Β-adrenoceptor Blocking Drug Research Articles

Betaxolol: A comprehensive profile.

Betaxolol is a relatively cardioselective β-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilizing (local anesthetic) activity. Betaxolol selectively and competitively binds to and blocks beta-1 (β1) adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. Betaxolol (S)-(-)-enantiomer shows higher pharmacological activity. This chapter provides a complete review of nomenclature, physiochemical properties, methods of preparation, identification techniques and various qualitative and quantitative analytical techniques as well as pharmacology of betaxolol. In addition, the chapter also includes review of several methods for enantiomeric separation betaxolol using chromatographic techniques.

Cardiological aspects in preoperative anaesthesiological evaluation: old heroes, new shadows

Cardiological aspects in preoperative anaesthesiological evaluation: old heroes, new shadows

Salivary secretion of immunoglobulin A by submandibular glands in response to autonomimetic infusions in anaesthetised rats

Salivary secretion of immunoglobulin A (lgA) by submandibular glands is increased by stimuli from autonomic nerves. Since it is unclear which specific autonomic receptors transduce such stimuli, we have infused autonomimetics intravenously and compared secretion of fluid, IgA and stored proteins (peroxidase and total protein) with secretory responses during electrical stimulation of the parasympathetic nerve supply in anaesthetized rats. The greatest secretion of IgA was evoked by the α-adrenoceptor agonist phenylephrine and this was reduced by the β-adrenoceptor blocking drug propranolol. The secretion of fluid or proteins but not IgA was increased with frequency of nerve stimulation and dose of methacholine (cholinergic), isoprenaline (β-adrenergic) or phenylephrine (α-adrenergic).

Effects of Chronic Celiprolol Treatment on Brown Fat, Feeding, and Drinking in fa/fa Zucker Rats

Celiprolol is a novel β-adrenoceptor blocking drug that displays clinically favorable effects on glucose and lipid metabolism. Because some other atypical β-adrenoceptor blocking drugs have been described to act as agonists on β 3-adrenoceptors, we aimed to investigate the effects of celiprolol on brown fat and β 3-adrenoceptors. Chronic treatment of obese fa/fa Zucker rats with celiprolol (50 mg/kg/day orally for 20 days) increased GDP binding to brown fat mitochondria by 1.5-fold, whereas β 3-adrenoceptor agonist ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyethyl)phenoxyacetamide, 3 mg/kg/day) increased the binding by 3.3-fold. Weight gain was reduced by 19% due to decreased water and food intakes in celiprolol-treated rats. Celiprolol did not activate lipolysis in rat adipocytes in vitro or stimulate human β 3-adrenoceptors expressed in Chinese hamster ovary cells as measured with Cytosensor microphysiometer. Therefore, celiprolol does not seem to activate brown fat via β 3-adrenoceptors.

Involvement of CYP2D1 in the metabolism of carteolol by male rat liver microsomes

1. The metabolism of carteolol, a β-adrenoceptor blocking drug, was investigated in male Sprague- Dawley rat liver microsomes. 2. The formation of 8-hydroxycarteolol was the principal metabolic pathway of carteolol in vitro and followed Michaelis-Mente n kinetics with a Km = 11.0 ± 5.4 μM and a Vmax = 1.58 ± 0.64 nmol/min/nmol P450 respectively (mean ± SD, n = 5). Eadie-Hofstee plot analysis of carteolol 8-hydroxylase activity confirmed single-enzyme MichaelisMenten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine (Ki = 0.06 μM) and quinidine (Ki = 2.0 μM), selective inhibitors of CYP2D1, competitively inhibited 8-hydroxycarteolol formation. Furthermore, only anti-human CYP2D6 antibody inhibited this reaction. 4. These results suggest that carteolol is metabolized to 8-hydroxycarteolo l by CYP2D1.The Km of carteolol for CYP2D1 in male rat liver microsomes was much greater than those of propranolol or bunitrolol, indicating that carteolol has a lower affinity for CYP2D1 compared with these other β-adrenoceptor blocking drugs.

The role of intracellular calcium in A-23187 stimulated and β-adrenoceptor blocking drug treated blood platelets

A significant concentration-dependent difference was found between β-adrenoceptor blocking drugs in their ability to inhibit A23187-induced isolated platelet aggregation. In the absence of extracellular calcium ions the following rank order of potency to inhibit calcium ionophore stimulated platelet aggregation was shown: propranolol > bevantolol > alprenolol > metipranolol > oxprenolol > atenolol > pindolol > metoprolol ≈ sotalol ≈ practolol. The interruption of induced aggregation, as well as inhibition of aggregation, in the absence of extracellular calcium ions indicated interference of inhibitory β-adrenoceptor blocking drugs with intramembrane or intraplatelet calcium pools activated with A23187. This suggestion was supported by the reversal of the inhibitory effect of β-adrenoceptor blocking drugs in the presence of extracellular calcium ions. The effect was dose dependent and occurred within 30 sec after calcium administration. The results indicated that inhibitory β-adrenoceptor blocking drugs, possessing a cationic amphiphilic structure, suppressed calcium mobilization in A23187-stimulated platelets, most probably after entering platelets. This explains why lipophilic drugs are more effective than hydrophilic ones in calcium ionophore A23187-stimulated platelets.

Uptake of radioligands by rat heart and lung in vivo: CGP 12177 does and CGP 26505 does not reflect binding to β-adrenoceptors

The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H-benzimidazol-2-one (CGP12177, a non-selective β-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5- 3H-phenoxy)]-2-propanol methanesuifonate, (CGP26505, a β-tadrenoceptor antagonist) was studied in rats pretreated with various α- and β-adrenoceptor blocking drugs (5 min before 3H injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [ 3H]CGP12177 was linked to binding to β-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [ 3H]CGP12177 uptake in heart (predominantly β 1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly β 2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [ 3HICGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by α-adrenoceptor antagonists. We conclude that [ 11C]CGP12177, but not [ 11C]CGP26505 will be suitable for positron emission tomography imaging of β-adrenoceptors in animals.

Guanine-nucleotide binding regulatory proteins as targets for novel drugs

Summary:Guanine-nucleotide regulatory binding proteins (G-proteins) serve to transduce information from agonist-bound receptor complexes to either effector enzymes or ion-channels. Drugs that perturb the function of G-proteins may do so by one of four mechanisms, (i) They may exert negative intrinsic activity toward the G-protein. For instance, we have shown that incubation of isolated plasma-membranes with the β-adrenoceptor blocking drug sotalol blocked both GTP-stimulated and isoprenaline-stimulated adenylyl cyclase. This suggests that the empty β-adrenoceptor is capable of tonically stimulating Gsα, and therefore adenylyl cyclase; that is, empty β-adrenoceptors promote GDP-GTP exchange, (ii) They may perturb the GDP-GTP exchange reaction. For instance, certain PDE inhibitors, including SKF 94836 and rolipram, stimulate a marked increase in the pertussis toxin-catalysed NAD+-dependent ADP-ribosylation of Giα. This effect is similar to that of GDP, which promotes stabilisation of the αβγ holomer of Gi. The effect of these PDE inhibitors is completely reversed by GppNHp, which triggers afly dissociation by binding to the guanine-nucleotide binding domain of the G-protein. PDE inhibitors may serve as a class of drugs which perturb GDP-GTP exchange, (iii) They may trigger uncoupling of receptor-G-protein complexes. For instance, the polycationic drug mastoparan binds to the C-terminal end of the G-protein and mimics the effect of receptor activation by promoting GTP-γ-S binding, a reduction in pertussis toxin-catalysed ADP-ribosylation, and inhibition of adenylyl cyclase activity. Other agents, such as polyanionic drugs, bind to the receptor to promote uncoupling of receptor-mediated activation of certain G-proteins. (iv) They may alter the cross-talk mechanisms that operate between different receptor signalling systems. For instance, protein kinase C promotes the phosphorylation and inactivation of Gi. This leads to an unopposed stimulation of adenylyl cyclase via Gsand, therefore, enhanced sensitivity to agents such as glucagon. Protein kinase C inhibitors may be usefully exploited to modulate these processes which appear to be abberant in certain disease states.

The effect of pindolol on creatine kinase is not due to beta 2‐ adrenoceptor partial agonist activity [letter; comment

We read with interest the recent article (Tomlinson et al., 1990) which demonstrated that an increase in serum creatine kinase (CK) activity occurs during treatment with the β-adrenoceptor blocking drug pindolol. As a possible explanation for this phenomenon the authors postulated that the β 2 -adrenoceptor partial agonist activity (PAA) of pindolol on skeletal muscle was responsible for this effect. Known effects of β 2 -receptor stimulation on skeletal muscle include finger tremor and hypokalaemia. However, the effect of β 2 -adrenoceptor stimulation on creatine kinase has not to our knowledge been previously reported in the literature. We therefore investigated the effects of inhaled terbutaline (a known selective β 2 -adrenoceptor agonist) on serum creatine kinase activity in 34 normal volunteers (mean ± s.e. mean age, 25 ± 3 years)

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The pharmacokinetic and pharmacodynamic interactions between diltiazem and propranolol, or atenolol were investigated in healthy volunteers. Diltiazem (30mg) or placebo was given three times daily for 3 days, and 30 min before administration of a β-adrenoceptor blocking drug given on the 4th day. A single dose of propranolol (20mg), or atenolol (50mg) was administered in a randomized, double-blind, crossover fashion. Exercise tests on a cycle ergometer were carried out before and after β-adrenoceptor blocking drug. Diltiazem significantly increased the AUC and elimination half-life of propranolol. The cardiac β-adrenoceptor blocking effect, as indicated by the percentage reduction in heart rate during exercise, tended to increase following diltiazem pretreatment, in comparison with placebo. In contrast, diltiazem did not significantly affect atenolol pharmacokinetics and pharmacodynamics. These results indicated that diltiazem impaired the total clearance of propranolol, which is principally metabolized by oxidative pathway in the liver. This kinetic interaction between diltiazem and propranolol may be partly related to the reduction in exercise-induced tachycardia.

A structured approach to the development of a controlledrelease drug delivery system for a β-adrenoceptor blocking drug

A structured approach to the development of a once-daily drug delivery system for the β-adrenergic receptor antagonist, metoprolol fumarate, is described. Performance attributes of the system were defined on the basis of the interrelationships between a relevant pharmacological property of the drug (attenuation in exercise heart rate), plasma drug concentrations after oral administration, and in vitro delivery rates for OROS systems. An analysis of exercise heart rate data suggested a therapeutic plasma concentration range of 45–150 ng/ml for this drug. Simulations based on a numerical convolution algorithm indicated that OROS itsystems with zero-order delivery rates of 11 mg/h or less should maintain plasma levels within the required range during multiple dosing. However, data in healthy volunteers showed that in vivo itabsorption is slightly slower than in vitro delivery and that an OROS system with a delivery rate of 14 mg/h should satisfy the requirements for a once-daily dosage form.

Determination of the β-adrenoceptor blocking drug B24/76 in serum by high-performance liquid chromatography with fluorimetric detection after pre-column dansylation

Determination of the β-adrenoceptor blocking drug B24/76 in serum by high-performance liquid chromatography with fluorimetric detection after pre-column dansylation

Some structural and dynamical properties of multilamellar vesicles incorporated with propranolol

Spin labelling ESR, calorimetry and31P NMR have been used to investigate dipalmitoyl phosphatidylcholine dispersions incorporated with propranolol which is a β-adrenoceptor blocking drug, widely used in the treatment of arrhythmy. The drug appears to enter the lipid bilayer also at the lowest concentrations and to induce a progressive fluidification of multilamellar vesicles. In fact, the presence of drug reduces the temperature of chain melting transition and the corresponding cooperation number. Furthermore the phase transitionL β′ −P β′ is not observable also at the lowest drug concentrations.

Effects of oral administration of bopindolol on circadian variations in blood pressure in patients with essential hypertension

In a study in 24 patients with essential hypertension, blood pressure was measured non-invasively throughout the day, before and during therapy with the long-acting β-adrenoceptor blocking drug bopindolol. Mean blood pressure was reduced from 161/96 mmHg to 147/87 mmHg, using a mean dose of 1.6 mg bopindolol once a day. There were no significant differences in the standard deviations of circadian variations of blood pressure, but those of the heart rate were reduced. Bopindolol therefore exerted a favourable antihypertensive effect in doses of 1–2 mg once a day, while maintaining the circadian profile of blood pressure.

The acute anti-anginal efficacy of bopindolol

The acute anti-anginal efficacy of 2 mg of the β-adrenoceptor blocking drug bopindolol was compared with placebo in a double-blind crossover study in 12 patients with stable, exercise-induced angina pectoris. Exercise tests were performed on a bicycle ergometer 3 h after oral administration of the test drugs. All patients showed an ischaemia-induced ST-depression in the electrocardiogram during and shortly after exercise. Bopindolol significantly reduced systolic and diastolic blood pressure and the heart rate during exercise. Exercise-induced ischaemia was effectively reduced, as shown by a significant reduction of the rate-pressure product and of the ST-segment depression.

Different Responses to β-Adrenoceptor Blocking Drugs of the Blood Pressure and Heart Rate in the Urethane-Anesthetized Dog and Rat

I.v. propranolol (Prop) produced sustained pressor responses in rats but not in dogs under urethane anesthesia. In the dogs there was a progressive reduction in systolic blood pressure (SBP) in accordance with a significant heart rate (HR) reduction. Even at the i.v. dose (5 mg/kg) where vasoconstrictor response to i.v. norepinephrine (NE) is changed to the vasodilator one in rats, phenoxybenzamine could not completely suppress the NE-induced vasoconstriction in dogs. In pithed dogs, unlike pithed rats, i.v. Prop augmented neither sympathetic nerve stimulation- nor i.v. epinephrine (Epi)-induced pressor responses. Urethane anesthesia brought much higher concentrations in plasma Epi and NE in the dog than in the rat. In comparison with their respective values under the conscious state, SBP and HR of the dog were higher and those of the rat were lower under urethane anesthesia. As in urethane-anesthetized dogs, i.v. Prop elicited remarkable HR reduction accompanied by progressive hypotension in coronary-ligated rats with high sympathetic activity. Thus the reason for the absence of pressor response to β-receptor blockage in the dog may be due to less functional significance of β2-adrenoceptor-mediated vasodilation in determining the peripheral vascular tone; and also, the possibility that there may be the involvement of an inverse influence of urethane on the cardiovascular regulatory system in terms of enhancing sympathetic nervous activity in the dog and a decreasing one in the rat can not be ruled out.

Role of catecholamines in regulation by feeding of energy balance following chronic exercise in rats

Two experiments examined the contribution of the two catecholamines—epinephrine (EPI) and norepinephrine (NE)—to the control of food intake and body weight gain in male rats during chronic exercise. Urinary excretion of both catecholamines rose significantly and was positively correlated to food intake inhibition (NE, n=54 , r=0.394 , p<0.01; EPI, n=54 , r=0.428 , p<0.01). Oral ingestion of the non-selective β-adrenoceptor blocking drug, pindolol, abolished the food intake reduction induced by exercise. Furthermore, rats that were treated with pindolol gained weight at a higher rate than untreated rats. These findings are consistent with the idea that catecholamines contribute to post-exercise inhibition of food intake and reduction of body weight in male rats. However, the exact physiological mechanism of catecholamine-induced decrease in food intake remains to be elucidated.

A Comparison of the Cardioselectivity of Five β-Adrenoceptor Blocking Drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.

Pharmacologic aspects of intrinsic sympathomimetic activity in beta-blocking drugs

The possession of intrinsic sympathomimetic activity (ISA) by a β-adrenoceptor blocking drug results in a number of different pharmacologic properties. Most profound are the central hemodynamic effects. A drug with a significant degree of ISA results in less of a decrease in heart rate at rest and cardiac output, and, at least partly because of this, less of a decrease in peripheral blood flow. If prevailing sympathetic tone is low enough (e.g., during sleep) and the degree of ISA is sufficient, an increase in heart rate may be seen from an ISA-possessing drug. If the drug possesses β 2 ISA, then a peripheral vasodilation action from stimulation of β 2 vasodilator receptors may also be relevant. If high levels of exercise and full dosages of the drugs are used, a β-blocking drug with ISA produces less of a decrease in heart rate. In asthmatic subjects, the modest β-stimulant action on bronchial smooth muscle is not important, as these patients are potentially sensitive to any receptor blockade. Isoprenaline responses are inhibited to a similar degree compared with inhibition of exercise tachycardia, by nonselective drugs with and without ISA, whereas β 1 selective agents produce much less inhibition of isoprenaline-induced tachycardia. A drug with ISA “down regulates” β receptors; thus, when the drug is withdrawn there is no post-β-blocking drug hypersensitivity in contrast to agents without ISA. There is evidence that ISA results in less of a disturbance in certain metabolic processess, particularly lipid metabolism and the metabolism of liver-metabolized drugs.

Antihypertensive and biochemical effects of the dihydropyridine felodipine in the long term treatment of moderate to severe hypertension.

Twenty-seven patients with severe hypertension, in 19 cases accompanied by renal failure, were treated with felodipine, a new dihydropyridine calcium antagonist, 23 patients completed a 24-week, and 19 a 48-week follow-up. At the end of the follow-up, felodipine was given in combination with a β-adrenoceptor blocking drug in most instances (80%), but in 60% of the cases no diuretic was needed. Antihypertensive treatment with felodipine caused a 25% reduction in blood pressure, which was sustained throughout follow-up. The drug was well tolerated and was as effective in patients with renal insufficiency as in patients with normal renal function. Plasma creatinine levels remained stable throughout follow-up. Plasma calcium levels rose during felodipine therapy. This finding could not be related to the change in blood pressure or to the use of thiazide diuretics. The data confirm the potency of felodipine in the long term treatment of hypertension.