Programmed Problem Set on Cardiovascular Drugs

W. Mark Vogel, Ph.D.
Adjunct Associate Professor of Pharmacology
Boston University School of Medicine

Questions or comments should be mailed to Carol Walsh

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 net effect of direct and reflex drug actions

Before solving these problems review the text and lecture notes on digitalis and other inotropic agents. Table 1 in this problem set lists some normal hemodynamic values, to help you evaluate the clinical data; please don’t try to memorize them.

Table 1. Some normal hemodynamic values
Heart Rate (beats/min) 60-100
Arterial Systolic Pressure (mmHg) 100-140
Arterial Diastolic Pressure (mmHg) 60-90
Mean Arterial Pressure (mmHg) 70-105
Left Ventricular End Diastolic Pressure (mmHg) 3-12
Mean Right Atrial Pressure (mmHg) 2-10
Pulmonary Capillary Wedge Pressure (mmHg) 2-10
Left Ventricular P/t (mmHg/sec) 1000-2000
Cardiac Output (L/min) varies with patient’s size
Cardiac Index (L/min/m^2) 2.6-4.2
Stroke Volume Index (ml/m^2/beat) 30-65
Systemic Vascular Resistance (dyne€sec€cm^5) 700-1600
Systemic Vascular Resistance (mmHg/L/min/m^2) 17-40

Figure 1 shows the effects of digitalis administered on five consecutive days to a 33 year old man with rheumatic heart disease (Stewart et al., Arch. Int. Med. 62:569, 1938).

Answer the next five items based on the data in Figure 1.

I. Why were the subsequent doses of digitalis smaller than the first dose?

II. What best explains the decrease in cardiac area seen on chest X-rays after digitalis?

III. What best explains the decrease in venous pressure after digitalis?

IV. What best explains the decrease in body weight after digitalis?

V. What best explains the increase in urine output after digitalis?

The next five items will be based on Tables 2 and 3, which describe the effects of digitalis in subjects with normal or failing hearts. Data in Table 2 are from studies by Seltzer et al. (Br. Heart J. 21:335, 1959; Circulation 25: 695, 1962). The 15 patients with heart failure were treated with sodium restriction and diuretics but no digitalis for a month before the study. They were asymptomatic upon ordinary activity. The patients with heart failure included several with hypertensive heart disease. Baseline hemodynamic values were measured 30 minutes after right heart catheterization. Post-drug values were measured 50 minutes after intravenous administration of 1.25 to 2.0 mg of digoxin.

Table 3 shows data from a similar study by Mason and Braunwald (J. Clin. Invest. 43: 532, 1964). All 6 heart failure patients were in New York Heart Association Class III or IV, none were treated with diuretics. In addition to systemic hemodynamics, forearm blood flow was measured by plethysmography. After right heart catheterization and baseline measurements, 0.5 to 0.6 mg of ouabain were administered intravenously and responses measured an hour later.

Table 2. (data from Seltzer et al)
Effects of digoxin in subjects with normal or failing heart
ARTERIAL PRESSURES HEART
RATE
(bpm)
CARDIAC
INDEX
(L/min/m^2)
SYSTEMIC
RESISTANCE
(MAP/CI)
SYST.
(mmHg)
DIAST.
(mmHg)
PULSE
(mmHg)
MEAN
(mmHg)
Normal no Rx 124
±4
78
±4
46
±4
94
±3
81
±2
3.1
±0.2
31
±2
+Digoxin 132
±5
79
±5
54*
±2
96
±5
77*
±3
2.9
±0.2
36*
±4
Failure no Rx 146
±10
88
±6
59
±6
107
±7
84
±4
2.0
±0.1
56
±4
+Digoxin 158*
±10
86
±6
72*
±7
110
±7
78
±3
2.5*
±0.1
47*
±4

Values are means ±SEM. * indicates significant effect of digoxin (p < 0.05) by paired t-test.

SYST = systolic, DIAST = diastolic, MAP = mean arterial pressure, CI = cardiac index.

Table 3. (data from Mason and Braunwald)
Hemodynamic effects of ouabain in subjects with normal or failing hearts
MAP
(mmHg)
FBF
(ml/min/100g)
FVR
(MAP/FBF)
HR
(bpm)
CI
(L/min/m^2)
SVI
(ml/beat/m^2)
SVR
(MAP/CI)
Normal no Rx 83
±3
3.1
±2
36
±0.4
69
±2
3.4
±0.1
49
±3
25
±1
+Ouabain 92*
±4
2.9*
±0.3
35*
±4
63*
±2
3.3
±0.1
53*
±2
28*
±1
Failure no Rx 80
±2
1.7
±0.2
52
±6
108
±8
1.7
±0.2
15
±1
51
±6
+Ouabain 79
±3
2.2*
±0.3
40*
±5
87*
±7
2.7*
±0.3
32*
±3
30*
±3

Values are means ±SEM. * indicates significant effect of ouabain (p < 0.05) by paired t-test.

MAP = mean arterial pressure, FBF = forearm blood flow, FVR = forearm vascular resistance, HR = heart rate, CI = cardiac index, SVI = stroke volume index, SVR = systemic vascular resistance.

In the following items “digitalis” will be used to refer to either digoxin or ouabain.

VI. Is there any evidence that digitalis exerted a positive inotropic effect in the two groups of normal subjects?

VII. What best explains the modest decrease in heart rate in normal and heart failure patients after digitalis?

VIII. In the Mason and Braunwald study (see Table 3) the heart failure patients had a high baseline heart rate and a large decrease in heart rate after digitalis. Of the 6 patients, 4 had atrial fibrillation, which often accompanies heart failure. Does some effect of digitalis specifically decrease ventricular rate in patients with atrial fibrillation?

IX. Why did cardiac index and forearm blood flow increase after digitalis in patients with heart failure, but not in patients with normal hearts?

X. In the study by Seltzer et al. (see Table 2) pulmonary capillary wedge pressure was measured in 7 of the patients with heart failure. Pulmonary capillary wedge pressure decreased from a baseline value of 24±4 mmHg to 16±3 mmHg after digoxin. What is the significance of a pulmonary capillary wedge pressure over 20 mmHg?

The remaining items refer to clinical studies of WIN47203, an investigational drug for treating heart failure. In animal studies, WIN47203 had positive inotropic activity, did not inhibit Na/K ATPase, and was not an adrenergic agonist. Maskin et al. studied WIN47203 in 11 patients with severe heart failure (Circulation 67: 1065, 1983). Hemodynamic values measured before and after administration of WIN47203 are presented in Table 4 and Figure 2.

Table 4. Hemodynamic effects of WIN47203
in patients with heart failure
HR
(beats/min)
MAP
(mmHg)
CI
(L/min/m^2)
PCWP
(mmHg)
SVR
(dyne€sec€cm^-5)
Baseline 90±4 75±2 1.9±0.1 27±3 1590±120
+WIN47203 88±4 72±2* 2.9±0.1* 16±2* 1070±90*

Values are means ±SEM. * indicates significant effect of drug (p < 0.05) by paired t-test.

HR = heart rate; MAP = mean arterial pressure; CI = cardiac index; PCWP = pulmonary capillary wedge pressure; SVR = systemic vascular resistance.

Figure 2. 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 ±SD.

XI. Which of the baseline values in Table 4 indicate that the patients are in heart failure?

XII. What symptomatic benefit might result from the hemodynamic effects of WIN47203 in patients with heart failure?

XIII. From the hemodynamic data above, what appears to be the primary action of WIN47203 in patients with heart failure.

To determine if WIN47203 has a clinically important cardiac inotropic effect, Ludmer et al. (Circulation 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±50 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.

Figure 3. Stroke volume index (SWI) as a function of left ventriclar end diastolic pressure (LVEDP)

Figure 4. Comparative hemodynamic effects of vehicle (D5W), intracoronary infusion of WIN47203 at 50µg/min (ICM), and intravenous infusion of WIN47203 (IVM) in eight consecutive patients. * = p < 0.01

XIV. What do you conclude about the action of WIN47203 in patients with heart failure from the data in Figures 3 and 4.