R. G. Shanks

Clinical pharmacologic observations on atenolol, a beta‐adrenoceptor blocker

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of aseries of single doses of atenolol reduced an exercise tachycardia. After a 200‐mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half‐life of 6.36 ± 0.55 hr: 43 ± 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a signi(icant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recoveredfrom the urine, ami the clearance was 97.3 ml/min. Comparison of AUCo→x after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half‐life, area under the plasma concentration‐time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.

Comparison of the effects of I.C.I. 50172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline and exercise

1 The intravenous infusion of I.C.I. 50172 in doses up to 20 mg reduced, although not significantly, the increase in heart rate produced by the infusion of isoprenaline in healthy volunteers; the response to adrenaline was significantly reduced. The infusion of 1 mg propranolol abolished these responses 2 After the pre‐treatment of subjects with atropine or hexamethonium, I.C.T. 50172 produced a significant reduction in an isoprenaline tachycardia. This reduction was not competitive and did not exceed 50%. 3 The intravenous injection of 4 mg I.C.I. 50172 reduced an exercise tachycardia; its effect was less than that of 4 mg propranolol. This difference became greater as the doses of the two drugs were increased. The dextro isomer of propranolol had no effect on the exercise tachycardia; I.C.I. 45763 reduced it to the same extent as propranolol. 4 The intravenous injection of I.C.I. 50172 reduced the increase in heart rate produced by tilting a normal subject from the supine to 80° head‐up position. After the administration of atropine, I.C.I. 50172 almost abolished the response. In the presence of atropine, I.C.I. 50172 was as active as propranolol in reducing the increase in heart rate on tilting. 5 The reason for the differences in the effects of I.C.I. 50172 on the increases in heart rate brought about by the three procedures is not clear. 6 The increase in forearm blood flow produced by the infusion of isoprenaline into the brachial artery was not reduced by the intra‐arterial administration of I.C.I. 50172.

Clinical Pharmacokinetics of β-Adrenoceptor Antagonists

SummaryThe β-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, Sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction.All the β-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of β-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug.Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma β-adrenoceptor antagonist concentration measurement is usually unnecessary.The investigation of the clinical pharmacokinetics of the β-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

The cardio‐toxicity of isoprenaline during hypoxia

1 The effects of the intravenous injection of isoprenaline on heart rate and arterial pressure has been studied in dogs artificially respired with room air or with 12% oxygen—88% nitrogen. 2 In dogs breathing room air, isoprenaline in doses from 0.02 to 500 μg/kg increased heart rate and reduced arterial pressure. Ventricular fibrillation was produced in one out of three dogs given 250 μg/kg. This was the only dog breathing room air which was killed by isoprenaline. 3 In dogs breathing room air the repeated intravenous injection at 5‐min intervals of 2.5 μg/kg increased heart rate and reduced arterial pressure. No ill effects were produced by six doses. 4 In dogs respired with 12% oxygen—88% nitrogen the Pao2 was reduced from 84 to 38 mm Hg with no changes in Paco2. In these dogs death was produced by doses of isoprenaline which in dogs breathing room air produced normal responses. 5 The fatal dose of isoprenaline (10–50 μg/kg) reduced heart rate and arterial and pulse pressures; sinus rhythm persisted until arterial pressure was less than 50 mm Hg. Ventricular fibrillation did not occur; death occurred from cardiac asystole. 6 Death was produced in a similar way in dogs with hypoxaemia by giving four or five doses of isoprenaline (2.5 μg/kg) at 5‐min intervals or by two doses of 25 μg/kg. 7 The final reduction in arterial pressure during a fatal response resulted from a reduction in cardiac contractility. 8 These lethal effects of isoprenaline could be prevented by pretreatment with propranolol.

Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade

Dose‐response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized exercise test and percentage reduction in exercise heart rate (EHR) as the index of drug effect. The dose‐response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor‐blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor‐blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetic activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor‐blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprellolol was given after sotalol or oxprenoloi, or practolol was given after sotaloi or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenoiol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenoloi or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose‐response curves with exercise.

Blood levels of practolol after oral and parenteral administration and their relationship to exercise heart rate

Blood levels of practolol after oral and parenteral administration were determined in normal subjects, and the effects of each dose on the heart rate induced by strenuous exercise were measured. Oral practolol was rapidly absorbed and produced peak blood levels in 1 to 3 hours. Between 2 and 7 hours blood levels varied little more than twofold either within or between subjects. The half‐life of practolol in blood was 10 to 11 hours. Practolol100 mg was the minimum dose to produce near maximum blockade at 2 hours; maintenance of this effect for 24 hours reqUired 400 mg. Near maximum blockade was produced as long as a blood practolol level of 1.0 to 1.4 µg per milliliter was maintained. There was a correlation between the logarithm of the blood practolollevel and the percentage reduction of exercise heart rate. Practolol 40 mg and 80 mg intravenously initially achieved near maximum blockade associated with blood practolol levels above 1.0 p.g per milliliter. The effects and blood levels fluctuated during the first 7 hours. Intramuscular doses up to 40 mg failed to produce near maximum blockade; higher doses were precluded by pain at the injection site.

Prophylactic lidocaine in the early phase of suspected myocardial infarction

Four hundred two patients with suspected myocardial infarction seen within 6 hours of the onset of symptoms entered a double-blind randomized trial of lidocaine vs placebo. During the 1 hour after administration of the drug the incidence of ventricular fibrillation or sustained ventricular tachycardia among the 204 patients with acute myocardial infarction was low, 1.5%. Lidocaine, given in a 300 mg dose intramuscularly followed by 100 mg intravenously, did not prevent sustained ventricular tachycardia, although there was a significant reduction in the number of patients with warning arrhythmias between 15 and 45 minutes after the administration of lidocaine (p less than 0.05). The average plasma lidocaine level 10 minutes after administration for patients without a myocardial infarction was significantly higher than that for patients with an acute infarction. The mean plasma lidocaine level of patients on beta-blocking agents was no different from that in patients not on beta blocking agents. During the 1-hour study period, the incidence of central nervous system side effects was significantly greater in the lidocaine group, hypotension occurred in 11 patients, nine of whom had received lidocaine, and four patients died from asystole, three of whom had had lidocaine. We cannot advocate the administration of lidocaine prophylactically in the early hours of suspected myocardial infarction.

Observations on the efficacy and pharmacokinetics of sotalol after oral administration.

SummaryThe effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 – 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subjects. The half-life of sotalol in plasma was 12.7 ± SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of β-adrenoceptors.

Time and frequency domain assessment of heart rate variability: A theoretical and clinical appreciation

Non-invasive techniques for assessing heart rate variability can be used either diagnostically, as in identification of autonomic neuropathy associated with diabetes mellitus or tissue rejection following cardiac transplantation, or as a prognostic indicator in coronary artery disease. The methodology is based upon calculation of successive R—R intervals from an electrocardiogram, which can then be plotted as a frequency histogram (time domain analysis), undergo power spectral analysis to yield information in the frequency domain or be applied to chaos theory. In this review, several parameters are discussed which can be derived to quantify heart rate variability in the time and frequency domains; the latter providing information on autonomic balance. In the frequency domain up to three peaks may be observed, with the peak below 0.15 Hz being mediated by sympathetic and parasympathetic activity and peaks above 0.15 Hz being of vagal origin. The effects of different physiological and pathophysiological conditions on various indices of heart rate variability, and the use of heart rate variability analysis as a pharmacological method to assess the impact of drug therapy on sympathovagal balance are discussed.

Spectrophotofluorometric and gas‐liquid chromatographic methods for the estimation of mexiletine (Kö 1173) in plasma and urine

Methods are presented for the spectrophotofluorometric and gas‐liquid chromatographic determination in plasma and urine of the anti‐arrhythmic compound, mexiletine (Kö 1173). Both methods involve extraction of the drug from alkaline plasma with ether. In the spectrophotofluorometric method the compound is re‐extracted into 0ṁ05n HCl and emission intensity determined at 300 nm with activation at 228 nm. In the chromatographic method the drug is acylated during evaporation of the ether. Both butyryl and acetyl derivatives could be used. Use of a nitrogen‐sensitive detector increased the sensitivity and selectivity of the method and allowed more rapid analyses. There was good agreement between results obtained by spectrophotofluorometric and chromatographic methods.