Cardiovascular and neurological effects of laudanosine. Studies in mice and rats, and in conscious and anaesthetized dogs.

The effects of laudanosine, a metabolite of atracurium, on the behaviour of conscious mice, rats and dogs, and on cardiovascular function in conscious and anaesthetized dogs have been evaluated: EEG studies were performed in anaesthetized dogs. In mice and rats, i.v. bolus doses of laudanosine 10-20 mg kg-1, caused convulsions and hind limb extensions; these effects were prevented by pretreatment with diazepam. After the continuous infusion of laudanosine to conscious dogs, plasma concentrations in the order of 1.2 micrograms ml-1 did not cause behavioural disturbances. In anaesthetized dogs, laudanosine plasma concentrations of more than 6 micrograms ml-1 caused hypotension and bradycardia, laudanosine concentrations greater than 10 micrograms ml-1 induced epileptic EEG spiking and plasma concentrations greater than 17 micrograms ml-1 produced prolonged seizures. There is a wide difference between laudanosine plasma concentrations in patients given atracurium by bolus injection or by short-term infusion for surgical use and those required to induce epileptic activity in dogs. However, during the prolonged infusion of atracurium to patients this difference will be decreased. It is unlikely that the use of atracurium, in patients, would result in plasma concentrations of laudanosine capable of producing neurological or cardiovascular disturbances.

Effects of an increase in haemoglobin O2 affinity produced by BW12C on myocardial function in the erythrocyte-perfused rabbit heart in vitro and myocardial infarct size in the dog.

The effects of BW12C on myocardial function in the erythrocyte-perfused rabbit heart and on myocardial infarct size in the anaesthetized dog have been evaluated. Perfusion of rabbit hearts with erythrocytes pretreated with BW12C (10(-3) M-4 X 10(-3) M) produced concentration-dependent decreases in left ventricular pressure (LVP), LVP dP/dt and coronary perfusion pressure. A concomitant decrease in PO2 and an increase in lactate production by the myocardium was also observed. Perfusion of rabbit hearts with Krebs Henseleit buffer containing BW12C (10(-5)-10(-4) M) caused no change in measured variables. Although BW12C (10(-3) M) caused a small decrease in LVP, coronary perfusion pressure and heart rate, these changes were not significant. In anaesthetized dogs, an infusion of BW12C (total dose 50 mg kg-1, i.v.) caused small, but significant, changes in haemodynamic status. The oxygen saturation curve was shifted to the left and relative % oxygenation (P20) was shifted to the left throughout the course of the experiment. (P20, control 16.3 +/- 0.4 mmHg; after BW12C 7.9 +/- 1.4 mmHg). Pretreatment with BW12C (total dose 50 mg kg-1) caused no change in area at risk but significantly increased the myocardial infarct size by 410%. These studies with BW12C demonstrate that alteration in haemoglobin-oxygen affinity can induce adaptive physiological changes in tissue function and metabolism and can assume a critical role when oxygen supply may be impaired due to a flow-limiting stenosis.

Pharmacological action of breakdown products of atracurium and related substances.

The neuromuscular and cardiovascular effects of the breakdown products of atracurium and related substances have been studied in cats anaesthetized with chloralose. Laudanosine, the quaternary acid and metholaudanosine had no neuromuscular blocking activity within the dose range 0.5-4 mg kg-1. However, the quaternary monoacrylate, the quaternary alcohol and the monoquaternary analogue produced a dose-dependent neuromuscular block within this dose range. At 4 mg kg-1 mean arterial pressure was significantly reduced by 30-70 mm Hg following the administration of the quaternary monoacrylate, laudanosine, the quaternary alcohol, metholaudanosine and the monoquaternary analogue. At this dose only the monoquaternary analogue caused significant sympathetic blockade after preganglionic nerve stimulation. Significant vagal blockade occurred after 4 mg kg-1 of the quaternary monoacrylate, the quaternary acid, the quaternary alcohol and the monoquaternary analogue. In view of the low potencies of these substances, it is likely that the quantities present either as an impurity or likely to be formed after administration of therapeutic doses of atracurium (0.3-0.6 mg kg-1 i.v.) are of no pharmacological importance.

Metabolism and kinetics of atracurium: an overview.

Atracurium, a new competitive neuromuscular blocking agent, is broken down in the body by two mechanisms, Hofmann elimination and ester hydrolysis. Chemical breakdown by Hofmann elimination is rapid at physiological pH and temperature, whereas ester hydrolysis is enzyme-catalysed but by enzymes other than pseudocholinesterase. The products of these reactions have been shown to lack neuromuscular or cardiovascular activity at the concentrations occurring after therapeutic doses of atracurium. Studies with radiolabelled drug in anaesthetized cats have shown that atracurium and its metabolites are readily excreted in bile and urine. Plasma kinetics are unaltered if renal function is negated by bilateral ligation of all renal blood vessels. Preliminary studies have indicated that atracurium does not cross the placenta to a significant extent and that the drug can be used safety in Caesarean section.

Interaction between atracurium and drugs used in anaesthesia.

The effects of various drugs used during anaesthesia on the neuromuscular blocking activity of atracurium have been studied in anaesthetized cats. Clinically effective doses of diazepam, morphine, pentazocine, pethidine, ketamine, Althesin, methohexitone, Septrin, lignocaine, propranolol, calcium chloride or azathioprine did not significantly alter the neuromuscular blocking action of atracurium. Recovery from atracurium was not prolonged during an infusion of hexamethonium or sodium nitroprusside, indicating that, despite the severe hypotension, the inactivation of atracurium was unimpaired. Similar to that of other competitive neuromuscular blocking agents, the action of atracurium was enhanced by tubocurarine, halothane, gentamycin, neomycin and polymixin and was antagonized by adrenaline and transiently antagonized by suxamethonium. However, pretreatment with suxamethonium did not affect the subsequent block by atracurium.

Metabolic studies in the cat with atracurium: a neuromuscular blocking agent designed for non-enzymic inactivation at physiological pH.

1. Atracurium is a novel bis-quaternary competitive neuromuscular blocking agent designed to undergo rapid non-enzymic inactivation at physiological pH and temperature. 2. Studies of [14C]atracurium in anaesthetized cats using h.p.l.c. techniques showed that the radioactivity eliminated in bile and urine was predominantly metabolites rather than unchanged drug. Both chemical decomposition and enzyme hydrolysis products were observed in vivo. 3. The plasma elimination half life of atracurium after administration via the jugular vein was c. 20 min. Similar results were obtained if the drug was given via the hepatic portal vein or in animals with bilateral renal ligation. These studies indicate that atracurium is rapidly inactivated in vivo and that neither the liver nor the kidneys play a major role in its metabolism or elimination, in accord with the premise on which the drug molecule was designed.

The pharmacology of atracurium: a new competitive neuromuscular blocking agent.

Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxy-benzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate, is one of a new series of competitive neuromuscular blocking agents. An i.v. dose of 0.25 mg kg-1 produced complete paralysis in anaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readily antagonized by neostigmine. Vagal blockade occurred only after doses 8--16 times greater than the full neuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension and bradycardia were evident after supramaximal doses of 4 mg kg-1 i.v. and these effects, together with circulatory depression, were probably attributable to histamine release. In vitro studies have shown that the non-enzymic decomposition of atracurium by "Hofmann Elimination" was enhanced by increasing pH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. There were indications that neither the liver nor the kidney plays a major role in the metabolism and elimination of unchanged drug. These results are of sufficient interest to merit the evaluation of atracurium in anaesthetized man.

Some direct and reflex cardiovascular actions of prostacyclin (PGI2) and prostaglandin E2 in anaesthetized dogs.

1 The aim of the study was to determine the mechanism of the hypotension and bradycardia produced by prostacyclin (PGI2). 2 Haemodynamic studies were carried out in nineteen open-chest beagle dogs anaesthetized with chloralose. PGI2 was infused intravenously or into the left atrium. 3 Infusions of PGI2 either intravenously or into the left atrium equally reduced arterial pressure and total peripheral resistance but bradycardia was greater after infusion into the left atrium. 4 Comparison of effects of PGI2 with those of prostaglandin E2 (PGE2) showed that although left atrial infusions both reduced aortic pressure and total peripheral resistance, PGE2 always increased heart rate, cardiac output and maximum acceleration. 5 Similar effects were observed with sodium nitroprusside except that it always caused tachycardia and reduced stroke volume. 6 Atropine (0.05 or 1 mg/kg i.v.) reduced or reversed the bradycardia induced by PGI2 but its hypotensive effects were reduced only after 1 mg/kg atropine. After vagotomy changes in cardiac output, stroke volume and maximum acceleration were increased, the hypotensive effects of PGI2 were reduced and the bradycardia was reversed; effects induced by PGE2 were not significantly altered. 7 The hypotension induced by prostacyclin is due to two components, a direct relaxation of vascular smooth muscle and a reflex, non-cholinergic vasodilatation. The bradycardia is reflex in nature and is partially mediated by the vagus pathway.

Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs.

Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.

Transient changes in plasma digoxin concentration and the development of cardiotoxicity.

1. Eight dogs were given two infusions of digoxin 0.1 mg/kg, one over 9 min and the other one over 90 min in a randomized sequence, allowing at least 12 days between each experiment. 2. Digoxin plasma profiles reflected the rate of digoxin infusion, the peak concentration of drug attained at the end of each infusion being considerably higher but more transient after the 9 min than after the 90 min transfusion. 3. Digoxin reduced the amount of acetylstrophanthidin required to produce electrocardiographic evidence of cardiotoxicity. This increase in cardiac sensitivity at 150 and at 360 min after the start of the digoxin infusion was independent of rate of infusion. 4. These results suggest that the development of cardiotoxicity is dependent upon the quantity of digoxin delivered into the systemic circulation regardless of the plasma concentration. 5. By inference, cardiotoxicity is related solely to the amount and not the rate of absorption from a given dose of digoxin.

Cardiovascular and neuromuscular effects of dimethyl tubocurarine in anaesthetized cats and rhesus monkeys.

Intravenous dose-response relationships for dimethyl tubocurarine showed that vagal blockade only became appreciable (50-83%) at doses 8-16 times those sufficient for full neuromuscular paralysis in anaesthetized cats (0.0625 mg/kg) and rhesus monkeys (0.125 mg/kg); heart rate was unchanged. Sympathetic function was unimpaired by supramaximal paralysing doses of 0.5 and 1 mg/kg in cats, but was reduced (20-41%) by comparable neuromuscular paralysing doses of 1 and 2 mg/kg in rhesus monkeys; these doses decreased carotid arterial pressure by 22-36%. The duration of action of dimethyl tubocurarine was prolonged; more than 60 min was required for recovery from full neuromuscular paralysis; the drug was even more persistent in rhesus monkeys than in cats. Thus the need remains for a drug resembling dimethyl tubocurarine in its highly specific action at the neuromuscular junction, but with a much shorter duration of action.

The relationship between cardiotoxicity and plasma digoxin concentration in conscious dogs.

1 The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetyl-strophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration. 2 Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose. 3 Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose-dependent. 4 There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin. 5 These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels of digoxin.

Effects on non-depolarizing neuromuscular blocking agents on peripheral autonomic mechanisms in cats.

Intravenous dose-response relationships were used to correlate neuromuscular paralysis with effects on autonomic mechanisms in anaesthetized cats. Whereas autonomic blockade with tubocurarine occurred at parasympathetic and sympathetic ganglia, neuromuscular paralysing doses of gallamine, alcuronium, pancuronium and fazadinium caused blockade at vagal postganglionic sites in the heart. The vagolytic (atropinic) activity of these compounds in cats relative to their neuromuscular blocking activity appeared to correlate well with their known liability to cause undesirable hypertension and tachycardia in man. The absence of cardiovascular effects after the administration of neuromuscular blocking doses of dimethyl tubocurarine would support its more extensive clinical use, but the need remains for a short-acting muscle relaxant with properties similar to those of dimethyl tubocurarine.