Ranitidine--a new H2-receptor antagonist.

The pharmacokinetics and gastric antisecretory effects of a new histamine H2-receptor antagonist, ranitidine hydrochloride, have been investigated in healthy subjects. In the pharmacokinetic study six subjects received 20 mg, 40 mg, and 80 mg ranitidine, both orally and intravenously. Plasma levels of ranitidine were dose-related and in most subjects after oral drug the concentration time curve was bimodal. The estimated elimination half-life was 140 minutes and the bioavailability of the oral drug was about 50%. Five subjects received bolus intravenous injections of ranitidine 20 mg, 40 mg, and 80 mg during continuous gastric stimulation with pentagastrin. There was a dose-related reduction in acid output (P less than 0.05).

Effects of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects.

1 Two studies have been carried out to investigate the effect of H1- and H2-receptor blocking agents on histamine-induced bronchoconstriction in non-asthmatic subjects. 2 The H2-receptor blocker cimetidine administered orally had no effect on histamine-induced bronchoconstriction on any of the subjects tested. In three of four subjects, the H1-receptor blocker, chlorpheniramine given orally, inhibited the effect of the histamine in the lung. 3 The effects of intravenous chlorpheniramine and cimetidine, both alone and in combination, upon histamine-induced bronchoconstriction, were also studied. Chlorpheniramine inhibited the effect of the histamine and this was significantly dose related. This was not so with cimetidine and there was no evidence that the dose response curve to chlorpheniramine was affected by the additional administration of cimetidine. 4 The results show that histamine-induced bronchoconstriction in non-asthmatic subjects is not mediated by H2-receptors, but it is likely that H1-receptors are involved.

Circulatory and alpha-adrenoceptor blocking effects of phentolamine.

1 Intravenously administered phentolamine provoked immediate decreases in diastolic blood pressure but increases in heart rate and cardiac output. 2 These immediate circulatory effects had largely disappeared twenty minutes after administration and at this time phentolamine did not inhibit increases in blood pressure which were provoked during hand immersion in ice-cold water. 3 Log dose-response curves of noradrenaline induced increases in systolic and diastolic pressure 20 min after intravenous phentolamine were shifted to the right in a parallel manner compared with the curves before phentolamine administration. 4 It was concluded that the immediate and short acting effects induced by phentolamine are due to a non-specific vasodilator effect but in addition phentolamine causes a longer acting alpha-adrenoceptor blockade at vascular adrenoceptor sites. However, by producing both pre- and post-synaptic alpha-adrenoceptor blockade this may explain why this drug exerts only a weak antihypertensive effect.

Effects of labetalol and propranolol on histamine-induced bronchoconstriction in normal subjects.

1 The effects of oral propranolol (80 mg), labetalol (400 mg) and placebo on blood pressure, pulse rate and FEV1 at rest and after inhaled histamine, have been compared in six healthy male volunteers. 2 At 90 and 120 min after ingestion propranolol reduced the pulse rate and labetalol reduced the blood pressure, thus confirming absorption of each drug. 3 At 120 min propranolol reduced resting FEV1 and enhanced the fall in FEV1 after histamine, whereas the alterations in FEV1 after labetalol did not differ from placebo. 4 These findings suggest that labetalol is less likely than propranolol to cause bronchoconstriction in asthmatic patients.

Comparison of the effects of labetalol and propranolol in healthy men at rest and during exercise.

1. Oral labeltalol and propranolol have been compared in healthy men with regard to the effects on heart rate, blood pressure and peak expiratory flow rate (PEFR) at rest and the changes induced by exercise. 2. Labetalol caused a dose-related reduction in standing diastolic pressure at rest whereas propranolol did not but neither drug altered standing systolic pressure at rest. 3. In the doses compared, propranolol was consistently more potent than labetalol in influencing blood pressure changes induced by exercise, in lowering heart rate at rest and reducing PEFR at rest. 4. Labetalol and propranolol are both beta-adrenoreceptor antagonists and the observed differences in the profiles of the two drugs are probably directly related to the additional alpha-adrenoreceptor blocking property of labetalol not possessed by propranolol. Because of these differences labetalol may be expected to have advantages in the treatment of hypertension.

Relationship between plasma concentrations and pharmacological effects of labetalol.

In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.

The effects of oral AH 5158, a combined α and ß-adrenoceptor antagonist, in healthy volunteers.

1 In healthy male volunteers after single oral doses, AH 5158 produced inhibition of exercise induced tachycardia, falls in systolic and diastolic pressure at rest and in response to exercise, which are probably related to combined ß- and α-adrenoceptor antagonism. 2 At increasing doses from 100 mg to 400 mg there exists a dose related antagonistic effect, though the dominant effect of ß-adrenoceptor antagonism is more easily demonstrable than is α antagonism. 3 As indicated by the pattern of pharmacological effects, absorption of the oral drug is good and the duration of action of a 400 mg dose is approximately 8 hours. 4 Despite being administered in ß-adrenoceptor blocking doses, AH 5158 had no adverse effects upon peak expiratory flow at rest or in response to exercise. 5 It is concluded that the pharmacological profile of this combined α- and ß-adrenoceptor antagonism suggests a potential therapeutic role as an antihypertensive drug.