overdose can result in thiocyanate and cyanide intoxication. The presence of drugs such as diazoxide and sodium nitroprusside has significantly decreased the possibility of a sharp drop in arterial blood pressure and urgent situations; which, how- ever, should be used under the constant care of medical personnel. Angiotensin I is a prohormone that is formed as a result of the action of renin on a pep- tide substrate produced by the liver. Renin, in turn, is a proteolytic enzyme that is produced by the kidneys, and it controls the physiological functions of other organs. The secretion of renin itself is controlled by the nervous system, and possibly by a recently discovered cardiac peptide hormone. As a result, peripheral resistance of vessels increases as heart rate increases, cardiac output increases, and water and sodium ion retention takes place. In turn, induced elevation of pressure by reverse binding causes a decrease in renin secretion. There is a hypothesis that irregularity of the rennin–angiotensin system lies at the base of etiology of all cases of essential hypertension. However, despite all of the apparent attractiveness of this theory, there is still not enough proof for it to be accepted as the sin- gle reason of elevated arterial blood pressure. Moreover, whether or not hypertension is caused by an elevated level of renin or other reasons, angiotensin-converting enzyme inhibitors lower both systolic and diastolic arte- rial pressure in hypertensive patients, and their effects are enhanced by diuretics. Angiotensin-converting drugs of this series (captopril, enalapril) are effective antihyper- tensive drugs used both independently and in combination with other drugs to treat all types of hypertension as well as to treat cardiac insufficiency. L-proline is acylated by phenylacetyl chloride, giving N-benzyloxycarbonyl L-proline (22. This is reduced using hydrogen and a palladium-on-carbon catalyst, which gives the L-proline tert-butyl ester 22. The ester part of the molecule is hydrolyzed using trifluoroacetic acid, giving 1-(3-acetylthio-2-methyl- propanoyl)-L-proline (22. Overall vascular peripheral tension is reduced, which results in the lowering of arterial pressure. Oxidation of this product with 3-chloroperbenzoic acid gives 2,4-diamino-6-(2,4- dichlorophenoxy)pyrimidine-3-oxide (22. Open calcium channels cause hyperpolarization of smooth muscle cells, which in turn, reduces the flow of calcium ions into the cell, which is necessary for sup- porting vascular tonicity. However, when taking minoxidil, tachycardia, elevated renin secretion, and water and sodium ion retention all appear simultaneously with hypotension. Because of potentially serious side effects, it is used only for severe hypertension that does not respond to treatment with other drugs, and absolutely in combination with two other antihypertensive drugs. In addition to hypotensive action, diazoxide causes a sharp increase in the level of glucose in the blood as a result of the inhibition of insulin release from adre- nal glands. Some of the undesirable effects are water and sodium ion retention in the body and increased concentrations of uric acid in the blood. It is used in urgent situations where blood pressure needs to be reduced in severe hypertension. Therapy of respiratory system ill- nesses generally consists of restoring appropriate physiological functions. In particular, antibiotics remove infections that have invaded the respiratory tract, glucocorticoids relieve inflammation, bronchodilators (broncholytics) relax smooth musculature of the bronchioles and open blocked air channel regions, and so on. Asthma has a particular place among pulmonary illnesses—it is a chronic lung condi- tion with clinical syndromes characterized by elevated excitability and contraction of the respiratory tract, and consequently, resulting in shortness of breath, breathing difficulties, and coughing. Patients suffering from asthma can develop signs of chronic bronchitis or pulmonary emphysema. Mainly because the molecular mechanism of these pathological changes has not been sufficiently studied, therapy of asthma, pulmonary illnesses, and other respiratory system illnesses are generally aimed at preventing and relieving symptoms that accompany the disease. Therefore, drugs for treating respiratory system illnesses can be examined as antiede- matous drugs whose vasoconstricting action can be taken in the form of nasal sprays, anti- cough and expectorant agents, as well as bronchiolytics and other drugs used to treat bronchial asthma, such as methylxanthine, anticholinergic drugs, adrenergic drugs, allergy mediator releasing inhibitors, and corticosteroids. When locally administered in the form of drops or sprays, arterioles of nasal mucous mem- branes constrict, leading to reduced edema, hyperemia, and exudation. Sympatomimetics with pronounced antiedema action are frequently taken for this purpose, and they include 311 312 23. Anticough drugs can have an effect at the ‘cough center’ level in the medulla, as well as an effect on various regions of the tracheobronchial tree. They are centrally acting drugs—narcotic anticough drugs or opiates such as codeine and hydrocodone, as well as various groups of drugs dis- playing both central and peripheral effects that suppress coughing, and the so-called non- narcotic anticough drugs (dextromethorphan, benzonatate). It is widely used in effective commercial anticough drugs in combination with guaiphenesin (entuss), with homatropine (hycodan), with phenylpropanolamine (hycomine), phenyltoloxamine (tussionex), and pseudoephedrine and guaiphenesin (tussened). The resulting racemic product ( )-3-methoxy-N-methylmorphinane is separated into isomers using D-tartaric acid, which produces dextromethor-phan [1,2]. Three of the most important methylxanthenes are theophylline, theobromine, and caf- feine. It is synthesized synthetically by the Traube method, a general method sug- gested for making purine bases. In the given example, reacting N,N-dimethylurea with cyanoacetic ether in the presence of acetic anhydride gives cyanoacetylmethylurea (23. The resulting compound trans- forms into 5-nitroso-6-amino-1,3-dimethyluracil (23. However, some hypotheses are based on its structural similarity to adenosine and 31,51-cyclic adenosinemonophosphate. Adenosine is an endogenic mediator that, reacting with membrane receptors, can cause bronchial contractions. Theophylline inhibits this reaction, thus preventing substrate– receptor reactions of bronchospasms caused therein. It is believed that theophylline can inhibit phosphodiesterase, which in turn can lead to elevated levels of cellular cyclic adenosine monophosphate, and subsequently, to the weakening of smooth musculature of the respiratory tract. However, theophylline is not a powerful phosphodiesterase inhibitor, and the necessary concentrations for this cannot be achieved in vivo. On the other hand, theophylline inhibits reverse uptake catecholamine uptake, which can elevate the level of cyclic adenosine monophosphate, thus causing a broncholytic effect. Finally, theophylline is an adenosine receptor blocker, and this may be responsible for its broncholytic effect. Despite the fact that the last mechanism may be basic for theophylline, a few xanthines, which in general lack the ability to bind with adenosine receptors, express the same, if not more broncholytic activity than theophylline.

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