11/16/2010

DIURETIK

Diuretik & Anti-Diuretik VOLUME URINE Dept. Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara ANTI DIURETIK

PENGHAMBAT Classes of Diuretics: DIURETIK KARBONIK OSMOTIK Definitions ANHIDRASE

Diuretic: • substance that promotes the DIURETIKDIURETIK excretion of urine DIURETIK DIURETIK HEMAT Natriuretic: KUAT KALIUM • substance that promotes the renal

excretion of sodium TIAZID

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Diuretik osmotik Osmotic Diuretic

Osmotic Diuretic Mechanism of Action: Characteristics Inhibition of Water Diffusion • Oral absorption: ( - ), parenteral • Free filtration in osmotically active administration concentration • Freely filterable • Osmotic pressure of non-reabsorbable solute prevents water reabsorption and • Little or no tubular reabsorption increase urine volume • Inert or non-reactive – Proximal tubule • Resistant to degradation by tubules – Thin limb of the loop of Henle

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Therapeutic Uses Osmotic Diuretics in Current Use Prophylaxis of renal failure • Mannitol (prototype) Mechanism: • Urea • Drastic reductions in GFR cause dramatically increased proximal tubular • Glycerin water reabsorption and a large drop in urinary excretion • Isosorbide • Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow

Therapeutic Uses (Cont.) Toxicity of Osmotic Diuretics

• Increased extracellular fluid volume Reduction of pressure in extravascular fluid compartments • Hypersensitivity reactions • Glycerin metabolism can lead to • Reduction of CSF pressure and hyperglycemia and glycosuria volume • Headache, nausea and vomiting • Reduction of intraocular pressure • Hypernatremia • Dehydration

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Prototype: Acetazolamide

Developed from Penghambat karbonik anhidrase sulfanilamide, CA Inhibitor after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine.

Mechanism of Action: Therapeutic Uses Na + Bicarbonate Diuresis • Urinary alkalinization • Inhibit carbonic anhydrase in • Metabolic alkalosis proximal tubule • Glaucoma: • Blocks reabsorption of bicarbonate – acetazolamide, dorzalamide ion, preventing Na/H exchange • Acute mountain sickness • Pharmacological effect • Epileptic seizure – Sodium bicarbonate diuresis • Periodic hypokalemia paralytic – metabolic acidosis • Increase phosphate excretion (for hyperphosphatemia)

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CA Inhibitor Toxicity • Hyperchloremic metabolic acidosis Diuretik Kuat • Nephrolithiasis: renal stones potent diuretics • Potassium wasting – Sleepy loop diuretics – Parastesia – Hypersensitivity Contraindicated : hepatic cirrhosis

Available Loop Molecular Mechanism of Action Diuretics • Enter proximal tubule via organic • Furosemide acid transporter (prototype) • Inhibition of the • Bumetanide apical Na-K-2Cl • Torsemide cotransporter of • Ethacrynic acid the TALH • Competition with Cl - ion for binding

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Pharmacological Effects of Pharmacokinetics Loop Diuretics • Loss of diluting ability: Increased Na, Cl and • Rapid oral absorption, bioavailability K excretion ranges from 65-100% • Loss of concentrating ability: • Rapid onset of action – reduction in the medullary osmotic gradient • extensively bound to plasma proteins – Loss in ADH-directed water reabsorption in collecting ducts • secreted by proximal tubule organic acid • Loss of TAL electrostatic driving force: transporters 2+ 2+ + increased excretion of Ca , Mg and NH 4 • Blah • Increased electrostatic driving force in CCD: • Blah + + increased K and H excretion • Blah

Therapeutic Uses Loop Diuretic Toxicity

• Edema of cardiac, hepatic or renal origin • Hypokalemia • Acute pulmonary edema – (parenteral • Magnesium depletion route) • Chronic dilutional hyponatremia • Chronic renal failure or nephrosis • Metabolic alkalosis • Hypertension • Hyperuricemia • Symptomatic hypercalcemia • Ototoxicity

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Drug Interactions thiazide and • Displacement of plasma protein binding of clofibrate and warfarin thiazide-like diuretics • Li + clearance is decreased • Loop diuretics increase renal toxicity of cephalosporin antibiotics • Additive toxicity w/ other ototoxic drugs • Inhibitors of organic acid transport (probenecid, NSAID's) shift the dose-response curve of loop diuretics to the right

Increased K + Excretion Due To: • Increased urine flow per se Mechanism • Increased Na +-K+ exchange • Increased aldosterone release of Action

Na+/K+ exchange in the cortical collecting duct • Thiazides freely filtered and secreted in proximal tubule • Bind to the electroneutral NaCl cotransporter • Thiazides impair Na + and Cl - reabsorption in the early distal tubule: “low ceiling”

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Whole Body Effects of Thiazides Pharmacokinetics

• Increased urinary excretion of: – Na + • Oral administration - absorption poor – Cl - – Exception Chlorothiazide, Chlorthalidone –K+ • Diuresis within one hour – Water •T1/2 for - – HCO 3 (dependent on structure) – chlorothiazide is 1.5 hours, • Reduced ECF volume (contraction) – chlorthalidone 44 hours • Reduce blood pressure (lower CO) • Reduced GFR

Therapeutic Uses Diabetes Insipidus

• Thiazides: paradoxical reduction in urine • Edema due to CHF (mild to moderate) volume • Essential hypertension • Mechanism: volume depletion causes • Diabetes insipidus (nephrogenic) decreased GFR + • Hypercalciuria • Treatment of Li toxicity: – Thiazides useful – Li + reabsorption increased by thiazides. Reduce Li dosage by 50%

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Thiazide Use in Hypercalciuria - Recurrent Ca 2+ Calculi Thiazide Toxicity • Thiazides promote • Hypokalemia due to: distal tubular Ca 2+ – Increased availability of Na + for exchange at reabsorption collecting duct • Prevent “excess” – Volume contraction induced aldosterone release excretion which could • Hyperuricemia form stones in the – Direct competition of thiazides for urate transport ducts of the kidney – Enhanced proximal tubular reabsorption efficiency • 50-100 mg HCT kept • Hyperglycemia most patients stone – Diminished insulin secretion free for three years of – Related to the fall in serum K + follow-up in a recent • Elevated plasma lipids study • Metabolic alkalosis

Diuretik Hemat Kalium “potassium-sparing” diuretics
Absorpsi melalui oral
Metabolisme melalui hati ( Diuretik Hemat Kalium triamteren ↑) “potassium-sparing” diuretics
Mekanisme kerja: - me ↓ absorpsi Na + di tubulus & duktus kolektifus. - melalui reseptor  spironolakton - tanpa melalui reseptor  triamteren & amiloride

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Spironolactone Pharmacokinetics

• Mechanism of action: • 70% absorption in GI tract aldosterone antagonist • Extensive first pass effect in liver and • Aldosterone receptor enterohepatic circulation function • Extensively bound to plasma proteins • Spironolactone prevents conversion • 100% metabolites in urine of the receptor to active form, thereby • Active metabolite: canrenone (active) preventing the action • Canrenoate (converted to canrenone) of aldosterone

Therapeutic Uses Administration

• Prevent K loss caused by other • Dose orally administered (100 mg/day) diuretics in: – Hypertension • Spironolactone/thiazide prep (aldactazide, 25 or 50 mg of each drug – Refractory edema in equal ratio) – Heart failure • Primary aldosteronism

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Toxicity Triamterene and Amiloride

• Hyperkalemia - avoid excessive K • Non-steroid in supplementation when patient is on structure, not spironolactone aldosterone • Androgen like effects due to it steroid antagonists structure • Gynecomastia • GI disturbances

Mechanism of Action Pharmacokinetics

• Blockade of apical Na + • Triamterine channel in the principal – 50% absorption of oral dose cells of the CCD – 60% bound to plasma proteins • Amiloride: blocks the Na/H – Extensive hepatic metabolism with active exchanger (higher metabolites concentrations) – Secreted by proximal tubule via organic cation • Blockade of the transporters electrogenic entry of • Amiloride sodium causes a drop in – 50% absorption of oral dose apical membrane potential – not bound to plasma proteins (less negative), which is – not metabolized, excreted in urine unchanged the driving force for K+ – Secreted by proximal tubular cation transporters secretion

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Therapeutic uses Toxicity

• Eliminate K wasting effects of • Hyperkalemia. Avoid K+ supplementation other diuretics in: • Drug interaction - do not use in combination with spironolactone since the potassium sparing – Edema effect is greater than additive – Hypertension • Caution with ACE inhibitors • Reversible azotemia (triamterine) • Triamterene nephrolithiasis. 1 in 1500 patients

summary Antagonis ADH
Absorpsi melalui oral • Indikasi
Metabolisme: hati • Keadaan mineralo kortikoid >> akibat
Eliminasi: melalui sekresi tubulus ginjal – hipersekresi primer : sindrom Cohn, produk ACTH ektopik
Mekanisme kerja : – aldosteronisme sekunder , misalnya: • gagal jantung kongestif menghambat efek ADH pd tub.kolektivus • sirosis hepatis • sindroma nefrotik Indikasi • Toksisitas – Hiperkalemia * SIADH (sindrome of Inappropriate ADH secretion) – Asidosis metabolik hiperkloremia * Penyebab lain yang menyebabkan pe ↑ ADH – Ginekomastia – Gagal ginjal akut – Batu ginjal

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Toksisitas Anti diuretik

* Diabetes insipidus nefrogenik 1. ADH * Gagal ginjal : - gagal ginjal akut - vasopresin (alamiah) - nepritis intertitial kronis - desmopresin (sintesis) * Lain :- gemetar - penurunan mental * Absorpsi peroral : tidak efektif karena segera mengalami - kardiotoksik inaktifasi oleh tripsin. - ggn.fungsi tiroid - leukositosis * Mekanisme kerja pengaturan sekresi ADH diatur oleh konsep : 1. Osmoreseptor dehidrasi  osmolalitas plasma >>  sekresi ADH >> 2. Reseptor volume volume darah yang beredar ↓  perangsangan sekresi ADH ↑ .

3. Stres emosional atau fisik 4. Obat : - nikotin - klofibrat - siklofodfamid - antidepresan trisiklik - karbamezepin - diuretik

2.Benzotiadiazid

 untuk yang resisten terhadap ADH (diabetes insipidus nefrogen) Mekanisme kerja Natriuretik  Na deplesi  reabsorbsi Na >> di tubulus proksimal. 3. Indometasin ( penghambat sintesa prostaglandin)

Indikasi: diabetes insipidus

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Function of ADH Diabetes Insipidus

• ADH increases the permeability of the renal • DI is a clinical condition due to a deficit of ADH distal tubule and collecting ducts to water. or due to the kidney’s resistance to the effects • Less free water is excreted in urine of ADH. • Urine volume is decreased • DI may be central (neurogenic) or nephrogenic. • Concentration of urine is increased • DI may be a transient or a permanent condition.

Clinical Management of DI Vasopressin • Goal is to prevent circulatory failure and • Available IV, subcutaneous, and intranasal hyperosmolar encephalopathy. forms • Replace volume deficit and ongoing losses • DDAVP given intranasally • Replace ADH • Pitressin IV • Close monitoring of serum and urine • Therapeutic effect: increase in specific gravity lytes/osmolality and decrease in urine output within 1 hour of dose.

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