Adrenergic Control of Potassium and Magnesium: Interaction with Drug Therapy

Whyte, Kenneth Frank (1989) Adrenergic Control of Potassium and Magnesium: Interaction with Drug Therapy. MD thesis, University of Glasgow.

Abstract

Hypokalaemia is potentially fatal (Chapter 2). The internal regulation of potassium, i. e. the movement of potassium between body compartments, has not been extensively investigated (Chapter 1). Rapid movements of potassium can occur across cell membranes, e. g. in diabetic ketoacidosis the hyperkalaemia can be rapidly reversed by insulin administration, and the existence of a specific membrane enzyme controlling movement of potassium and sodium between the intracellular and extracellular compartments, Na+/K+ ATPase, has been known for 30 years (Chapter 1. 5). Some acutely ill patients have hypokalaemia on admission to hospital which resolves without treatment. This observation led to the hypothesis that increased sympathetic activity, raising circulating adrenaline levels, stimulates a Na+/K+ ATPase linked to a beta2-adrenoreceptor on cell membranes pumping potassium into cells. Animal work by Clausen supported this theory and several studies in humans, some carried out in the Department of Materia Medica, were also supportive, demonstrating that infusing adrenaline resulted in hypokalaemia (Chapter 1). In the studies presented in this thesis both the mechanism and the clinical relevance of adrenaline induced hypokalaemia, with particular emphasis on the effects of a number of widely used drugs, have been studied. Many drugs have been designed to specifically act on receptors in the sympathetic nervous system, either as agonists or antagonists, e. g. beta-blockers and beta2-agonists, and they are frequently administered to patients with cardiovascular disease who are at increased risk of dysrhythmias should hypokalaemia occur. Such patients are at increased risk of suffering acute stress, such as myocardial infarction, which increases circulating adrenaline levels. An infusion regimen of (-)-adrenaline which would safely raise circulating adrenaline to concentrations similar to those seen in acute severe illness was developed (Chapter 3). This regimen consistently raised adrenaline levels seen in normal subjects during supine rest by 10 fold or more. During the infusions adrenaline levels did fluctuate, but they remained in the pathophysiological range. The regimen involved stepwise increases in the rate of adrenaline infusion and proved safe despite the adrenaline infusion being combined with other drugs with sympathomimetic activity. The mechanism of adrenaline induced hypokalaemia in man is unproven. However, the possibility that adrenaline induced hypokalaemia could be the result of B-agonist induced changes in plamsa insulin was excluded (Chapter 4.2). Both plasma insulin and potassium concentrations fell during the adrenaline infusion. Attenuation of adrenaline induced hypokalaemia by beta-adrenoceptor antagonists with varying degrees of cardioselectivity (B1) was studied and demonstrated that adrenaline induced hypokalaemia was mediated via the B2 adrenoceptor (Chapter 4.3 & 4.4). Whether the fact that cardioselective beta-antagonists will be less effective in protecting patients from adrenaline induced hypokalaemia during the acute stress of severe illness is of any clinical significance remains unknown. Salbutamol, a selective beta2-agonist, was also shown to cause hypokalaemia when given intravenously (Chapter 4.2). It is administered in high doses in acute attacks of asthma, where it might be expected that circulating adrenaline levels are raised. An additive hypokalaemic effect of exogenous adrenaline and salbutamol was demonstrated (Chapter 4.2) . Hypokalaemia is a relatively common adverse effect of many diuretics and such hypokalaemia could increase the severity of hypokalaemia during acute stress. No synergistic action on potassium levels was demonstrated (Chapter 5) between adrenaline and any diuretic. However, both frusemide and bendrofulazide lowered plasma potassium and, therefore, during the adrenaline infusion more profound hypokalaemia was observed because baseline potassium was lower. Theophylline, widely used as a bronchodilator, has been reported to increase circulating catecholamine levels and to interact with sympathomimetics (Chapter 6.1 & 6.2). Hypomagnesaemia can occur in situations in which circulating adrenaline levels are known to be raised, such as acute myocardial infarction (Chapter 7.1). The control of internal regulation of magnesium is not understood. The role of adrenaline in the control of magnesium levels was studied, using the same adrenaline infusion regimen, and a small but significant fall in plasma magnesium was observed (Chapter 7.2). This was unaltered by pretreatment with diuretics (Chapter 7.3). The mechanisms and clinical relevance of adrenaline induced hypomagnesaemia require further study but these have not yet been attempted.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Keywords: Physiology, Pharmacology
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-78063
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Feb 2020 12:09
• Last Modified: 28 Feb 2020 12:09
• URI: https://theses.gla.ac.uk/id/eprint/78063