Lipophilicity, Hydrophilicity, and the Central Nervous System Side Effects of Beta Blockers

Drayer, Dennis E.

doi:10.1002/j.1875-9114.1987.tb04029.x

Cited by 70 publications

(42 citation statements)

References 22 publications

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“…We observed no hemodynamic effects ofpropranolol at rest or beyond 30 min after dosing. The reported t1/2 for the L-isomer is 40 min (26). Phentolamine (Ciba Pharmaceuticals, Summit, NJ) was used for alpha blockade ( 13 ).…”

Section: Methodsmentioning

confidence: 99%

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

Kane¹,

Tesauro²,

Koizumi³

et al. 1994

J. Clin. Invest.

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We studied the effects of inhibition of nitric oxide (NO) (endothelium-derived relaxation factor) synthase in combination with alpha and beta adrenergic receptor blockade on pulmonary vascular tone during exercise. In paired studies, we exercised sheep on a treadmill at a speed of 4 mph, and measured blood flow and pressures across the pulmonary circulation with and without inhibition of NO synthase (Nw-nitro-L-arginine 20 mg/kg intravenous Ii.v.I), alpha receptor blockade (phentolamine 5 mg i.v.), beta receptor blockade (propranolol 1 mg i.v.), and combined alpha and beta receptor blockade. Activation of both types of adrenergic receptors occurs with exercise, and because increased release in NO is hypothesized to occur during exercise, these studies were designed to determine the magnitude of effect and interactions of these competing dilator and constrictor influences. We found that inhibition of NO synthase raised pulmonary vascular resistance (PVR) at rest and that, although a reduction in PVR occurred with exercise from this new baseline, vasoconstriction persisted. Combined beta blockade and NO synthase inhibition unmasked unopposed alpha vasoconstriction; PVR rose at rest and continued to rise with exercise; and mean pulmonary arterial pressures approached very high levels, 43.8±4.4 cmH20. Using a distal wedged pulmonary artery catheter technique, most of the vasoconstriction was found to be in vessels upstream from small pulmonary veins. During exercise in sheep there appears to be a high degree of alpha and beta adrenergic-mediated tone in the pulmonary circulation. Endogenous production of NO actively dilates pulmonary vessels at rest and opposes potent alpha-mediated pulmonary vasoconstriction during exercise. (J. Clin.

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Section: Methodsmentioning

confidence: 99%

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

Kane¹,

Tesauro²,

Koizumi³

et al. 1994

J. Clin. Invest.

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“…Sedation induced by ß-receptor blockade is distinct from the non-receptor-mediated membrane-stabilizing effects [38]. It is possible that the sedative effect of the ß-antagonists prevents the perception of stress and the rise in Tb.…”

Section: Discussionmentioning

confidence: 99%

β-Adrenergic Receptor Subtype Effects on Stress Fever and Thermoregulation

Mayfield¹,

Soszyński²,

Kozak³

et al. 1999

Neuroimmunomodulation

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Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or ‘open field.’ The β-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these β-antagonists discriminates between subtypes of β-receptors. The purpose of this study was to determine the relative contribution of the different β-receptor types to stress fever using β₁-, β₂-, and β₃-receptor subtype selective antagonists (atenolol [β₁], ICI-118551 [β₂], and SR 59230A [β₃]) and agonists (dobutamine [β₁], salbutamol [β₂], and BRL 37344 [β₃]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system β-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the β₃-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective β₂-agonist, salbutamol, and the β₃-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by β-blockers may be due to the sedative actions of these drugs.

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“…Case reports of clinically significant depression appeared soon after the introduction of propranolol (Wall 1967), the most lipid soluble agent in this class, and depression has been the subject of continuing interest and debate (Carney et al 1987;Drayer 1987;Griffin & Friedman 1986;McNeil et al 1982;Oppenheim 1983;Parker 1985;Pollack et al 1985;Rosen & Kostis 1987). The reports often involved 2 or 3 cases in which propranolol administration was temporally associated with the onset of depression, which waned when the agent was discontinued (Oppenheim 1983;Parker 1985;Pollack et al 1985).…”

Section: Jj-adrenergic Blocking Agentsmentioning

confidence: 95%

“…There has been much debate recently on the CNS side effects of jj-blockers (Dimsdale et al 1989;Drayer 1987;Frohlich 1988;Rosen & Kostis 1985) and a related debate on the role of lipophilicity: these agents vary widely in their lipid solubility Drug Safety 6 (2) 1991 (Drayer 1987), which could serve as a major determinant of their CNS penetration, and thus their CNS side effects. Case reports of clinically significant depression appeared soon after the introduction of propranolol (Wall 1967), the most lipid soluble agent in this class, and depression has been the subject of continuing interest and debate (Carney et al 1987;Drayer 1987;Griffin & Friedman 1986;McNeil et al 1982;Oppenheim 1983;Parker 1985;Pollack et al 1985;Rosen & Kostis 1987).…”

Section: Jj-adrenergic Blocking Agentsmentioning

confidence: 99%

Quality of Life as a Therapeutic End-Point An Analysis of Therapeutic Trials in Hypertension

1991

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The term 'quality of life' is finding increasing use in the popular press and the medical community. In both areas, its use often lacks precision: a comprehensive and universal definition probably does not exist. Indeed, the precise elements contributing probably vary from person to person and from time to time. There is broad agreement that 5 major areas always need assessment, including physical and emotional state, performance of social roles, intellectual function and general feelings of well-being or life satisfaction. A wide range of instruments has been employed in a large number of studies on the effects of antihypertensive agents on quality of life in the patient with hypertension. Hypertension represents a special problem in which the patient is thought to be free of related symptoms, and treatment designed to improve natural history brings with it the burden of adverse reactions. Although some insights have been gained on the relative influence of various therapeutic regimens on the quality of life of treated patients, in many of the studies too little consideration has been given to the use of instruments that have been validated in the patient population to be studied, to the power of the study and its design, to the contribution of confounding variables such as age and gender, and to evidence that short term trials (measured in weeks) can miss important changes that occur over months in a process where treatment is life-long. For these reasons, we believe, the literature on the subject is burdened by many reports that describe no difference among treatment regimens where important differences might exist. On the positive side, important advances have been made in our understanding of the elements that contribute to quality of life and in approaches to its assessment.

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Lipophilicity, Hydrophilicity, and the Central Nervous System Side Effects of Beta Blockers

Cited by 70 publications

References 22 publications

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

β-Adrenergic Receptor Subtype Effects on Stress Fever and Thermoregulation

Quality of Life as a Therapeutic End-Point An Analysis of Therapeutic Trials in Hypertension

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