Xipamide

Pharmacological properties

Xipamide is a diuretic that inhibits reabsorption in the distal tubule of the nephron and first leads to the removal of chlorine and sodium, then to polyuria due to osmotically bound water. by increasing the current in the distal tubule, potassium secretion is stimulated. excretion of bicarbonate, calcium and magnesium also increases. The mechanism of action of xipamide differs from thiazides, despite the structural affinity. Xipamide does not affect renal hemodynamics, the proportion of glomerular filtration. diuretic effect occurs after 1 hour and reaches its maximum between the 3rd and 6th hour. The removal of chlorine and sodium is carried out at the 12-24th hour, therefore there is no rebound effect. the maximum dose of xipamide is 5 mg (oral). in excess of a dose of 80 mg there is no further saluresis and diuresis.

The hypotensive effect of xipamide occurs at the beginning of treatment. The maximum effect of lowering blood pressure is achieved after 2-3 weeks.

Pharmacokinetics After approximately 1 h, C_max xipamide in blood plasma. The ability to bind to proteins is 99%. T_½ is 7 hours. Oral resorption of xipamide is complete.

In renal failure T_½ increases to 9 hours, with cirrhosis of the liver, despite an increased level of xipamide in the blood plasma, it remains unchanged.

Renal excretion of unchanged substance is 30–40%. Emergency excretion (only about ⅔ of natural xipamide) is carried out in half due to glucuronidation. An inactive metabolite formed in this way is excreted through the kidneys, the rest through the intestines.

Indications

Ag cardial, renal and hepatogenic edema.

Application

Adults take 10–20 mg of xipamide once a day for both ag and edema.

For the treatment of patients with edema, the dose may be 40 mg of xipamide. With significant impairment of renal function, the daily dose of xipamide can be increased to 80 mg.

A dose increase of more than 80 mg of xipamide per day is not recommended.

After eliminating edema, you can go to a dose of 20 or 10 mg of xipamide to prevent relapse.

After prolonged treatment, the drug should be gradually withdrawn.

Tablets, without chewing, drink plenty of water (about 1 glass), it is best in the morning after breakfast.

Impaired liver function. In case of impaired liver function, the dose of xipamide should correspond to the degree of restriction of function.

Decreased heart function. In severe cardiac decompensation, resorption of xipamide can be significantly limited.

Contraindications

• Hypersensitivity to xipamide, other sulfonamide derivatives or thiazides or other components of the drug; severe hepatic impairment (precoma and coma hepaticum); severe renal failure; untreated hypokalemia; severe hyponatremia; hypercalcemia; hypovolemia; gout; hereditary galactose intolerance, lactase deficiency malabsorption, glucose and galactose.

Side effects

The frequency of adverse reactions is defined as follows: very often (≥10%), often (≥1% –10%), sometimes (≥0.1% –1%), rarely (≥0.01% –0, 1%) very rarely (0.01% or unknown).

From the nervous system: often - headache, dizziness, fatigue, dry mouth, sweating.

From the cardiovascular system: often - orthostatic hypotension, palpitations; at high doses, in particular with venous diseases, the risk of thrombosis and embolism increases.

From the digestive system: often - abdominal pain, spastic abdominal pain, diarrhea, constipation; acute cholecystitis with existing gallstone disease; rarely - hemorrhagic pancreatitis; very rarely - jaundice.

On the part of the skin: allergic reactions, including pruritus, erythema, urticaria, chronic photosensitivity (discontinuation of therapy).

From the side of the organ of vision: rarely - minor visual impairment, an increase in the degree of myopia already existing (cessation of therapy).

From the hematopoietic organs and lymphatic system: very rarely - thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia (discontinuation of therapy).

Mental disorders: often - apathy, lethargy, feelings of anxiety, agitation.

Metabolic disorders: rarely - hyperlidemia. Latent diabetes mellitus may occur. Elevated blood glucose may indicate a patient has diabetes.

From the urinary system: very rarely - acute interstitial nephritis.

From the musculoskeletal system: often - muscle cramps and cramps.

Electrolyte and water balance: the violation of the water-electrolyte balance is often observed during treatment with xipamide as a result of increased excretion of fluid and electrolytes. Therefore, it is necessary to control the level of electrolytes (potassium, sodium and calcium).

Patients very often develop hypokalemia, which can be expressed in symptoms such as nausea, vomiting, ECG changes, increased sensitivity to glycosides, heart rhythm disturbance, or skeletal muscle hypotension.

Potassium intake is reduced or its loss increases in cases of vomiting, chronic diarrhea, and excessive sweating. The result of increased renal loss of potassium can be hypokalemia, which can manifest itself in the form of neuromuscular symptoms (muscle weakness, paresthesia, paresis), gastrointestinal symptoms (vomiting, constipation, flatulence), symptoms from the kidneys (polyuria, polydipsia) and cardiological symptoms (e.g. impaired pulse generation and conduction of the heart). Severe hypokalemia can lead to paralytic ileus, loss of consciousness, or coma.

Due to increased sodium loss, patients may develop hyponatremia. The most commonly reported symptoms of hyponatremia are apathy, cramps, loss of appetite, weakness, drowsiness, vomiting, and confusion.

Increased excretion of calcium by the kidneys can lead to hypocalcemia. With hypocalcemia, tetany is possible.

In the case of increased excretion of magnesium by the kidneys, tetany or cardiac arrhythmias can occasionally occur.

As a result of the loss of fluid and electrolytes during therapy with xipamide, the existing metabolic alkalosis may develop or intensify in patients.

An increase in the level of uric acid in the blood can lead to the development of gout in patients who are susceptible to this.

Excessive diuresis can cause dehydration. As a result - hypovolemia, hemoconcentration, occasionally - convulsions, loss of consciousness, vascular collapse, dizziness.

Other: rarely - anaphylactoid reactions.

special instructions

The drug contains lactose monohydrate. with rare hereditary galactose intolerance, lapase lactase deficiency or glucose / galactose malabsorption, this drug cannot be used.

Xipamide should not be used in cases of electrolyte imbalance that cannot be treated, orthostatic dysregulation of blood pressure, disorders of the central nervous system, pancreatitis, changes in the blood picture (anemia, leukopenia, thrombocytopenia), acute cholecystitis, the development of vasculitis, an increase in the severity of existing myopia.

With liver diseases, hepatic encephalopathy is possible. In this case, you must immediately stop taking the drug.

With prolonged excessive use of diuretics, Bartter pseudosyndrome (extraadrenal hyperaldosteronism) with edema can occur. Such edema is a manifestation of an increase in renin level followed by secondary hyperaldosteronism.

The level of sodium in serum should be checked before starting treatment, and then regularly at regular intervals.Since a decrease in blood sodium levels may initially be asymptomatic, it is necessary to constantly monitor the condition of patients, especially the elderly and patients with cirrhosis.

Serum Potassium Level. During prolonged treatment with xipamide, hypokalemia is possible. It is necessary to regularly check the content of electrolytes in blood serum (in particular potassium, sodium, calcium), bicarbonate, creatinine, urea and uric acid, as well as glucose in the blood. Potassium replenishment may be required in elderly patients who do not absorb enough of it.

Hypokalemia should be avoided (potassium level in the blood 3.4 micromol / l), especially with a large loss of fluid (due to vomiting, diarrhea or intense sweating) and in risk groups, that is, in elderly patients; debilitated patients; patients who have repeatedly received medical treatment; patients with cirrhosis with the formation of edema and ascites; patients with ischemic heart disease and heart failure. In such patients, due to hypokalemia, cardiotoxicity of cardiac glycosides and the risk of heart rhythm disturbances increase. It is necessary to control hypovolemia or dehydration, as well as electrolyte disturbances or disturbances in the acid-base balance. If necessary, temporarily discontinue treatment with Xipogamma.

Patients at risk include patients with an extended Q – T interval, regardless of the congenital or acquired nature of the pathology. The presence of hypokalemia and bradycardia contributes to the occurrence of serious cardiac arrhythmias, in particular, potentially lethal tachycardia of the pirouette type.

In all the above cases, it is necessary to check the level of potassium in the blood more often, and the first analysis must be done at the 1st week of treatment. Hypokalemia must be corrected.

The level of calcium in the blood. Treatment with thiazide diuretics and related drugs can lead to a decrease in urinary calcium excretion and a significant temporary increase in blood calcium levels. Explicit hypercalcemia can occur with hyperfunction of the parathyroid glands.

Before examining the function of the parathyroid glands, treatment should be discontinued.

Blood glucose In patients with diabetes mellitus, it is necessary to check the level of glucose in the blood, especially with simultaneous hypokalemia.

Kidney function and diuretics. Thiazide diuretics and their derivatives are fully effective in case of normal renal function or slight impairment (plasma creatinine level 25 mg / l or 220 μmol / l in adults). In elderly patients, the level of creatinine in the blood plasma should be adapted in accordance with the age, body weight and gender of the patient.

Hypovolemia caused by loss of fluid or sodium as a result of taking diuretics at the beginning of treatment leads to a decrease in glomerular (glomerular) filtration. Because of this, the level of urea and nitrogen in the blood can increase. This temporary functional renal failure in people with healthy kidneys does not leave consequences, but can worsen existing kidney failure.

In case of unsuccessful correction of the electrolyte balance, treatment should be discontinued.

Use during pregnancy and lactation. The use of xipamide during pregnancy and lactation is contraindicated.

Children. Xipamide should not be used in children, since the safety and effect of the drug in this category of patients have not been determined.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Since the reaction to the drug is individual, the reaction rate can vary so much that the ability to drive a vehicle, the balance can be disturbed.This may be at the beginning of treatment, with increasing doses and changing drugs.

Interactions

The following interactions that have been reported with thiazide diuretics and similar drugs may also occur with xipamide.

Not recommended combination

Lithium. With simultaneous treatment with lithium preparations, the cardio and neurotoxic effects of lithium are enhanced. If treatment with diuretics cannot be avoided, it is necessary to control the level of lithium in the blood and adjust the dosage.

Combinations that require special precautions

Substances that can cause tachycardia such as pirouette:

• class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);
• some antipsychotic drugs: phenothiazines (e.g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroorazine), benzomides (e.g. sulpiride, sultopride, thiapride), butyrophenones (e.g. droperidol, haloperidol);

others: bepridil, cisapril, difemanil, erythromycin, halofantrine, misolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine iv.

The risk of ventricular arrhythmia, tachycardia such as pirouette (with hypokalemia) increases.

Control and, if necessary, correct hypokalemia should be before treatment with such a combination. It is necessary to control the level of electrolytes in blood plasma and ECG control.

It is necessary to mainly use substances that do not cause tachycardia of the pirouette type, if the patient has hypokalemia.

NSAIDs, including selective COX-2 inhibitors, high doses of salicylic acid (3 g / day). Possible decrease in the hypotensive effect of xipamide. The risk of acute renal failure during dehydration (glomerular (glomerular) filtration). It is necessary to monitor the sufficient intake of fluid and monitor renal function at the beginning of treatment. High-dose salicylate therapy may enhance its toxic effect on the central nervous system.

ACE inhibitors. The risk of lowering blood pressure and / or developing acute renal failure with the initiation of treatment with ACE inhibitors in patients with pre-existing sodium deficiency (in particular with renal artery stenosis).

If treatment with xipamide for hypertension leads to a decrease in sodium levels, it is necessary:

• or refuse to take xipamide 3 days before the start of treatment with ACE inhibitors and then add xipamide;
• or start treatment with ACE inhibitors with low doses and then gradually increase them.

In decompensated heart failure, you should start with a very low dose of ACE inhibitors.

In any case, kidney function (determination of blood creatinine level) should be monitored in the first weeks of treatment with ACE inhibitors.

Other diuretics, antihypertensive drugs, β-adrenergic receptor blockers, nitrates, vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, alcohol. The hypotensive effect of xipamide may be enhanced.

Other potassium-lowering drugs: amphotericin B (iv), gluco- and mineralocorticoids (systemic use), tetracosactide, stimulant laxatives. The risk of hypokalemia (additive effect) increases. It is necessary to control and correct the level of potassium in the blood plasma, in particular in the treatment of cardiac glycosides.

Baclofen. Enhances a decrease in blood pressure. It is necessary to ensure sufficient fluid intake and monitor kidney function at the beginning of treatment.

Cardiac glycosides. Hypokalemia and / or hypomagnesemia, enhancing the toxic side reactions of digitalis glycosides. It is necessary to control the level of potassium in the blood and ECG.

Combinations in which additional interactions are possible

Potassium-sparing diuretics (amiloride, spironolactone, triamteren).Even if this combination is considered appropriate for some patients, it can lead to hypokalemia or hyperkalemia (especially in patients with kidney failure or diabetes mellitus). A check of the level of potassium in the blood plasma and ECG is necessary, as well as correction of therapy if necessary.

Diuretics that promote the elimination of potassium (e.g. furosemide), GCS, ACTH, carbenoxolone, penicillin G, amphotericin or laxatives. Concomitant use with xipamide can lead to an increase in potassium loss. With the simultaneous use of xipamide and loop diuretics (such as furosemide), the risk of developing imbalances in fluid and electrolytes increases. Careful monitoring of the patients condition is necessary.

Metformin. The risk of metformin-induced lactic acidosis is increased due to the possibility of functional renal failure during therapy with diuretics, especially loop diuretics. Metformin is not used if the creatinine level in the blood is 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Contrast media with iodine content. With hydration caused by diuretics, there is an increased risk of acute renal failure with the use of contrast agents containing iodine (in particular in high doses). Before using contrast agents with iodine content, rehydration is necessary.

Tricyclic antidepressants (imipramine), antipsychotics. Antihypertensive effect and increased risk of orthostatic hypotension.

Calcium (salt). The risk of hypercalcemia due to a decrease in excretion of calcium in the urine.

Cyclosporin, tacrolimus. Risk of increased serum creatinine.

GCS, tetracosactide (systemic use). Decrease in hypotensive effect (fluid and sodium retention due to GCS).

Cytostatics (e.g. cyclophosphamide, fluorouracil, methotrexate). The risk of toxicity, in particular a decrease in the number of granulocytes.

Antidiabetic drugs, drugs that reduce the level of uric acid in the blood serum, norepinephrine, epinephrine. The effect of these drugs may be weakened while taking with xipamide.

Quinidine. Quinidine excretion may be slowed down.

Muscle relaxants (curare alkaloids). Strengthened and lasting effect of muscle relaxants.

Colestipol and colestyramine. Xipamide absorption may decrease.

Overdose

Acute intoxication is manifested primarily in the violation of the water and electrolyte balance (hyponatremia, hypokalemia). clinical manifestations may include nausea, vomiting, a sharp decrease in hell, cramps, dizziness, drowsiness, confusion, polyuria or oliguria up to anuria (due to hypovolemia).

Urgent measures: intake of activated carbon. Restoration of water and electrolyte balance.

In case of an overdose, you must immediately stop taking the drug and consult a doctor. The treatment is symptomatic.

Storage conditions

At a temperature of 25 ° c.