Gus 157 Slide Diuretik Anti-diuretik

7/27/2019 Gus 157 Slide Diuretik Anti-diuretik

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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 theexcretion 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 DiureticCharacteristics

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 activeconcentration

Osmotic pressure of non-reabsorbablesolute prevents water reabsorption andincrease 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 failure

Mechanism:

Drastic reductions in GFR causedramatically increased proximal tubularwater reabsorption and a large drop inurinary excretion

Osmotic diuretics are still filtered under

these conditions and retain an equivalentamount of water, maintaining urine flow

Reduction of CSF pressure andvolume

Reduction of intraocular pressure

Therapeutic Uses (Cont.)

Reduction of pressure in extravascular fluidcompartments

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 fromsulfanilamide,

after it wasnoticed thatsulfanilamide

causedmetabolic

acidosis andalkaline urine.

Mechanism of Action:Na+ Bicarbonate Diuresis

Inhibit carbonic anhydrase inproximal 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 (forhyperphosphatemia)


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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 proximaltubule via organic

acid transporter

Inhibition of theapical Na-K-2Clcotransporter of

the TALH

Competition with

Cl- ion for binding


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Pharmacological Effects ofLoop Diuretics

Loss of diluting ability: Increased Na, Cl andK excretion

Loss of concentrating ability: reduction in the medullary osmotic gradient

Loss in ADH-directed water reabsorption incollecting 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, bioavailabilityranges from 65-100%

Rapid onset of action

extensively bound to plasma proteins

secreted by proximal tubule organic acidtransporters

Blah

Blah Blah

Therapeutic Uses

Edema of cardiac, hepatic or renal origin

Acute pulmonary edema (parenteralroute)

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 ofclofibrate and warfarin

Li+ clearance is decreased

Loop diuretics increase renal toxicity ofcephalosporin 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 andthiazide-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 earlydistal 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 collectingduct


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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 poorException 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 urinevolume

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 promotedistal tubular Ca2+

reabsorption

Prevent excessexcretion which couldform stones in theducts of the kidney

50-100 mg HCT keptmost patients stone

free for three years offollow-up in a recentstudy

Thiazide Toxicity Hypokalemia due to:

Increased availability of Na+ for exchange atcollecting 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 diureticsAbsorpsi 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 conversionof the receptor to

active form, thereby

preventing the actionof aldosterone

Pharmacokinetics

70% absorption in GI tract

Extensive first pass effect in liver andenterohepatic 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 otherdiuretics 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 drugin equal ratio)


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Toxicity

Hyperkalemia - avoid excessive Ksupplementation when patient is onspironolactone

Androgen like effects due to it steroidstructure

Gynecomastia

GI disturbances

Triamterene and Amiloride

Non-steroid instructure, notaldosteroneantagonists

Mechanism of Action

Blockade of apical Na+

channel in the principal

cells of the CCD

Amiloride: blocks the Na/H

exchanger (higherconcentrations)

Blockade of theelectrogenic entry of

sodium causes a drop inapical 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 cationtransporters

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 ofother diuretics in:

Edema

Hypertension

Toxicity

Hyperkalemia. Avoid K+ supplementation

Drug interaction - do not use in combination withspironolactone since the potassium sparingeffect 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 ektopikaldosteronisme sekunder , misalnya:

gagal jantung kongestif sirosis hepatis sindroma nefrotik

ToksisitasHiperkalemia

Asidosis metabolik hiperkloremiaGinekomastiaGagal ginjal akutBatu 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 volumevolume 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 NatriuretikNa 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 renaldistal 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 ADHor due to the kidneys resistance to the effects

of ADH.

DI may be central (neurogenic) ornephrogenic.

DI may be a transient or a permanentcondition.

Clinical Management of DI

Goal is to prevent circulatory failure andhyperosmolar encephalopathy.

Replace volume deficit and ongoing losses

Replace ADH

Close monitoring of serum and urinelytes/osmolality

Vasopressin

Available IV, subcutaneous, and intranasalforms

DDAVP given intranasally

Pitressin IV

Therapeutic effect: increase in specific gravityand decrease in urine output within 1 hour of

dose.

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Gus 157 Slide Diuretik Anti-diuretik