DIURETICS AND ELECTROLYTE DISTURBANCES

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DIURETICS AND ELECTRO-LYTE DISTURBANCES

• DAVID G. WARNOCK, MD
• UNIVERSITY OF ALABAMA
• AT BIRMINGHAM

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DIURETICS AND ELECTROLYTE DISTURBANCES

• REVIEW TUBULAR TRANSPORT AND DIURETIC MECHANISMS
  OF ACTION
• REVIEW INDICATIONS AND SIDE EFFECTS OF DIURETIC
  CLASSES
• DEVELOP AN UNDERSTANDING OF CLINICAL SITUATIONS
  WHERE THE CHOICE OF A SPECIFIC DIURETIC AGENT
  MAKES A DIFFERENCE

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DIURETICS AND ELECTROLYTE DISTURBANCES

• PROXIMAL TUBULE - CA INHIBITORS
• THICK ASCENDING LIMB -
• LOOP AGENTS
• DISTAL CONVOLUTED TUBULE -
• THIAZIDE DIURETICS
• COLLECTING TUBULE -
• K SPARING DIURETICS
• OSMOTIC DIURETICS

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DIURETICS AND ELECTROLYTE DISTURBANCES

• DIURETIC-INDUCED RENAL K WASTING
• Increased Distal Na Delivery Drives K Secretion
• High Renin and Aldo
• H Secretion is Also Enhanced
• Associated Metabolic Alkalosis

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PROXIMAL TUBULE CARBONIC ANHYDRASE INHIBITORS

• SITE OF ACTION
• INHIBITS HCO3 REABSORPTION IN PROXIMAL TUBULE
• BICARBONATURIA RESULTS FROM ??CA ACTIVITY IN BBM
• SHORT TERM ??IN URINE pH

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PROXIMAL TUBULE CARBONIC ANHYDRASE INHIBITORS

• INDICATIONS
• GLAUCOMA, URINE ALKALINIZATION, MOUNTAIN SICKNESS
• TOXICITIES
• HYPERCHLOREMIC METABOLIC ACIDOSIS
• CaPO4 STONES
• RENAL K WASTING
• NH3 INTOXICATION

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THICK ASCENDING LIMB

• LOOP AGENTS INHIBIT Na, K, 2Cl- CO-TRANSPORTER
  AT THE LUMEN SIDE
• REDUCE THE POSI-TIVE TRANSPORT POTENTIAL TO ZERO
• INCREASE URINARY NaCl and K, Mg2 AND Ca2
  EXCRETION

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THICK ASCENDING LIMB

• INDICATIONS FOR LOOP AGENTS
• Pulmonary Edema
• Refractory Edema
• Hypercalcemia
• TOXICITIES
• K and Mg2 Wasting
• Metabolic Alkalosis
• Hypercalciuria
• Ototoxicity

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DISTAL CONVOLUTED TUBULE

• THIAZIDES INHIBIT THE LUMINAL NaCl COTRANSPORTER
• REDUCE THE NEGA-TIVE TRANSPORT POTENTIAL TO 0 mV
• INCREASE URINARY NaCl and K, BUT NOT Ca2
  EXCRETION

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DISTAL CONVOLUTED TUBULE THIAZIDES

• Ca2 ABSORPTION IS ENHANCED
• Negative Transepithelial Potential Retards Ca2
  Absorption
• Thiazides Take the Brake Off by Reducing the
  Transport PD to Zero
• Alternatively, Hyperpolarization of Membrane PD
  May Activate Ca2 Entry
• Thiazide Effect on Ca2 Absorption is Blunted by
  Excess Dietary NaCl

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DISTAL CONVOLUTED TUBULE

• INDICATIONS FOR THIAZIDES
• HTN and CHF
• Hypercalciuria
• TOXICITIES
• Renal K Wasting
• Metabolic Alkalosis
• Increased Lipids, Uric Acid and Glucose

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COMBINED USE OF AGENTS

• THIAZIDES AND LOOP AGENTS HAVE DISTINCT SITES AND
  MECHANISMS OF ACTION
• TRUE SYNERGIC EFFECT OCCURS
• UNMASKING OF A PROXIMAL EFFECT
• ADAPTATION OF DISTAL CONVOLUTED TUBULE TO CHRONIC
  INHIBITION OF THICK ASCENDING LIMB FUNCTION

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COMBINED USE OF AGENTS

• INDICATIONS FOR COMBINED THERAPY
• REFRACTORY EDEMA
• SEVERE HYPERKALEMIA
• TOXICITIES
• RENAL K WASTING
• METABOLIC ALKALOSIS

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DIURETICS AND ELECTROLYTE DISTURBANCES

• DIURETIC-INDUCED RENAL K WASTING
• Increased Distal Na Delivery Drives K Secretion
• High Renin and Aldo
• H Secretion is Also Enhanced
• Associated Metabolic Alkalosis

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COLLECTING TUBULE

• SITE OF FINAL REGULATION OF SALT, WATER AND
  ACID-BASE BALANCE
• MULTITUDE OF HORMONAL CONTROL MECHANISMS
• 3 SPECIFIC FUNCTIONAL ASPECTS
• Na and K Transport
• Water Transport
• H Transport

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COLLECTING TUBULE

• K SPARING AGENTS INHIBIT LUMINAL Na CHANNEL
  ACTIVITY
• REDUCE THE NEGA-TIVE TRANSPORT PD TO ZERO
• INCREASE URINARY NaCl EXCRETION

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COLLECTING TUBULE

• INDICATIONS FOR K SPARING AGENTS
• Primary and Secon-dary Aldosteronism
• TOXICITIES
• Hyperkalemia
• Metabolic Acidosis
• BPH, Gynecomastia with Spironolactone
• ARF, Stones

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DIURETIC INDUCED K WASTING

• REDUCE DIURETIC DOSING TO ? ALDO
• REDUCE DIETARY NaCl INTAKE
• K SUPPLEMENTS
• ADD K SPARING DIURETICS IN CON- JUNCTION WITH
  SALT RESTRICTION

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COLLECTING TUBULEADH RESPONSE

• HYDRO-OSMOTIC RESPONSE TO ADH CONCENTRATES THE
  URINE
• AQP-3 Expressed in the Baso-Lateral Membrane
• ADH causes insertion of AQP-2 into the apical
  membrane

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COLLECTING TUBULE OSMOTIC DIURETICS

• OSMOTIC H2O FLOW IS DRIVEN BY MEDUL-LARY
  HYPERTONICITY
• OSMOTIC DIURETICS OBLIGATE FREE WATER EXCRETION
• MAJOR EFFECT IN H2O PERMEABLE SEGMENTS

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COLLECTING TUBULE OSMOTIC DIURETICS

• INDICATIONS FOR OSMOTIC AGENTS
• REDUCTION OF INTRACELLULAR VOLUME (eg. CEREBRAL
  EDEMA)
• INTRA-TUBULAR OBSTRUCTION (CAST NEPHROPATHY,
  RHABDOMYOLYSIS)
• TOXICITIES
• HYPERNATREMIA
• VOLUME DEPLETION
• ACUTE RENAL FAILURE

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DIURETICS AND ELECTROLYTE DISTURBANCES

• REVIEW TUBULAR TRANSPORT AND DIURETIC MECHANISMS
  OF ACTION
• Specificity of Diuretic Effects Are a Reflection
  of Their Sites of Action
• Tubular Transport Mechanisms Have Been Recently
  Illuminated By Studies of the Effects of Specific
  Diuretic Agents
• Linear Heterogeneity and Integrative Function
  Explain Global Effects

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DIURETICS AND ELECTROLYTE DISTURBANCES

• REVIEW INDICATIONS AND SIDE EFFECTS OF DIURETIC
  CLASSES
• Side Effects Are in Large Part Dose-Dependent and
  Predictable From the Known Effects of Each
  Diuretic Class
• Specific Indications Are Predicated On the
  Effects of Each Class of Agents
• Combination Agents Can Be Rational Therapeutic
  Choices