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A sensitive and specific GLC method for the determination of urinary chlorthalidone levels was developed using on-column methylation. Chlorthalidone is converted to a tetramethylated derivative with trimethylanilinium hydroxide in methanol. This method which permits the determination of as little as 0.1 microgram of chlorthalidone/ml of dog urine, should be adequate for use with human subjects receiving a clinical dose.
A reliable and selective high-pressure liquid chromatographic procedure for the quantitative determination of chlorthalidone in pharmaceutical dosage forms is described. A comparison of this stability-indicating procedure with the USP spectrophotometric assay is presented for chlorthalidone tablets and chlorhalidone tablets containing reserpine.
A renewed application of potentiometric acid-base titrations is described, by which dissociation constants of practically water-insoluble drugs can be measured accurately. The method uses the difference in the amount of titrant between a suitable aqueous solvent and a solution of the drug in that solvent. Such potentiometric difference titrations were conducted on a 3.7 X 10(-4) M solution of chlorthalidone in 0.1 M aqueous KCl in the pH 3.5--10.6 range at 25 degrees. Nonlinear least-squares regression analysis was applied to the data. From four determinations, a value of 9.24 +/- 0.02 (mean +/- SEM) resulted for the apparent dissociation constant of the first chlorthalidone acid group. The thermodynamic dissociation constant was calculated at pKa1 = 9.35 (25 degrees) by using a correction for activity.
In a multicentre, double-blind, crossover, placebo-controlled study, the antihypertensive effect of labetalol 100 mg and chlorthalidone 10 mg, given alone or in combination, has been assessed in 32 hypertensive patients. The combination had a greater effect in reducing blood pressure than did its separate components. This was particularly evident after exercise. Heart rate increased during chlorthalidone therapy, decreased during labetalol therapy, and a summation effect was observed during treatment with the combination. In most cases additivity was observed, as no interaction between the single components was observed, except for heart rate after exercise, and for diastolic blood pressure in the upright position. No interaction was observed either in the biochemical indices or in the clinical side-effects.
The relationship between the whole blood concentration of carbonic anhydrase and the biological half life of chlorthalidone has been investigated in six volunteers. A linear relationship was observed and on the basis of this, a pharmacokinetic model to explain the long and variable biological half life of chlorthalidone is proposed and discussed.
The effects of indapamide, hydrochlorothiazide and chlorthalidone were studied on isometric contractions, calcium contractures (in depolarized preparations) and membrane potentials in isolated longitudinal strips from rat portal veins. Indapamide inhibited all three responses more potently than did current diuretics. The effects of hydrochlorothiazide and chlorthalidone appeared at concentrations at which indapamide reduced electrical and mechanical activity by more than 50%. These results confirmed that the depressing action of indapamide on vascular smooth muscle was exerted through a reduction in the transmembrane calcium influx.
The pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), that go beyond those typical of an NSAID were examined. The extent to which meloxican shows NSAID-like interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide was also investigated. In the dose range studied, meloxicam had no influence on the blood pressure of the unanaesthetized rat, blood flow, heart rate, ECG and respiratory minute volume of the anaesthetized cat or on the blood pressure, heart rate and respiratory minute volume of the anaesthetized dog. The acute toxicity level of meloxicam after oral and parenteral administration to the rat and mouse proved considerably lower than that of indomethacin. Meloxicam showed excellent tissue tolerability following parenteral administration. The effects against inflammatory pain and acute antiexudative effects of meloxicam were enhanced by simultaneous low doses of paracetamol. Pirenzepine showed an antagonistic effect on the ulcerogenicity of meloxicam in the rat stomach. The diuretic effect of chlorthalidone in the rat was not influenced by high doses of meloxicam. The effect of phenprocoumon in the rat was enhanced by high doses of meloxicam. However, the hypoglycaemic effect of tolbutamide in the rabbit was not influenced by meloxicam.
A simple and rapid on-line method for the determination of chlorthalidone in urine is proposed. The sample containing the internal standard is injected in a CN precolumn. After a 2-ml water rinsing, the precolumn is coupled for 30 s to the HPLC column via a switching, valve, allowing the on-line elution of the compounds of interest. Analysis is carried out by reversed-phase chromatography with an acetonitrile-0.01 M phosphate buffer pH 7 (20:80, v/v) eluent, using UV detection at 214 nm. While the LC separation is performed, the precolumn is regenerated and conditioned, and is ready to receive the next sample at the end of the run. Accurate (> 95%) and precise (< 10%) analyses, in the range of 0.1-20 micrograms/ml of chlorthalidone in urine, have been achieved using this method.
In seven patients with severe idiopathic hypercalciuria and recurrent calcium oxalate nephrolithiasis, we have determined the effects on mineral balance of chronic treatment with chlorthalidone or trichlormethiazide, drugs that are widely used to lower urine calcium losses and reduce stone recurrence. Each person excreted above 350 mg of calcium daily while untreated, and was studied twice, before and after three to six months of treatment. Compared to pretreatment, the drugs reduced intestinal calcium absorption; but they reduced urine calcium loss even more, so calcium retention increased. Phosphate retention also increased. Serum levels of calcitriol, parathyroid hormone, calcium, phosphate, and magnesium were unchanged. At least in patients of this type, chlorthalidone and trichlormethiazide seem ideal treatments, that lower urine calcium yet increase calcium and phosphate retention. Whether patients with less severe hypercalciuria respond this way is unknown.
1. A double-blind cross-over evaluation of the anti-hypertensive effect of metoprolol vs placebo was carried out in a series of twenty-three patients with mild or moderate essential hypertension who were receiving 25 mg of chlorthalidone daily as their basic treatment. An individually determined dose of metoprolol (75-300 mg) was used. 2. Metoprolol, as compared with placebo, produced a statistically significant reduction of blood pressure, both in supine and standing positions. 3. During the double-blind cross-over study mild side effects were more common at the beginning of metoprolol/chlorthalidone treatment than during placebo/chlorthalidone, but these tended to diminish or disappear with time. 4. Metoprolol in combination with chlorathalidone appears to be an effective and well-tolerated treatment for mild and moderate hypertension in patients not responding to chlorthalidone alone.
In an effort to maintain normal serum calcium levels without inducing hypercalciuria, we treated seven hypoparathyroid patients for up to 25 months with chlorthalidone, a thiazide-like sulfonamide diuretic, plus a salt-restricted diet, without added vitamin D. Mean 24-hour calcium excretion decreased from 179 to 88 mg (P less than 0.001), and mean serum calcium increased from 8.2 to 9.3 mg per deciliter (P less than 0.05). Diuretic therapy or moderate salt restriction alone was not as effective as combined therapy. Beneficial effects were sustained for as long as therapy was maintained. The rise in serum calcium, which involves the filterable and ionized fractions, cannot be due entirely to reduced excretion and may in part be explained by increased intestinal absorption. Oral chlorthalidone plus a low salt diet appears to be an effective alternative to vitamin D in the maintenance therapy of at least some patients with hypoparathyroidism.
The solubility of chlorthalidone in 16 solvent systems was determined in the absence and presence of different amounts of beta-cyclodextrin (beta-CD). Chlorthalidone (CT) was shown to be more soluble in hydrophilic organic solvents, with the highest solubility in ethylacetate (EtOAc) saturated with water. The solubility of CT in water, butanol, octanol, and dichloromethane (DCM) was enhanced by the addition of beta-cyclodextrin. The enantioselective partitioning of CT between water and EtOAc, DCM, butan-1-ol, butan-2-ol, and octan-1-ol was determined in the presence of beta-CD at pH 5, 7, and 9. According to the results, both the solubility and partitioning properties of CT are affected by beta-CD in aqueous solution. It was also shown that the solubility of the individual enantiomers differs in the presence of beta-CD.
A double-blind crossover trial of atenolol and chlorthalidone was done in black Jamaican hypertensive patients. After an initial four weeks of single drug therapy, the beta blocker and thiazide diuretic were used in combination. Chlorthalidone at a daily dose of 25 mg produced a significant (P less than .05) fall in the mean systolic and diastolic pressures (19.4 mm Hg and 12.2 mm Hg, respectively); atenolol produced a significant fall in the diastolic blood pressure (6.5 mm Hg); and combination therapy produced a reduction in systolic and diastolic blood pressures (27.8 mm Hg and 17.8 mm Hg, respectively). The study showed that combination therapy using a low dose of thiazide diuretic and a beta blocker was synergetic, but that a thiazide was more effective than a beta blocker in lowering the blood pressure in black hypertensive patients.
The forearm resistance vessels of men with primary hypertension respond to verapamil with a greater than normal dilatation relative to that induced by sodium nitroprusside. We have examined the effect on this functional abnormality of treatment with chlorthalidone (50 mg daily in 16 patients) and atenolol (100 mg daily in eight patients and 200 mg daily in two). The responsiveness of the forearm resistance vessels to local intra-arterial infusion of verapamil and sodium nitroprusside was assessed before treatment and again after a minimum of 1 month of drug therapy. Forearm blood flow was measured by venous occlusion plethysmography. Chlorthalidone induced significant reductions in calculated mean arterial pressure, which fell from 135 +/- 4 to 117 +/- 4 mm Hg, and the dilator response to verapamil at 5 micrograms/min, which was reduced from 2.4 +/- 0.2 to 1.5 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside at 3.2 micrograms/min was not significantly changed. Atenolol induced significant reductions in mean arterial pressure, which fell from 134 +/- 6 to 123 +/- 6 mm Hg, heart rate which fell from 72 +/- 3 to 55 +/- 2 beats/min, and response to verapamil at 5 micrograms/min which fell from 2.7 +/- 0.2 to 2.1 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside was not significantly changed. Both drugs caused reversion towards normal of the relative enhancement of responsiveness to verapamil that was present before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Beta adrenoceptor blocking drugs and diuretics are frequently given together to control hypertension and increasingly the two agents are being combined in a single preparation. Possible interactions between the two agents are therefore of interest. In this study the addition of chlorthalidone has been shown not to influence the plasma levels or beta-blocking action of a sustained release form of metoprolol. In addition, when the combination product containing sustained release metoprolol and chlorthalidone is given over 21 days, the plasma levels of each drug are similar to those reported for each drug when given alone.
The effect on blood pressure of high (400 mg/day-S400) and moderate dose (200 mg/day-S200) spironolactone and chlorthalidone (100 mg/day-C100), given in a random double-blind manner was related to plasma renin activity and plasma volume in 38 essential hypertensives. The fall in pressure from a control of 154/103 mm Hg was essentially the same after four weeks of each drug--S400 deltaBP 24/13 mm, S200 18/9 mm, C100 17/12 mm (all P less than 0-001). Twelve of 37 patients (32%) had low initial renin, but this appeared as responsive to the chlorthalidone stimulus as that of the normal renin group. The antihypertensive effect of all regimens was unrelated to plasma renin activity. Plasma volume was significantly lowered at the end of each treatment period, but the decline could not be correlated with blood pressure effects. Patients with initially low plasma volume were more likely to respond to S400 (r = 0-545, P less than 0-001), whereas the antihypertensive effect of the S200 and C100 regimens was independent of this variable.
Chlorthalidone given to 40 hypertensive women significantly decreased blood pressure and serum potassium levels and increased the serum urate concentration. There were no individual correlations between the reduction in blood pressure and the decrease in serum potassium or the increase in serum urate. A reduction in dosage from 50 mg daily to 50 mg three times a week produced no significant changes in the diastolic or mean blood pressures though the systolic blood pressure was moderately increased. Concomitantly, serum potassium increased and serum urate decreased significantly on the lower chlorthalidone dose. We conclude that high doses of oral diuretics compared with lower ones are of limited further benefit and may increase the risk of clinically significant hypokalaemia and hyperuricaemia.
Combined treatment with low doses of different drugs is widely used for moderate hypertension. The effects of atenolol and methyldopa at two dose levels and in combination at the lower doses were studied in patients with moderate hypertension on continuous treatment with moderate hypertension on continuous treatment with chlorthalidone. The mean reduction in standing blood pressures obtained with atenolol 150 and 300 mg/day was about 27/17 mm Hg and with methyldopa 750 and 1500 mg/day about 28/14 mm Hg. Combined treatment with atenolol 150 mg/day and methyldopa 750 mg/day for four weeks resulted in a reduction of 38/25 mm Hg. No difference was observed between the two doses of methyldopa. The lower dose of atenolol was better than the lower dose of methyldopa in reducing lying and standing diastolic blood pressures. These findings show that in patients on continuous treatment with chlorthalidone the addition of atenolol alone or methyldopa alone or of atenolol and methyldopa in combination is effective in the treatment of moderate hypertension.