\n| +WIN47203<\/th>\n | 88\u00b14<\/td>\n | 72\u00b12*<\/td>\n | 2.9\u00b10.1*<\/td>\n | 16\u00b12*<\/td>\n | 1070\u00b190*<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Values are means \u00b1SEM. * indicates significant effect of drug (p < 0.05) by paired t-test.<\/p>\n HR = heart rate; MAP = mean arterial pressure; CI = cardiac index; PCWP = pulmonary capillary wedge pressure; SVR = systemic vascular resistance.<\/p>\n ![\"\"](\"https:\/\/www.bumc.bu.edu\/ppb\/files\/Images\/Problem5.Graph2.gif\") <\/p>\n
Figure 2.<\/strong> Stroke volume index and pulmonary capillary wedge pressure in 11 patients during the control period (closed circles) and at maximum response (open circles) after i.v. and oral WIN 47203. Values are means \u00b1SD.<\/p>\nXI. Which of the baseline values in Table 4 indicate that the patients are in heart failure?<\/p>\n a. High pulmonary capillary wedge pressure.<\/h4><\/p>\n True, a pulmonary capillary wedge pressure over 12 mmHg is abnormal and over 20 mmHg suggests the presence of pulmonary edema. These patients have additional hemodynamic evidence of heart failure. But consider other answer choices; go back to Item XI.<\/p>\n <\/div>\n<\/div>\n\n b. Low cardiac index.<\/h4><\/p>\n True, a cardiac index lower than 2.5 L\/min\/m^2 is evidence of heart failure. These patients have additional hemodynamic evidence of heart failure. Go back to Item XI and look for another correct answer.<\/p>\n <\/div>\n<\/div>\n\n c. High systemic vascular resistance.<\/h4><\/p>\n True, the average systemic vascular resistance for this group of patients is at the upper limit of the normal range, suggesting a high sympathetic tone. But there are other hemodynamic abnormalities in these patients. Go back to Item XI and look for another correct answer.<\/p>\n <\/div>\n<\/div>\n\n d. All of the above.<\/h4><\/p>\n Correct; these patients have a high pulmonary capillary wedge pressure, low cardiac index, and high systemic vascular resistance; all are indicators of heart failure. Heart rate is somewhat high but within the normal range. Mean arterial pressure is normal because baroreceptor reflexes keep arterial pressure constant. Now, go on to Item XII.<\/p>\n <\/div>\n<\/div>\n\n XII. What symptomatic benefit might result from the hemodynamic effects of WIN47203 in patients with heart failure?<\/p>\n a. Increased cardiac index might decrease symptoms of fatigue.<\/h4><\/p>\n True, increased cardiac index should improve skeletal muscle perfusion and decrease fatigue. You may have forgotten, however, that decreased pulmonary capillary pressure will produce an added benefit of decreased congestive symptoms. Go to Item XIII.<\/p>\n <\/div>\n<\/div>\n\n b. Decreased pulmonary capillary pressure might decrease congestive symptoms (e.g. dyspnea).<\/h4><\/p>\n True, decreased pulmonary capillary pressure will relieve congestive symptoms. You forgot that increased cardiac index will improve skeletal muscle perfusion and decrease symptoms of fatigue. Now go on to Item XIII.<\/p>\n <\/div>\n<\/div>\n\n c. Both a and b above.<\/h4><\/p>\n Correct, go on to Item XIII.<\/p>\n <\/div>\n<\/div>\n\n d. The drug acts only as a vasodilator and, thus, would not diminish symptoms of heart failure.<\/h4><\/p>\n Yes. Arteriolar vasodilation can relieve symptoms of fatigue by increasing cardiac output. Venodilation can relieve congestive symptoms by decreasing cardiac filling pressure. Go to Item XIII to see if this drug is a vasodilator.<\/p>\n <\/div>\n<\/div>\n\n XIII. From the hemodynamic data above, what appears to be the primary action of WIN47203 in patients with heart failure.<\/p>\n a. It acts as an arteriolar vasodilator.<\/h4><\/p>\n No. WIN47203 has some arteriolar dilator activity; mean arterial pressure and systemic vascular resistance were both decreased, with an increase in cardiac output. However, it must have an additional action because pure arteriolar dilators do not cause large decreases in pulmonary capillary wedge pressure. Go back to Item XIII and make another selection.<\/p>\n <\/div>\n<\/div>\n\n b. It acts as a mixed arteriolar and venous\/capacitance vasodilator.<\/h4><\/p>\n True, a mixed arteriolar\/venous vasodilator can increase cardiac index (as a result of decreased systemic resistance) and can decrease pulmonary capillary wedge pressure (as a result of venous pooling and decreased filling pressure). The Starling curve would be shifted upward and to the left as in Figure 2. But, remember, an inotropic agent can cause similar results by increasing ejection fraction (which decreases ventricular diastolic pressure), and secondarily by decreasing vascular resistance by withdrawal of sympathetic tone (like digitalis). WIN47203 must have some vasodilator activity, because mean arterial pressure was decreased, unlike a pure inotropic effect which would leave arterial pressure unchanged or slightly increased. To see if the drug has inotropic activity, go on to Item XIV.<\/p>\n <\/div>\n<\/div>\n\n c. It acts as a positive inotropic agent with a reflex decrease in systemic vascular resistance.<\/h4><\/p>\n Yes. Ionotropic agents can decrease pulmonary capillary wedge pressure by increasing ejection fraction (thus decreasing ventricular diastolic pressure), and can decrease vascular resistance by withdrawal of sympathetic tone (like digitalis). A mixed arteriolar\/venous vasodilator can produce the same result, increasing cardiac index by decreasing systemic resistance, and decreasing pulmonary capillary pressure due to venous pooling and decreased filling pressure. The Starling curve would be shifted upward and to the left as in Figure 2. The drug is a vasodilator because it decreased mean arterial pressure, unlike a pure inotropic agents, which would leave arterial pressure unchanged or slightly increased. To see if the drug has inotropic activity, go to Item XIV.<\/p>\n <\/div>\n<\/div>\n\n d. The drug could act by any one or a combination of 1 - 3 above; additional data are needed to distinguish these possibilities.<\/h4><\/p>\n Correct; for more explanation, read the comment to Item XIIIc before going on to Item XIV.<\/p>\n <\/div>\n<\/div>\n\n To determine if WIN47203 has a clinically important cardiac inotropic effect, Ludmer et al. (Circulation<\/em> 73: 130, 1986) compared the effects of drug vehicle (5% dextrose in water, D5W), drug administered intravenously, and drug administered directly into the left main coronary ostium. They reasoned that effects of intracoronary administration would be due to direct actions on the heart, while effects of intravenous administration would be due to both cardiac and vascular effects. Plasma drug concentration was 372\u00b150 ng\/ml after intravenous administration. Intracoronary infusion achieved a similar coronary plasma concentration with a negligible systemic concentration of 52 ng\/ml. The results of this experiment are presented in Figures 3 and 4.
\n![\"\"](\"https:\/\/www.bumc.bu.edu\/ppb\/files\/Images\/Problem5.Graph3.gif\") <\/p>\nFigure 3.<\/strong> Stroke volume index (SWI) as a function of left ventriclar end diastolic pressure (LVEDP)<\/p>\n![\"\"](\"https:\/\/www.bumc.bu.edu\/ppb\/files\/Images\/Problem5.Graph4.gif\") <\/p>\n
Figure 4.<\/strong> Comparative hemodynamic effects of vehicle (D5W), intracoronary infusion of WIN47203 at 50\u00b5g\/min (ICM), and intravenous infusion of WIN47203 (IVM) in eight consecutive patients. * = p < 0.01<\/p>\nXIV. What do you conclude about the action of WIN47203 in patients with heart failure from the data in Figures 3 and 4.<\/p>\n a. The drug acts primarily as a vasodilator with very little direct inotropic effect on the heart.<\/h4><\/p>\n No, intracoronary drug administration had no effect on mean arterial pressure but it increased LV+dP\/dt and stroke volume while decreasing filling pressures. This indicates that the drug had some direct inotropic activity. Return to Item XIV and choose again.<\/p>\n <\/div>\n<\/div>\n\n b. The drug acts primarily as a positive inotropic agent with a reflex decrease in vascular resistance similar to that produced by digitalis.<\/h4><\/p>\n You conclude correctly that direct positive inotropic activity contributes to the effects of this drug (intracoronary administration increased both stroke volume and LV +dP\/dt). The decrease in heart rate probably results from decreased sympathetic tone, secondary to the inotropic effect. However, the decrease in mean arterial pressure after intravenous administration suggests that the drug has vasodilator activity. A pure positive inotropic drug would not decrease mean arterial pressure. Thus, both cardiac and vascular actions contribute to the hemodynamic effects of this drug, which we now know as milrinone. Congratulations, you have completed the problem set!<\/p>\n <\/div>\n<\/div>\n\n c. The drug has both significant inotropic activity and direct vasodilator activity.<\/h4><\/p>\n Correct, a direct inotropic effect is indicated by the increase of LV+dP\/dt and stroke volume during intracoronary administration. That resulted in decreased filling pressures and a reflex decrease in heart rate. The decrease in arterial pressure after systemic administration of the drug indicates that the drug also has a direct arteriolar vasodilator action. WIN47203 is now known as milrinone. Congratulations, you have completed the problem set!<\/p>\n <\/div>\n<\/div>\n\n d. The drug has relatively pure venous capacitance dilator activity, like that produced by organic nitrates<\/h4><\/p>\n No, the effect of intracoronary administration shows that the drug has direct effects on the heart. Go back to Item XIV and choose another answer.<\/p>\n <\/div>\n<\/div>\n\n","protected":false},"excerpt":{"rendered":" W. Mark Vogel, Ph.D. Adjunct Associate Professor of Pharmacology Boston University School of Medicine Questions or comments should be mailed to Carol Walsh Return to Pharmacology Problem Sets This problem set will: familiarize you with hemodynamic measurements used to evaluate cardiovascular drugs review the pharmacology of digitalis glycosides demonstrate how initial hemodynamic status determines the […]<\/p>\n","protected":false},"author":2,"featured_media":0,"parent":69,"menu_order":5,"comment_status":"closed","ping_status":"closed","template":"page-templates\/no-sidebars.php","meta":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/79"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/comments?post=79"}],"version-history":[{"count":30,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/79\/revisions"}],"predecessor-version":[{"id":18798,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/79\/revisions\/18798"}],"up":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/69"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/media?parent=79"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}} |
![\"\"](\"https:\/\/www.bumc.bu.edu\/ppb\/files\/Images\/Problem5.Graph1.jpg\")
<\/p>\n