Diuretics | Definition | Mechanism of Action | Classes of Drugs

This presentation provides knowledge about Diuretics,Role of sodium, types of urine output, General mechanism of action, Normal Physiolofy of urine formation, GFR Formation, Classes of Diuretics, diuretics abuse and recent discovery. An assignment for the subject, Advanced Pharmacology-I, 1st year M.Pharm, 1st semester.

1. Advanced Pharmacology - I “ Diuretics ” By Chetan A., M.pharm 1 st Year(Pharmacology) K.K. College of Pharmacy Chennai, TamilNadu

2. Learning Objective Introduction Role of Sodium ion General Mechanism of Action Normal physiology of Urine GFR Formation Classes of Diuretics Abuse in sports Recent Discovery Facts Conclusion Reference

3. Diuretics A diuretic (“water pills”) is any substance that promotes diuresis , the increased production of urine. This includes forced diuresis . There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way. Alternatively, an antidiuretic, such as vasopressin (antidiuretic hormone), is an agent or drug which reduces the excretion of water in urine. D iuretics are used to treat heart failure, liver cirrhosis, hypertension, influenza, water poisoning, Pregnancy associated oedema and certain kidney diseases. Some diuretics, such as acetazolamide , help to make the urine more alkaline and are helpful in increasing excretion of substances such as aspirin in cases of overdose or poisoning.

4. Diuretics Diuretics are sometimes abused by people with an eating disorder, especially people with bulimia nervosa, with the goal of losing weight. The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect. T hat is, the reduction in blood pressure occurs through other mechanisms and at lower doses than that required to produce diuresis. A N atreuretic is a ny drug (agent) when introduce d into the body increases the out put of sodium ie., loss of sodium in urine.

5. Role of Sodium ions Where sodium goes, water follows. 20 to 25% of all sodium is reabsorbed into the bloodstream in the loop of Henle, 5 to 10% in the distal tubules, and 3% in collecting ducts. If it is not absorbed, it is excreted with the urine.

6. Types of Urine output Normal output - 800 to 2,000 milliliters per day. Oliguria - Low urine output - 400 to 500 milliliters per day Polyuria - High urine output - 2500 to 3000 milliliteres per day

7. General Mechanism of Action Diuretics usually exert their actions by lowering significantly the reabsorption of electrolytes from the tubules. Eg, Loop of henle, Distal & Proximal convulated tubule. The enhanced electrolyte excretion is invariably associated with a corresponding increase in water excretion to maintain the desired osmotic balance.

8. Purpose of Diuretics To maintain urine volume. Eg, Renal Failure To mobilize edema fluid. Eg, Heart failure, Liver failure, Nephrotic syndrome. To control High blood pressure. Normal Values

9. Normal Physiology of Urine formation Urine formation occurs by Glomerular filtration Tubular Re-absorption Tubular Secretion Two important functions of the kidney are:- To maintain a homeostatis balance of electrolytes and water. To excrete water soluble end products of metabolites. Each ki d ney contai n s appr o xi m a t ely one million nep h ro n s a n d is capable of forming urine independently. The nephrons are composed of glomerulus, proximal tubule,loop of henle, distal tubule.

10. Normal Physiology of Urine formation Approximately 1200 ml of blood per minute flows through both kidneys. Ions such as sodium, chloride,calcium are reabsorbed. Total amount of glucose, amino acids, vitamins, proteins are reabsorbed. If the urine contains any of the above elements, it represents the disorders. For example proteins such as albumin in higher amounts causes albuminaria.

11. GFR Formation Normal cardiac output -5 lit/min. (exactly 4.7 litres) Out of that 20% goes to kidneys i.e.1 lit/min. 1 lit of blood of has 40% of cells and 60%of plasma. 600 ml of plasma is not entered into glomerulus only a part of plasma can enter into it and the rest pass through the efferent arteriole. Only 20% can enter into glomerelus that is 120 ml. This 120 ml/min makes glomerular filtrate.

12. Classes of Diuretics High Ceiling/ Loop Diuretics Furosemide, Torasemide, Ethacrynic acid Thiazides Hydrochlorothiazide, Chlorothiazide Carbonic Anhydrase Inhibitors Acetazolamide, Methazolamide Potassium-Sparing Diuretics Spirinolactone, Amiloride, Triamterene Osmotic Diuretics Glucose, Mannitol, Urea Low Ceiling Diuretics Thiazides Calcium-Sparing Diuretics Thiazides, K+ Sparing Diuretics

13. 1. Loop diuretics Mechanism of Action Loop diuretics, such as furosemide, inhibit the body's ability to reabsorb sodium at the ascending loop in the nephron, which leads to an excretion of water in the urine . They act by inhibiting the luminal Na/K/2Cl symporter. Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance. Brands B umetanide (Bumex) - (0.5 to 20 mg) E thacrynic acid (Edecrin) F urosemide (Lasix) - (2.5 to 20 mg)

14. 1. Loop diuretics Potent diuresis and subsequent loss of fluid . It causes Potassium depletion .

15. 1. Loop diuretics Pharmacological action: Increase reabsorption of Uric acid in proximal tubule Furosemide (weak carbonic anhydrous inhibitor) increases excretion of HCO 3 - and phosphate ions. Pharmacokinetics These are completely absorbed orally. Onset of action is 2-5 hrs. Half life is 1.5 hrs Duration of action is 2-4 hrs.

16. 1. Loop diuretics Therapeutic use Edema associated with CHF or hepatic or renal disease . Control of hypertension . In Acute renal failure In Hyperkalemia In Hypercalcemia Side Effects Ototoxicity Hypovolemia, H ype r g l y ce mi a Hypokalemia, Hyperuricemia Metabolic Alkalosis Dizziness, headache, tinnitus, blurred vision Nausea, vomiting, diarrhea Agranulocytosis, neutropenia, th r o m bo c y t open i a

17. 2. Thiazide Diuretics Mechanism of action Thiazide diuretics such as hydrochlorothiazide act on the distal convoluted tubule and inhibit the sodium-chloride symporter leading to a retention of water in the urine, as water normally follows penetrating solutes . The short-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure. T he long-term effect is due to an unknown vasodilator effect that decreases blood pressure by decreasing resistance. Brands H ydrochlorothiazide (Esidrix, HydroDIURIL) C hlorothiazide (Diuril) T richlormethiazide (Metahydrin)

18. 2. Thiazide Diuretics Drug Effects Lowered peripheral vascular resistance Depletion of sodium and water Therapeutic use Hypertension Edematous states Idiopathic hypercalciuria Diabetes insipidus Adjunct agents in treatment of CHF, hepatic cirrhosis Treatment of glaucoma. These are given in combination with amiloride,allopurinol to prevent the formation of calcium stones in hyper calciuric patients.

19. 2. Thiazide Diuretics Side effects Dizziness, headache, blurred vision, paresthesias, decreased libido Anorexia, nausea, vomiting, diarrhea , Vertigo Impotence Urticaria, photosensitivity Hypokalemia, glycosuria, hyperglycemia Ortho static Hypotension

20. 3. Carbonic Anhydrous Inhibitor Carbonic anhydrase inhibitors inhibit the enzyme carbonic anhydrase which is found in the proximal convoluted tubule. This results in several effects including bicarbonate accumulation in the urine and decreased sodium absorption. Acetazolamide (Diamox) Methazolamide (Neptazane)

21. 3. Carbonic Anhydrous Inhibitor Therapeutic use: Used as weak diuretic Used in glaucoma Urinary alkalinization, High-altitude sicknes s In Epilepsy Used with miotics to lower intraocular pressure before ocular surgery Side effects: Hypo kalaemia. Renal calculi. Nausea, loss of hearing, loss of apetite.

22. 4. Potassium Sparing Diuretics These are diuretics which do not promote the secretion of potassium into the urine; thus, potassium is retained and not lost as much as with other diuretic s. Brands Spirinolactone (Aldactone) Amiloride (Midamor) T riamterene (Dyrenium)

23. 4. Potassium Sparing Diuretics Mechanism of action: Prevent potassium from being pumped into the tubule, thus preventing its secretion They act by inhibiting sodium reabsorption in the late distal tubule and thus i ndirectly spare potassium excretion. W ork in collecting ducts and distal convoluted tubules Interfere with sodium-potassium exchange Competitively bind to aldosterone receptors Block the resorption of sodium and water usually induced by aldosterone .

24. 4. Potassium Sparing Diuretics Therapeutic use: Hyperaldosteronism Hypertension Reversing the potassium loss caused by P otassium-losing drugs Treatment of CHF (Amiloride) Liddle’s syndrome(pseudo-hyper aldosteronism). Amiloride is used to treat lithium induced nephrogenic diabetes insipidus. Side effects Dizziness, headache Cramps, nausea, vomiting, diarrhea Urinary frequency, weakness G ynecomastia, A menorrhea, irregular menses (Spirinolactone)

25. 5. Osmotic Diuretics Mechanism of action : Osmotic diuretics (e.g. mannitol) are substances that increase osmolarity but have limited tubular epithelial cell permeability. They work primarily by expanding extracellular fluid and plasma volume, therefore increasing blood flow to the kidney, particularly the peritubular capillaries. This reduces medullary osmolality and thus impairs the concentration of urine in the loop of Henle. Mannitol are low molecular weight compounds that are freely filtered through bowmans capsule. They have limited reabsorption because of high water solubility & produce osmotic effect. Pull water into the blood vessels and nephrons from the surrounding tissues Brand M annitol (Resectisol, Osmitrol)

26. 5. Osmotic Diuretics Therapeutic use: Used in the treatment of patients in the early, oliguric phase of ARF To promote the excretion of toxic substances Reduction of intracranial pressure Treatment of cerebral edema Side effects: Convulsions Thrombophlebitis Pulmonary congestion H eadaches, chest pains, tachycardia, blurred vision, chills, and fever

27. Abuse in Sports A common application of diuretics is for the purposes of invalidating drug tests. Diuretics increase the urine volume and dilute doping agents and their metabolites. Another use is to rapidly lose weight to meet a weight category in sports like boxing and wrestling.

28. Recent Discovery 1. Who May Benefit from Diuretics in OSA? A Propensity Score-Match Observational Study (B.Revol et,al. 2020) Background : Diuretics have been reported as effective for reducing obstructive sleep apnea (OSA) severity by preventing fluid retention and reducing rostral fluid shift. This study was included a propensity score-matched cohort analysis of data . Result : In this study it was found that Diuretics reduced OSA severity in overweight or moderately obese patients (p=0.03) and in patients with hypertension (p<0.01), particularly in hypertensives with a body mass index between 25 and 35 kg/m2 (p<0.01). Diuretics had no significant effect on OSA severity in patients with self-reported low physical activity or heart failure. Conclusion: Diuretics appear to have a positive impact on OSA severity in overweight or moderately obese patients with hypertension. A prospective study is needed to confirm that diuretics are of interest in combined therapies for hypertensive patients with OSA.

29. Recent Discovery 2. Effect of Loop Diuretics on the Fractional Excretion of Urea in Decompensated Heart Failure (Zachary L.Cox et,al. 2020) Background : Fractional excretion of urea (FEUrea) is often used to understand the etiology of acute kidney injury (AKI) in patients receiving diuretics. Although FEUrea demonstrates diagnostic superiority over fractional excretion of sodium (FENa), clinicians often assume FEUrea is not affected by diuretics. Prospective cohort study. Result : Mean baseline FEUrea was 35.2% ± 10.5% and increased by a mean 5.6% ± 10.5% following 80 mg (40–160 mg) of furosemide equivalents (P < .001). The magnitude of change in FEUrea was clinically important as the distribution of change in FEUrea was similar to the overall distribution of baseline FEUrea. Conclusion: FEUrea is meaningfully affected by loop diuretics. The degree of change in FEUrea is highly variable between patients and commonly of a magnitude that could reclassify across categories of FEUrea.

30. Facts Rapid parenteral administration of loop diuretics can cause hearing loss and tinnitus . High doses can trigger profound diuresis, leading to hypovolemia and cardiovascular collapse. With Furosemide p atient may develop photosensitivit y . Be caution from sunburns. Some loop diuretics may pass into breast milk . Can relieve shortness of breath . Help patient to live longer with heart failure

31. Conclusion Diuretics are the first line agents to treat hypertension. When effects are not sufficient, it can be given in the form of combinations with other anti hypertensive's. Some of these agents has the capacity to reabsorb more calcium so they can be prescribed for the patients suffering from osteoporosis.

32. Reference Google Search Wikipedia Slideshare Elsevier Inc. Padhmaja Tripathi

33. Quote ~“Series of failures teaches us to be patient & to work even harder. If you’re having a bad day, don’t worry, some of them didn’t woke up this morning, atleast you had a day.” “ Positivity is everywhere. There is good in every bad. We just need a mindset to visualize it”.

34. Thank you