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					DIURETICS
Salt and Water Reabsorption in
       Proximal Tubule


     Insert fig. 17.14
                    Ascending Limb LH

   NaCl is actively
    extruded from the          Insert fig. 17.15
    ascending limb
    into surrounding
    interstitial fluid.
   Na+ diffuses into
    tubular cell with
    the secondary
    active transport of
    K+ and Cl-.
   Occurs at a ratio
    of 1 Na+ and 1 K+
    to 2 Cl-.
               Ascending Limb LH    (continued)




   Na+ actively
    transported across
    the basolateral        Insert fig. 17.15
    membrane by Na+/
    K+ ATPase pump.
   Cl- passively
    follows Na+ down
    electrical gradient.
   K+ passively
    diffuses back into
    filtrate.
   Ascending walls
    are impermeable to
    H20.
                    Descending Limb LH
   Deeper regions of medulla
    reach 1400 mOsm/L.              Insert fig. 17.16
   Impermeable to passive
    diffusion of NaCl.
   Permeable to H20.
   Hypertonic interstitial fluid
    causes H20 movement out
    of the descending limb via
    osmosis, and H20 enters
    capillaries.
   Fluid volume decreases in
    tubule, causing higher [Na+]
    in the ascending limb.
                          Secretion
   Secretion of substances from the peritubular capillaries
    into interstitial fluid.
       Then transported into lumen of tubule, and into the urine.
   Allows the kidneys to rapidly eliminate certain potential
    toxins.
                            K+ Secretion

 90% filtered K+ is reabsorbed in early part of
  the nephron.
 Secretion of K+ occurs in CD.
       Amount of K+ secreted depends upon:
          Amount of Na+ delivered to the region.
          Amount of aldosterone secreted.

       As Na+ is reabsorbed, lumen of tubule becomes
        –charged.
          Potential   difference drives secretion of K+ into tubule.
               Transport carriers for Na+ separate from transporters for K+.
                           K+ Secretion   (continued)




   Final [K+]
    controlled in CD
    by aldosterone.
       When                                    Insert fig. 17.24
        aldosterone is
        absent, no K+ is
        excreted in the
        urine.
   High [K+] or low
    [Na+] stimulates
    the secretion of
    aldosterone.
   Only means by
    which K+ is
    secreted.
    Diuretic Drugs       pharmacological class

       SITES OF ACTION                           thiazides




                                                                         K+-sparing

osmotic
diuretics



 carbonic
anhydrase
inhibitors




                                                 structural class
                                                               loop diuretics
Diuretic Drugs                                                 H2NSO 2
                                                                                     O       O
                                                                                                    H
                                                                                         S
                                                                                             N
                O
                            S                                            Cl              N                     thiazides
          C H 3C NH             SO 2NH 2
                         N N                                                chlo roth ia zide
                                                              (Alu rene®, Diu ril®, Urinex®, Saluric®,
                acetazolamide                                                among others)

   carbonic anhydrase inhibitor
         in proximal tubule by                                               inhibit Na+, Cl-
            reducing HCO3-
                                                                         cotransport in the early
              reabsorption
                                                                            convoluted tubule
            OC H2C OOH
                Cl                                 C OOH
                                                       NHC H2                                    H2N       N       N       NH2
                                                                         O
                    Cl
                                                                                                                       N
     O      C                         NH2SO 2                                                              N
 C H2       C C H2C H3                             Cl
                                                 furosemide (Las ix ®)
 ethacrynic ac id (Edec rin®)                                                                    triamterene (Jatropur®, Dytac®)

           loop diuretic                        loop diuretic
                                                                                                       K+-sparing
              inhibit Na+-K+/2Cl- cotransport                                                    inhibit Na+/K+ pump
            system in ascending limb of loop of                                                    by reducing Na+
                          Henle                                                                          entry
   DIURETICS ??????
   DRUGS THAT INCREASE THE

   EXCRETION OF            Na+ AND H2O

   FROM THE              BODY

   BY ACTING ON

    directly on the tubular epithelial cells to
    inhibit renal reabsorption of
    ions and water
DIURETICS ACTS DIRECTLY ON
 THE CELLS OF THE NEPHRON
Methylxanthenes    CA Inhibitors,      Loop Diuretics,     Thiazides
 Glomerulus       Osmotic diuretics   Osmotic diuretics   Distal tubule
                  Proximal tubule      Loop of Henle
                                                                   5%
                                                                            Antikaliuretics


                                                             Thick
                         70%                                 Ascending
                                                             Limb                   4.5%
                                                                                 Collecting
                                                                                 duct


                                                              20%
       100%
    GFR 180 L/day
Plasma Na 145 mEq/L
 Filtered Load 26,100
       mEq/day                                                              0.5%
                                                                        Volume 1.5 L/day
                                                                      Urine Na 100 mEq/L
                                                                    Na Excretion 155 mEq/day
       METHYLXANTHENES

     Theobromine, caffeine, theophylline



Mild diuretics
 GFR by HR
 Na+ resorption
  in diluting
 segment
    Carbonic anhydrase Inhibitors
 Carbonic anhydrase:
 Location: PCT
 Function:
 catalyzes the dehydration of H2CO3, a
  critical step in the proximal reabsorption of
  H2CO3.
CARBONIC ANHYDRASE INHIBITORS

Acetazolamide, dichlorphenamide, methazolamide


Developed from
sulfanilamide,
after it was
noticed that
sulfanilamide
caused metabolic
acidosis and
alkaline urine
                     MOA
   Inhibition of carbonic anhydrase activity
    profoundly depresses bicarbonate
    reabsorption in the proximal tubule.

 ------ sodium bicarbonate diuresis
 ----- decrease in total bicarbonate stores
     CARBONIC ANHYDRASE INHIBITORS


                     CA
         CO2 + H2O        H2CO3   H+ + HCO3-


•   mild diuretics
• decrease acidity of urine
• action limited by hyperchloremic
    metabolic acidosis
            Pharmacokinetics
 Well absorbed after oral administration
 Increase in urine pH in 30 m9in: due to


             Bicarbonate diuresis


   Excretion is by tubular secretion in
    proximal tubule.
           Pharmacodynamics
   Inhibition of carbonic anhydrase--------------
    ---- decrease bicarbonate reabsorption in
    proximal tubule.

   Maximal acetazolamide administration -----
    ----- 45 % inhibition of whole kidney
    bicarbonate reabsorption.
         Therapeutic Uses
 Glaucoma    (dorzalamide, brinzolamide)
 Urinary alkalinization
 Metabolic Alkalosis
 Acute mountain Sickness
 Epilepsy
        Urinary alkalinization
 Uric acid and cystine
 Renal excretion of weak acid “Aspirin” is
  enhanced by acetazolamide
            Metabolic Alkalosis
   When the alkalosis is due to excessive use of
    diuretics in patients with severe heart failure

   Metabolic alkalosis secondary to Respiratory
    acidosis
      Acute mountain sickness
 Symptoms
 Weakness, dizziness, insomnia,
  headache, nausea
 Progressive pulmonary and cerebral
  edema ------ life threatening.



    What is the role of acetazolamide?
   Decrease cerebrospinal fluid formation

   Decrease pH of the cerebrospinal fluid
    and Brain

   Can be used for prophylaxis 24 hour
    before ascent.
                 Toxicity
 Hyperchloremic metabolic acidosis
 Renal stones
 Renal potassium wasting
 Hypersensitivity reactions --- fever, rashes,
  bone marrow supression
     Contra indications

Hepatic   cirrhosis
         THIAZIDE DIURETICS

 variable effects on CA inhibition
 block Na+-Cl- co-transport
 relax vascular smooth muscle




                       General Structure of Thiazide Diuretics
          Pharmacokinetics
 Chlorothiazide is less lipid soluble ---- must
  be given in relatively large doses
 Chlorothalidone: slowly absorbed longer
  duration of action
 Idapamide: excreted primarily by biliary
  system
 All thiazides compete with uric acid
  secretion
Pharmacodynamics
     CLINICAL USES Of THIAZIDES

1) HYPERTENSION

2) EDEMA (cardiac, liver, renal)

3) NEPHROLITHIASIS (IDIOPATHIC
   HYPERCALCIURIA)

4) NEPHROGENIC DIABETES INSIPIDUS
             Toxicity

 Hypokalemic   metabolic alkalosis
 Hyperuricemia
 Impaired carbohydrate tolerance –
  Hyperglycemia
 Hyperlipidemia
 Hyponatremia
 Allergic reactions
          LOOP DIURETICS


   Furosemide,
   Bumetanide,
   Ethacrynic acid
           Pharmacokinetics
 Rapidly absorbed
 Eliminated by renal secretion as well as
  glomerular filtration
 Rapid diuresis after IV administration


   DOA: 2-3 hours
Pharmacodynamics
   strong diuretics

   block Na+-K+-2Cl- co-transport

   increase K+, Mg++ and Ca++ excretion
                      Actions

   Induce renal prostaglandin synthesis
   These prostaglandins participate in the renal
    actions of these drugs.
   Direct effect on blood flow
   Increases renal blkood flow
   Redistribution of blood flow within the renal
    cortex.
   Relieve pulmonary congestion
   Reduce let ventricular filling pressures in CHF
Therapeutic uses
    CLINICAL USES OF LOOP DIURETICS
 EDEMA due to CHF, nephrotic syndrome or
  cirrhosis
 Acute heart failure with PULMONARY
  EDEMA
 Acute renal failure ---- enhance K+
  excretion, increase rate of urine flow
 HYPERCALCEMIA
 Anion overdose: bromide, fluoride and
  iodide are reabsorbed in thick ascending
  limb
    Adverse Effects of Loop Diuretics

 Hypokalemic metabolic alkalosis,
 Hyperuricemia
 Hyperglycemia
 Hyponatremia
 Hypocalcemia (in contrast to thiazides)
 Hypomagnesemia
 Hypersensitivity
 Dehydration and postural hypotension
 Ototoxicity (especially if given by rapid IV
  bolus)
 POTASSIUM-SPARING DIURETICS

Spironolactone
Triamterene,
Amiloride
   Antagonize the effects of aldosterone

   at cortical collecting tubule and late distal
    tubule
 Mechanisms of inhibition
 Direct pharmacological antagonism of
  mineralocorticoid receptors ---
  spironolactone

   Inhibition of Na+ flux through ion channels
    in the luminal membrane --- triamterene,
    amiloride
POTASSIUM-SPARING DIURETICS

• spironolactone is an aldosterone
antagonist
• triamterene and amiloride directly
inhibit electrogenic Na+ transport
• useful adjuncts with K+-depleting
diuretics
         Therapeutic uses

Mineralocorticoid excess -----
Primary hypersecretion:
Conns syndrome,
Ectopic ACTH production


Secondary aldosteronism:
CHF, Hepatic cirrhosis,
Nephrotic syndrome,
             Toxicity
 Hyperkalemia
 Hyperchloremic   metabolic
  acidosis
 Gynecomastia
 Acute renal failure
 Kidney stones
 Agents that
enhance water
  excretion
Osmotic diuretics
OSMOTIC DIURETICS
                 HO
    CH2OH

    -
             H        H       O
 HO-C-H
    -
 HO-C-H
    -
  H-C-OH
    -


  H-C-OH
    -



    CH2OH         O H             OH
  Mannitol                H

                 Isosorbide
   H2COH

   H2COH                      O



                              =
                      H2N-C-NH2
   H2COH

  Glycerol                Urea
   Proximal tubule and descending limb of
    loop of henle are freely permeable to
    water.

   Osmotic agent causes water to be
    retained in these segments and promote a
    water diuresis
                Mannitol
 Not metabolized
 Handled by glomerular filtration
 Poorly absorbed
          Pharmacodynamics
 Limits water reabsorption in those segments of
  nephron that are freely permeable to water ----
  - the proximal tubule and descending limb of
  loop of henle by exerting an osmotic force------
  - increase urine volume with mannitol
  excretion.
 Hypernatremia.





            Therapeutic Uses
   To increase urine volume

   Reduction of intracranial and intraocualr
    pressure
             Toxicity

 Extra   cellular volume Expansion

 Dehydration   and Hypernatremia
          ADH antagonists

 Lithium
 Demeclocycline
      OSMOTIC DIURETICS
 relatively inert pharmacologically
 freely filtered at the glomerulus
 limited reabsorption by renal tubules
   OSMOTIC DIURETICS: 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
    Adverse Effects of Osmotic Diuretics

   Increased extracellular fluid volume
   Hypersensitivity reactions
   Glycerol metabolism can lead to hyperglycemia
    and glycosuria
   Headache, nausea and vomiting
THANKS

				
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