Diuretics

Diuretics are used to:

1. Reduce edema;
2. Reduce  blood pressure during hypertension;
3. Treat of heart failure;
4. For excretion of toxic substances from the body in cases of poisoning.

Edema may develop during heart failure, kidney disease and other diseases.

Pathogenesis of edema in case of heart failure

• Decrease of cardiac output
• Decrease of renal blood supply
• Increased secretion of renin by juxtaglomerular kidney cells
• Formation of angiotensin II
• Stimulation of aldosterone secretion
• Stimulation of Na + reabsorption in the renal tubules
• The increase in Na + concentration in the extracellular fluid
• Activation of tissue osmoreceptors
• Increased secretion of antidiuretic hormone
• The increase of water reabsorption in the collecting tubes
• The increase in volume of intercellular fluid, formation of edema

Diuretics remove the excess of Na from the body.

Hypertension is often associated with the accumulation of Na + in the body and increased blood volume. Normally, Na + excess is removed from the body: the atrial Na +-uretic peptide, cerebral Na +-uretic peptide (formed in the brain and ventricles of the heart) and Na +-uretic C peptide (formed in the ventricles of the heart).

Pathogenesis of arterial hypertension

• Many elderly people have reduced level of  Na +- uretic peptides and the excessive consumption of NaCl Na + and H2O is retained in the body
•  When the content of Na + in vascular smooth muscle increases, the function of  Na + / Ca2 + - exchanger (input 3 Na + and Ca2 + output 1) is impaired: Na + ions do not enter the cell, and Ca2 + ions do not leave the cell. The content of Ca2 + in vascular smooth muscle increases.
•  Chains of myosin interact with actin. Vascular smooth muscle shrink. Vessels constrict.
• Blood pressure rises. 

Diuretics have hypotensive effect, remove excess Na + out of the body, decrease the volume of circulating blood. The content of Na + in arteriolar smooth muscle decreases. 

Vessels dilate and blood pressure drops. In healthy people, diuretics do not reduce arterial pressure. 

Heart failure is accompanied by accumulation of fluid in the body. Diuretics reduce blood volume, reduce overload on the heart and slow the progression of heart failure, increase myocardial contractility.      

However, during the use of diuretics in reducing the volume of blood plasma the activity of sympathetic nervous system increases, the renin – angiotensin system is activated. Therefore, diuretics in heart failure used only if there is edema.

in case of poisoning by toxic substances that are excreted by kidneys, even partially in an unchanged form, for the faster elimination of these substances from the body one uses the method of forced diuresis. 

1-2 liters of physiological solution is administered i/v and then a high-performance diuretic is given.    

Urine output is measured and isotonic solution is being introduced  with the same rate with which the liquid is being removed from the body. Toxic substance is removed together with the fluid.

Classification of diuretics

• Diuretics, causing mostly water diuresis – carbonic anhydrase inhibitors, osmotic diuretics influence mainly on the proximal tubules of the nephron. 
• Loop diuretics have the most pronounced diuretic effect, inhibiting the reabsorption of sodium and water in the ascending part of Henle’s loop. Increase sodium excretion by 15-25%.
• Thiazides, operating mainly in the area of  distal tubules of the nephron, increase the excretion of sodium by 5-10%. 
• Potassium-sparing diuretics, acting mainly in the collecting tubules. Increase the excretion of sodium by no more than 5%.

Derivatives of benxothiadiazine (thiazides) and thiazide-like diuretics

Thiazide diuretics include hydrochlorothiazide, dichlothiazide (gipotiazid). Indapamide belong to thiazide-like diuretics.  

Pharmacodynamics. Thiazides and thiazide diuretics, affecting the co-transporter of Na - Cl-in the apical membrane of the epithelium of the initial division of the distal tubules, inhibit reabsorption of Na and Cl- and thus increase the excretion of Na and Cl- from the body. Since these diuretics remove NaCl, they are called saluretics.

During slowing down of reabsorption of Na + in the initial parts of the distal tubules more Na + enters the final section of the distal tubules and cortical part of collecting tubules, where part of the Na + is reabsorbed. Consequently, the secretion of K +, Mg2 +, H+ is increased. As a result hypokalemia is developing, hypomagnesemia, metabolic alkalosis. The excretion of water increases.

Hydrochlorthiazide (Hypothiazid)

Pharmacokinetics. It is well-absorbed in GIT, binds to proteins in blood very well, excreted by kidneys. The onset of action is  in 30-60 min., the maximal effect is achieved in 4 hours and lasts for 6-12 hours. Т1/2 – 1,5 – 13 hours. The duration of antihypertensive action is 12-18 h. It is excreted with urine (60-80%) in an unchanged form (more than 95%).  

Adverse reactions are dose-dependent. Hypokalemia, fatigue, paresthesia, hyponatremia, metabolic alkalosis, glycosuria and hyperglycemia, hyperuricemy, hyperlipemia, dyspeptic reactions, allergic reactions, hemolytic anemia, cholestatic jaundice, pulmonary edema, nodular necrotizing vasculitis.

Dosage form: tablets – 0,025; 0,05 and 0,1 g.

Indapamide (arifon)

Pharmacodynamics. It has a weak diuretic effect, hypotensive effect, dilates systemic and renal arteries. Reduction in blood pressure is associated with a decrease in the concentration of sodium and a decrease in total peripheral resistance. During long-term use in patients with moderate hypertension and impaired renal function indapamide accelerates glomerular filtration. It is used as an antihypertensive. It has prolonged hypotensive effect with no significant effect on the diuresis. The latent period is 2 weeks. Maximum sustained action develops in 4 weeks.

Pharmacokinetics. The drug is well absorbed in the GIT, the maximum concentration in the blood is in 2 hours. In the blood it binds with proteins (75 %), can reversibly bind to red blood cells. T1 / 2 is about 14 hours. 70% is excreted by the kidneys, and the rest - through the intestine.  

Adverse drug reactions during the use of indapamide are revealed in 5-10% of patients. Nausea, diarrhea, skin rash, weakness are possible reactions. 

Dosage forms: tablets and capsules in 0.0025 g (2.5 mg), retard in 0.00125 g (1.25 mg).

Loop diuretics

Loop diuretics: furosemide, bumetanide, ethacrynic acid.

Pharmacodynamics. Operate in the large segment of the ascending part of Henle’s loop, break joint reabsorbtion (co-transport) of Na +-K + -2 Cl-, and the reabsorption of Ca2 + and Mg2 +. These ions together with the water are removed from the body. Excretion of uric acid is delayed. 

Furosemide(Furosemid; Lasix).

Pharmacodynamics. Effective, high-performance diuretic. Removes about 20 Na + filtrate. Administered orally its onset of action is in 30 minutes. Duration of actions – for 4-6 hours. Administered i/v, the onset of actions is in 15 minutes and lasts for 2-3h. The drug remains effective at low glomerular filtration rate, so it can be used in patients with renal failure.

Indications : 

acute pulmonary edema with left ventricular failure;

peripheral edema during heart failure;

renal disease;

hypertension (hypertensive crises);

to remove toxic substances from the body (forced diuresis).

Pharmacokinetics. Furosemide is rapidly and completely absorbed when administered by any route. Bioavailability is 60-70%, plasma protein binding is more than 90%. T1 / 2 - 30-60min. Undergoes biotransformation in the liver, removed mainly by kidneys.

Adverse drug reactions. Disturbances in mineral metabolism: hyponatremia, hypochloremic alkalosis, hypokalemia and hypomagnesemia. Ototoxicity during impaired renal function, rapid parenteral administration of large doses or during coadministration with another ototoxic drugs. 

Dosage form. Tablets of 0.005, 0.02, 0.04, 0.08, 0.5 g, 1% solution for injection in ampoules of 1.2, 5, 10, 25ml.

Potassium-sparing diuretics 

Pharmacodynamics. Drugs in this group – triamterene, spironolactone – act in the final part of the distal tubules and cortical part of collecting tubules, violate the reabsorption of Na ions. Triamterene directly blocks the Na-channels.  

Spironolactone blocks aldosterone receptors and violates the action of aldosterone. When sodium reabsorption is disturbed, the secretion of K+, Mg+, H+ is reduced. Thus the drugs of this group increase the excretion of Na and delay the excretion of K, Mg, H.

Due to the decreased  secretion of H+ metabolic acidosis is possible.      

Potassium-sparing diuretics do not increase diuresis significantly. They are used in combination with other diuretics to reduce the loss of potassium.

Spironolactone (Veroshpiron, Aldactone)

Spironolactone (veroshpiron, Aldactone) is an aldosterone antagonist, weak potassium-sparing diuretic of long action.

Pharmacodynamics. The diuretic effect is noticed on the 2-5th  days of treatment and continues for 2-3 days after termination. Hypotensive effect is observed on 2-3 weeks of treatment.

Indications for use:

• primary hyperaldosteronism, edema;
• hypertension;
• Congestive heart failure;
• Combination with other diuretics to maintain K +.

Pharmacokinetics. The drug is well absorbed in the the GIT. Bioavailability is 100%. Protein binding – more than 90%. T1 / 2 - 2.6 hours. 25-30% of  spironolactone is transformed in the liver to the active metabolite (canrenone), which in many ways provides a diuretic effect.

Adverse drug reactions. Nausea, vomiting, diarrhea, and headache. Hyperkalemia, spasms of skeletal muscles. Impotence, gynecomastia, menstrual irregularities. Skin rash.

Dosage form. Tablets of 0.025, 0.05 g, 0.1 g 0.2% solution for injection in ampoules of 10ml.

Triamteren

Pharmacodynamics. Increases the excretion of Na + with urine without increasing of K+  discharge. Reduces hypokalemia caused by thiazide diuretics, increasing their diuretic effect.  

The diuretic effect after oral administration starts in 15-20min, reaches its peak in 2-3 hours and lasts for 12 hours.

Pharmacokinetics. Fast, but is not completely absorbed (30-70%). Protein binding is moderate (67%). Biotransformation in the liver. T1 / 2 - 5-7 hours. Excreted mainly with bile.

Adverse drug reactions. Nausea, headache. Hyperkalemia, gipermagniemiya, bradycardia, paresthesia. Leg convulsions

Dosage form. Capsules of 0.05 g. 

Osmotic diuretics 

Mannitol (Mannit) has dehydrating effect. By filtering it is released into the renal tubules, increases osmotic pressure in them. 

Primarily, it disturbs the reabsorption of water and secondly – the reabsorption of Na + and Cl-.    

 A compound that does not penetrate into biological membranes. 

Ineffective when administrated perorally. Mannitol is administered IV by infusion of 10-20% solution in large doses. This increases the osmotic pressure of blood plasma, dehydration of the brain tissue and eyes happens. 

Reduces intracranial and intraocular pressure. It can induce dehydration of cells and increase in volume of interstitial fluid. It can complicate the course of interstitial pulmonary edema.

Indications:

• Cerebral edema;
• severe attacks of glaucoma
• oliguria in case of injuries, burns
• forcing diuresis during poisoning with substances that are excreted via the kidneys

Pharmacokinetics. Poorly absorbed in  the gastrointestinal tract. During peroral use it can cause osmotic diarrhea. It is not metabolized. Excreted by renal filtration without subsequent tubular reabsorption.

Adverse reactions:

• Dry mouth, thirst
• tachycardia
• muscle weakness
• convulsive reaction

Dosage forms. Lyophilized powder in sealed vials in 30g, 15% solution in ampoules of 200 and 400 ml, 20% - for 500ml