John Hamer

Hemodynamic changes after beta adrenergic blockade

Abstract Nine patients with mild left ventricular disease have been studied at rest and on exercise before and after beta adrenergic blockade. The intravenous injection of 5 mg. of propranolol was followed by statistically significant changes: (1) the cardiac output and left ventricular work were both about 20 per cent lower at rest and on effort; (2) oxygen uptake was reduced by 8 per cent during exercise at 300 kpm./min.; (3) heart rate was reduced by 15 per cent during exercise; (4) both the absolute value for the pulmonary artery pressure and the percentage increase with effort were higher.

EFFECTS OF BETA-ADRENERGIC BLOCKADE DURING EXERCISE IN HYPERTENSIVE AND ISCHÆMIC HEART-DISEASE

Abstract In ten patients with hypertension and eight with angina pectoris, β-adrenergic blockade with a single intravenous injection of propranolol produced a decrease in systolic and diastolic blood-pressure, heartrate, cardiac output, and left ventricular work at rest and during walking exercise. The effects were more striking in hypertensive patients than in those with ischaemic heart-disease. Six patients with hypertension and four with ischaemic heart-disease showed no essential difference in the haemodynamic findings in a second test period after a placebo injection. The decrease in blood-pressure after propranolol was due entirely to the effect on the heart, there being no change in the peripheral resistance. The findings suggest that propranolol should be a useful agent for the treatment of hypertension and angina pectoris.

Effects of propranolol on exercise tolerance in angina pectoris

I do not think it is necessary for me to go into the details of the pharmacology and the effects of Propranolol as this has been so well covered by the previous speakers. I would like to say particularly how much I agree with Dr. Meesmann und his views on the action of these drug. I feel that the idea of an oxygen wasting effect of catecholamine stimulation of the myocardium has been somewhat overplayed.

CARDIAC AND PULMONARY EFFECTS OF ACEBUTOLOL

In a double-blind randomised study, single intravenous doses of propranolol (0-1 mg. per kg.), practolol (1 mg. per kg.), acebutolol (1 mg. per kg.), or placebo were each administered at weekly intervals to six healthy volunteers. Forced expiratory volume in 1 second (F.E.V.1), resting and exercise heart-rate, and resting and exercise peak flow-rate (P.F.R.) were determined before and at 2, 3, 4, and 6 hours after each treatment. Venous blood-samples were also obtained at these times. Compared with placebo, resting heart-rate was reduced after all three drugs, but the corresponding differences in exercise heart-rate were much greater, more consistent, and of greater statistical significance. At 2, 3, and 4 hours when acebutolol and propranolol produced equivalent cardiac beta-blocking activity (judged by reductions in exercise heart-rate), their mean plasma concentratios were in the ratio of about 8/1; and at 2 hours when practolol and acebutolol gave rise to almost equivalent cardiac beta blockade, their mean plasma concentratio ration was 3/1. At times, reductions in F.E.V.1 and resting P.F.R. after propranolol (but not after practolol or acebutolol) were significantly greater than the corresponding changes after placebo. The reductions in exercies P.F.R. after propranolol (6 hours) and acebutolol (4 hours) (but not after practolol) were significantly greater than the changes after placebo. Changes in F.E.V.1, resting and exercise P.F.R. after propranolol, and the corresponding changes after practolol, were significantly different, all of which confirmed that practolol was more cardioselective than propranolo. In general, the reductions in F.E.V.1 and resting P.F.R. after acebutolol were slightly smaller than after propranolol, excepting at 6 hours when the difference between them was significant. The reductions in exercise P;F.R. after acebutolol and propranolol were of the same order, there being no significant differences between the two, whereas the reductions after acebutolol were clearly greater than the corresponding changes after practolol, the differences being significant at 2, 3, and 4 hours.

Cardiac arrhythmias during cytotoxic chemotherapy: role of domperidone.

1 Four patients receiving platinum-containing chemotherapy were treated with domperidone (20 mg) by slow intravenous injection followed by a continuous infusion for 24 h at a dose of 10 mg 24 h-1 kg-1. Cardiac monitoring and plasma potassium and domperidone concentration measurements were performed. Severe cardiac arrhythmias occurred in two patients. 2 A control group of 14 patients treated with similar chemotherapy, without domperidone, also underwent cardiac and plasma potassium monitoring. No significant arrhythmias were seen. 3 The electrophysiologic effects of domperidone are discussed. 4 It is concluded that treatment with intravenous domperidone is associated with the occurrence of cardiac arrhythmias.

Therapeutic Non-equivalence of Digoxin Tablets in United Kingdom: Correlation with Tablet Dissolution Rate

Seven types of digoxin 0·25 mg tablet in common use in the United Kingdom were administered to a total of 38 patients. Significant differences were found in the mean plasma digoxin levels and in the control of atrial fibrillation achieved with these brands. There was a close correlation between the dissolution rate of the tablets and the plasma digoxin levels. Measurement of in-vitro dissolution rate appears to be a valid method of ensuring that different tablets of digoxin are of equal efficacy. However, in some patients absorption of the drug is markedly sensitive to changes in dissolution rate and new pharmacopoeal standards should not be defined until very rapidly-dissolving formulations have been studied.

Observations on the pharmacokinetics of acebutolol.

Using a balanced, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N‐acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the data of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (±SD) values were found: distribution half‐life (T½D), 0.60 (±0.43) hr, plasma elimination half‐life (T½El), 3.2 (±1.1) hr, apparent volume of distribution (VD), 224 (±69) L, and apparent VD/kg, 3.0 (±0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T½El was 3.2 (±0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (±7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (±68) ml/min and the corresponding plasma clearance was 818 (±64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.

A Qualitative Distinction between the Beta-Receptor-Blocking and Local Anesthetic Actions of Antiarrhythmic Agents

Fragmented cardiac sarcoplasmic reticulum was isolated by differential centrifugation from canine myocardium. The effects of propranolol, quinidine, lidocaine (lignocaine) and tetracaine (amethocaine) on calcium uptake in sarcoplasmic reticulum in vitro were then measured. All the drugs are antiarrhythmic agents with local anesthetic activity, but propranolol and quinidine are known also to have beta-receptor-blocking actions in that they can prevent the cardiac effects of isoprenaline and depress the myocardium. Lidocaine and tetracaine do not generally depress the heart and had no effect on the calcium uptake, but propranolol and quinidine both significantly inhibited it. It was concluded that the antiarrhythmic actions of propranolol (and quinidine) may be independent of beta-receptor-blocking activity, and that the safety of lidocaine as an antiarrhythmic agent may be related to a lack of effect on the sarcoplasmic reticulum.

Significance of Electrocardiographic Changes in Hypertension

Studies in 17 hypertensive patients showed that the electrocardiographic features of T-wave inversion and S–T segment depression distinguish those patients with higher systolic blood pressures. They do not indicate impaired cardiac function.

Long-term Results of Aortic Valve Replacement with the Starr-Edwards Valve

Review of the 74 patients undergoing aortic valve replacement with a Starr–Edwards ball-valve prosthesis between October 1963 and December 1967 showed that 16 died during surgery or within the first month after operation, usually owing to myocardial failure; and there were nine late deaths. The remaining patients developed few major complications, and the long-term results of operation are considered satisfactory, no patient being grossly incapacitated and most of them are leading active, symptom-free lives.