Degree Of Beta-adrenoceptor Blockade Research Articles

Comparaison chez le volontaire sain du blocage bêta-adrénergique systémique par les collyres bêta-bloquants

The isoproterenol dose-response curve was used to assess quantitatively the degree of systemic beta-adrenoceptor blockade induced by metipranolol (Bétanol ®) and betaxolol (Bétoptic ®) eye drops. The study was carried out in twelve healthy volunteers, aged 22 ± 1.4 yr. In a randomized doubleblind trial, each volunteer received, on separate occasions at least one week apart, one drop in each eye of either placebo (physiological saline) or either of the ophthalmic beta-blockers. The intraocular pressure (Pio), heart rate (f c), arterial systolic (Pa sys) and diastolic (Pa dia) pressures were measured before instillation of the eye drops after 15 to 30 min rest, and 3 h afterwards. The isoproterenol dose-response curve was studied 3 h after instillation of the drops. The CD 25 (the amount of isoproterenol needed to increase f c by 25 b · min −1) was obtained by extrapolation on the least square linear regression curve. Both beta-blockers gave a significant fall in Pio compared with placebo, metipranolol more than betaxolol (p < 0.02). There was also a significantly greater fall in f c with both metipranolol and betaxolol than with placebo. There were no changes in Pa sys and Pa dia. CD 25 was significantly increased with both beta-blocker eye drops as compared with placebo (p < 0.05 for betaxolol ; p < 0.01 for metipranolol), but there was no difference between the two. Systemic absorption after topical application of ocular beta-blockers was thus confirmed for both metipranolol and betaxolol. However, the degree of beta-adrenoceptor blockade was weaker than that observed with other older ocular beta-blockers (timolol and carteolol). Although these results suggest a greater safety margin with both metipranolol and betaxolol, anaesthesiologists should be aware and wary of this phenomenon.

Absence of excess peripheral muscle fatigue during beta-adrenoceptor blockade.

1. In eight normal volunteers, the adductor pollicis (AP) was fatigued using intermittent trains of programmed, supramaximal stimulation at 1, 10, 20, 50, 100 and 1 Hz. Activity protocols were performed both with and without circulatory occlusion, both without and during propranolol 80 mg thrice daily in order to investigate the effects of beta-adrenoceptor blockade on 'peripheral' fatigue mechanisms. 2. The degree of beta-adrenoceptor blockade was assessed by the reduction of exercise tachycardia during cycle ergometry, e.g. pulse rates at 210 watts were reduced from 190 +/- 15 to 127 +/- 5 beats min-1 (mean +/- 1 s.d.) indicating that beta-adrenoceptor blockade was substantial and highly significant (P less than 0.001). 3. Before, during and following fatiguing activity with circulatory occlusion force declines were identical during and without beta-adrenoceptor blockade. During and following activity without occlusion, there were slight declines in force which were questionably significantly different at 20 Hz (P less than 0.05). 4. The compound muscle action potential (CMAP) amplitude, measured from the skin surface over the muscle, was unaltered by beta-adrenoceptor blockade before, during or after activity whether with or without circulatory occlusion. 5. The maximal relaxation rate (MRR) was not significantly reduced in previously unfatigued muscle during beta-adrenoceptor blockade. During activity, both with and without circulatory occlusion, there was no evidence that MRR was reduced significantly more during beta-adrenoceptor blockade. 6. The absence of a convincing effect of beta-adrenoceptor blockade on peripheral fatigue mechanisms may indicate that central mechanisms are involved or that impairments of peripheral force production, of a specific nature or as a result of exacerbation of limitations of circulatory oxygen transport, though small are detected during voluntary exercise and give rise to increases in motor unit recruitment and/or firing rates, and hence increased perception of fatigue.

Effect of ??-blockade on exercise core temperature in coronary artery disease patients

The effect of pharmacologic blockade of beta-adrenoceptors on the relationship between rectal (Tre) and pulmonary artery (Tpa) temperatures was studied in six coronary artery disease patients during 30 min of exercise. Exercise was performed at a set work rate (120 W) on a cycle ergometer before and 2 h after the ingestion of 80 mg propranolol. The heart rate on completion of exercise was reduced (P less than 0.001) from 140 +/- 5 to 108 +/- 3 beats.min-1 by propranolol demonstrating a considerable degree of beta-adrenoceptor blockade. At rest, neither Tre nor Tpa were modified by propranolol. Likewise, propranolol failed to modify the Tre response to exercise. However, propranolol induced an alteration of the normal relationship between Tre and Tpa during exercise. In particular, although Tre was essentially unchanged, propranolol accentuated both the initial fall (by 0.28 degrees C, P less than 0.001) and the subsequent rise (by 0.46 degrees C, P less than 0.01) in Tpa during exercise. The present data therefore demonstrate a considerable limitation to the use of Tre when assessing thermal homeostasis during acute beta-adrenoceptor blockade. Furthermore, although research with more chronic therapy is warranted, our study suggests an accentuated risk of hyperthermia and, by implication, its adverse physiologic consequences during prolonged exercise performed by coronary artery disease patients treated with propranolol.

Antihypertensive effect and degree of beta-adrenoceptor blockade after short-term and semi-chronic propranolol therapy.

In patients with normal-renin, mild (n = 6) or moderate (n = 6) hypertension, the antihypertensive effects of propranolol (80 mg/day) for 1 day or for 2 weeks were evaluated in relation to the degree of beta-adrenoceptor blockade induced. A significant and similar fall in systolic blood pressure was observed after 1 day and 2 weeks on propranolol in both groups of patients. In contrast, diastolic blood pressure showed only a minor decrease after 1 day of therapy (-2 +/- 2 and -3 +/- 1 mm Hg) but a significant drop (-7 +/- 3 and -9 +/- 3 mm Hg) after 2 weeks in the mild and moderate hypertension groups, respectively. Plasma propranolol levels and decreases in resting heart rate and PRA were similar after 1 day and 2 weeks of treatment. Isoprenaline dose-response curves for systolic and diastolic blood pressure, heart rate and PRA showed similar parallel shifts after 1 day and 2 weeks of treatment. The effect of graded bicycle exercise on these parameters were also similarly blunted. These results indicate that over time, systolic blood pressure decreases rapidly whereas diastolic blood pressure shows a delayed fall following initiation of low-dose propranolol therapy, despite the same degree of beta-adrenoceptor blockade.

Alpha-adrenoceptor blockade by labetalol during long-term dosing.

The hypotensive effect of short-term labetalol, the alpha- and beta-adrenoceptor blocker, is greater in subjects in the orthostatic position, possibly because of the alpha-adrenoceptor blockade. During prolonged use the orthostatic blood pressure fall disappears. To verify whether or not this is due to reduction in alpha-blocking activity, phenylephrine-induced increase in blood pressure was studied in six subjects with mild essential hypertension before and after 3 and 6 days and 1 and 6 mo of continuous treatment with 200 mg labetalol three times a day by mouth. At the same intervals, isoproterenol-induced tachycardia was followed to assess beta-blockade. After 3 days on labetalol, the log dose-response curve of phenylephrine-induced increase in blood pressure shifted to the right and the dose of agonist required to elicit a 20% increase in systolic pressure was 1.7 times that before treatment. There was a progressive decline in the dose of agonist that induced the same increase in pressure so that after 6 mo of continuous labetalol it was the same as control. In contrast, the amount of isoproterenol needed to induce a 20% increase in heart rate was two to three times that before labetalol and did not change throughout 6 mo of therapy. These data indicate a decline in the alpha-adrenoceptor-blocking effect of oral labetalol without concomitant change in the degree of beta-adrenoceptor blockade. This might account for the disappearance of orthostatic hypotension early in the course of treatment and for some decrease in the antihypertensive efficacy of labetalol.

Pharmacokinetics, beta‐adrenoceptor blockade and anti‐hypertensive action of labetalol during chronic oral treatment

1 beta-Adrenoceptor blockade, plasma labetalol concentrations and anti-hypertensive actions were investigated at 2 hourly intervals during the interdose period of chronic oral therapy in six hypertensive patients. 2 beta-adrenoceptor blockade varied during the inter-dose period and was maximal 2 and 4 h after the oral dose (P < 0.05). 3 Systolic pressure rose during the interdose period (P < 0.05). A significant correlation was found between the degree of beta-adrenoceptor blockade and the change in systolic pressure at 2 h after the oral dose. 4 Efficacy of labetalol as a beta-adrenoceptor antagonist and anti-hypertensive drug was assessed 2 h after an oral dose during chronic eight hourly dosage in sixteen hypertensive patients. Pharmacokinetics of labetalol were studied in the same patients. 5 Peak plasma labetalol concentration occurred 2 h after the oral dose and subsequently the plasma concentration declined monoexponentially. 6 The steady state concentration (CSS) of labetalol was correlated significantly with the daily oral dose in mg kg-1, the mid point labetalol concentration (Cmax+Cmin) divided by 2 and the isoprenaline dose ratio-1 at 2 h after the oral dose. 7 No correlation was found between the antihypertensive effect and the CSS ng ml-1 labetalol or between the isoprenaline dose ratio-1 and the CSS labetalol ng ml-1.