11/16/2010

1
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
DIURETIK
DIURETIK
DIURETIK
OSMOTIK
PENGHAMBAT
KARBONIK
ANHIDRASE
DIURETIK
KUAT
TIAZID
DIURETIK
HEMAT
KALIUM
11/16/2010
2
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
11/16/2010
3
Osmotic Diuretics in Current Use
Mannitol (prototype)
Urea
Glycerin
Isosorbide
Therapeutic Uses
Prophylaxis of renal failure
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
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
11/16/2010
4
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)
11/16/2010
5
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
11/16/2010
6
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 Ca
2+
, Mg
2+
and NH
4
+
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
11/16/2010
7
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
11/16/2010
8
Whole Body Effects of Thiazides
Increased urinary excretion of:
Na
+
Cl
-
K
+
Water
HCO
3
-
(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
T
1/2
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%
11/16/2010
9
Thiazide Use in Hypercalciuria -
Recurrent Ca
2+
Calculi
Thiazides promote
distal tubular Ca
2+
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
11/16/2010
10
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)
11/16/2010
11
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
11/16/2010
12
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
11/16/2010
13
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 NatriuretikNa deplesi
reabsorbsi Na >> di tubulus proksimal.
3. Indometasin ( penghambat sintesa prostaglandin)
Indikasi: diabetes insipidus
11/16/2010
14
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.