Diuretic drugs / Classification Of Diuretic drugs / Pharmacology Of Diuretic drugs

 Introduction Diuretic drugs 

Diuretic drugs promote urine output. They act directly on the kidneys and increase the excretion of water and ions (Na+ , Cl− , or  HCO3 ) from the body. Diuretics are also used for the treatment of cardiac oedema (accumulation of fluid in extra vascular tissues), especially the one associated with congestive heart failure. They are also employed in the treatment of various disorders like nephrotic syndrome, diabetes insipidus, hypertension, nutritional oedema, oed ema of pregnancy, and liver cirrhosis. They also decrease the intracellular and cerebrospinal fluid pressure

3.1.2. Classification On the basis of their intensity, diuretics are categorised as follows: 

1) High Efficacy Diuretics (Inhibitors of Na+ /K + /2Cl– Co-transport) i) Sulphamoyl Derivatives: Furosemide and Bumetanide. ii) Phenoxyacetic Acid Derivatives: Ethacrynic acid. iii) Organomercurials: Mersalyl. 

 2) Medium Efficacy Diuretics (Inhibitors of Na+ /Cl– Symporter) 

i) Benzothiadiazines (Thiazides): Chlorothiazide, Hydrochloroth iazide, Benzthiazide, Hydroflumethiazide, and Clopamide. 

ii) Thiazide-like Diuretics (Related Heterocyclics): Chlorthalidone, Metolazone, Xipamide, and Indapamide. 

3) Weak or Adjunctive Diuretics

 i) Carbonic Anhydrase Inhibitors: Acetazolamide. 

ii) Potassium Sparing Diuretics 

a) Aldosterone Antagonists: Spironolactone.

 b) Directly Acting Diuretics (Inhibitors of Renal Epithelial Na + Channel): Triamterene and Amiloride.

 iii) Osmotic Diuretics: Mannitol, Isosorbide, and Glycerol.

 iv) Xanthine Derivatives: Theophylline. 

 3.1.3. High Efficacy Diuretics(High Ceiling or Loop Diuretics) High efficacy diuretics exhibit their effects by acting on the ascending limb of the loop of Henle, therefore also known as loop diuretics. They are the most effective amo ng all diuretic agents , since the reabsorptive capacity of the ascending limb of the loop of Henle is very high . The loop diuretics are also known as high ceiling diuretics or Na + /K + /2Cl– co-transporter inhibitors. The most commonly used loop diuretic is furosemide.  

3.1.3.1. Mechanism of Action Furosemide inhibits the reabsorption of NaCl and the Na+ /K + /2Cl– symporter in the thick ascending limb of Henle’s loop. It facilitates or increases urinary excretion of Na + and Cl – ions (figure 3.1). High efficacy diuretics prove to be highly efficient and show dose -dependent response (increase in dose results in greater action). However, administration of exceedingly large amounts of the dose may cause dehydration (high ceiling effect, i.e., maximal effect)

3.1.3.1. Pharmacokinetics On oral administration, furosemide absorbs rapidly from the GIT. After intravenous administration, its action furosemide is even more rapid, i.e., within 10 minutes and duration of action is 2 hours. About 95% of furosemide is bound to t he plasma proteins. Furosemide undergoes metabolism in the liver and excretion by the kidneys. It has the ability to cross the placental barrier and is also excreted in the breast milk. The pharmacokinetic profile of some important loop diuretics is enlisted in table 3.1:

3.1.3.2. Therapeutic Uses Therapeutic uses of loop diuretics include: 

1) Acute Pulmonary Oedema: These agents are found to be highly effective in acute pulmonary oedema. In this condition, the vascular effect precedes the onset of diuretic effect. A decrease in the left ventricular pressure is responsible for its therapeutic effect.

2) Refractory Oedema: Furosemide is used to treat refractory oedema related to congestive cardiac failure and renal disease, in case other diuretics are not effective. 

 3) Acute Renal Failure: The rate of urine flow and excretion of K + ions increases during acute renal failure. Loop diuretics can effective ly convert oliguric renal failure into non-oliguric renal failure. Yet, the duration of renal failure cannot be decreased by these agents. 

4) Hypercalcaemia: In patients with hypercalcaemia, intravenous administration of loop diuretics along with normal salin e infusion stimulates the excretion of Ca2+ ions. As a result, the serum calcium level decreases. 

 5) Hyperkalaemia: Intravenous administration of furosemide along with saline infusion helps treating hyperkalaemia. 

6) Poisoning by Barbiturates and Halides:Furosemide with copious intravenous saline (forced diuresis) is used in barbiturate and halide poisoning. 

7) Raised Intracranial Pressure: Loop diuretics decrease the blood volume , and hence reduce intracranial tension. Though utilised for the treatment of several diseases, the high efficacy diuretics are not employed as antihypertensive agents since they have a high diuretic potential, short duration of action, and high dose requirement.

3.1.3.3. Adverse Effects The adverse reactions of high efficacy diuretics include: 

1) Effects Related to Renal Actions: Loop diuretics severely disrupt water and electrolyte balance and may manifest as: 

i) Hypokalaemia and metabolic hypochloremic alkalosis resulting from the exchange of K+ and H+ ions with Na+ ions in the distal tubule. 

ii) Depletion of calcium on chronic administration. 

iii) Hypovolemia and hypotension. 

iv) Hyperuricemia ( may precipitate attack of gout), except with the uricosuric drugs (indacrinone and ticrynafen). 

 v) Hypomagnesaemia which is reversed by oral magnesium supplementation. There may be wasting on chronic administration.

 2) Effects Related to Extra-Renal Actions: These effects include:

 i) Dose-related, reversible ototoxicity with loss of hearing. It is more with ethacrynic acid. 

ii) Pancreatitis. 

iii) Hypersensitivity (e.g., skin rash, blood dyscrasias, and allergic interstitial nephritis) in patients allergic to sulphonamides. 

iv) Myalgia may occur with bumetanide and piretanide.

 v) GIT upset may occur due to ethacrynic acid. 

vi) Hepatic encephalopathy in hepatic cirrhosis.

 3.1.3.4. Drug Interactions Loop diuretics interact with the following drugs and cause toxicity: 

1) They interact with aminoglycoside, antibiotics, and increase ototoxicity. 

2) They interact with cephalosporins and cause kidney damage. 

 3) Indomethacin decreases the efficiency of loop diuretics because t hey inhibit the synthesis of vasodilator prostaglandins in the kidney. 

4) They increase the toxicity caused by digitalis and result in cardiac abnormalities due to hypokalaemia. 

3.1.3.5. Contraindications Contraindications to the use of furosemide include: 

1) Presence of anuria. 

2) Hypersensitivity to compounds. 

3) Allergy to sulpha drugs

3.1.4. Medium Efficacy Diuretics (Thiazides and ThiazideLike Drugs) Thiazide diuretics are referred to as moderately efficacious diuretics as a majority (nearly 90%) of the filtered sodium is already re-absorbed even before it reaches the distal tubule. They comprise of two distinct groups of diuretics: 

1) Thiazide: These d iuretics, e.g., chlorothiazide, hydrochlorothiazide, polythiazide, etc., contain a benzothiadiazine ring. 

2) Thiazide-Like: These diuretics, e.g., chlorthalidone, indapamide, metolazone, etc., do not contain benzothiadiazine ring, but an un -substituted sulphonamide group. The most commonly used thiazide is chlorothiazide

3.1.4.1. Mechanism of Action Thiazide diuretics act by blocking the Na+ /Cl– co-transport system and exert their actions on the distal convoluted tubules (figure 3.2). Carbonic anhydrase activity is also inhibited by these drugs and they increase the excretion of bicarbonate ions, Mg+ and K+ . These agents also inhibit the excretion of Ca ++ ions and uric acid in the urine which leads to hypercalcaemia and hyperuricaemia , respectively.

3.1.4.2. Pharmacokinetics Absorption of thiazides is fast, when they are administered orally. The organic acid secretory system excretes these agents in the proximal tubule of kidneys. They inhibit the excretion of uric acid resulting in hyperuricaemia. Onset of action generally occurs in 1-2 hours, with the maximal effect occurring in 4 -6 hours. The action lasts for 8-12 hours. Actions of bendroflumethiazide last for 24 hours. The duration of action of chlorthalidone is 48-72 hours as it undergoes slow absorption. The medium efficacy diuretics differ from each other only in the onset and duration of action. The mechanism of action of all the drugs in this group is similar , thus resistance to any one compound in this group makes the other drugs of this group also resistant for that pati ent. Moreover, beyond an acceptable limit, the actions of this group of drugs do not depend on the dosage administered. 

3.1.4.3. Therapeutic Uses Medium efficacy diuretics have the following therapeutic uses:

 1) Oedema: Cardiac, hepatic and renal oedema associated with chronic heart failure, cirrhosis, nephrotic syndrome, chronic renal failure , and glomerulonephritis can be successfully treated using thiazides. However, when the GFR falls below 30ml/min, thiazides are not effective. These agents cannot be employed in the treatment of acute pulmonary oedema. 

2) Hypertension: It can be effectively treated using thiazides. In the elderly and obese patients, thiazides alone (as monotherapy) are useful in the treatment of mild hypertension. For the treatment of moderate and severe hypertension, they are employed as a combinational therapy along with other anti - hypertensives. Advantages of thiazides as anti-hypertensives include:

 i) Low-cost, good efficiency and tolerability, decreased cardiovascular morbidity and mortality, 

ii) Effective even when administered once a day, 

iii) Shows better patient compliance, and 

iv) Additive or synergistic effect with other anti-hypertensive agents. 

3) Calcium Nephrolithiasis: Calcium re-absorption is increased by the use of thiazides by the following two mechanisms:

 i) Increased re-absorption in the proximal tubule due to volume depletion. 

ii) Direct increase in Ca2+ ion re-absorption in the distal convoluted tubule. Thus, the excretion of Ca 2+ ions i n urine is increased by the action of thiazides, and hence these agents effectively treat calcium nephrolithiasis. 

4) Diabetes Insipidu s: Nephrogenic diabetes insipidus is primarily treated using thiazides. Upto 50% of urine volume is decreased by the action of thiazides. They act possibly by the following mechanisms:

 i) They promote complete re-absorption of water in the proximal tubule by volume depletion. 

ii) They increase the sensitivity of the collecting tubules to ADH