Kwan E. Kim

Digitalis toxicity and hypomagnesemia.

Abstract Four patients with digitalis toxicity were found to be hypomagnesemic and normokalemic. A significantly lower mean serum magnesium was noted in a group of digitalized heart failure patients (1.40 mEq./L.) than in matched normal subjects (1.93 mEq./L.). These observations, coupled with the fact that both digitalis and magnesium deficiency lead to a decrease in intracellular potassium, suggested that hypomagnesemia might contribute to the development of digitalis toxicity. To determine whether hypomagnesemia facilitates the development of digitalis toxicity, serial acetyl strophanthidin infusions were performed in 19 adult mongrel dogs. Hypomagnesemia was achieved by Kiil kidney dialysis. While dialysate electrolyte concentration corresponded to normal canine plasma, acetyl strophanthidin was infused (100 μg per minute) three times at three hour intervals. Hypomagnesemia was then induced by three hours of magnesium-free dialysis and acetyl strophanthidin was again infused. Mean serum magnesium was reduced 44 per cent (1.67 to 0.93 mEq./L.). This was accompanied by a 26 per cent reduction in the amount of acetyl strophanthidin needed to produce a toxic arrhythmia (42.4 to 31.4 μg per kilogram). Restitution of sinus rhythm was observed in 13 dogs immediately after the intravenous infusion of 2 to 7 c.c. of 25 per cent magnesium sulfate. These studies have shown that hypomagnesemia facilitates digitalis toxicity which can be promptly terminated with magnesium sulfate. Since diuretic drugs may produce hypomagnesemia as well as hypokalemia and both may predispose to digitalis toxicity, it is suggested that serum magnesium as well as potassium levels be determined in patients with digitalis toxicity.

Antihypertensive Effect of Clonidine

Clonidine hydrochloride is a sympathetic inhibitor with central site of action. The antihypertensive effect in man in the supine position is associated with a decrease in cardiac output and no consistent changes in total peripheral resistance. In the standing position, however, in addition to the decrease in cardiac output, a fall in total peripheral resistance becomes evident. The fall in blood pressure results in no significant alteration in renal blood flow or glomerular filtration rate in the supine position. In the standing position a consistent decrease in renal vascular resistance is seen. In the anesthetized dog the intravenous administration of clonidine produces a significant reduction of renal vein plasma renin activity. Similarly, in patients with essential hypertension oral administration of the drug results in a decrease in peripheral plasma renin activity. In ambulatory essential hypertensive patients treated with clonidine alone in doses of 400 to 900 μg per day, a modest antihypertensive effect is achieved. When clonidine is used with a diuretic, antihypertensive efficacy is achieved in 80% of the patients treated. In higher doses (up to 3,600 μg per day) and in combination with a diuretic, the antihypertensive effect appears to be superior to that of many of the standard agents. Drowsiness and dryness of the mouth are the most frequent and serious side effects with the higher doses.

Creatinine clearance in renal disease. A reappraisal

To determine the validity of endogenous creatinine clearance as a measure of glomerular filtration rate in patients with renal disease 308 simultaneous determinations of inulin clearance and endogenous creatinine clearance were reviewed and analysed. The ratio of creatinine clearance/inulin clearance increased progressively with the decline in inulin clearance, while the finding of a normal endogenous creatinine clearance masked a definite but mild decrease of glomerular filtration rate in 42% of the patients and a moderate decrease of glomerular filtration rate in 23%. This indicates that with declining glomerular filtration rates the endogenous creatinine clearance progressively overestimates actual glomerular filtration rates. Hence a single determination of creatinine clearance can be misleading as a screening measurement of glomerular filtration rate.

Pharmacodynamic Effects of a New Antihypertensive Drug, Catapres (ST-155)

Catapres is a new imidazoline compound with potent antihypertensive properties. Significant reduction in blood pressure occurs between 1 and 4 hours after oral administration, with the peak effect occurring at 2 to 4 hours and the antihypertensive effect extending for 6 to 10 hours. Blood pressure is reduced in both the supine and erect positions, although the orthostatic response is the more prominent.Cardiac output is reduced moderately in both the supine and erect positions. Peripheral vascular resistance is also reduced, particularly in the erect posture. Accordingly, the cardiac hemodynamic findings suggest that the antihypertensive effect of Catapres is related to the combination of reduction in cardiac output plus decrease in peripheral resistance. Renal blood flow and glomerular filtration rate are preserved in both the supine and erect positions following Catapres administration. Contrasting with the preservation of renal blood flow and glomerular filtration rate, however, is the marked reduction in sodium chloride excretion which follows acute administration of the drug.The clinical utility of the drug was demonstrated in the chronic outpatient study. Although Catapres administered alone exerted only modest antihypertensive effects, a markedly enhanced antihypertensive response was achieved when the drug was combined with a potent oral diuretic, with 80% of patients so treated achieving significant blood pressure reduction in both the supine and erect positions.

Acute renal failure after administration of low-molecular weight dextran.

THE infusion of low-molecular-weight dextran (Dextran 40) has been associated with acute renal failure in 14 patients.14 Three of these cases, not previously reported but submitted to Pharmacia Lab...

Magnesium sulfate in digitalis toxicity

Abstract This study was undertaken to evaluate the mechanism of the antiarrhythmic effect of magnesium sulfate in digitalis toxicity. The egress of potassium from the myocardium after the administration of 1 mg of acetyl strophanthidin into the right atrium was determined in 16 dogs by measurement of the coronary sinus-femoral artery potassium concentration difference. Three infusions of acetyl strophanthidin were given at 2 1 2 hour intervals. Twenty-five percent magnesium sulfate was given simultaneously with the third infusion. Arterial and coronary sinus samples were collected at 2 minute intervals after each infusion. The mean maximal arteriovenous potassium concentration difference was 0.47 mEq/liter after the first dose of acetyl strophanthidin and 0.80 mEq/liter after the second dose. When magnesium sulfate was given with acetyl strophanthidin, the arteriovenous difference was not significantly different from that of control subjects (0.15 mEq/ liter). A high level of magnesium concentration may overcome the acetyl strophanthidin-induced inhibition of transport adenosine triphosphatase. This may explain the efficacy of magnesium sulfate in the treatment of the arrhythmias of digitalis toxicity associated with hypomagnesemia. Although magnesium sulfate blocked myocardial egress of potassium in all studies, arrhythmias still occurred in 60 percent of the animals. This suggests that factors independent of potassium loss from the myocardium underlie the development of some digitoxic arrhythmias.

Esophageal varices in adult patients with polycystic kidney and liver disease.

IN the cases presented below, two middle-aged patients had polycystic kidneys and esophageal varices secondary to polycystic liver disease. One patient died after hemorrhage, which might have been ...

Timolol kinetics in chronic renal insufficiency

A single‐dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function—(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; Ccn 20 to 50 ml/min); (3) 4 patients with end‐stage renal disease (ESRD)—to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (Cmax) was 84.3 ± 44.8 ng/ml at 0.8 ± 0.4 hr for N and 87.1 ± 22.8 ng/ml at 1.7 ± 1.2 hr (p, NS) for MCRI. Nand MCRI mean half‐lives (5.2 ± 2.6 hr and 4.0 ± 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 Nand 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration oftimolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.

Long-Term Clinical Effects, Bioavailability, and Kinetics of Minoxidil in Relation to Renal Function

Minoxidil was used to treat 26 patients (17 to 67 years old) with severe hypertension and varying degrees of renal function. Our object was to assess long-term clinical efficacy, kinetics (acute and chronic), and bioavailability of minoxidil in chronic renal insufficiency. Minoxidil, 27 to 30 mg per day, decreased systolic and diastolic blood pressure during the first three months of therapy. Between the third and 24th months (30 months in one patient) there was no further change. Propranolol or clonidine was needed to control heart rate, and furosemide or dialysis was needed to control edema induced by minoxidil. Renal function improved in some of the mildy azotemic patients. Minoxidil kinetics after the customary dose did not differ whether the drug was taken as tablet or solution. Kinetic parameters during chronic administration of minoxidil did not differ from those after acute administration. The kinetics in chronic renal insufficiency do not differ from these in subjects with normal renal function.

Creatinine clearance and glomerular filtration rate.

only unnecessary but may be positively dangerous, and should be carried out only for two reasons. One indication is to provide evidence where none other exists of a head injury having been sustained (the child who has been found unexplainably unconscious or where battering is suspected). The other is to confirm a clinical diagnosis of depressed fracture of more than trivial degree. The really crucial part of the management of head injuries consists of careful observation in order to detect the onset of complications, haemorrhage, and meningitis. This is just as necessary for patients without a fracture as it is for those who have one, and this is the reason why I regard the taking of a skull x-ray as potentially dangerous. For if on the strength of a negative skull x-ray the patient is sent home and no warning given to the parents, they may have a false impression that all must be well and so be reluctant to associate any untoward symptoms that come on within the next 48 hours with the head injury. What is needed is a period of careful observation by someone (the parents may be excellently suitable for this) who will notice the onset of untoward symptoms and, having been warned by the doctor to take them seriously in the unlikely event of their occurring, will not hesitate to bring the child back to the family doctor or the casualty department for re-appraisal. The decision whether to admit a child to hospital for observation following a head injury depends not on the presence or absence of a skull fracture but on the quality of the observation which is available in the home, the time of day, and, perhaps, the degree of disturbance of consciousness with which the injury is accompanied. The lawyers ask for a skull x-ray simply because they have been wrongly led by the medical profession to believe that it is an essential part of the proper management of all head injuries. They would as readily ask for the burning of a candle at the bedside or the letting of a pint of blood if the profession had led them to suppose these things to be equally necessary. Does the medical profession really believe that this wasteful and often frightening ritual non-investigation is always necessary? If so, let it say so and give convincing reasons for saying so. If not, let it speak out against it so that casualty officers and hospital junior staff can come off this absurd medicolegal hook.-I am, etc.,