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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.