J. G. Riddell

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.

Characterization of the beta-adrenoreceptors which mediate the isoprenaline-induced changes in finger tremor and cardiovascular function in man.

SummaryWe have studied the contribution of beta1- and beta2-adrenoceptors to the isoprenaline-induced changes in heart rate, blood pressure, forearm blood flow, peripheral vascular resistance, and finger tremor. This was achieved by a comparison of the effects of atenolol 50 mg, ICI 118551 25 mg, propranolol 80 mg, atenolol 50 mg combined with ICI 118551 25 mg, propranolol 80 mg combined with ICI 118551 25 mg, and placebo.Atenolol 50 mg and ICI 118551 25 mg caused similar attenuations in the isoprenaline-induced changes in heart rate and diastolic blood pressure, but the responses after the combination of atenolol and ICI 118551 were similar to those after propranolol 80 mg.There was no difference in the forearm blood flow responses to isoprenaline after atenolol 50 mg and ICI 118551, but atenolol 50 mg did not reduce peripheral vascular resistance compared with placebo. Both responses after treatment with atenolol combined with ICI 118551 were similar to those after propranolol 80 mg.Finger tremor responses to isoprenaline were antagonized by ICI 118551 alone and in combination with propranolol and atenolol but not by atenolol alone, suggesting that the response is beta2-adrenoceptor-mediated.We conclude that the cardiovascular responses to isoprenaline are mediated by both beta1- and beta2-adrenoceptors, whereas the finger tremor response is mediated by beta2-adrenoceptors.

Alinidine reduces heart-rate without blockade of beta-adrenoceptors.

Alinidine is a new drug which reduces heart-rate in animals by an unknown mechanism. Oral administration of 40 and 80 mg significantly reduced an exercise tachycardia in healthy people, with small reductions in heart-rate in the standing and supine positions. Alinidine 80 mg reduced arterial pressure in the standing and supine positions. The reduction in exercise tachycardia produced by 80 mg alinidine was similar to that after 40 mg propranolol, but alinidine had no effect on an isoprenaline tachycardia. These observations indicate that alinidine reduces heart-rate without blocking beta-adrenoceptors and may be useful in patients with angina and in patients with tachyarrhythmias.

Effects of betaxolol, propranolol, and atenolol on isoproterenol‐induced beta‐adrenoceptor responses

Five healthy young men received, in a double‐blind fashion, single oral doses of 10 mg betaxolol, 40 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and placebo. After the dose each received serial 12‐minute infusions of isoproterenol sulfate through the dose range 0.5 to 32 µg/min until the heart rate rose by 40 bpm or the subject could not tolerate the effects of the infusion. Heart rate, finger tremor, blood pressure, and forearm blood flow were measured after each infusion. Dose‐response curves were constructed for the changes in these parameters with increasing doses of isoproterenol. The ascending order of potency of the drugs in preventing the changes in heart rate, finger tremor, diastolic blood pressure, forearm blood flow, and forearm vascular resistance induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg betaxolol, and 40 mg propranolol. The ascending order of potency of the drugs in preventing the change in systolic blood pressure induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and 40 mg betaxolol. Betaxolol, 10 mg, is equally cardioselective to 50 mg atenolol and at a dose of 40 mg betaxolol also exhibits cardioselectivity.

Effects of thyroid dysfunction on propranolol kinetics

Propranolol kinetics was studied in six hyperthyroid and six hypothyroid patients who received single oral and intravenous doses of propranolol when they had thyroid dysfunction and again when they had become euthyroid. Change in thyroid status from hyperthyroid to euthyroid produced no change in the elimination half‐life (t½) of oral propranolol (3.2 ± 0.5 to 4.1 ± 0.7 hr), the oral clearance (38.4 ± 7.3 to 27.4 ± 2.4 ml/min/kg), the elimination t½ of intravenous propranolol (2.5 ± 0.3 to 3.5 ±0.7 hr), and the apparent volume of distribution (4.8 ± 0.4 to 3.8 ± 0.5 l/kg). The systemic clearance of propranolol, however, was greater when the patients were hyperthyroid (20.8 ±2.5 ml/min/kg) than when they had become euthyroid (11.7 ± 1.7 ml/min/kg). The elimination t½ after oral propranolol was longer in the hypothyroid (3.7 ± 0.5 hr) than in the euthyroid state (2.0 ±0.1 hr). No other changes were observed in the kinetic parameters measured when these hypothyroid patients had become euthyroid. Adequate β‐adrenoceptor blockade in hyperthyroid patients may require higher propranolol dosage than expected.

Effect of acute administration of propranolol and atenolol on baroreflex function in normal man

SummaryThe acute administration of the β-adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers.Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p<0.05) to the left compared to placebo.

Circadian Variation of α1-Adrenoceptor-mediated Pressor Response to Phenylephrine in Man

The variability in the pressor effects of the α1‐adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later.

Contrasting actions of celiprolol and metoprolol on cardiac performance in normal volunteers.

A double-blind, randomized, placebo-controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers. Rest and exercise (supine bicycle) hemodynamics were assessed at 0, 2, 4, 6, and 8 hours following single oral doses of medication administered at weekly intervals. The influence of the ancillary pharmacological properties of metoprolol and celiprolol on cardiac pumping indices was assessed from heart rate and peak aortic acceleration (pkA − Exerdop). Following placebo, the heart rate and pkA increased progressively with exercise duration and workload. Following metoprolol 50 mg, the heart rate (−9.7 beat/min at 75 watts exercise) and pkA decreased. The blunting of acceleration was greater at higher exercise workloads (−6.7 m/sec2 at 75 watts exercise). Celiprolol reduced heart rate (−6.9 beat/min at 75 watts exercise) without a change in pkA. The heart rate/pkA relationship showed significant parallel displacement, downwards after metoprolol but upwards after celiprolol. Thus, for a given heart rate increment there was a greater decrease in pkA after metoprolol compared with celiprolol. The different ancillary pharmacological profiles of metoprolol and celiprolol resulted in contrasting hemodynamic profiles. The observed differences in the heart rate/pkA relationships may be attributable to the peripheral actions of these agents. The therapeutic relevance of the better maintained cardiac pumping indices on celiprolol for ischemic patients with impaired cardiac function warrants further investigation.

Studies of the agonist and antagonist activity of cicloprolol in man

SummaryTo assess the partial agonist activity of cicloprolol in man, four studies were carried out in normal male volunteers.I and II. Open dose escalating studies of the effects of oral doses of the drug on exercise tachycardia and sleeping heart rate.III and IV. Double-blind randomized studies of the effects of placebo, cicloprolol 25 mg, cicloprolol 50 mg, cicloprolol 100 mg, atenolol 50 mg, pindolol 10 mg, salbutamol 8 mg and prenalterol 50 mg on sleeping heart rate, resting supine heart rate, blood pressure, forearm blood flow, finger tremor and exercise tachycardia.All doses of cicloprolol above 2.5 mg reduced an exercise tachycardia but there was no increase in effect above a dose of 50 mg.Cicloprolol caused a dose dependent increase in sleeping heart rate up to 200 mg.Cicloprolol increased resting supine heart rate, systolic blood pressure, forearm blood flow and finger tremor.None of the drugs affected quality of sleep.Cicloprolol has significant partial agonist activity at the beta1-adrenceptor as indicated by increases in heart rate and systolic blood pressure. The increases in finger tremor and forearm blood flow suggest that cicloprolol has some partial agonist activity at the beta2-adrenoceptor.

Baroreceptor function in man following peripheral alpha1- and alpha2-adrenoceptor stimulation

SummaryMethoxamine and α-methyl-noradrenaline were administered to six healthy male subjects on separate days as rapid bolus injections until blood pressure increased by approximately 30 mmHg; Valsalvas Manoeuvre was carried out on each occasion. Propranolol (80 mg) or placebo was administered (random order, double-blind, weekly intervals) and the observations were repeated after 2 h.Baroreceptor sensitivity (ΔR-R interval ms/mmHg systolic BP) was less (p<0.05) with α-methyl-noradrenaline than methoxamine.Propranolol abolished the differences in baroreceptor-mediated bradycardia following α-methyl-noradrenaline and methoxamine, and shifted the baroreceptor sensitivity regression lines (p<0.05) to the left.During the release phase of Valsalvas Manoeuvre baroreceptor sensitivity was increased following propranolol.The smaller baroreceptor-mediated bradycardia response observed with α-methyl-noradrenaline does not support the hypothesis that pre-synaptic α-adrenoceptors have a physiological role in the modulation of baroreceptor function in man, and may be due to α-methyl-noradrenaline having β1-agonist activity.