Clinical experience with metolazone-a new diuretic in cases of edema and ascites due to hepatic cirrhosis, C.C.F.,, and malnutritionUK Sheth1, JM Mehta2, Teresa Paul3, Sumati Nair4, Bharati Sanghvi5
1 Clinical Pharmacology Unit, K.E.M. Hospital and Seth G. S. Medical College, Parel, Bombay 400 012, India
2 Department of Pharmacology and Medicine, K.E.M. Hospital and Seth G. S. Medical College, Parel, Bombay 400 012, India
3 Clinical Drug Trial Unit, (CSIR), K.E.M. Hospital and Seth G. S. Medical College, Parel, Bombay 400 012, India
4 Tata Blood Bank, Bombay, India
5 J.J. Hospital and the Department o f Statistics, University of Bombay, Bombay., India
Metolazone [2-methyl-3-(0-tolyl)-6-sulpharnyl-7-chloro-1, 2, 3, 4tetra hydro-4-quinazolinone] is recently introduced as a new orally acting diuretic. It is structurally related to sulfonamides and benzothiazidines. 41 male patients suffering from generalised edema due to various causes including 7 cases of congestive cardiac failure, 6 cases of malnutrition and 28 cases of hepatic cirrhosis were treated with metolazone given orally in a dose varying from 5 to 60 mg per day. The optimum effective dose was found to be 5 mg per day. 36 cases responded well with a loss of body weight ranging from 2.5 kg. to 12 kg. There was a significant increase in the urine volume and the urinary sodium, potassium and chloride excretion. Saluretic response was marked. Urinary sodium increased from 8-20 mEq/ day to 100 to 120 mEq in 24 hours. No serious side effects were observed during this study. Hypokalemia and hyponatremia occurred on increase of the dose. Occasionally leg cramps and abdominal distress were observed. Metolazone was found to be an effective orally active diuretic in a dose of 5 to 10 , mg/day.
Metolazone is a recently introduced diuretic, and has the formula; 2-methyl3- (0-tolyl) -6-sulphamyl-7-chloro-1, 2, 3, 4; tetrahydro-4-quinazolinone, and is structurally related to the sulfonamides and benzothiazidine diuretics. It is similar to quinithazone, but differs from the compound by the replacement of the ethyl group in position 2 with a methyl group, and by the introduction of the 0-tolyl group in position 3. 
In laboratory animals, metolazone has shown a potent diuretic and saluteric activity. The primary site of action is at the cortical diluting segment of the loop of Henle. ,,, In dogs, micropuncture technique has shown that metolazone also acts at the proximal tubule.  On weight basis, in animals, it is 10 times as active as hydrochlorthiazide. It does not resemble mercurial diuretics and has no carbonic anhydrase inhibitor activity, or antialdosterone actions. Clinical evaluation of metolazone as a diuretic and hypotensive agent has been reported by many workers. ,,,,,,,,,, We have studied the effectiveness and safety of metolazone as a diuretic in cases of edema due to hepatic cirrhosis, congestive cardiac failure and malnutrition.
Forty one male adult patients (age varying from 20 to 50 years) suffering from generalised edema admitted in the Clinical Pharmacology ward at the K. E. M. Hospital were included in the study. The cause of the edema was congestive cardiac failure in 7 cases, malnutrition in 6 cases and hepatic cirrhosis in 28 cases.
The diagnosis was established on the basis of clinical history, physical examination, and laboratory investigations. Congestive cardiac failure was secondary to rheumatic heart disease in 4 cases, corpulmonale in 2 cases, and hypertension in one case. All patients had dyspnoea, raised J.V.P., palpable tender liver, and bilateral pitting edema of the lower extremeties. All hepatic cirrhosis cases had edema and ascites of varying grades. The etiology was not definite. Some of them had history of previous jaundice and a large number gave history of moderate to heavy alcohol intake. Diagnosis of hepatic cirrhosis was confirmed by liver biopsy.
On admission, after complete physical examination, the following investigations were carried out. Complete blood count, urine analysis, stool examination, biochemical investigations, including S.G.O.T., S.G.P.T., alkaline phosphatase, bilirubin, plasma proteins total and electrophoresis pattern, blood sugar, urea nitrogen, uric acid, cholesterol, serum electrolytes, ECG and chest X-rays, were recorded.
The patients were kept at bed rest for 48 hours for basal studies. In cases where necessary, digoxin was the only drug given during this period. The patient was weighed every morning as described previously.  Urine was collected 2 hourly from 8 a.m. to 2 p.m.; and then from 2 p.m. to 8 p.m. and from 8 p.m. to 8 a.m. Volume was measured, and each sample was analysed for sodium, potassium and chloride. Sodium and potassium were estimated by flame photometer and recorded as mEq/1.
Serum electrolytes were estimated very 4th day, or more often if necessary, and other laboratory tests were repeated periodically and at the end of the treatment.
During the hospital stay patient received low salt hospital diet. Additional protein in diet was added in cases of low plasma proteins.
Metolazone was given from the 3rd day onwards as a single 5 mg. dose at 10 a.m. daily, and continued in the same dose or increased to 10 mg. or 20 mg. till the patient reached dry body weight, or failed to respond, when the diuretic was changed. In seven hepatic cirrhosis cases, increasing doses of metolazone were administered. The doses used were 5 mg., 7.5 mg., 10 mg., and 15 mg. daily. Each dose schedule lasted for 3 days. In some patients who did not respond, the dose was raised to 40 mg. and 60 mg. per day.
All patients on treatment days, received orally 40 mEq per day of potassium chloride in the form of 30 ml. of potassium mixture, three times a day.
Improvement as measured by loss of body weight, diuresis, saluresis and disappearance of edema was noted in 28 cases out of 41 patients treated with 5 mg. to 10 mg. P.O. once a day. Partial to complete failure to respond was noted in 13 cases of hepatic cirrhosis.
Body weight loss averaged from 2.5 kg. to
Average response in terms of loss of body weight, increase in urine volume and loss of urinary sodium, potassium, and chloride over a 2 week period in 28 cases of hepatic cirrhosis [Figure 1], 7 cases of congestive cardiac failure [Figure 2] and 6 cases of malnutrition [Figure 3] and[Figure 4] are graphically shown in [Figure 1],[Figure 2],[Figure 3],[Figure 4]
In cases which responded, there was a significant increase in the urine volume and urine sodium, potassium and chloride excretion. [Table 2] Saluretic effect was marked, the urinary sodium increasing from pre-treatment values of 8 to 20 mEq/day to 100 to 120 mEq. in
Average sodium excretion in urine was calculated at different doses and compared to basal values, and between different doses. Taking average over all the days, the highest average sodium excretion was 86 mEq. for 5 mg. as compared to 43 mEq. for basal, 65 mEq. for 10 mg. and 48 mEq. for 20 mg. Thus with 5 mg. dose, the increase in excretion over basal was 43 mEq., 23 mEq. with 10 mg. and only 5 mEq. over basal with 20 mg. As the dose was increased above 5 mg., the sodium excretion decreased, and at 20 mg., it was almost near the corresponding pretreatment value. Thus for sodium loss the optimum dose of Metolazone was found to be 5 mg. per day.
Potassium excretion: (Mean values)
With 5 mg-total potassium excretion was 63 mEq/24 hrs.
With 10 mg.-total potassium excretion was 61 mEq/24 hrs.
With 20 mg-total potassium excretion was 64 mEq/24 hrs
As most of the patients received oral potassium supplement during the treatment, exact significance of potassium loss over basal is difficult to judge. However, the above figures shows that the level of potassium excretion remained almost similar even when the dose of Metolazone was increased from 5 to 20 mg. The same trend is also evident in [Table 3], where comparison is done between 5, 7.5, 10 or 15 mg. doses of Metolazone.
Average changes in serum and urinary electrolytes are shown in [Table 2]. In seven patients of hepatic cirrhosis effect of increasing dose of Metolazone, when each dose was given for 3 days was studied and results are shown in [Table 3].
Compared to, basal values, urinary volume and Na excretion at 5 mg. dose showed optimum increase. Increasing the dose to 7.5 mg., 10 mg. and 15 mg., decreased the diuretic response, though the responses at all doses were higher than the basal values. We have observed similar findings of decreasing a diuretic response with hydrochlorthiazide in rats. The dose response curve was parabolic reaching a ceiling effect at a dose of 5 mg/kg. Further increase in the dose of the drug showed a diminished response.  The potassium loss at all doses was nearly similar, where as sodium loss was much less at higher doses. This dissociation between the effect on sodium loss as compared to potassium loss at higher doses has also been reported by Lowenthal and Shear.  In all these cases, the major loss of sodium was seen in the first 3 days of therapy as compared to the succeeding days. The analysis of 32 patients treated with 5 to 10 mg of Metolazone [Table 4] shows distinctly a greater change in days 1, 2, 3 of the treatment as compared to the average loss during total treatment-both in urine volume and sodium and chloride excretion.
There was no significant change in pre and post-treatment values of various parameters studied for safety of the drug [Table 5].
No serious side effects were observed in any of these cases during the study. Hypokalemia and hyponatremia occurred on increasing the dose. Leg cramps and abdominal distress were occassionaly observed. None of the cases developed encephalopathy.
A number of reports on usefulness of Metolazone as diuretic, in congestive cardiac failure, renal failure and hypertension have appeared in the literature since its introduction in 1970. ,,,, But, there are only a few papers on its usefulness in cases of edema and ascites due to hepatic cirrhosis. ,
We have used it in 28 cases of hepatic cirrhosis to evaluate its usefulness. At the same time, 7 cases of CCF and 6 of malnutrition were admitted in the wards and the drug was tried in these cases also as diuretic. All the cases of CCF, irrespective of etiology, and malnutrition, cleared successfully with metolazone in a dose of 5 mg. p.o, daily.
In cases of hepatic cirrhosis, 15 cases out of 28 reached dry weight, 8 responded partially and 5 cases failed to respond. The pattern of response is similar to our experience with other diuretics in hepatic cirrhosis. It is well accepted that circulating aldesterone levels are raised in hepatic cirrhosis. Those cases with high aldosterone levels fail to respond satisfactorily to thiazides or furosemide, unless anti-aldesterone drug like spironolactone is added. We have used unsuccessfully organic mercurials, combination of mercurials with acetazolamide or hydrochlorthiazide in some cases of hepatic cirrhosis, who responded dramatically to addition of spironolactone. 
The onset of action of metolazone occurred in 2 to 3 hours and reached a peak action in 6 to 8 hurs. The action persisted over 24 hours. This is consistent with the studies in normal volunteers where it was shown that onset of action, occurs in 1 to 2 hours, peak activity in 2 to 4 hours and duration of action is 12 to 24 hours or even longer. ,,, Human pharmacokinetic studies using radioactive compound have been reported by Modi et al.  The long duration of action of metolazone can be explained by the observation that the drug is bound to proteins and red blood cells.  It also undergoes enterohepatic recycling to a considerable degree. 
In man, this drug acts probably at both the proximal tubule and cortical diluting segment of the loop of Hence ,,,, Increased phosphaturia, increased free water diuresis and increased excretion of calcium and magnesium indicate action at the proximal tubule. On the other hand increase in osmolar clearance, and decreased clearance of solute-free water, points to an inhibition of tubular reabsorption of sodium in the loop.
Cases which are resistant to metolazone have responded to furosemide,  showing that though both drugs have chemical similarity and certain common sites of action, there is a difference in the mechanism of action of these two diuretics. Cases of chronic renal failure, where furosemide has produced poor action even at doses higher than 500 mg. i.v. have responded dramatically to addition of 5 mg. of metolazone orally to furosemide regimen.  Metolazone has also shown supra-additive effect in hepatic cirrhosis cases resistant to furosemide alone. 
When given for a longer period in increasing doses in hepatic cirrhosis, metolazone showed, a dissociation of effects in sodium and potassium excretion. As the dose was increased beyond 5 mg. to 7.5, 10 and 15 mg. per day, the sodium excretion gradually decreased, where as potassium excretion continued to be high compared to the basal values [Table 3]. Similar dissociation was reported by Lowenthal and Shear,  when they used metolazone intravenously in cases of edema and ascites.
Hillenbrand and Sherlock  reported high incidence of hypokalemia. encephalopathy, hypochloremia and hyponatremia with the use of metolazone in hepatic cirrhosis. We did not have such experience in our study. Hypokalemia was noted, similar to that occurring with other diuretics but was controlled on the use of oral potassium supplements, or use of spironolactone (not reported in this series). No other serious side effects were noted. Out of 28 cases, a number of cases were fairly advanced cases of hepatic cirrhosis. The difference in the side effects may be due to very high doses used by previous workers who used metolazone in doses of 20 to 150 mg./day whereas we have mostly used 5 to 10 mg. per day and higher doses till 80mg. only in a few cases for short periods. As the drug shows best activity at dose of 5 to 10 mg. per day, there is no advantage to be gained by using higher doses. If the patient of hepatic cirrhosis does not respond to metolazone in doses of 5 to 10 mg./day, it would be best to combine it with potassium sparing and anti-aldosterone drugs like spironolactone. In our hands metolazone at a dose of 5 mg. to 10 mg. per day has proved to be a useful diuretic in cases of hepatic cirrhosis, congestive cardiac failure and malnutrition. Its potentiating action to high doses of furosemide in refractory renal cases and hepatic cirrhosis is being reported elsewhere.
We are thankful to the Scientific Division, Pennwalt Corporation, Rochester, New York, USA-14603 for the generous research support through their Indian Associates, Indo-Pharma Ltd. and supply of the drug.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]