Xipamide

Diuretic, of the thiazide family, which inhibits sodium chloride reabsorption in the early distal tubule and leads primarily to chloruresis and natriuresis, and secondarily to an increase in urine flow through osmotically bound water. Increase in flow in the late distal tubule results in stimulation of potassium secretion. Bicarbonate, calcium and magnesium are also acutely increased in excretion. Xipamide reaches its point of action from the peritubular (blood side, so the mechanism of action differs from that of thiazides despite structural similarity. Xipamide does not affect renal hemodynamics or glomerular filtration rate and is effective up to end-stage renal failure. The diuretic effect occurs after approximately 1 hour and reaches its maximum between the 3rd and 6th hour. Sodium and chloride excretion is above basal levels for 12 to 24 hours, so there is no rebound effect (Fachinfomration).

The antihypertensive effect of Xipamide at the start of therapy is due to a decrease in the extracellular volume, resulting in a lowered peripheral resistance. With prolonged use, the extracellular volume normalizes while the antihypertensive effect is maintained, which may be due to a decrease in the sodium concentration in the vessel wall and thus to a decreased responsiveness to norepinephrine. The maximum antihypertensive effect is reached after 2 3 weeks.

Pharmacokinetic properties: Maximum plasma concentrations of xipamide are reached approximately 1 hour after application. Protein binding is 99%. After a single administration, the elimination half-life is approximately 7 hours. Oral absorption of xipamide is complete. In renal insufficiency, the half-life is prolonged to 9 hours, which is not clinically relevant, and in liver cirrhosis it remains unchanged despite increased plasma levels of xipamide. Renal excretion of unchanged substance is %. Extrarenal elimination (a total of about 2 / 3 of native xipamide occurs half by glucuronidation. The resulting inactive metabolite is excreted via the kidney, the remainder via the intestine.

Arterial hypertension

Cardiac, renal and hepatogenic edema

There is no experience with the use of Xipamide in pregnant women.

Thiazide diuretics cross the placenta and may cause electrolyte changes, hypoglycemia, and hemolytic anemia and thrombocytopenia in the unborn or newborn child. No studies on diaplacental crossover are available for xipamide.

In general, diuretics such as xipamide are contraindicated in pregnancy. Furthermore, diuretics should not be used under any circumstances in the treatment of pregnancy-related, i.e. physiological, edema, especially since fetoplacental ischemia with the risk of fetal growth disturbance can occur with these substances.

As it is not known whether xipamide passes into breast milk, the use of xipamide is contraindicated during breastfeeding.

For both hypertension and edema, adults take 10-20 mg of xipamide 1 time daily.

For the treatment of oedema, dosages of up to 40 mg of xipamide may be required. In more severely impaired renal function, the dosage may be increased to up to 80 mg of xipamide daily. Increasing the dose to more than 80 mg of xipamide per day is not recommended.

After edema clearance has occurred, xipamide may be switched to 20 mg or 10 mg to prevent relapse. After long-term treatment, xipamide should be gradually discontinued.

Impaired hepatic function: In hepatic impairment, xipamide should be dosed according to the limitation.

Impaired cardiac function: In severe cardiac decompensation, absorption of xipamide may be markedly impaired.

Xipamide should not be used in children because safety and effectiveness have not been established in this population.

Plasma potassium levels: As with other diuretics, hypokalaemia may occur during long-term therapy with Xipamide. Potassium substitution may be required, particularly in elderly patients in whom adequate potassium intake is not assured. The fall in plasma potassium levels to hypokalaemia is the main risk of treatment with thiazide diuretics and closely related drugs. The occurrence of hypokalaemia (potassium plasma level < 3.4 mmol/l) should be avoided in particular in the event of severe fluid loss (e.g. through vomiting, diarrhoea or intensive sweating) and in risk groups, i.e. in elderly and/or malnourished patients and/or patients treated with multiple medications as well as in patients with liver cirrhosis and oedema or ascites formation, furthermore in patients with coronary heart disease and those with cardiac insufficiency. In this patient population, hypokalemia also increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Hypovolemia or dehydration, as well as significant electrolyte disturbances or disturbances in acid-base balance, must be corrected. This may require temporary discontinuation of treatment with xipamide.

Also at-risk patients include those with a long QT interval, whether congenital or iatrogenically acquired. The presence of hypokalemia as well as bradycardia then favors the occurrence of severe cardiac arrhythmias, especially torsade de pointes, which can be fatal.

Calcium plasma levels: Treatment with thiazide diuretics and related drugs may result in decreased urinary calcium excretion and a small, transient increase in plasma calcium levels. Manifest hypercalcemia may also have developed on the floor of unrecognized hyperparathyroidism.

Blood glucose: In diabetics, blood glucose should be monitored closely, especially in the presence of hypokalaemia .

Uric Acid Levels: Patients with hyperuricemia may have an increased tendency to gout attacks.

Nephrologic UIAW: Thiazide diuretics and related drugs are fully effective only in normal or at most mildly impaired renal function (serum creatinine level < 25 mg/l or < 220 µmol/l in an adult). The dosage of xipamide for elderly patients should be adjusted according to their age, weight and sex, based on serum creatinine levels.

Hypovolemia, caused by diuretic-induced water and sodium loss at the start of therapy, leads to a decrease in glomerular filtration. This may result in an increase in blood urea nitrogen (BUN) and serum creatinine. This transient functional renal insufficiency is without consequence in healthy renal patients but may worsen pre-existing renal insufficiency.

Children: Xipamide should not be used in children as safety and efficacy have not been established in this population.

Dermatologic ADR: Photosensitivity (Schauder S 1990);

Cave: The use of xipamide may lead to positive results in doping controls.

Xipamide must not be used:

• in case of hypersensitivity to xipamide, other sulphonamide derivatives or thiazides or to any of the other constituents of the medicinal product
• severe hepatic impairment (praecoma and coma hepaticum)
• refractory hypokalaemia
• severe hyponatremia
• hypercalcaemia
• hypovolaemia
• in gout
• during pregnancy
• during breastfeeding

In liver disease, hepatic encephalopathy may occur during treatment with thiazide diuretics and related substances. In this case, Xipamide should be discontinued immediately. In chronic diuretic abuse, a pseudo-Bartter syndrome may occur resulting in edema. These oedemas are an expression of an increase in renin resulting in secondary hyperaldosteronism.

Water and electrolyte balance: Serum electrolytes (especially potassium, sodium, calcium), bicarbonate, creatinine, urea and uric acid, and blood glucose should be monitored regularly.

Sodium plasma level: This should be checked before starting therapy and at regular intervals during treatment. In principle, hyponatremia can occur with any diuretic therapy, sometimes with very serious consequences. Since a drop in the sodium plasma level may initially be asymptomatic, regular monitoring is essential; in elderly patients and patients with liver cirrhosis, close monitoring should be carried out.

close monitoring should be carried out

1. Technical information Xipamide
2. Kumar S et al (1984) A randomized double-blind clinical trial of xipamide and hydrochlorothiazide in essential hypertension. Int J Clin Pharmacol Ther Toxicol 22:549-551. PMID: 6392119.
3. Schauder S (1990) Photosensitivity to enoxacin and xipamide: combined phototoxic and photoallergic reaction to enoxacin, photoallergic reaction to xipamide followed by transient light reaction. Z Hautkr 65:253-262.
4. Selvaag E et al. (1997) Phototoxicity to sulphonamide derived oral antidiabetics and diuretics. Comparative in vitro and in vivo investigations. In Vivo 11:103-107.