Cardio-selective Beta-adrenergic Therapy Report

Beta adrenergic therapy with propranolol is the therapy of choice in the treatment of hypertrophic obstructive cardiomyopathy. However, it is contraindicated in the presence of severe asthma. Recendy a cardio-selective β-1 adrenergic antagonist, pindolol, or 4-(2-hydroxy-3-isopropylaminopropoxy) indole has been developed with a potency equal to or greater than that of propranolol. Specific β-2 adrenergic agonists also are available for use in patients with asthma. Their effects on the cardiovascular system are minimal.

We recently encountered a patient with severe asthma and hypertrophic obstructive cardiomyopathy in whom it was desirable to use cardio-selective adrenergic therapy. The combined use of these agents has not previously been reported, and the combination of these disease states in a single patient is relatively rare. The present study was undertaken to establish the effectiveness and specificity of the β1 adrenergic antagonist pindolol and the β-2 adrenergic agonist albuterol.

Case Report

A 22-year-old man with steroid-dependent asthma since childhood was referred for evaluation of a systolic heart murmur. For three months before admission he experienced episodes of tachycardia, dyspnea, and dull precordial chest pain. These symptoms usually occurred following exertion or after isoproterenol or metaproterenol nebulizations. When symptomatic, a prominent systolic murmur was noted; however, on repeated examinations at rest only an intermittent faint systolic murmur was audible. There was no history of syncope, rheumatic fever, or childhood murmur.

Asthmatic Man

Current medications included methylprednisolone, 12 mg every other morning choline theophyllinate (Choledyl) 250 mg four times daily, and albuterol, two inhalations (100 /tg per dose) four times daily, the last under an experimental protocol.

Physical examination showed a Cushingoid appearance; blood pressure, 120/70 mm Hg; pulse was 90/min and regular. The jugular venous pressure was not elevated, and die peripheral pulses were normal. The chest was clear to percussion and auscultation. Cardiac examination revealed normal St and S2, with no S3 or S4. A grade 1/6 systolic ejection murmur was present at the left lower sternal border, radiating toward die base and the apex. The murmur increased to grade 4/6 with exercise and diminished with squatting. The remainder of the cardiovascular examination results were within normal limits.

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Chest x-ray film showed increased anteroposterior diameter, with flattening of the hemidiaphragms. The cardiac silhouette was normal. The ECG was within normal limits.

Echocardiogram was technically difficult owing to poor sound transmission through hyperinflated lungs but suggested asymmetric septal hypertrophy.

Following informed consent, the patient underwent cardiac catheterization. The left ventricular outflow gradient was measured at rest, following exercise, and after cardio-selec-tive 0-adrenergic stimulation and blockade. The results of cardiac catheterization are summarized in Table 1. A resting subvalvular gradient of 33 mm Hg was present, which increased to 68 mm Hg following the Valsalva maneuver. The gradient increased to 50 mm Hg with exercise. After two inhalations of albuterol, the left ventricular outflow gradient was 30 mm Hg. Control left ventricular pressures were recorded and the patient was given 0.05 mg of pindolol intravenously (IV) every five minutes to a total dose of 0.4 mg. The left ventricular outflow gradient after administration of the pindolol was 23 mm Hg. After a two-minute period of exercise, the heart rate increased to 135 beats/min, and a left ventricular outflow gradient of 14 mm Hg was recorded.

Several days later pulmonary function tests were conducted to establish whether pindolol was indeed a cardio-selective β-adrenergic blocking agent Pindolol was given, 0.05 mg IV over five minutes, followed at 10- to 15-minute intervals by increments of 0.05 mg to reach a total dose of 0.30 mg, with two placebos interspersed. Then 0.1 mg was given IV for a total cumulative dose of 0.4 mg. Obstructive changes in all pulmonary function measurements were present, as well as wheezing following pindolol administration (Table 2 and Fig 1). A similar sequence was repeated three days later to a total dose of 0.55 mg. Obstructive changes and symptoms were again present. Sub-sequendy, a single oral tablet of 0.25 mg was given, which caused airway obstruction peaking at 30 to 45 minutes. In all studies with pindolol, the heart rate decreased significantly and remained so, as did systolic blood pressure.

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Albuterol aerosol caused marked improvement in pulmonary function lasting up to four hours compared with isoproterenol, which lasted only IX hours. Heart rate increased slightly with albuterol but was not uncomfortable to the patient. Albuterol (200 *ig) given concomitantly with oral pindolol (either 0.25 mg or 0.125 mg) did not prevent airway obstruction.

Table 1—Result from Cardiac Catheterization

State Pressure, mm HgA
/- LVApex LVSub-valvular Ao SubvalvularGradient
Rest 146/8 113/8 113/76 33
Valsalva maneuver 190/40 122/40 122/88 68
Exercise 174/12 124/12 124/68 50
Albuterol 162/10 132/10 132/77 30
Pindolol
Control 130/6 107/6 107/74 23
Exercise 122/11 108/11 108/76 14

Table 2—Pulmonary Function Studies After Intravenous Pindolol

FEVi, L FVC, L FEF25-75%,L/sec Raw, cm H*0/ L/sec SGaw,L/cmH*0/sec Blood Pressure, mm Hg Pulse
Baseline 3.39 5.49 2.65 2.04 .12 135/90 116
Cumulative dose pindololf
.05 mg 3.15 5.50 2.29 2.85 .08 135/90 108
.10 mg 3.05 5.35 2.03 3.07 .08 120/85 102
.15 mg 2.93 5.46 1.78 4.25 .05 128/90 84
.20 mg 2.63 5.27 1.44 6.00 .04 122/90 90
.25 mg 2.37 5.22 1.58 6.62 .03 112/88 90
Placebo 2.76 5.34 1.48 6.06 .04 115/90 84
Placebo 2.72 5.11 1.60 4.99 .04 112/88 90
.30 mg 2.34 4.82 1.52 5.03 .04 110/90 84
.40 mg 2.07 4.61 1.64 6.18 .04 108/88 84
1 hr after isoproterenol 2.72 5.19 1.83 3.54 .06 110/88 84

 

Pulmonary Function Tests
Figure 1. Pulmonary function tests after intravenous pindolol. Doses of pindolol and placebo were given at 10-15 min intervals. Raw = airway resistance; FVC = forced vital capacity; FEVX = forced expiratory volume in one second; FEF25-75% = mean forced expiratory flow during middle half of FVC; and SGaw = specific airway conductance.