Prezentace aplikace PowerPoint

1
Diuretics drugs that increase sodium and water
excretion from the body by an action on the
kidney. (2006)
2
According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
3

• Proximal convoluted tubule
• - isosmotic reabsorbtion of aminoacids, glucose
  and cations
• - secretion and reabsorption of weak acids org.
  anions
• sodium and water reabsorption 50 of sodium
  reabsorption
• free water permeation
• - bicarbonate reabsorption HCO3- is not
  reabsorbet itself ? carbonic anhydrase

According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
4

• Thick portion of the ascending limb of the loop
  of Henle
• - pumps Na, K and Cl- into interstitium - 30-40
  of Na
• major site of Ca2 and Mg reabsorption driven
  by K

According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
5
Distal convoluted tubule pumps Na and K out of
lumen 10 of Na Ca2 reabsorption
parathyroid hormone Na/Ca2 exchanger
According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
6
Cortical collecting tubule Na reabsorption/ K
secretion aldosteron ? a) ? expression of Na
channels at apical membrane, b) increase
expression and activity of Na/KATP-ase exchange
2-4 Na reabsorbed H/KATPase - primary site
of urine acidification movement of K is
accompanied by an equivalent movement of H
According to Katzung's Basic Clinical
Pharmacology. McGraw-Hill Medical 9 edition
(December 15, 2003)
7

• Carbonic anhydrase inhibitors
• Loop diuretics
• Thiazide diuretics
• Potasium-sparing diuretics
• Osmotic diuretics

8
1. CARBONIC ANHYDRASE INHIBITORS
Acetazolamide, dorzolamide inhibition of CA in
brush border and intracelular CA in PCT
depletion of bicarbonate metabolic
acidosis HCO3- ? ? Na inside the tubuli ? ?
exchange for K in DCT mild hypokalemia after
2-3 days HCO3- excretion slows (HCO3- depletion)
diuretic action is self limiting CA in ciliary
epitelium secretion of HCO3- into aqueous humor
? intraocular pressure - glaucoma CA in
choroid plexus secretion of HCO3- into
cerebrospinal fluid acidification
hyperventilation protect against mountain
(high-altitude) sickness
9
1. CARBONIC ANHYDRASE INHIBITORS
Clinical uses glaucoma mountain (high-altitude)
sickness significant metabolic
alkalosis Toxicity drowsiness and
paresthesias alergic reactions
(sulfonamides) renal stones precipitation of
Ca2 salts in alkaline urine potassium wasting
10
2. LOOP DIURETICS

• Furosemide
• - act from luminal site
• - inhibits the cotransport Na K 2Cl- ? Na
  excretion from 1 to 35 - massive sodium
  chloride diuresis
• - ? reabsorption of Ca2 and Mg2
• - pulmonary vasodilating effect venodilatation
  -
• - i.v. or orally - short acting 3-6 h
• Clinical use
• heart failure
• refractory oedema
• renal failure with fluid overload
• hypertension
• hypercalcaemia

11
2. LOOP DIURETICS
Pharmacokinetics F ? rapid, protein binding gt
95 , elimination mainly via kidney (filtration
and secretion), t1/2 2 h ? prolonged in renal
failure ? 10 hAdverse effects acute renal
failure prerenal failure - 2,5
l/h hypokalaemia (! digoxin !) metabolic
alkalosis hypomagnesaemia correct K (!
digoxin !) hyperuricaemia ototoxicity alergic
rare blood dyscrasias ? Li
12
3. THIAZIDE DIURETICS

• Hydrochlorothiazide
• act from luminal site- inhibit Na Cl-
  cotransport in early segment of DCT - ?
  Na/Ca2-ATPase - ? Ca2 reabsorption- mild
  inhibition of CA- orally in the morning onset
  2 h - duration 6-12-20 h (dependent on
  drug)Clinical use hypertension cardiac
  failure resistant oedema prevention of stones
  idiopatic hypercalciuria maintain high
  urine output diabetes insipidus

13
3. THIAZIDE DIURETICS
Pharmacokinetics orally F 60-80 , protein
binding 65, Vd 0,5-1,1 l/kg, elimination
kidney 95 unchanged - CLtot of
hydrochlorothiazide CLCR ? main mech. is GF but
also secretion is involved (interaction at OAT),
t1/2 6-8 h.Adverse effects impotence hypoka
laemia and hypomagnesaemia (! digoxin
!) hyponatremia hyperuricaemia impaired
glucose tolerance allergy ? Li
14
4. POTASIUM-SPARING DIURETICS
inhibit Na/K exchange in CCL K retention
mild natriuresis combination with thiazides and
loop diuretics Spironolactone act from
basolateral site in CCL competitive antagonist
on intracelular aldosteron receptor ? ?
expression of Na channels and Na/K
ATPase Clinical useprimary hyperaldosteronismsec
ondary hyperaldosteronism cirhosis, heart
failure Adverse effects men - gynaecomastia,
breast tenderness, women menstrual
irregularity oestrogen action tumours in rodent
15
4. POTASIUM-SPARING DIURETICS

• Amiloride, triamteren
• - act from luminal site (apical, canalicular) in
  CCL block Na channels ? ? Na clearance and ?
  K and H clearance
• long acting 12-24 h (8 h by Ritter 2000)
  Clinical use potassium wasting diuretics
  combination
• Adverse effects !!! hyperkalemia !!!
  monitoring risk factors diabetes mellitus,
  ACEI, NSAID metabolic acidosis
• Pk triamteren t1/2 2 h, diuresis 8 h,
  metabolized prior to excretion

16
5. OSMOTIC DIURETICS

• Manitol, ureal, glycerine
• filtered at the glomerulus but poorly reabsorbed
  - holds water in the lumen by virtue of its
  osmotic effect - proximal tubulus -
  descending limb of the loop of Henle -
  collecting tubule ? ? volume of urine ? Na
  lost
• - ? volume of plasma (water from the tissues to
  the circulation) unsuitable for treatment of
  oedema (!!! cardiac failure !!!)

17
Clinical use to maintain high urine flow - solute
overload from severe hemolysis or rhabdomyolysis
reducing intraocular pressure in acute glaucoma
reducing intracranial pressure Adverse
effect pulmonary edema headache, nausea, and
vomiting