Robert E. Kates

Hypersensitivity to Adrenergic Stimulation after Propranolol Withdrawal in Normal Subjects

The cardiac response to isoproterenol after propranolol withdrawal was studied in six normal persons. Serial isoproterenol infusions were done before and after oral propranolol administration, 160 mg daily for 2 days. Changes in electromechanical systole corrected for heart rate (QS2I) and pulse pressure were used to assess the inotropic response to isoproterenol, and changes in heart rate were used to assess the chronotropic response. As shown in previous studies, the negative inotropic effect of propranolol lasted only 12 to 15 h, while the negative chronotropic effect lasted 24 to 36 h. After the disappearance of blockade a hypersensitivity to isoproterenol was found 24 to 48 h after propranolol withdrawal in all three measured determinants. The explanation of this phenomenon most likely lies in the nature of adrenergic receptors that become activated during long-term blockade.

Dobutamine pharmacokinetics in severe heart failure

Dobutamine pharmacokinetics was investigated in 7 patients with severe cardiac failure. Dobutamine was administered by a constant intravenous infusion at rates of 2 .5, 5.0, 7.5, and 10.0 µg/kg/min. Steady‐state plasma levels increased in proportion to the infusion rate, indicating that there was no saturation of the disposition processes. The average total body clearance was found to be 2.35 ± 1.01 L/min/m2. After termination of the final infusion, plasma levels of dobutamine were monitored to determine the elimination half‐life. The disappearance half‐life of dobutamine was calculated to be 2.37 ± 0.7 min and the distribution volume was 0.202 ± 0.084 L/kg. The limited data suggest that the volume of distribution of dobutamine was related to the extent of edema.

The relationship between plasma dobutamine concentrations and cardiovascular responses in cardiac failure

Plasma dobutamine concentrations and hemodynamic and noninvasive cardiac measurements were made during dobutamine infusions in eight patients with congestive cardiomyopathy and low output heart failure. Plasma concentrations correlated well with infusion rates (2.5, 5.0, 7.5 and 10 microgram/kg/min). Cardiac output and stroke volume increased linearly, whereas pulmonary capillary wedge pressure, and total pulmonary and systemic resistances decreased linearly with increasing dobutamine concentrations. No constant relationship existed between plasma dobutamine levels and changes in heart rate or mean arterial pressure. The noninvasive left ventricular function data (echocardiographic and systolic time intervals) correlated linearly with plasma concentrations and suggest that these noninvasive technics be employed in guiding the administration of this new inotropic agent.

Safety and rationale for continuation of propranolol therapy during coronary bypass operation.

Thirty consecutive patients undergoing coronary bypass were studied. Oral propranolol therapy was maintained up to 4 to 10 hours before operation. Nineteen of the patients had a history of myocardial infarction (MI), 14 had hypoakinetic areas, and 8 had decreased ejection fraction indicating advanced coronary artery disease. Twenty-four-hour urinary epinephrine and norepinephrine obtained the day before operation were markedly increased at 136 +/- 12 microgram per 24 hours (normal, 39 +/- 4 microgram, rho less than 0.01). There were 4 perioperative MIs (13%) and no deaths. Plasma propranolol 1 hour before operation was 43.3 +/- 8 ng per milliliter, indicating good beta blockade. Propranolol was started within 24 hours postoperatively. There were no preoperative, intraoperative, or postoperative complications related to propranolol therapy. We conclude that because of markedly increased adrenergic tone the day before operation and transient hypersensitivity to adrenergic stimulation after withdrawal of propranolol, this agent should be continued through coronary bypass operation.

Binding of quinidine to plasma proteins in normal subjects and in patients with hyperlipoproteinemias

Quinidine in the plasma binds to the various lipoproteins as well as to albumin. With the use of computer simulations the effect of varying the serum level of each of the lipoproteins as weil as albumin was examined. The results suggested that the overall binding of quinidine is relatively insensitive to changes in any one serum pro tein provided the others are present in normal concentrations. Evaluation of the degree of protein binding of quinidine in plasma from normal subjects and patients with types IV and IIa hyperlipoproteinemias supported the computer predictions. The degree of pro tein binding in plasma from normal subjeets and patients with types IV and IIa hyperlipoproteinemias were 71.2% ± 11.4%, 75.9% ± 8.7%, and 69.9% ± 15.0%, respectively. The quinidine bin ding in plasma of patients with hyperlipoproteinemias did not differ statistically from that in the normal subjects.

Time Course of the Blockade Effect of Propranolol on Sinus Node and Atrioventricular Node

The time course of the blockade effect of propranolol on the sinus node (SN) and the atrioventricular node (AVN) was studied in six normal volunteers. Serial isoproterenol infusions were done before and after oral propranolol administration, 160 mg daily for two days. The inhibition by propranolol of the heart rate increases due to isoproterenol was used to assess the blockade of the sinus node, and the diminution by propranolol of the shortening in the PR interval due to isoproterenol was used to assess the blockade of the atrioventricular node. The blockade effects on the sinus node and the atrioventricular node were identical and persisted more than 24 hours. There was no good relationship between plasma propranolol and blockade effect on sinus node and/or atrioventricular node as propranolol was no longer detectable in the plasma 24 hours after the last dose. A transient hypersensitivity to isoproterenol was present 36 to 48 hours after propranolol withdrawal. The explanation of these phenomena most likely lies in the peculiar nature of beta-adrenergic receptors.

Disposition Kinetics of Oral Quinidine When Administered Concurrently with Propranolol

Q IJINIDINE and propranolol are frequently administered concurrently to patients with cardiovascular disorders. In addition to concurrent administration for the treatment of separate but coexisting problems, for example, angina and ventricular dysrhythmias, these two drugs are also used in combination for the management of quinidine-resistant arrhythmias.13 It has recently been reported that this combination is more effective in the treatment of both atrial and ventricular tachyarrhythmias than quinidine alone.4’5 When concurrently administering any combination of drugs, the potential always exists for an interaction to occur. In the case of concurrent administration with propranolol, one must be sensitive to the possible consequences of propranolol-induced alterations in hemodynamics. It has been shown that propranolol can alter the disposition kinetics of drugs by reducing hepatic blood flow and subsequently hepatic clearance.#{176}8 One can hypothesize that any flow-dependent transport phenomena could be inhibited by a propranolol-induced decrease in perfusion. Several investigators have reported the effect of altered hemodynamics on the disposition kinetics of quinidine.#{176}1 It