Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Alliance Pharmaceuticals Limited, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB
Chlortalidone is a benzothiadiazine (thiazide)-related diuretic with a long duration of action.
Thiazide and thiazide-like diuretics act primarily on the distal renal tubule (early convoluted part), inhibiting NaCl¯ reabsorption (by antagonising the Na+Cl¯ cotransporter) and promoting Ca++ reabsorption (by an unknown mechanism). The enhanced delivery of Na+ and water to the cortical collection tubule and/or the increased flow rate leads to increased secretion and excretion of K+ and H+.
In persons with normal renal function, diuresis is induced after the administration of 12.5mg Hygroton/Chlortalidone. The resulting increase in urinary excretion of sodium and chloride and the less prominent increase in urinary potassium are dose dependent and occur both in normal and in oedematous patients. The diuretic effect sets in after 2 to 3 hours, reaches its maximum after 4 to 24 hours, and may persist for 2 to 3 days.
Thiazide-induced diuresis initially leads to decreases in plasma volume, cardiac output, and systemic blood pressure. The renin-angiotensin-aldosterone system may possibly become activated.
In hypertensive individuals, chlortalidone gently reduces blood pressure. On continued administration, the hypotensive effect is maintained, probably due to the fall in peripheral resistance; cardiac output returns to pretreatment values, plasma volume remains somewhat reduced and plasma renin activity may be elevated.
On chronic administration, the antihypertensive effect of Hygroton/Chlortalidone is dose dependent between 12.5 and 50mg/day. Raising the dose above 50mg increases metabolic complications and is rarely of therapeutic benefit.
As with other diuretics, when Hygroton/Chlortalidone is given as monotherapy, blood pressure control is achieved in about half of patients with mild to moderate hypertension. In general, elderly and black patients are found to respond well to diuretics given as primary therapy. Randomised clinical trials in the elderly have shown that treatment of hypertension or predominant systolic hypertension in older persons with low-dose thiazide diuretics, including chlortalidone, reduces cerebrovascular (stroke), coronary heart and total cardiovascular morbidity and mortality.
Combined treatment with other antihypertensives potentiates the blood-pressure lowering effects. In the large proportion of patients failing to respond adequately to monotherapy, a further decrease in blood pressure can thus be achieved.
In renal diabetes insipidus, Hygroton/Chlortalidone paradoxically reduces polyuria. The mechanism of action has not been elucidated.
The bioavailability of an oral dose of 50mg Hygroton/Chlortalidone is approximately 64%, peak blood concentrations being attained after 8 to 12 hours. For doses of 25 and 50mg, Cmax values average 1.5µg/ml (4.4µmol/L) and 3.2µg/ml (9.4µmol/L) respectively. For doses up to 100mg there is a proportional increase in AUC. On repeated daily doses of 50mg, mean steady-state blood concentrations of 7.2µg/ml (21.2µmol/L), measured at the end of the 24 hour dosage interval, are reached after 1 to 2 weeks.
In blood, only a small fraction of chlortalidone is free, due to extensive accumulation in erythrocytes and binding to plasma proteins. Owing to the large degree of high affinity binding to the carbonic anhydrase of erythrocytes, only some 1.4% of the total amount of chlortalidone in whole blood was found in plasma at steady state during treatment with 50mg doses. In vitro, plasma protein binding of chlortalidone is about 76% and the major binding protein is albumin.
Chlortalidone crosses the placental barrier and passes into the breast milk. In mothers treated with 50mg chlortalidone daily before and after delivery, chlortalidone levels in fetal whole blood are about 15% of those found in maternal blood. Chlortalidone concentrations in amniotic fluid and in the maternal milk are approximately 4% of the corresponding maternal blood level.
Metabolism and hepatic excretion into bile constitute a minor pathway of elimination. Within 120 hours, about 70% of the dose is excreted in the urine and the faeces, mainly in unchanged form.
Chlortalidone is eliminated from whole blood and plasma with an elimination half-life averaging 50 hours. The elimination half-life is unaltered after chronic administration. The major part of an absorbed dose of chlortalidone is excreted by the kidneys, with a mean renal clearance of 60ml/min.
Renal dysfunction does not alter the pharmacokinetics of chlortalidone, the rate-limiting factor in the elimination of the drug from blood or plasma being most probably the affinity of the drug to the carbonic anhydrase of erythrocytes.
No dosage adjustment is needed in patients with impaired renal function.
In elderly patients, the elimination of chlortalidone is slower than in healthy young adults, although absorption is the same. Therefore, close medical observation is indicated when treating patients of advanced age with chlortalidone.
There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.
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