DIURETICS PHARMACOLOGY. pptx. ........

“A complete overview of diuretic pharmacology including classification, mechanism of action, pharmacokinetics, uses, adverse effects, and mnemonics for easy learning.
Presented by Syed Mubasheer Ali, Pharm D, Moonray Institute of Pharmaceutical Sciences.”

1. DIURETICS PHARMACOLOGY PRESENTED BY : SYED MUBASHEER ALI , PHARM D

2. DEFINITION DIURETICS : Drugs which cause a net loss of Na+ and water in urine. (Exception- Osmotic diuretics (Mannitol) don't cause natriuresis but produce diuresis) • Natriuresis : increased sodium (Na+ ) excretion • Kaliuresis : Increased Potassium (K + ) excretion

3. CLASSIFICATION OF DIURETICS Other high ceiling diuretics → are only historical. ➢ Ethacrynic acid ➢Organomercurials ( mersalyl )

4. MNEMONIC OF DIURETICS Classification of Diuretics (K.D. Tripathi ) 1.High Ceiling (Loop) Diuretics Examples: Furosemide, Bumetanide, Torasemide , Ethacrynic acid Mnemonic: 💡 “Furious Bum Tore Ethically” → Furosemide, Bumetanide, Torasemide , Ethacrynic acid 2. Thiazide and Thiazide-like DiureticsExamples : Hydrochlorothiazide, Chlorthalidone , Indapamide , Metolazone , Mnemonic: 💡 “High Chloride Intake Makes Thirsty” → Hydrochlorothiazide, Chlorthalidone , Indapamide , Metolazone 3. Potassium-sparing Diuretics(A) Aldosterone AntagonistsExamples : Spironolactone, Eplerenone Mnemonic: 💡 “Spare Electrolytes” → Spironolactone, Eplerenone (B) Sodium Channel BlockersExamples : Amiloride , TriamtereneMnemonic : 💡 “Am I Tri to spare K⁺?” → Amiloride , Triamterene 4. Carbonic Anhydrase InhibitorsExamples : Acetazolamide, Methazolamide , Dorzolamide Mnemonic: 💡 “Ace My Carbon” → Acetazolamide, Methazolamide 5. Osmotic DiureticsExamples : Mannitol, Glycerol, Isosorbide , Urea Mnemonic: 💡 “My Great Inner Urge” → Mannitol, Glycerol, Isosorbide , Urea Master Mnemonic for Major Classes: 💡 “High Thinkers Prefer Clean Osmosis” → High ceiling – Thiazide – Potassium-sparing – Carbonic anhydrase inhibitors – Osmotic

5. SITE OF ACTION ON NEPHRON “C HACHA O RS L ALO T IME P A” Carbonic anhydrase inhibitors (at the proximal tubule) Osmotic diuretics (at the descending Loop of Henle) Loop diuretics (at the ascending loop) Thiazides (at the distal tubule) Potassium-sparing diuretics (at the collecting tubules) MNEMONIC OF SITE OF ACTION ON NEPHRON

6. HIGH CEILING DIURETICS (LOOP DIURETICS) DRUGS • Furosamide •Bumetanide • Torasemide Historical importance • Ethacrynic acid •Organomercurials ( mersalyl ) Introduction Loop diuretics are called Loop diuretics because they acts on ascending limb of the loop of Henle They are called high ceiling diuretics because, progressive increase in dose is matched by increasing diuresis, i . e. they have a high ceiling effect. ON X AXIS DOSE ON Y AXIS DIURESIS Loop diuretics

7. MECHANISM OF ACTION: SITE OF ACTION : Loop diuretics acts on “ ascending limb of the loop of Henle” Loop diuretics Enter tubular lumen via proximal tubular secretion(organic acid transport) Inhibit the cotransport of Na+/K+/2Cl− in the luminal membrane of ascending limb of the loop of Henle They attaches to the Cl binding site of this protein to inhibit its transport function. Therefore, reabsorption of these ions is decreased. So these drugs increase the concentration of Na+, k+and Cl− (also water) in the tubular fluid and cause Diuresis MOA OF LOOP DIURETICES

8. PHARMACOKINETICES OF LOOP DIURETICS 1 . Absorption :Well absorbed from the gut (oral route). Furosemide absorption can vary — sometimes less reliable.Can also be given by injection (IV) for faster effect. 2. Onset & Duration:Oral : Acts within 30–60 minutes, lasts 4–6 hoursIV : Acts within 5 minutes, lasts 2–3 hours 3. Distribution : Highly protein-bound (mainly to albumin).Enters the renal tubules by active secretion (in the proximal tubule). 4. Metabolism : Furosemide: partly metabolized in the liver. Bumetanide & Torsemide: more extensively metabolized in the liver. 5. Excretion : Mainly through the kidneys (in urine).A small part through bile.

9. Uses { BE E( CH) 2 } B lood Transfusion E dema C HF → decreases preload as well as afterload C hemical inToxication (to increase urine flow) H ypertension H ypercalcaemia of malignancy

10. ADVERSE EFFECTS 1.Hypokalemia 2.Hypomagnesemia 3.Hypocalcemia 4.Dilutional hyponatremia 5.Dehydration – acute saline depletion Hyperuricemia 6.Hyperglycemia 7.Hyperlipidemia 8.Hyperurecimia (Gout) 9.Not safe in pregnancy (all diuretics) 10.Sulphonamide hypersensitivity Mnemonic : HYPO CH A MPs C alcium H 2 O M g P otassium S odium Hyper GLU • G lycemia • L ipidemia • U ricemia (Gout)

11. MEDIUM EFFICACY DIURETICS: THIAZIDES DIURETICS Comparison of loop and thiazide diuretics High doses do not produce stronger diuresis than low doses 'Low ceiling'

12. MECHANISM OF ACTION : SITE OF ACTION → The thiazide diuretics acts on “ Distal convoluted tubule (DCT)” INHIBIT Na+/CI COTRANSPORT SYSTEM IN THE DISTAL CONVOLUTED TUBULE Thiazide diuretics Enter tubular lumen via proximal tubular secretion(organic acid transport) Inhibition of a Na+/Cl− symport on the luminal membrane of DCT Therefore, reabsorption of these ions is decreased. So these drugs increase the concentration of Na+, k+and Cl− (also water) in the tubular fluid cause Diuresis MOA :

13. Absorption: Well absorbed orally. Onset of action: ~1–2 hours after oral dose. 2. Distribution: Widely distributed in the body. Protein binding: moderate to high. 3. Metabolism: Minimal metabolism in the liver (mostly excreted unchanged). 4. Excretion: Mainly excreted by the kidneys. Half-life: varies 6–15 hours (depends on the specific thiazide) PHARMACOKINETICES

14. USES ( CHERD ) C HF → decreases preload as well as afterload H ypertension :Thiazides are one of the first line drugs E dema - best in cardiac edema R enal calcium stones with Hypercalciuria → cause decreased Ca excretion D iabetes insipidus→ They reduce urine volume in Chronic renal failure

15. ADVERSE EFFECTS 1.Hypokalemia 2.Hypomagnesemia 3.Hypocalcemia 4.Dilutional hyponatremia 5.Dehydration – acute saline depletion Hyperuricemia 6.Hyperglycemia 7.Hyperlipidemia 8.Hyperurecimia (Gout) 9. Hypercalcemia 10.Not safe in pregnancy (all diuretics) 11.Sulphonamide hypersensitivity Mnemonic : HYPO H A MPS H 2 O M g P otassium Sodium Hyper GLU C • G lycemia • L ipidemia • U ricemia (Gout) • Calcium Hypercalcemia - Thiazide increases paratharmone regulated reabsorption of Ca2+ in the distal convoluted tubule. This effect contrasts with the loop diuretics.

16. WEAK EFFICACY DIURETICS POTASSIUM SPARING DIURETICS CARBONIC ANHYDRASE INHIBITORS OSMOTIC DIURETICS

17. POTASSIUM SPARING DIURETICS They conserve K+ while inducing mild natriuresis and diuresis so called ‘ potassium sparing diuretics ’ MOA SITE OF ACTION → COLLECTING TUBE

18. MOA of Aldosteron antagonist Spironolactone Spironolactone acts combines with the mineralocorticoid receptor on interstitial side of CD cell Inhibits the formation of AlPs Antagonises the effects of Aldosteron Increases Na+ and water excretion → Diuresis Decreases K+ excretion → Hyperkalamia

19. PK OF Aldosteron antagonist Spironolactone Absorption Glides in smoothly after oral administration, well absorbed from the gut, though food can boost its bioavailability. Distribution Loves hitching rides on plasma proteins (high protein binding).Distributes widely through tissues like a wanderer with a purpose. Metabolism It doesn’t stay itself for long. Rapidly converted in the liver into active metabolites, including canrenone , which continues the magic of blocking aldosterone. Onset and Duration Although spironolactone acts slowly at first (gradual onset), the party lasts long because its metabolites have prolonged activity. Elimination Says goodbye mostly via the kidneys, with a smaller farewell through bile. Quick Memory Spark “Spironolactone: Slow start, Strong stay, Second-life metabolites”

20. USES ( PE A CH ) P rimary Hyperaldosteronism (Conn’s syndrome) E dema - edema of liver cirrhosis C HF H ypertension: combined with thiazide They are used only in conjunction with a thiazide diuretic to prevent K+ loss H ypokalamia → To counteract K loss due to thiazides, frusemide

21. Adverse Effects 1.Hyperkalemia risk • In CRF patients • Patients taking ACEI ( Enalapril ) or ARB (Losartan) • KCl supplement 2. Antiandrogen • Gynaecomastia, Impotence in males • Hirsutism, menstrual irregualarities in female

22. WEAK EFFICACY DIURETICS : CARBONIC ANHYDRASE INHIBITORS DRUGS Acetazolamide Dichlorphenamide Methazolamide Brinzolamide Dorazolamide Carbonic anhydrase inhibitor diuretics are drugs that block the enzyme carbonic anhydrase in the kidney. This enzyme normally helps in the reabsorption of sodium bicarbonate in the proximal convoluted tubule. When it is inhibited, more sodium, bicarbonate, and water are excreted in the urine, producing a mild diuretic effect and causing alkaline urine with metabolic acidosis DEFINATION

23. Mechanisms of Action: SITE OF ACTION → Acts on PCT Noncompetitively but reversibly inhibits Carbonic anhydrase enzyme • Carbonic anhydrase enzyme is present in the brush border as well as PCT cell NORMALLY • CA converts HCO3 - + H+ H2O + CO2 in tubular lumen • CO2 diffuses into cell (water follows Na+ ), CA converts CO2 + H2O HCO3 - + H+ • H+ now available again for counter transport with Na+ through the Na+-H+ antiporter. • Na+ and HCO3 - now transported into peritubular capillary

24. CARBONIC ANHYDRASE INHIBITORS (Acetazolamide) Reversibly inhibits carbonic anhydrase enzyme Retards dehydration of H2CO3 in the tubular fluid less CO2 diffuses back into the cells decreased availability of H+ to exchange with luminal Na+ through the Na+ - H+ antiporter Concentration of Na+ is increased in tubular fluid Diuresis MOA :

25. Pharmacokinetics of Carbonic Anhydrase Inhibitors Absorption: Carbonic anhydrase inhibitors like acetazolamide and methazolamide are well absorbed orally. Peak plasma concentrations are usually reached within 1–3 hours after administration. Some agents, like dorzolamide and brinzolamide , are used topically (as eye drops) for glaucoma and are absorbed mainly through the corneal and conjunctival membranes. Distribution: These drugs are widely distributed throughout the body, including into red blood cells, where carbonic anhydrase is present. They are moderately bound to plasma proteins (mostly to albumin).The drugs can cross the placenta and may appear in breast milk. Metabolism: Acetazolamide is not extensively metabolized; most of the drug remains unchanged. Methazolamide , however, undergoes partial hepatic metabolism before excretion. Excretion: The primary route of elimination is renal excretion. Acetazolamide is excreted unchanged in urine, with an elimination half-life of about 6–9 hours. The rate of excretion depends on urine pH—alkaline urine promotes ionization and faster excretion. Duration of Action: The diuretic effect begins within 1–2 hours of oral administration and lasts for about 8–12 hours. Topical agents like dorzolamide have prolonged ocular effects due to local tissue binding. Alkaline urine and acidosis in blood- • The urine produced is alkaline and rich in HC03 • Continued action of acetazolamide depletes body HCO3 and causes acidosis; less HCO3 is filtered at glomerulus, So self-limiting diuretic action.

26. USES [ GAME PA ] 1. G laucoma 2. To A lkalinise urine: for urinary tract infection 3. M etabolic alkalosis 4. E pilepsy: as adjuvant in absence seizures when primary drugs are not fully effective 5. P eriodic paralysis 6. A cute mountain sickness: due lowering of brain pH. Because of self-limiting action, production of acidosis and hypokalaemia , acetazolamide is not used as diuretic .

27. Adverse effects Mnemonic: “HAD A PH” Each letter stands for one key Adverse effect:H → Hypokalaemia A → Acidosis D → Drowsiness, paresthesias , fatigue A → Abdominal discomfort P → Precipitate hepatic coma (in liver disease) H → Hypersensitivity reactions Hypokalamia - For the same degree of natriuresis CA inhibitors cause the most marked kaliuresis Potency of producing hypokalaemia CAsI >Thiazides>Loop

28. OSMOTIC DIURETICS DRUGS Mannitol Isosorbide Glycerol Do not interact with receptors or directly block renal transport • Activity dependent on development of Osmotic pressure SITE OF ACTION : ACTS ON LOOP OF HENLEY

29. MOA Nonelectrolyte of low molecular weight • pharmacologically inert • not metabolized in the body •freely filtered at the glomerulus • not reabsorped • raise osmolarity of tubular fluid •prevents passive reabsorption of H2O

30. PK OF OSMOTIC DIURETICS Absorption: Mannitol is poorly absorbed orally, so it is given intravenously. Oral administration may cause diarrhea due to osmotic effects in the gut. 2. Distribution: After IV administration, it is distributed in extracellular fluid (ECF) but does not enter cells.It does not cross the blood-brain barrier or placenta. Volume of distribution ≈ that of extracellular water (~0.2–0.3 L/kg). 3. Metabolism: Not metabolized significantly; mannitol remains unchanged in the body. 4. Excretion: Excreted unchanged by glomerular filtration in the urine. Half-life: around 1–2 hours (prolonged in renal impairment).As it is filtered but not reabsorbed, it increases osmolality of tubular fluid → reduces water reabsorption → diuresis.

31. USES( BEK DD ) Brain→ To lower intracranial tension Before brain surgery Cerebral edema 2. Eye→ To lower intraocular tension Acute glaucoma Before intraocular surgeries 3. Kidney→ ARF : treatment & prevention To maintain GFR during major surgeries, trauma 4. To counteract low plasma osmolality after dialysis 5. Drug poisoining→forced diuresis (barbiturate poisoning)

32. Adverse Effects (blood vol , Na ) Acute Intravascular volume expansion • Before diuresis starts it exerts osmotic effect in the blood • Contraindicated in pulmonary edema , Cardiac edema (CHF) and intracranial hemorrage , 2.Results in large water loss, smaller electrolyte loss → can result in hypernatremia → Headache , Nausea

33. SYED MUBASHEER ALI PHARM D