Diuretics with cardiac edema

Cut off by A.G. Shulenin S.N.

DIURETHICS IN THE THERAPY OF CHRONIC HEART FAILURE "PHARMINDEX-Praktik" issue 6 release date 2004 page 3-11 Proposals of manufacturers and suppliers, descriptions from the "Encyclopedia of medicines" for the drugs mentioned in the article:


History of study and practical applicationsynthetic diuretics has a little more than 50 years. The first thiazide diuretic hydrochlorothiazide was synthesized in 1952 and, after a relatively short period of time, in 1956, was introduced into clinical practice. After intensive laboratory studies, in 1963, a loop diuretic furosemide was first used. The following years were characterized by the active use of diuretics, the accumulation of clinical experience, the development of new classes of diuretics (osmotic, potassium-sparing). The last decades in the history of diuretics are marked by the appearance of drugs with new pharmacological properties (indapamide).

Diuretics occupy an important place, above all, intreatment of chronic heart failure (CHF), which is due to their unique pharmacological properties. This circumstance allows us to consider some practical aspects of their application by the example of this nosological form, which is the final stage of development of many cardiovascular diseases.

Modern classification of diuretics can be represented as follows [1]:

· Acting on the glomerulus:
- Eufillin

· Acting on the proximal tubule:
- osmotic diuretics - Mannitol, Carbamide, Isosorbit, Potassium acetate ;
- inhibitors of carbonic anhydrase - Acetazolamide .

· Loop:
- Furosemide, Etacrynic acid, Bumetanide, Piretanide, Torasemide ;

· Acting on the initial part of the distal tubule:
- Thiazide sulfonamides - Hydrochlorothiazide, Polythiazide, Cyclopentiazide, Metolazone
- non-azide sulfonamides - Clopamide, Chlortalidone, Indapamide, Xipamid.

· Acting on the end part of the distal tubule:
- competitive antagonists of aldosterone - Spironolactone, Potassium Candrine ;
- transport blockers Na - Triamterene, Amyloride.

· Plant diuretics: Bearberry leaf, Birch buds, Cowberry leaf, Horsetail field grass, Juniper fruit, Cornflower blue grass.

· Combined diuretics: Triampur, Moderetik.

Diuretics reduce preload and postloadon the heart, eliminate stagnant phenomena in the internal organs and peripheral edema. The effectiveness of their action depends on which department of the nephron they affect. The most potent diuretics are furosemide and uretit, since they act throughout the loop of Henle, where the main reabsorption of sodium occurs. Less pronounced effect of thiazide diuretics, which exert their effect only in the cortical segment of the loop of Henle. Aldosterone antagonists have a weak diuretic activity, but unlike other diuretics, they retain potassium in the body, their effectiveness increases with secondary hyperaldosteronism, and with primary hyperaldosteronism they are the drugs of choice [2].

Diuretics, actually used in the treatment of CHF,possess a number of features. Thiazide and thiazide-like have a diuretic and natriuretic effect that are more moderate than diuretics, diuretic and natriuretic, are ineffective in renal failure, increasing diuretic effect with increasing dose occurs in a very limited range (for hydrochlorothiazide 25-100 mg).

Loops have a powerful diuretic effect,high efficiency in renal failure, a pronounced dependence of the effect on the dose (furosemide in chronic renal insufficiency is administered up to 2000 mg / day);

Potassium-sparing (relatively weak) are effective in primary and secondary aldosteronism. They can cause hyperkalemia, they are more often used in combination with other drugs.

The main diuretics used to treat CHF [5] and their patented names are presented in Table 1.

Table 1
The main diuretics used to treat CHF and their proprietary names

The use of diuretics in CHF is usually associated with loop diuretics. Indeed, furosemide is more commonly used in heart failure.

Furosemide (Lasix) causes a fast, powerful, but not long-lastingdiuretic effect. Has a pronounced withdrawal syndrome. Enhances the excretion of potassium, phosphate, calcium and magnesium, without affecting the speed of glomerular filtration, increases the excretion of bicarbonates and increases the pH of urine. Can be used for kidney failure. Usually, the drug is administered internally at 20-240 mg / day. When administered orally, its effect begins after 1 hour and lasts 4-6 hours. With the / in the introduction of the effect comes in 10-15 minutes and lasts 2-3 hours. The standard scheme of application of furosemide in CHF involves taking the drug 1-2 times inside a week. In case of development of renal failure and in the absence of adequate diuresis from therapeutic doses, the last maximum dose is doubled and continues to double every 30-60 minutes until the effect is achieved (sometimes up to 2-3 g per day).

Etacrynic acid (uretit) is somewhat less active than furosemide inthe rest of the preparations are similar. Assigned to 50-200 mg / day. The onset of action - after 30 minutes, the maximum effect on ingestion occurs after 2 hours and lasts about 4-6 hours. With / in the introduction of diuretic effect occurs after 15 minutes and lasts 2-3 hours.

Furosemide and ethacrynic acid introducedintravenously, reduce the pressure in the pulmonary artery and the filling pressure of the left ventricle, cause veno-and arteriolodilation, and this is associated with an improvement in the contractility of the myocardium. Drugs affect different links of sodium reabsorption (furosemide has an additional effect on the proximal tubule section), so they can be prescribed simultaneously or replaced with one another with a decrease in the diuretic effect. Biotransformation of both drugs is disrupted in liver cirrhosis.

Side effects of loop diuretics: hyperchloremic alkalosis, hypokalemia, hyperuricemia, hyperglycemia, potentiation of toxic effects when combined with antibiotics (cephalosporins, aminoglycosides).

Somewhat less important in the treatment of CHF are thiazide and thiazide-like diuretics.

Hydrochlorothiazide (hypothiazide, dichlorothiazide, nephrix, ezidrex)used internally at 25-200 mg / day. 6,25-12,5-50 maintenance dose of 1 mg once daily in the morning, can be 1-3 times a week. Valid - 2 hours, its peak - after 4 h, the duration of action of diuretic -. About 10-12 hours most expedient when receiving hydrochlorothiazide associated with hypertensive heart failure because prolonged and moderate hypotensive effect of the drug is largely consistent with the goals of treatment gipertonicheskkoy disease.

Klopamid (brinaldix) unlike other thiazide andother thiazide-like diuretics increases venous tone (shown in patients with orthostatic reactions). It is used in doses of 10-40 mg in the morning, maintaining a dose of 10-20 mg once a day or every other day. The onset of action is 1-3 h, its duration is 8-20 h. The main feature of the drug is a prolonged diuretic effect without forced diuresis.

CHF is often a consequence ofarterial hypertension, which makes the combined treatment of patients with ACE inhibitors and diuretics preferable. One of the drugs of choice among diuretics may be considered indapamide, which reduces the level of intracellular calcium, retains the magnesium content, reduces the rigidity of the vascular wall and promotes more efficient relaxation of the cardiomyocyte in the diastole. At the same time, there is an increase in the synthesis of prostacyclin, a reduction in platelet aggregation and thromboxane A2 release, which ultimately has a positive hemodynamic effect due to a decrease in post-loading for the left ventricle. Presence of cardioprotective action in indapamide comparable with ACE inhibitors is suggested. The effect of the drug on blood pressure without a significant effect on diuresis is manifested in a daily dose of up to 2.5 mg, with an increase in which the diuretic effect becomes dominant. Taking indapamide in the morning, the duration of the action is up to 24 hours.

Side effects of thiazide diuretics . atherogenic and diabetogenic effect,hypokalemia, hyperuricemia. It should be noted that these side effects were noted in the study of maximum doses of diuretics and with their long-term administration, however, clinical observations show that hypokalemia and hyperuricemia can develop with minor doses of thiazides, especially in patients with "compromised" metabolism of electrolytes and purines. The great advantage of indapamide is the lack of recoil syndrome and side metabolic disturbances (negative effects on carbohydrate and lipid metabolism).

A special place in the treatment of CHF in recent years is occupied by potassium-sparing diuretics.

Triamterene (pterofen) as a potassium-sparing agentIt is applied on 25-100 mg / day, with the further individual selection of a dose (no more than 300 mg / day in 2 receptions). When CHF is often used combined with hydrochlorothiazide drugs (triampur 1-2 tablets at reception 1-2 times a day). The onset of action is 2-4 hours, its peak is 6-8 hours, and the duration is 7-9 hours. The intake of triamterene in elderly people is associated with an increased risk of hyperkalemia and hyponatremia.

Spironolactone (veroshpiron) has a diuretic effect,dependent on the level of aldosterone in the blood plasma. The main feature of the drug is neuro-hormonal modulation of activated RAAS. In CHF it is prescribed together with hydrochlorothiazide or furosemide. Spironolactone is prescribed after the diuretic effect of more active thiazide or loop diuretics after 1 to 2 weeks of therapy is weakened. The onset of action is in 24-48 hours, its peak is 2-3 days of administration, and the duration is 4-6 days. Assign the drug at 50-100 mg / day in 1-2 doses, but not more than 400 mg / day.

The standard recommended dose withthe effect of maximum neurohormonal modulation is 25 MHz. If necessary, increase the concentration of potassium in patients with CHF on the background of aggressive diuretic therapy, the dose of spirolactone can be increased to 200-400 mg, but only for a short period of time, as higher doses of veroshpiron contribute to the reduction of antitumor protection.

Eplerenone (inspr) - a new potassium-sparing diuretic, actively studied at the stage of practical application in the clinic.

Side effects of potassium-sparing diuretics: hyperkalemia, menstrual irregularity, coarsening of the voice, hirsutism, gynecomastia.

Contraindicated potassium-sparing diuretics forHyperkalemia (chronic renal failure or combination of potassium preparations and ACE inhibitors). The latter circumstance in clinical practice seems very relative, because with persistent and pronounced hypokalemia associated with impaired repolarization, arrhythmogenesis to increase potassium concentration is used the entire available arsenal, which includes, as a rule, potassium-sparing diuretics, and ACE inhibitors and directly potassium preparations.

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Diuretics are prescribed at the appearance of the first signs of edematous syndrome, and the activity of therapy should directly depend on the degree of its severity [3, 4].

Begin treatment with small doses of thiazide orthiazide-like drugs (25 mg hydrochlorothiazide or equivalent doses of others) to avoid large and rapid losses of water and electrolytes. This is due to the rapid emergence of tolerance to diuretics and the activation of renin-angiotensin-aldosterone and sympatho-adrenal systems, antidiuretic hormone, playing in CHF leading role in the maintenance of violations of central and peripheral hemodynamics.

As necessary, increase the dosedrugs, instead of thiazide appoint loop diuretics or combine 2-3 diuretics with different mechanisms of action. This allows for an increase in diuresis, correct unfavorable electrolyte metabolic shifts, reduce the risk of developing resistance to therapy. To avoid excessive loss of potassium in the treatment of thiazide or loop diuretics, it is necessary to limit the intake of table salt (up to 5 g / day) and water (up to 1.5 l / day). It is better to combine thiazide or loop diuretics with one of potassium-sparing drugs - veroshpiron, triamterene. In patients with chronic heart failure, emergency diuretics should cause loss of fluid in a volume of not more than 1.0 l / day (weight loss per kg), so as not to cause a sharp decrease in the volume of circulating blood, which in turn adversely affects the systemic hemodynamics and neurohumoral regulation.

In stage II CHF, hydrochlorothiazide is administered at 50mg 1-2 times a week, if necessary increasing the dose to 100-150 mg. The effectiveness of treatment is assessed by diuresis, which should increase by 1.5-2 times (1.5-2 L of urine). With pronounced edematous syndrome, powerful "loop" diuretics are used. Furosemide is administered 40 mg parenterally or intravenously 2-3 times a week and more often. If the effect is insufficient, the dose can be increased to 160 mg / day or more. Accumulation of fluid in the abdominal or other cavities indicates the presence of secondary hyperaldosteronism, in such cases, furosemide is expediently combined with spironolactone (150-200 mg / day).

It should be borne in mind that an active diuretictherapy can be complicated by dehydration, hypokalemia (muscle weakness, anorexia, ST segment depression, decreased T wave amplitude), hyponatremia. Therefore, as the patient's condition improves, diuretics should be used less often and in a smaller dose.

Causes of Diuretic Resistanceare: dilution hyponatremia, hyperaldosteronism, active inflammatory process, hypoproteinemia, plethorus (polycythemia), hypotension, hypoxia. Patients may become immune to high doses of diuretics if they consume large amounts of sodium in food, take drugs that can block the effects of diuretics (for example, NSAIDs, including COX-2 inhibitors) or have significant impairment of kidney function or perfusion.

You can avoid resistance (depending onits causes) the introduction of solutions of sodium chloride, the use of veroshpiron, anti-inflammatory and antibacterial agents, the introduction of albumin and plasma, bleeding, the use of cardiac glycosides and glucocorticoid drugs. Resistance to diuretics can often be overcome by their intravenous administration (including the use of continuous infusions), using two or more diuretics in combination (for example, furosemide and metolazone), or using diuretics with drugs that increase renal blood flow (for example, positive inotropic agents).

To overcome the refractoriness to diuretic treatment, a more advanced set of methods can be applied [5]:

1. Strict limitation of salt intake (and not liquids!).
2. Purpose of diuretics only intravenously.
3. The use of high doses of diuretics. There are reports of overcoming refractoriness to therapy when prescribing up to 2000 mg of lasix. In particularly difficult cases, bolus administration of lasix intravenously at a dose of 40-80 mg, followed by drip at a rate of 10-40 mg for 48 hours is recommended.
4. Creating conditions for the normalization of pressure:

- refusal to take vasodilators, most often - these are nitrates, administered without indications, only because of a diagnosis of CHD;

- if necessary, the use of steroid hormones (prednisone intravenously up to 180-240 mg and orally up to 30 mg), cordiamine;

- in critical situations appliesintravenous drip infusion of dopamine with a “renal” rate of 0.5-2.0 mg / kg / min, lasting up to a day. In this case, the drug due to the effect on dopaminergic receptors in isolation increases the renal fraction of the blood flow, glomerular filtration and somewhat reduces the proximal reabsorption. With an increase in the duration of dopamine administration, as well as with an increase in the rate of infusion, other effects of the drug (stimulation of beta-1 and then alpha-1 receptors) begin to predominate, accompanied by an increase in blood pressure and inotropic effects that help maintain an acceptable level of glomerular filtration.

five. Normalization of neurohormonal profile (the appointment of an ACE inhibitor and aldosterone antagonists). Aldactone (Verohpiron) is best prescribed in the morning, during the maximum circadian rise in aldosterone levels in a dose of 200-300 mg / day. It must be remembered that the drug administered orally begins to act only on the 3rd day, therefore in the first 2-3 days it is better to administer the drug intravenously.
6. Normalization of the protein profile - the use of albumin (200-400 ml / day), it is possible together with diuretics, which increases the speed of their filtration.
7. At a sufficient level of blood pressure, additional administration of drugs that increase the glomerular filtration rate (positive inotropic drugs, aminophylline) is possible.
8. Combining several diuretics. We have already talked about the feasibility of combining active diuretics with carbonic anhydrase inhibitors, which allows us to avoid the development of alkalosis, under which the action of thiazide and loop diuretics weakens. Diakarb, firstly, acidifies the urine, and secondly, due to the violation of sodium reabsorption in the proximal tubule retains a higher concentration of this ion in the primary urine. Because of this, the ascending part of the loop of Henle is more “loaded” with sodium ions and the substrate for the action of loop and thiazide diuretics increases.

Similarly, the combined use of loop andThiazide diuretics enhances the flow of sodium ions into the distal tubules, where aldosterone antagonists act, and thereby increases the effectiveness of the use of veroshpiron.

This is an important rule: the appointment of any diuretic drug leads to the fact that due to a violation of sodium reabsorption, the “load” of more distal parts of the nephron by this ion increases. As a result, the effect of diuretic drugs aimed at the lower tubules is potentiated.

Methods of use and dosing regimensspironolactone can be represented as the following sequence of actions: 1) assess the severity of CHF (spironolactone is advisable to appoint only in severe CHF); 2) make sure that the content of potassium in blood serum is lower than 5.0 mmol / l, and creatinine is lower than 250 mmol / l; 3) first assign spironolactone at a dose of 25 mg / day; 4) assess the level of potassium in 4-6 days; 5) when the concentration of potassium from 5 to 5.5 mmol / l should reduce the dose by 2 times; if the level of potassium is higher than 5.5 mmol / l, the use of spironolactone should be discontinued; 6) if after 1 month of therapy symptoms of HF persist and there is no hypokalemia, it is advisable to increase the dose of spironolactone to 50 mg / day, followed by an assessment of the level of potassium in the blood after 1 week.

Controlled studies have demonstrateddiuretic ability to increase urinary sodium excretion and reduce symptoms of fluid retention in patients with CHF. In these short-term studies, diuretic therapy led to a reduction in CVP, pulmonary congestion, peripheral edema, and body weight, all of which were observed in the first days of therapy. In studies with medium-term follow-up, diuretics improved cardiac function and exercise tolerance, reduced symptoms in patients with CHF. Long-term studies of diuretic therapy in CHF have not been conducted, and thus, their effect on morbidity and mortality is not known.

Optimal use of diuretics is the cornerstone of any successful approach to treating HF. When using diuretics in patients with CHF, physicians should remember the following points [6]:

one. Diuretics provide clinical improvement more quickly than any other drug for the treatment of CHF. They can reduce pulmonary and peripheral edema within hours or days, while the clinical effects of cardiac glycosides, ACE inhibitors, or beta-blockers may take weeks or months to become apparent.

2 Diuretics are the only drugs used to treat CHF that can adequately correct fluid retention. Although both cardiac glycosides and low doses of ACE inhibitors can increase the excretion of sodium in the urine, few patients with CHF can maintain sodium balance without the use of diuretics. Attempts to replace diuretics with ACE inhibitors can lead to fluid accumulation in the periphery and in the cavities.

3 Diuretics should not be used as monotherapy in the treatment of CHF. Even when diuretics are successful in managing symptoms and fluid retention, they alone are not able to maintain the clinical stability of patients with CHF for a long time. The risk of clinical decompensation can be reduced when diuretics are combined with digoxin, an ACE inhibitor, a beta blocker.

four. The use of diuretics in adequate doses and appropriate regimens is a key element in the effectiveness of other drugs used to treat CHF. Improper use and inappropriately low doses of diuretics cause fluid retention, which can reduce the response to an ACE inhibitor and increase the risk of complications when using beta-blockers. On the contrary, the use of inappropriate high doses of diuretics will lead to a reduction in BCC, which may increase the risk of hypotension with the use of ACE inhibitors and vasodilators and the risk of renal failure in the treatment of ACE inhibitors and angiotensin II receptor antagonists.

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Patient selection. Diuretics should be prescribed to all patientshaving symptoms (and most patients with a previous history) of fluid retention. Diuretics should be combined with an ACE inhibitor and a beta blocker (and usually with digoxin) [7].

Start and conduct therapy. The most commonly used loop diuretic fortreatment of CHF is furosemide, but some patients respond favorably to newer drugs in this category (for example, torasemide) because of their higher bioavailability. Studies have shown that torsemide may reduce the risk of CHF progression more effectively than furosemide, but this problem remains controversial.

In outpatients with CHF, therapy is usuallyIt starts with low doses of diuretics, and the dose increases until diuresis increases and body weight decreases, on average, by 0.5–1.0 kg daily. A further increase in the dose or frequency of diuretic intake may be required to maintain active diuresis and weight loss. The ultimate goal of treatment is to eliminate the symptoms of fluid retention, either by restoring CVP to normal, or by eliminating the presence of edema, or by combining these mechanisms.

Diuretics are usually combined with moderatelimiting sodium intake with food (less than 3 g daily). If signs of electrolyte imbalance appear, they must be fought with persistence and diuretic therapy should be continued. If hypotension or azotemia appears before treatment goals are reached, the doctor may choose to reduce the dose of diuretics, but diuresis must however be maintained until fluid retention is eliminated, even if this strategy leads to a moderate reduction in blood pressure or kidney function, while the patient remains asymptomatic. Excessive anxiety regarding hypotension and azotemia can lead to inadequate diuretic prescription and the appearance of resistant edema.

Permanent volume overload not only contributescontributing to the persistence of symptoms, but may also limit the effectiveness and compromise the safety of using other drugs used to treat HF.

As soon as fluid retention is stopped, treatmentdiuretic should be continued to prevent repetition of volume overload. Patients are usually given a fixed dose of diuretic, but doses of these drugs should be periodically adjusted. In many cases, this adjustment can be made by measuring the patient’s daily body weight by advising him on dose adjustment with an increase or decrease in body weight beyond certain limits.

The response to diuretic depends on the concentrationdrug and time of its excretion with urine. Patients with moderate CHF respond favorably to low doses, because their absorption in the intestines is fast and these drugs quickly reach the renal tubules. However, with progressive CHF, drug absorption may decrease due to bowel edema or insufficient intestinal perfusion, and drug delivery may decrease due to a chronic decrease in renal perfusion. Therefore, the clinical progression of CHF is characterized by the need to increase doses of diuretics.

The dangers of diuretic treatment. Main adverse effects of diureticsinclude electrolyte imbalance, hypotension and azotemia. Diuretics can also cause hearing impairment, but this usually fits within the frame of individual intolerance or occurs when prescribing very high doses of drugs. Diuretics can cause the loss of important cations (potassium and magnesium), which can predispose patients to serious arrhythmias, especially with cardiac glycoside therapy [7, 8]. The risk of electrolyte depletion increases markedly when two diuretics are used in combination. The loss of electrolytes is associated with an increased delivery of sodium to the distal renal tubules and the exchange of sodium to other cations, a process that is potentiated by the activation of the renin-angiotensin-aldosterone system. Potassium deficiency can be corrected by short-term administration of potassium and, in severe cases, by additional administration of magnesium. The concomitant use of an ACE inhibitor or their combination with potassium-preserving agents can prevent electrolyte depletion in most patients taking loop diuretics. When these drugs are prescribed, prolonged oral administration of potassium is not needed and may even be harmful.

Excessive use of diuretics mayreduce blood pressure, impair kidney function and exercise tolerance. Hypotension and azotemia may also occur as a result of the progression of CHF, which can be enhanced by attempts to reduce the dose of diuretics. If there are no signs of fluid retention, hypotension and azotemia are likely to be associated with a decrease in BCC and may be resolved after reducing the diuretic dose. If symptoms of fluid retention are present, hypotension and azotemia appear to reflect progressive CHF and a decrease in effective peripheral perfusion. Such patients should be treated by taking maintenance doses of diuretics and improving target organ perfusion.

The criteria for the positive effect of diuretic drugs for CHF are . improving the clinical condition of patients(reduction of edema, weight loss, shortness of breath, increased exercise tolerance, etc.), a persistent decrease in ventricular filling pressure at rest and during physical exertion, a decrease in the frequency of sudden death, the development of acute vascular accidents, an increase in life expectancy.

Thus, in the presented analysis,Based on available literature data and practical experience in the use of diuretic drugs, the main clinical aspects of the use of diuretics in chronic heart failure are reflected. The authors of the material hope that the reference, theoretical and practical information given in the article will help doctors optimize the administration of diuretics to patients with CHF.

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