Renal Pharmacology ( Diuretics)

Mechanisms of diuretic drugs. Diuretic drugs increase urine output by the kidney (i.e., promote diuresis). This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase.

1. Renal Pharmacology ( Diuretics) Md. Saiful Islam B.Pharm, M.Pharm (PCP) North South University Join Facebook : Pharmacy Universe

2. BIMM118 Renal Pharmacology Diuretic s : Carbonic Anhydrase Inhibitors Thiazides Loop Diuretics Potassium-sparing Diuretics

3. BIMM118 Renal Pharmacology Kidney s : Represent 0.5% of total body weight, bu t receive ~25% o f the total arterial blood pumped by the heart Each contains from one to two million nephron s : Th e glomerulus Th e proxima l convolute d tubule Th e loo p o f Henle Th e dista l convolute d tubule

4. BIMM118 Renal Pharmacology Functions Clean extracellular flui d an d maintain ECF volume and composition Acid-base balance Excretion o f waste s an d toxic substances Renal processes Filtration - glomerulus Reabsorption Tubular secretion In 24 hours the kidneys reclai m : ~ 1,30 g o f NaCl ~ 40 g NaHC O 3 ~ 18 g glucose almos t al l o f th e 18 L o f wate r tha t entere d th e tubules

5. BIMM118 Renal Pharmacology Bloo d enter s th e glomerulu s unde r pressure Thi s cause s wate r , small molecule s (bu t not macromolecule s lik e proteins ) an d ion s t o filter throug h th e capillar y wall s int o th e Bowman' s capsule Thi s flui d i s calle d nephri c filtrate No t muc h differen t fro m interstitia l fluid Nephri c filtrat e collect s withi n th e Bowman' s capsule an d flow s int o th e proxima l tubule: Her e all of the glucos e an d amino acid s , >90 % o f the uric aci d , an d ~60 % o f inorganic salt s ar e reabsorbe d b y activ e transport Th e activ e transpor t o f N a + ou t o f th e proxima l tubul e i s controlle d b y angiotensi n II. Th e activ e transpor t o f phosphat e (P O 4 ) 3 - i s regulate d (suppresse d by ) th e parathyroi d hormone. As thes e solute s ar e remove d fro m th e nephri c filtrate , a large volume of the wate r follow s the m b y osmosis: 8 – 85 % o f th e 18 liter s deposite d i n th e Bowman' s capsule s i n 2 4 hours As th e flui d flow s int o th e descendin g segmen t o f th e loo p o f Henle , water continue s t o leav e b y osmosi s becaus e th e interstitial fluid is very hypertoni c : Thi s i s cause d b y th e activ e transpor t o f N a + ou t o f th e tubula r flui d a s i t move s u p th e ascending segmen t o f th e loo p o f Henle I n th e dista l tubules , mor e sodiu m i s reclaime d b y activ e transport , an d stil l more wate r follow s b y osmosis.

6. BIMM118 Renal Pharmacology Diuretic s : Increase outpu t o f urine Primary indications ar e hypertension and mobilization of edematous fluid (e.g. kidney problems, heart failure, cirrhosis, … ) Basic mechanis m : Block reabsorption of sodium and chloride => water will also stay in the nephron Diuretics that work on the earlier nephron have greatest effect, since they are able to block more sodium and chloride reabsorption

7. BIMM118 Renal Pharmacology Diuretic s : Carbonic anhydrase inhibitor s : Azetazolamide Can trigger metabolic acidosis No t i n us e a s diureti c anymore Primary indications i s glaucoma (prevents productio n o f aequou s humor) Dorzolamide CA-inhibitors are sulfonamides => cross-allergenic with antibiotics etc.

8. BIMM118 Renal Pharmacology Diuretic s : Loop diuretics (= high ceiling diuretics ) : Strong, bu t brie f diuresi s (within 1 hr , last s ~ 4hrs) Use d fo r moderate to severe fluid retention and hypertension Most poten t diuretic s available Ac t b y inhibiting th e N a + / K + /2C l - symporter in the ascending limb in the loop of Henle Major side effect s : los s o f K + (an d C a + + an d M g + + ) F urosemide Bumetanide T orasemide

9. BIMM118 Renal Pharmacology Diuretic s : Thiazide diuretic s : Use d for mil d to moderate hypertension, mild heart failure, Medium potenc y diuretics Ac t b y inhibiting th e N a + /C l - symporter i n the dista l convoluted tube Major side effect s : los s o f K + (and M g + + , bu t no t C a + + ) Hydrochlor o thiazide Ben z thiazide Cycl o thiazide …

10. BIMM118 Renal Pharmacology Major side effects of these diuretic s : Hypokalemi a , hyponatremia, hypochloremia Hypotension and dehydration Interaction with Cardiac Glycosides => Potassium can be given orally or IV or Potassium-sparing diuretic s : Often used in combination with high-ceiling diuretics or thiazides due to potassium-sparing effects Produce little diuresis on their own

11. BIMM118 Renal Pharmacology Diuretic s : Potassium-sparing diuretic s : Act on the distal portion of the distal tube (where N a + i s exchange d for K + ) Aldosteron e promote s reabsorptio n o f N a + i n exchang e for K + (transcriptionally upregulates the N a + / K + pum p an d sodium channels) Spironolactone Aldosterone receptor antagonist Onset of action requires several days Amiloride; Trimterene Block sodium channels Quic k onset Aldosterone Spironolactone

12. BIMM118 Renal Pharmacology Small, non-reabsorbable molecules that inhibit passive reabsorption of water Predominantly increase water excretion without significantly increasing N a + excretio n => limite d use Use d to prevent renal failure, reduction of intracranial pressure (does no t cross blood-brai n barrie r => wate r i s pulle d ou t o f the brai n int o the blood) Mannitol – Only given IV – can crystallize (=> given with filter needle or in-line filter) Diuretic s : Osmotic diuretic s :

13. BIMM118 Renal Pharmacology

14. BIMM118 Renal Pharmacology Uric acid onl y slightl y solubl e i n wate r an d easily precipitate s ou t o f solutio n formin g needle- lik e crystal s o f sodiu m urate sodium urat e crystals contribute to the formation o f kidney stones and produc e the excruciatin g pai n o f gou t when deposited in the joints. Curiously , ou r kidneys reclai m most o f th e uri c aci d filtere d a t th e glomeruli . Why, i f it ca n caus e problems? Uri c aci d i s a poten t antioxidan t and thus can protect cells from damage by reactiv e oxygen species (ROS). The concentration of uric acid is 100-times greater in the cytosol than in the extracellular fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens released at the same time to T cells leadin g to a stronger immune respons e . => risk of kidney stones and gout may be the price w e pay for these protections. Most mammals hav e a n enzym e — uricas e — fo r breakin g dow n uri c aci d int o a solubl e product . However , durin g th e evolutio n o f grea t ape s an d humans , th e gene encodin g uricas e becam e inactive. Uric acid is the chief nitrogenous waste of insects, lizards, snakes and birds (th e whitis h materia l tha t bird s leav e o n statues)

15. BIMM118 Renal Pharmacology Uricosuric agent s : At therapeuti c dose s promot e excretio n an d inhibi t reabsorptio n o f uri c acid (normally , onl y 8-12 % o f th e initiall y filtere d urate s ar e eliminated) At low , subtherapeuti c doses , bot h excretio n an d reabsorptio n ar e inhibited = > possibilit y o f a n increas e i n uri c aci d concentration Probenicid Inhibit s reabsorptio n o f urate s i n th e proxima l convolute d tubule Stron g inhibitor y effec t o n penicilli n excretion Sulfinpyrazone