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However discount lotensin 10mg on line, when two or more enzymes contribute to metabolite formation buy lotensin 10mg otc, corre- lation analysis may lack the statistical power to establish the identity of each enzyme 10mg lotensin visa. Statistically significant correlations should always be confirmed with a visual inspection of the graph because there are two situations that can produce a misleadingly high correlation coefficient: (1) the regression line does not pass through or near the origin and (2) there is an outlying data point that skews the correlation analysis, as illustrated in Figure 25. Correlation analysis works particularly well when a single enzyme dominates the formation of a particular metabolite. This approach success- fully identifies the enzymes involved when each enzyme contributes 25% or more to metabolite formation, but it will likely not identify an enzyme that contributes only approximately 10%. A graphical representation of the application of multivariate analysis to the results of a reaction phenotyping experiment is shown in Figure 26, on the basis of an examination of the sample-to-sample variation in the 1-hydroxylation of bufuralol (12 mM) by a panel of human liver microsomes. The sample-to-sample variation in bufuralol 1-hydroxylation correlates reasonably well with In Vitro Study of Drug-Metabolizing Enzymes 327 Figure 25 Common pitfalls in correlation analysis. Correlation analysis is suspected when the regression line is unduly affected by a single outlying data point, or when the regression line does not pass near the origin. When two enzymes contribute significantly to metabolite formation, their identity and relative con- tribution can be established by performing correlation analysis in the presence and absence of an inhibitor of one of the participating enzymes (preferably the major contributor). This approach works even when one of the enzymes contributes substantially less than 25% to metabolite formation, as was demonstrated by 328 Ogilvie et al. Chemical and Antibody Inhibition Chemical and antibody inhibition represent the second and third approaches to reaction phenotyping. As in the case of correlation analysis, chemical and antibody inhibition experiments must be conducted with pharmacologically relevant concentrations of the drug candidate in order to obtain clinically relevant results. Therefore, appropriate solvent and preincubation controls should be included in all chemical inhibition experiments. The lack of specificity can complicate the interpretation of chemical inhibition experiments. If a drug candidate is metabolized by a high-affinity enzyme, the con- centration of a competitive chemical inhibitor must be increased with increasing concentration of the drug candidate in order to achieve a high degree of inhi- bition. A good rule of thumb is to use multiples (generally up to 10-fold) of the lowest inhibitor concentration, which is calculated from the following equation: ½DrugŠÁKiðinhibitorÞ Lowest½InhibitorŠ¼ ð10Þ KmðDrugÞ where [Drug] is the intended final concentration of the drug candidate added to the microsomal incubation, Ki is the inhibition constant of the inhibitor for a given enzyme, and Km is the Michaelis constant of the drug candidate (as determined in Step 3). This method of calculating of the lowest concentration of inhibitor is applicable to competitive inhibitors but not to noncompetitive or metabolism-dependent inhibitors. A range of inhibitor concentrations is rec- ommended to demonstrate concentration dependence. For example, if the lowest concentration of the chemical inhibitor were calculated to be 1 mM (from the above equation), then the range of inhibitor concentration should span at least 10-fold (e. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. When chemical inhibition experiments are conducted with a relatively metabolically stable drug candidate (one that must be incubated with relatively high concentrations of human liver microsomes for a relatively long time in order to generate quantifiable levels of metabolite), it is important to take into account the metabolic stability of the inhibitors themselves. Lack of metabolic stability makes some compounds poor choices as chemical inhibitors despite their selectivity. Finally, appropriate controls should be included in each chemical inhibi- tion experiment to evaluate whether any of the chemical inhibitors interfere with the chromatographic analysis of the metabolites of interest and whether metabolite formation is inhibited by any of the organic solvents used to dissolve the chemical inhibitors. Unfortu- nately, the utility of this method is limited by the availability of specific inhibitory antibodies and by nonspecific effects associated with the addition of antiserum and ascites fluid to the microsomal incubation. The use of antiserum (for polyclonal antibodies) and ascites fluid (for monoclonal antibodies) rather than purified antibodies often necessitates adding a large amount of albumin and other proteins to the micro- somal incubation. For this reason, control (preimmune) serum and ascites fluid should be included as negative controls in antibody inhibition experiments. These issues are lessened when purified antibodies are used instead of antisera and ascites fluid. As in the case of chemical inhibition, a lack of specificity can complicate the interpretation of antibody inhibition experiments. A lack of specificity and the nonspecific effects outlined above likely account for the majority of cases where the sum of the inhibitory effects of a panel of inhibitory antibodies adds up to greater than 100%. If an antibody inhibits the metabolism of a marker substrate by 80%, and if the same antibody inhibits the metabolism of drug candidate by 80%, there is uncertainty as to whether the inhibited enzyme contributes 80% or 100% to the metabolism of the drug candidate. Genetic or drug- mediated loss of an enzyme that accounts for 80% of a drug’s clearance will cause a fivefold increase in systemic exposure, whereas loss of an enzyme that accounts for 99% of a drug’s clearance will cause a 100-fold increase in exposure. In both cases, cytochrome b5 increases Vmax/Km, which is a measure of in vitro intrinsic clearance. The kinetic constants are only determined for those enzymes that were shown in preliminary experiments to be capable of metabolizing the drug candidate. Unfortunately, this method is complicated by the empirical observation that Km, 334 Ogilvie et al. The Relative Merits of the Four Approaches to Reaction Phenotyping Many of the potential pitfalls and advantages or disadvantages of the four approaches to reaction phenotyping have been mentioned in the preceding sec- tions, and they are summarized in Table 10.

Sotalol and dofetilide carry a moderate risk of torsades de pointes for all patients discount lotensin 10 mg with visa. Amiodarone carries a substantial risk of significantend-organ toxicity for all patients safe 10mg lotensin, thoughonly a rela- tively small risk of proarrhythmia order lotensin 10 mg otc. 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.

Experimentally generic lotensin 10mg with visa, if one removes the source of external calcium from skeletal muscle buy 10 mg lotensin with visa, contraction is little affected generic lotensin 10mg with mastercard. On the other hand, removing the external source of calcium from cardiac muscle reduces contractile function rapidly. The passive length- tension properties of skeletal muscle are less stiff than cardiac muscle. Since the length of skeletal muscle is usually fixed in the body by attachment to bone, they cannot be stretched out beyond their optimum length. Thus, they do not require a stiff passive length tension relation to prevent overstretching. In in vitro experiments, however, it is easier to passively stretch skeletal muscle than cardiac muscle. Stretching heart muscle, however, does not stretch sarcomeres much beyond about 2. This increased stiffness of cardiac muscle presumably relates to an increased collagen content. Skeletal Heart Mitochondria + ++ Sarcoplasmic Reticulum ++ + Resting Force at L max Low High Number of Sarcomeres in >2. Skeletal muscle contraction can be tetanic and sustained when stimulated by a train of electrical stimuli. On the other hand, cardiac muscle responds only to a single stimulus and has a long refractory period before it responds again to another stimulus. Thus, cardiac muscle is characterized by a twitch contraction, whereas skeletal muscle can contract tetanically. Furthermore, cardiac muscle contraction is all or none and cannot be graded (by recruitment of additional motor units) as can skeletal muscle. There is a predictable relationship between sarcomere length at the onset of contraction and the amount of force developed by the muscle. Classical studies in skeletal muscle suggest that the developed force is related to the degree of overlap of thin and thick filaments (Figure 4). As muscle is stretched beyond this point, there is less overlap between thin and thick filaments and thus less opportunity for crossbridges to form. This has been postulated as the primary mechanism for the reduction in force at shorter muscle lengths. Figure 4: Classical relation between the force of development of skeletal muscle and the overlap of thin and thick filaments. Figure 5: Representative series of isometric contractions in a cat papillary muscle studied in vitro in a muscle bath. Contractions are superimposed on a memory oscilloscope and then photographed with a Polaroid picture. The lower line represents the passive length-tension curve of the muscle at that length. Cardiac muscle is relatively stiff as one tries to stretch it out to longer muscle lengths. The resting and developed force at a series of muscle lengths are shown in Figure 5 in a representative experiment. At longer lengths, the resting force (bottom line) rises abruptly because of the stiffness of the muscle. Note that as length increases, the force developed by the muscle (height of vertical lines) progressively increases until one reaches the L max point, Muscle Mechanics - Robert Turcott, M. Figure 6 plots representative resting and developed length-force relations of cardiac muscle. The developed force rises to a peak at the length designated L max and then declines. The resting force rises relatively slowly at shorter lengths but as one approaches and passes L max, there is an abrupt rise in resting force along its exponential passive length-force curve. The simple addition of resting and developed force is the total force which is a relatively straight line over much of its course. Figure 6: Resting and developed force-length curves as obtained in isolated heart muscle. The relation between myocardial and sarcomere lengths and the passive and active length-force curves of cardiac muscle are illustrated in Figure 7. There are few cross-bridges at the center of the myosin filament in the vicinity of the M line so that the ends of the opposite actin filaments are slightly separated. At longer lengths in skeletal muscle the sarcomeres are pulled out slightly and force is reduced due to fewer cross-bridges formed. Because the passive length-tension relation is so stiff, however, it is difficult to pull cardiac muscle sarcomeres out much beyond 2. The reduction in force at small sarcomere lengths presumably relates to the cross-over of actin filaments through the middle of the sarcomere, which interfere with each other. Although classical studies have suggested that the active length- tension curve of cardiac muscle is due entirely to the changing relationship of cross-bridge overlap, some studies have suggested that another factor (length-dependent activation) may be important. If one plots the relative force development of both skeletal and cardiac muscle, one might expect that they would be identical curves since the overlap of thin and thick filaments would be the same at different muscle lengths.