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Diuretik & Anti-Diuretik

Dept. Farmakologi dan Terapeutik,

Fakultas Kedokteran

Universitas Sumatera Utara

VOLUME URINE

DIURETIK

ANTI DIURETIK

Classes of Diuretics:Definitions

Diuretic: • substance that promotes the

excretion of urine

Natriuretic: • substance that promotes the renal

excretion of sodium

DIURETIKDIURETIK

DIURETIK

OSMOTIK

PENGHAMBAT

KARBONIK

ANHIDRASE

DIURETIK

KUAT

TIAZID

DIURETIK

HEMAT

KALIUM

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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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Osmotic Diuretics in Current Use

• Mannitol (prototype)• Urea• Glycerin• Isosorbide

Therapeutic Uses

Prophylaxis of renal failureMechanism:

• 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

• Reduction of CSF pressure and volume

• Reduction of intraocular pressure

Therapeutic Uses (Cont.)

Reduction of pressure in extravascular fluid compartments

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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Penghambat karbonik anhidrase

CA Inhibitor

Prototype: Acetazolamide

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

• Loss of TAL electrostatic driving force: increased excretion of Ca2+, Mg2+ and NH4

+

• Increased electrostatic driving force in CCD: increased K+ and H+ excretion

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

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

Mechanism of Action

• 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”

Increased K+ Excretion Due To:

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

Na+/K+ exchange in the cortical collecting duct

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Whole Body Effects of Thiazides

• Increased urinary excretion of:– Na+

– Cl-

– K+

– Water– HCO3

- (dependent on structure)

• Reduced ECF volume (contraction)

• Reduce blood pressure (lower CO)

• Reduced GFR

Pharmacokinetics

• Oral administration - absorption poor– Exception Chlorothiazide, Chlorthalidone

• Diuresis within one hour• T1/2 for

– chlorothiazide is 1.5 hours, – chlorthalidone 44 hours

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

• Primary aldosteronism

Administration

• Dose orally administered (100 mg/day)• Spironolactone/thiazide prep

(aldactazide, 25 or 50 mg of each drug in equal ratio)

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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

• Toksisitas– Hiperkalemia

– Asidosis metabolik hiperkloremia

– Ginekomastia

– Gagal ginjal akut

– Batu ginjal

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

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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 kidney’s 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.