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Sodium Nitroprusside: Theory and Practice IAN R Postgrad Med J: first published as 10.1136/pgmj.50.587.576 on 1 September 1974. Downloaded from Postgraduate Medical Journal (September 1974) 50, 576-581. Sodium nitroprusside: theory and practice IAN R. VERNER M.B.Ch.B., F.F.A.R.C.S., D.A. The Middlesex Hospital, London Summary form a lattice which contains the sodium and water Sodium nitroprusside, by a peripheral vasodilator molecules. The exact mode of action of the com- action, is a powerful hypotensive drug. In contrast to pound is unknown, but since many nitrites have established agents, its hypotensive action is accom- vasodepressor actions, it is assumed that the iron- panied by an unchanged or augmented cardiac output. nitrosyl group is the active part of the molecule. It Intravenous administration of sodium nitroprusside has been estimated that the nitrosyl group is be- rapidly produces a profound and controllable hypo- tween 30 and 1000 times more powerful than nitrites tension. Normotension is swiftly restored by ceasing (Johnson, 1929). The primary action of sodium to infuse the agent, and antidotes are unnecessary. Its nitroprusside is smooth muscle relaxation; this attributes make it especially suitable for neurosurgical action is direct and most readily seen in the anaesthesia, and although free cyanide is liberated vascular system (Johnson, 1929; Page et al., 1955). during biotransformation, side effects are virtually Intravenous sodium nitroprusside rapidly producesProtected by copyright. absent provided that dosage is reasonable. Special a profound hypotension which is readily reversible contraindications to its use are hypothyroidism and and is not accompanied by tachyphylaxis. Recent altered cobalamin metabolism. controlled studies by Wildsmith et al. (1973) and Styles, Coleman and Leary (1973) have delineated SODIUM nitroprusside was discovered in 1893 by the cardiovascular changes which accompany Playfair, and by 1929 Johnson had outlined its basic sodium nitroprusside-induced hypotension both pharmacology. By 1955 Page et al. had shown that in anaesthetized and non-anaesthetized humans. it could be used to treat hypertensive patients, and Both investigations are in close agreement. The that even with prolonged administration its toxic lowered arterial pressure was accompanied by a effects were minimal. It was not until 1970 that the profound fall in both central venous pressure and first definitive paper on its use to produce hypoten- peripheral resistance, the heart rate was slightly sion during anaesthesia appeared (Taylor, Styles and elevated and the cardiac output was either un- Lamming, 1970). During the following 3 years changed or else rose slightly. Changes in stroke numerous papers describing its use during anaes- volume were neither consistent nor significant. It is thesia have appeared, all of which have testified to important to note that the hypotension was not http://pmj.bmj.com/ the efficiency and lack of side effects of the agent. accompanied by a reduction in cardiac output, for Sodium nitroprusside is now established as an in this respect sodium nitroprusside differs from effective and malleable hypotensive agent, and is other hypotensive agents such as halothane or gang- the drug of choice in many centres. It is, however, lion blocking agents. The pharmacodynamics of still a relatively untried drug, and its potential sodium nitroprusside would seem to be such that toxicity should be constantly born in mind. Doubt- any improvement in operating conditions is achieved less its possible lethal effects delayed its adoption by not by a reduction in tissue perfusion, but rather by on September 25, 2021 by guest. anaesthetists, but experience so far has shown that, a reduction in arterial pressure. Provided that provided care is taken in the use of the drug, it is arterial oxygenation is satisfactory, combination of remarkably free from deleterious effects. an unchanged or enhanced cardiac output coupled with a decreased peripheral resistance means that Pharmacology tissue oxygen availability will be adequate even Sodium nitroprusside (Na2Fe++(CN)5NO.2H2O) under hypotensive conditions. forms reddish-brown crystals which are soluble in water. In solution it is relatively stable, resisting Heart rate oxidation at a neutral or slightly acidic pH. The Early reports of sodium nitroprusside hypotension structural unit is the nitroprusside radical, which indicated a variable cardiac response. Schiffmann consists of one iron atom linked to one nitrosyl and and Fuchs (1966), Jones and Cole (1968) and Taylor five cyanide groups. The basic units link together to et al. (1970) all stated that the heart rate could Postgrad Med J: first published as 10.1136/pgmj.50.587.576 on 1 September 1974. Downloaded from Sodium nitroprusside 577 remain unchanged, slow or accelerate. The more can relieve bronchoconstriction occurring during recent studies have shown that there is normally a general anaesthesia, objective improvement does not 20%0 increase in heart rate during the hypotensive occur until arterial tension is grossly depressed. It phase. The rarity of a markedly elevated pulse rate would therefore seem that, at least unaided, sodium following upon the use of sodium nitroprusside un- nitroprusside has little place in the therapy of doubtedly plays a part in the ease with which it can bronchoconstriction. produce satisfactory operating conditions. In a few instances a pronounced tachycardia will be seen Combination with other drugs after sodium nitroprusside has been given. In such Since sodium nitroprusside acts directly upon the circumstances hypotension may be difficult to smooth muscle of vessel walls, it is to be expected establish, but the rate can be slowed by administer- that agents which reduce the muscle tone will aug- ing 0-adrenergic blocking drugs. ment the hypotensive effects of nitroprusside. Page et al. (1955) observed that many ganglioplegic and Myocardial function o-adrenergic blocking drugs substantially augmented No adverse effects of sodium nitroprusside upon the hypotensive actions of sodium nitroprusside in myocardial function have been reported. Franciosa animals. A similar picture is seen in human beings. et al. (1972) studied the effects of sodium nitro- Patients who have received oc-adrenergic blocking prusside upon cardiac output and left ventricular agents are markedly sensitive to sodium nitro- function in a series of patients who had suffered prusside, and the administration of ganglion blockers recent myocardial infarction. They found that, with before or after an infusion of sodium nitroprusside a mild degree of hypotension, left ventricular filling greatly increases the response to the latter. Drugs pressure fell and cardiac output was enhanced. which reduce cardiac output (e.g. halothane or - From these observations and the condition of their adrenergic blockers) also augment its hypotensive Protected by copyright. patients they concluded that the coronary circulation action. Conversely, the inhalation of 15-20% carbon- was not embarrassed by the procedure. dioxide was shown to decrease the hypotension of sodium nitroprusside (Page et al., 1955). Effects on other organs Kidneys. Johnson (1929) observed dilatation in the Metabolism and toxicity isolated and perfused renal artery on exposure to The evanescent action of sodium nitroprusside sodium nitroprusside, which was accompanied by may be attributed to its rapid bio-transformation. increased renal perfusion. The renal haemodynamic The iron atom of the nitroprusside radical reacts effects in both dogs and humans were studied by with free sulphydryl groups found in erythrocytes, Page et al. (1955). In dogs they found that both renal and releases cyanide radicals. This reaction is non- perfusion pressures and renal vascular resistance enzymatic, and its slow time course precludes the were lowered. Para-amino hippurate and creatinine release of cyanide from being the mechanism of clearance values were largely unchanged, as was the action of nitroprusside. The free cyanide radicals are tubular reabsorptive capacity for glucose. In human then linked enzymatically to sulphydryl groups, beings similar results were obtained, and it was noted forming thiocyanate. The enzyme, which is present http://pmj.bmj.com/ that in both species the hypertensive were more in human erythrocytes and liver, was discovered sensitive to the effects of sodium nitroprusside than and named rhodanese by Lang (1933). The ending were the normotensive. Clear evidence of a vaso- 'ese' indicates that the enzyme is responsible for an dilator action upon the renal vasculature was ob- irreversible reaction. The observation that the tained radiographically by Moraca et al. (1962). chronic administration of thiocyanate to human Intestines and uterus. Johnson (1929) found that beings was followed by a rise in the serum levels of the irreversibility of the sodium nitroprusside inhibited contractions of cyanide cast doubts upon on September 25, 2021 by guest. isolated and perfused strips of muscle excised from reaction. Goldstein and Rieders (1953) found that the uterus and intestines. However, Page et al. (1955) the reaction was indeed irreversible but that the con- found that nitroprusside did not relax the virgin or version of thiocyanate to cyanide was under the pregnant uterus of rabbits or the duodenum of dogs control of yet another enzyme present in human red even when given in markedly hypotensive dosage. cells. This enzyme, thiocyanate oxidase, gives a yield Bronchial musculature. It might be expected
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