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DIURETIK

Diuretik & Anti-Diuretik

Dept. Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara

VOLUME URINE

ANTI DIURETIK

Classes of Diuretics:
Definitions
Diuretic: substance that promotes the excretion of urine Natriuretic: substance that promotes the renal excretion of sodium

DIURETIK OSMOTIK

PENGHAMBAT KARBONIK ANHIDRASE

DIURETIK DIURETIK DIURETIK HEMAT KALIUM DIURETIK KUAT

TIAZID

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Diuretik osmotik Osmotic Diuretic

Osmotic Diuretic Characteristics

Oral absorption: ( - ), parenteral administration Freely filterable Little or no tubular reabsorption Inert or non-reactive Resistant to degradation by tubules

Mechanism of Action: Inhibition of Water Diffusion

Free filtration in osmotically active concentration Osmotic pressure of non-reabsorbable solute prevents water reabsorption and increase urine volume
Proximal tubule Thin limb of the loop of Henle

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Therapeutic Uses Osmotic Diuretics in Current Use

Prophylaxis of renal failure

Mannitol (prototype) Urea Glycerin Isosorbide

Mechanism:
Drastic reductions in GFR cause dramatically increased proximal tubular water reabsorption and a large drop in urinary excretion Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow

Therapeutic Uses (Cont.)

Reduction of pressure in extravascular fluid compartments Reduction of CSF pressure and volume Reduction of intraocular pressure

Toxicity of Osmotic Diuretics

Increased extracellular fluid volume Hypersensitivity reactions Glycerin metabolism can lead to hyperglycemia and glycosuria Headache, nausea and vomiting Hypernatremia Dehydration

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

Mechanism of Action: Na+ Bicarbonate Diuresis

Inhibit carbonic anhydrase in proximal tubule Blocks reabsorption of bicarbonate ion, preventing Na/H exchange Pharmacological effect
Sodium bicarbonate diuresis metabolic acidosis

Therapeutic Uses
Urinary alkalinization Metabolic alkalosis Glaucoma:
acetazolamide, dorzalamide

Acute mountain sickness

Epileptic seizure Periodic hypokalemia paralytic Increase phosphate excretion (for hyperphosphatemia)

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CA Inhibitor Toxicity
Hyperchloremic metabolic acidosis Nephrolithiasis: renal stones Potassium wasting
Sleepy Parastesia Hypersensitivity Contraindicated : hepatic cirrhosis

Diuretik Kuat potent diuretics loop diuretics

Available Loop Diuretics

Furosemide (prototype) Bumetanide Torsemide Ethacrynic acid

Molecular Mechanism of Action

Enter proximal tubule via organic acid transporter Inhibition of the apical Na-K-2Cl cotransporter of the TALH Competition with Cl- ion for binding

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Pharmacological Effects of Loop Diuretics

Loss of diluting ability: Increased Na, Cl and K excretion Loss of concentrating ability:
reduction in the medullary osmotic gradient Loss in ADH-directed water reabsorption in collecting ducts

Pharmacokinetics
Rapid oral absorption, bioavailability ranges from 65-100% Rapid onset of action extensively bound to plasma proteins secreted by proximal tubule organic acid transporters Blah Blah Blah

Loss of TAL electrostatic driving force: increased excretion of Ca2+, Mg2+ and NH4+ Increased electrostatic driving force in CCD: increased K+ and H+ excretion

Therapeutic Uses
Edema of cardiac, hepatic or renal origin Acute pulmonary edema (parenteral route) Chronic renal failure or nephrosis Hypertension Symptomatic hypercalcemia

Loop Diuretic Toxicity

Hypokalemia Magnesium depletion Chronic dilutional hyponatremia Metabolic alkalosis Hyperuricemia Ototoxicity

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Drug Interactions
Displacement of plasma protein binding of clofibrate and warfarin 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

thiazide and thiazide-like diuretics

Increased K+ Excretion Due To: Mechanism of Action

Increased urine flow per se Increased Na+-K+ exchange Increased aldosterone release

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

Increased urinary excretion of:
Na+ ClK+ Water HCO3- (dependent on structure)

Pharmacokinetics
Oral administration - absorption poor
Exception Chlorothiazide, Chlorthalidone

Diuresis within one hour T1/2 for

chlorothiazide is 1.5 hours, chlorthalidone 44 hours

Reduced ECF volume (contraction) Reduce blood pressure (lower CO) Reduced GFR

Therapeutic Uses
Edema due to CHF (mild to moderate) Essential hypertension Diabetes insipidus (nephrogenic) Hypercalciuria

Diabetes Insipidus
Thiazides: paradoxical reduction in urine volume Mechanism: volume depletion causes decreased GFR 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 Ca2+ Calculi

Thiazides promote distal tubular Ca2+ reabsorption Prevent excess excretion which could form stones in the ducts of the kidney 50-100 mg HCT kept most patients stone free for three years of follow-up in a recent study

Thiazide Toxicity
Hypokalemia due to:
Increased availability of Na+ for exchange at collecting duct Volume contraction induced aldosterone release

Hyperuricemia
Direct competition of thiazides for urate transport Enhanced proximal tubular reabsorption efficiency

Hyperglycemia
Diminished insulin secretion Related to the fall in serum K+

Elevated plasma lipids Metabolic alkalosis

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

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Spironolactone
Mechanism of action: aldosterone antagonist Aldosterone receptor function Spironolactone prevents conversion of the receptor to active form, thereby preventing the action of aldosterone

Pharmacokinetics
70% absorption in GI tract Extensive first pass effect in liver and enterohepatic circulation Extensively bound to plasma proteins 100% metabolites in urine Active metabolite: canrenone (active) Canrenoate (converted to canrenone)

Therapeutic Uses
Prevent K loss caused by other diuretics in:
Hypertension Refractory edema Heart failure

Administration
Dose orally administered (100 mg/day) Spironolactone/thiazide prep (aldactazide, 25 or 50 mg of each drug in equal ratio)

Primary aldosteronism

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Toxicity
Hyperkalemia - avoid excessive K supplementation when patient is on spironolactone Androgen like effects due to it steroid structure Gynecomastia GI disturbances

Triamterene and Amiloride

Non-steroid in structure, not aldosterone antagonists

Mechanism of Action
Blockade of apical Na+ channel in the principal cells of the CCD Amiloride: blocks the Na/H exchanger (higher concentrations) Blockade of the electrogenic entry of sodium causes a drop in apical membrane potential (less negative), which is the driving force for K+ secretion

Pharmacokinetics
Triamterine
50% absorption of oral dose 60% bound to plasma proteins Extensive hepatic metabolism with active metabolites Secreted by proximal tubule via organic cation transporters

Amiloride
50% absorption of oral dose not bound to plasma proteins not metabolized, excreted in urine unchanged Secreted by proximal tubular cation transporters

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Therapeutic uses
Eliminate K wasting effects of other diuretics in:
Edema Hypertension

Toxicity
Hyperkalemia. Avoid K+ supplementation Drug interaction - do not use in combination with spironolactone since the potassium sparing effect is greater than additive Caution with ACE inhibitors Reversible azotemia (triamterine) Triamterene nephrolithiasis. 1 in 1500 patients

summary
Indikasi
Keadaan mineralo kortikoid >> akibat
hipersekresi primer : sindrom Cohn, produk ACTH ektopik aldosteronisme sekunder , misalnya:
gagal jantung kongestif sirosis hepatis sindroma nefrotik

Antagonis ADH
Absorpsi melalui oral Metabolisme: hati Eliminasi: melalui sekresi tubulus ginjal Mekanisme kerja : menghambat efek ADH pd tub.kolektivus

Indikasi
* SIADH (sindrome of Inappropriate ADH secretion) * Penyebab lain yang menyebabkan pe ADH

Toksisitas
Hiperkalemia Asidosis metabolik hiperkloremia Ginekomastia Gagal ginjal akut Batu ginjal

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Toksisitas
* Diabetes insipidus nefrogenik * Gagal ginjal : - gagal ginjal akut - nepritis intertitial kronis * Lain :- gemetar - penurunan mental - kardiotoksik - ggn.fungsi tiroid - leukositosis

Anti diuretik
1. ADH - vasopresin (alamiah) - desmopresin (sintesis) * Absorpsi peroral : tidak efektif karena segera mengalami inaktifasi oleh tripsin. * 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
ADH increases the permeability of the renal distal tubule and collecting ducts to water. Less free water is excreted in urine Urine volume is decreased Concentration of urine is increased

Diabetes Insipidus
DI is a clinical condition due to a deficit of ADH or due to the kidneys resistance to the effects of ADH. DI may be central (neurogenic) or nephrogenic. DI may be a transient or a permanent condition.

Clinical Management of DI
Goal is to prevent circulatory failure and hyperosmolar encephalopathy. Replace volume deficit and ongoing losses Replace ADH Close monitoring of serum and urine lytes/osmolality

Vasopressin
Available IV, subcutaneous, and intranasal forms DDAVP given intranasally Pitressin IV Therapeutic effect: increase in specific gravity and decrease in urine output within 1 hour of dose.

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