The mode of action of muscle relaxants and allied drugs

Mir, Bilquees Jamal (1962) The mode of action of muscle relaxants and allied drugs. PhD thesis, University of Glasgow.

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The studies described in this thesis fall into two main parts. Part one is devoted first to an investigation of the mechanism of the antihypertensive action of 10-methoxydeserpidine and some allied compounds and second to that of chlorothiazide and some other thiazide diuretics. Part two describes investigations carried out to study the nature and mechanism of the muscle relaxant activity of a group of volatile anaesthetics including ether, chloroform, halothane and methyl-n-propyl ether. 10-Methoxydeserpidine is a structural isomer of reserpine, the methoxy group in ring A being on C(10) instead of on C(11). It has been shown clinically to possess mild antihypertensive activity qualitatively similar to that of reserpine but to be devoid of the central nervous system depressant effects characteristic of reserpine. Work was undertaken to investigate the mechanisms by which 10-methoxydeserpidine exerted its antihypertensive actions. Experimental evidence suggests that 10-methoxydeserpidine causes a generalised depression of preparations of isolated cardiac muscle, vascular and intestinal smooth muscle and skeletal muscle. It does not prolong pentobarbitone-induced sleeping time in mice and has no effect on gastrointestinal motility in the rat or the mouse. 10-Methoxy-deserpidine was found to depress the in vitro respiration of rat brain and liver slices and also to inhibit the in vitro adenosine triphosphatase activity of rat brain, liver and skeletal muscle homogenates. From the data presented, it was concluded that 10-methoxydeserpidine exerted its antihypertensive actions by virtue of an effect at peripheral sites and had little central nervous system depressant activity. It may act by interfering with tissue metabolism at cellular levels probably influencing that part which supplies the energy required for muscular contraction and the maintenance of tone. Studies were also canrried out to investigate the mode of anti-hypertensive action of the diuretic and saluretic agent chlorothiazide and some allied compounds. It was shown that chlorothiazide produced no observable fall in the blood pressure level of the normotensive anaesthetised cat or rat but a slight inhibition of the hypertensive response to adrenaline in the cat and adrenaline and noradrenaline in the rat was noted. Chlorothiazide inhibited the responses of isolated isolated strips of horse carotid artery to adrenaline, noradrenaline, 5-hydroxytryptamine and acetylcholine. It also produced a significant depression of the uptake of sodium-24 by isolated strips of rabbit thoracic aorta but did not modify the adenosine triphosphatase activity of rat skeletal muscle homogenates, tending, thereby, to indicate that the supply of energy yielded by adenosine triphosphate for the flux of sodium ions was not interfered with. The significant depression of the uptake of sodium-24 by strips of rabbit aorta suggested that chlorothiazide might reduce the sodium content of the artery wall by depressing sodium uptake from the plasma or extracellular fluids. A fall in the sodium content of the artery wall may also reduce their water content and by reducing the swelling or oedema, lead to a decrease in the peripheral resistance. This may in turn cause a fall in the arterial blood pressure level. In Part 2, a study has been made upon the muscle relaxant action of ether, halothane, chloroform and methy-n-propyl ether. It has been shown that these volatile anaesthetics cause an increase in the permeability of the muscle cell membrane to sodium and potassium ions. An increase in the uptake of sodium-24, a corresponding decrease in the uptake of potassium-42 and an increase in the efflux of potassium-42 both in isolated tissue preparations and in the intact cat were also observed. Ether and other volatile anaesthetics were found to inhibit the acetylcholine acetylcholine-induced contractions of the isolated frog rectus abdominis muscle. This inhibitor effect was preceded by a reversible contracture and an increase in the efflux of potassium ions. In the same preparation, ether caused a potentiation of the effect of tubocurarine on acetylcholine-induced contractions. Ether was found to be capable of depressing neuromuscular transmission in the rat phrenic-nerve diaphragm preparation, an effect which was also associated with an increase in the efflux of potassium ions. Ether produced an inhibition of the indirectly induced contractions of the gastrocnemius muscle of the pentobarbitone-anaesthetised cat. This was associated with an increase in the serum potassium-42 level. Adrenaline and neostigmine were found to antagonise the effects of ether on muscular contractions but produced an increase in the serum potassium-42 level. Depolarising agents have also been shown to cause an increase in the permeability of the cell membrane. From a consideration of the experimental results, it was concluded that the muscle relaxant actions of ether and other volatile anaesthetics were due to a mechanism which resembled that of depolarising agents rather than that of non-depolarizing drugs.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: J J Lewis
Keywords: Pharmacology
Date of Award: 1962
Depositing User: Enlighten Team
Unique ID: glathesis:1962-73526
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 14 Jun 2019 08:56

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