Problem 5

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?

  1. Toxicity developed after the first dose
  2. Volume of distribution decreased after the first dose due to the decrease in body weight.
  3. Due to its long plasma half life, digitalis is often administered as a large loading dose, followed by smaller maintenance doses.
  4. Due to its short plasma half life, digitalis is often administered as a large loading dose, followed by smaller maintenance doses.

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

  1. Digitalis decreased heart size by decreasing venous return.
  2. Digitalis decreased heart size by increasing ejection fraction.
  3. Digitalis decreased heart size by increasing cardiac diastolic tone.
  4. Digitalis decreased heart size by decreasing circulating plasma volume.

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

  1. Digitalis decreased circulating plasma volume.
  2. Digitalis increased ejection fraction, thus decreasing left ventricular diastolic volume and pressure, with a secondary decrease in venous pressure.
  3. Both a and b above contribute to the decrease in venous pressure.
  4. Digitalis is a direct venodilator.

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

  1. Digitalis caused a diuresis.
  2. Digitalis caused nausea and anorexia.
  3. The slight decrease in body weight is probably unrelated to administration of digitalis.
  4. Digitalis decreased appetite by a direct effect on the CNS medullary nuclei that control appetite.

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

  1. Digitalis inhibited Na/K ATPase in the distal tubule of the kidney.
  2. Digitalis increased fluid intake by a direct effect on the CNS medullary nuclei that control thirst.
  3. Digitalis caused an increase in sympathetic tone which decreased renin production by the juxtaglomerular apparatus.
  4. Digitalis decreased renin and aldosterone production by improving perfusion of the kidney.

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?

  1. No, one would not expect digitalis to have a positive inotropic effect in a normal, non- failing, heart.
  2. No, in fact, the effects of cardiac index and forearm blood flow suggest that digitalis exerted a negative inotropic effect.
  3. Yes, as indicated by the effects on mean arterial pressure.
  4. Yes, as indicated by the effects on arterial pulse pressure and stroke volume index.

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

  1. Digitalis directly depresses sinus node automaticity.
  2. Digitalis slows conduction through the AV node, mainly by increasing parasympathetic (vagal) tone.
  3. Digitalis stimulates parasympathetic (vagal) tome and, particularly in patients with heart failure, causes reflex withdrawal of sympathetic tone.
  4. All of the above contribute to the effect of digitalis on heart rate.

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?

  1. Yes, digitalis increases the refractory period and slows conduction through the AV node.
  2. Yes, digitalis usually converts atrial fibrillation to normal sinus rhythm.
  3. Yes, digitalis directly decreases atrial automaticity.
  4. No, the greater decreases of heart rate in these patients was probably related to the higher initial heart rate.

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

  1. Mean arterial pressure increased to a greater extent after digitalis in patients with heart failure.
  2. Digitalis increased sympathetic tone and vascular resistance in normal subjects, but decreased vascular resistance in heart failure patients by withdrawal of sympathetic tone.
  3. Digitalis increased vascular resistance in normal subjects by a direct vascular effect, but decreased vascular resistance in heart failure patients by withdrawal of sympathetic tone.
  4. Digitalis increases cardiac contractility in failing myocardium but not in normal myocardium.

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?

  1. A pulmonary capillary wedge pressure over 20 mmHg suggests the presence of pulmonary edema.
  2. A pulmonary capillary wedge pressure above the normal range of 2 – 10 mmHg suggests the presence of right ventricular failure.
  3. A pulmonary capillary wedge pressure over 20 mmHg indicates the presence of pulmonary hypertension (cor pulmonale).
  4. A pulmonary capillary wedge pressure over 20 mmHg suggests that these patients had only mild heart failure.

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?

  1. High pulmonary capillary wedge pressure.
  2. Low cardiac index.
  3. High systemic vascular resistance.
  4. All of the above.

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

  1. Increased cardiac index might decrease symptoms of fatigue.
  2. Decreased pulmonary capillary pressure might decrease congestive symptoms (e.g. dyspnea).
  3. Both a and b above.
  4. The drug acts only as a vasodilator and, thus, would not diminish symptoms of heart failure.

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

  1. It acts as an arteriolar vasodilator.
  2. It acts as a mixed arteriolar and venous/capacitance vasodilator.
  3. It acts as a positive inotropic agent with a reflex decrease in systemic vascular resistance.
  4. The drug could act by any one or a combination of 1 – 3 above; additional data are needed to distinguish these possibilities.

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.

  1. The drug acts primarily as a vasodilator with very little direct inotropic effect on the heart.
  2. The drug acts primarily as a positive inotropic agent with a reflex decrease in vascular resistance similar to that produced by digitalis.
  3. The drug has both significant inotropic activity and direct vasodilator activity.
  4. The drug has relatively pure venous capacitance dilator activity, like that produced by organic nitrates
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