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Flashcards in 10 Pharmacology of Diuretics Deck (33)
1

Diuretics

  • Nephrons
  • Diseases that disrupt this balance
  • Diuretics

  • Nephrons
    • Regulate total body fluid & electrolyte balance via the processes of secretion & reabsorption
  • Diseases that disrupt this balance
    • --> edema
    • Ex. heart failure, renal failure, nephrotic syndrome, & cirrhosis
  • Diuretics
    • Increase the rate of urine flow and sodium excretion
    • Used to adjust the volume and/or composition of body fluids in these disorders

2

Kidney

  • Nephron
  • Kidney functions
  • Kidney consumption of total body oxygen intake

  • Nephron
    • Urine forming unit of the kidney
    • ~1 million in each kidney
    • Consists of a filtering apparatus (glomerulus) attached to a long tubular portion that reabsorbs and conditions the ultrafiltrate
  • Kidney functions
    • Filter large quantities of plasma
    • Reabsorb substances that the body must conserve
      • >99% of ultrafiltrate is reabsorbed
    • Leave behind &/or secrete substances that must be eliminated
  • Kidney consumption of total body oxygen intake
    • 7% despite only being 0.5% of body weight

3

Nephron

  • PT
  • LOH
    • TDL
    • TnAL
    • TkAL
  • Macula densa
  • DCT
  • Early distal tubule
  • CD
  • % of filtered Na reabsorbed at each site of the nephron
    • PT
    • LOH
    • DT
    • CD

  • Bowman's capsule --> PT --> straight portion that enters renal medulla
    • 65% of filtered Na is reabsorbed in the PT
    • Reabsorption is isotonic b/c the PT is permeable to water
  • LOH
    • Proximal straight tubule --> TDL at the junction of the outer & inner stripes of the outer medulla
    • TDL penetrates inner medulla --> U-turn --> forms TnAL
    • TnAL --> TkAL at the border b/n the inner & outer medulla
      • Medullary portion
      • Cortical portion
      • Post macular segment
    • 25% of Na is reabsorbed in the LOH (mostly TkAL)
  • TkAL --> b/n AffA & EffA --> contacts AffA via macula densa
    • Specialized columnar epithelial cells
    • Regulates renin secretion from adjacent JG cells in the wall of the AffA
  • Macula densa --> DCT
    • Actively transports NaCl
    • Impermeable to water
    • Tubular fluid is always hypotonic compared to plasma
  • Early distal tubule: postmacular TkAL + DCT
    • Aka diluting segment of the nephron
  • CD beings where the DCT ends
    • Region of fine modulation of ultrafiltrate volume & composition
    • FInal adjustments in electrolyte composition are made
    • Regulated by aldo (Na) & ADH (water)
  • % of filtered Na reabsorbed at each site of the nephron
    • PT: 70%
    • LOH: 20%
    • DT: 5%
    • CD: 1-4%

4

Loop diuretics

  • Aka
  • Drugs
  • Pumps/channels
  • Efficacy
  • Luminal vs. basolateral membrane potentials & net result
  • Loop diuretics
  • Main syndrome

  • Aka
    • Na/K/2Cl symport inhibitors
    • High ceiling diuretics
  • Drugs
    • Furosemide (contains sulfonamide)
    • Bumetanide (contains sulfonamide)
    • Torsemide (sulfonylurea)
    • Ethacrynic acid (phenoxyacetic acid derivative)
  • Pumps/channels
    • Inhibit Na/K/2Cl symporter in the luminal membrane of the TkAL
      • Symporter uses the energy of the Na electrochemical gradient to transport K & Cl against their gradients into the cell
    • ROMK channels in the luminal membrane recycle K into the lumen
    • Cl channels in the basolateral membrane move Cl into the interstitium
  • High efficacy
    • TkAL has a large reabsorptive capacity (25%) & reabsorbs most rejectate from the PT
    • Nephron segments distal to the TkAl don't possess the same reabsorptive capacity
  • Luminal vs. basolateral membrane potentials & net result
    • Luminal membranes: hyperpolarized (more negative) b/c of K channels
    • Basolateral membranes: depolarized (less negative) b/c of Cl channels
    • Net result
      • Lumen: (+), interstitium: (-)
      • Transepithelial potential difference of 10 mV drives Na, Ca, & Mg into the interstitium
  • Na/K/2Cl inhibitors
    • Bind the Na/K/2Cl symporter in the TkAL --> block its function --> impair salt transport
    • Abolish the transepithelial potential difference --> attenuate Ca & Mg reabsorption
  • Bartter's syndrome
    • Inherited hypokalemic alkalosis w/ salt wasting & HoTN
    • Mutation in genes coding for the Na/K/2Cl symporter, apical K channel, basolateral Cl channel, or Cl channel subunit Barttin

5

Thiazide diuretics

  • Aka
  • Drugs
  • Pumps/channels
  • Thiazide diuretics
  • Main syndrome

  • Aka
    • Na/Cl symport inhibitors
    • Thiazide-like diuretics
  • Drugs
    • Chlorothiazide
    • Hydrochlorothiazide
    • Metolazone
    • Chlorthalidone
  • Pumps/channels
    • Tranport is powered by the basolateral Na pump
    • Luminal Na/Cl symporter harnesses this energy to move Na & Cl into the cell 
      • Na moves down conc gradient, Cl moves against conc gradient
    • Cl exits the cell passively via a basolateral Cl channel
  • Thiazide diuretics
    • Inhibit the Na/Cl symporter
  • Gitelman's syndrome
    • Mutations in the Na/Cl symporter --> inherited hypokalemic alkalosis

6

Na channel inhibitors

  • Aka
  • Drugs
  • Drug characteristics
  • Effects
  • Mechanism in principal cells
  • Loop & thiazide diuretics
  • Mechanism in intercalated cells (type A)
  • RAAS activation by diuretics
  • [2nd drug] effects
  • Main syndrome

  • Aka
    • K sparing diuretics
  • Drugs
    • Triamterene (pteridine derivative)
    • Amiloride (pyrazinoylguanidine derivative)
  • Drug characteristics
    • Organic bases
    • Transported by the organic base secretory mech in the PT
  • Effects
    • Increase NaCl excretion
    • Antikaliuretic actions offset the effects of other diuretisc that increase K secretion
  • Mechanism in principal cells
    • Principal cells in the CD have epithelial Na channels in the luminal membranes
      • Allow Na entry down the gradient created by the basolateral Na/K pump
    • Higher Na permeability of the luminal vs. basolateral membrane
      • Depolarizes the luminal membrane
      • Creates a lumen-negative transepithelial potential difference --> drives K secretion into the lumen via ROMK in the luminal membrane
  • Loop & thiazide diuretics
    • Increase Na delivery to the DT & CD
    • Increase luminal Na --> depolarizes luminal membrane --> increases lumen-negative potential difference --> increases K & H excretion
  • Mechanism in intercalated cells (type A)
    • Intercalated cells mediate H secretion into the tubular lumen
    • H-ATPase + partial lumianl membrane depolarization --> tubular acidification
  • RAAS activation by diuretics
    • Contribues to diuretic induced K & H excretion
  • Amiloride effects
    • Blocks epithelial Na channels (ENACs) in the luminal membrane of principal cells
    • ENAC consists of alpha, beta, & gamma subunits
  • Liddle's syndrome
    • AD form of low-renin, volume expanded HTN
    • Mutations in the alpha or gamma ENAC subunits --> increased basal ENAC activity

7

Mineralocorticoid receptors (MR) antagonists

  • Aka
  • Drugs
  • Effects
  • Mechanism

  • Aka
    • K sparing diuretics
    • Aldo antagonists
  • Drugs
    • Spironolactone
    • Eplerenone
  • Effects
    • Retain salt & water
    • Increase K & H excretion
  • Mechanism
    • Epithelial cells in the late distal tubule and CD contain cytosolic MRs w/ a high aldo affinity
    • Aldo enters into the epithelial cell from the basolateral membrane & binds to MRs
    • MR-aldo complex translocates to the nucleus & binds to specific sequences of DNA (hormone responsive elements)
      • Regulates the expression of multiple gene products called aldosterone-induced proteins (AIPs)
    • Net effect of AIPs
      • Increase Na+ conductance of the luminal membrane and Na pump activity of the basolateral membrane
    • Transepithelial NaCl transport is enhanced & the lumen negative transepithelial voltage is increased
      • Increases the driving force for secretion of K+ and H+ into the tubular lumen

8

Edema & diuretics

  • Edema
  • Local edema
  • Generalized edema
  • Edema pathophysiology

  • Edema
    • Palpable swelling & accumulation of abnormal amts of fluid in extravascular, EC compartment (IT fluid volume)
    • Diuretics relieve edema
  • Local edema
    • Causes: inflammation, lymphatic obstruction, venous obstruction, thrombophlebitis
    • Diuretics have no therapeutic role
  • Generalized edema
    • More widespread
    • CHF & renal disease --> peripheral edema, pulmonary edema, & ascites
    • Increase venous pressure --> LV dysfunction & liver cirrhosis --> pulmonary edema & ascites
    • Anasarca: severe generalized edema
    • Diuretics are useful in managing cardiac, hepatic, & renal edema
  • Edema pathophysiology
    • Altered starling forces --> Na & water movement from the vascular to IT space
    • Retain Na & water --> expand EC fluid volume

9

Mechanism of edema formation

  • Edema formation
  • Starling forces
  • Hydrostatic capillary pressure (Pcap) & oncotic interstitial pressure (πIT)
  • Hydrostatic interstitial pressure (PIT) & oncotic capillary pressure (πcap)
  • Net driving force for fluid filtration across the capillary wall
  • Effect of lymphatics

  • Edema formation
    • Most often due to elevatd capillary hydraulic pressure due to blood volume expansion or venous obstruction
  • Starling forces
    • Imbalance of starling forces in capillary beds &/or alterations in capillary premeability
    • Net filtration = (unit permeability/porosity) * (surface area for filtration) * [ (Pcap - PIT) - (πcap - πIT) ]
  • Hydrostatic capillary pressure (Pcap) & oncotic interstitial pressure (πIT)
    • Drive fluid into the IT space
  • Hydrostatic interstitial pressure (PIT) & oncotic capillary pressure (πcap)
    • Drive fluid into the capillaries
  • Net driving force for fluid filtration across the capillary wall
    • --> net flux of water into the IT space
    • Rate depends on the net driving force & capillary permeability
  • Effect of lymphatics
    • Lymphatic system can drain away the fluid fast enough --> no edema
    • Lymphatic drainage is overwhelmed --> edema

10

Edema

  • Renal Na retention
    • Primary
    • Secondary
  • Common causes

  • Renal Na retention
    • Primary
      • Advanced renal failure
      • Acute glomerulonephritis
      • Nephrotic syndrome
    • Secondary ("appropriate")
      • CHF
      • Liver cirrhosis
  • Common causes
    • CHF
    • Liver disease
      • Cirrhosis
      • Portal HTN
    • Renal disease
      • Nephrotic syndrome
      • Glomerulonephritis
      • Chronic renal failure
    • Pregnancy
    • Anemia
    • Drugs
      • NSAIDs
      • Estrogens
      • Steroids
      • Minoxidil
      • CCB
    • Venous & lymphatic obstruction
    • Idiopathic edema
    • Myxedema

11

Cardiac edema

  • Due to...
  • Signs & symptoms
  • LV dysfunction
  • RV dysfunction
  • Pathophysiology

  • Due to CHF
  • Signs & symptoms
    • Hx of heart disease
      • Orthopnea
      • SOB
      • Exertional dyspnea
    • Cogestive symptoms
      • Hepatic congestion
      • Hepatojugular reflux
    • Evidence of volume expansion
    • Ventricular gallop rhythm
  • LV dysfunction
    • Increased pulmonary venous pressure as fluid backs up in the pulm circulation behind the failing LV --> pulmonary edema
    • HoTN --> renal Na retention --> systemic edema
  • RV dysfunction
    • HoTN --> renal Na retention --> systemic edema
  • Pathophysiology
    • Cardiac failure --> decreaed CO
    • --> arterial underfilling
    • --> activation of ventricular & arterial receptors
      • --> stimulation of non-osmotic vasopressin, SNS, & RAAS
      • --> renal Na/water retention & increased systemic & renal arterial vascular resistance
      • -> maintenanc eo farterial circulatory integrity
    • --> primary peripheral arterial vasodilation
      • --> renal vasoconstriction, decreased renal perfusion pressure, increaed alpha-adrenergic activity, & increased AII
      • --> decreased GFR & increased Na/water reabsorption
      • --> decreased distal Na & water delivery
      • --> impaired aldo escape

12

Hepatic edema

  • Due to...
  • Risk factors
  • Mechanism
  • Pathophysiology

  • Due to liver disease
  • Risk factors
    • Hx of liver disease
    • Decreased CrCl (nromal serum Cr)
    • Evidence of chronic liver disease
      • Spider angiomata
      • Palmar erythema
      • Jaundice
      • Hypoaluminemia
    • Evidence of portal HTN
      • Venous pattern on abdmoinal wall
      • Esophogeal varices (can rupture)
      • Ascites
  • Mechanism
    • Chronic damage to hepatocytes
    • --> fibrotic changes in the liver (cirrhosis)
    • --> distorted, constricted, & compressed hepatic sinusoids & veins
    • --> sinusoidal & portal HTN
    • --> favored filtration into interstitial spaces
    • --> rate of fluid into interstitium > rate of lymph drainage
    • --> exudate weeps from surfaces of liver, gut, & mesentery into peritoneal cavity
      • --> reduced blood volume & kidney perfusion
        • --> RAAS activation
        • --> aldo reabsorbs Na
        • --> systemic edema
      • --> ascites
  • Other processes that contribute to systemic edema
    • Hypoalbuminemia due to decreased liver production of albumin
    • Lymphatic blockade due to lympahtic vessel compression by visceral congestion
  • Pathophysiology
    • Cirrhosis
    • --> sytemic arterial vasodilation
      • --> arterial underfilling
        • --> activation of arterial baroreceptors
        • --> stimulation of non-osmotic vasopressin, SNS & RAAS
      • --> increased CO, Na & water retention, & increased peripheral arterial vascular & renal resistance
    • --> maintenance of arterial circulatory integrity

13

Renal edema

  • Due to
  • Risk factors
  • Mechanism: nephrotic pathway
  • Mechanism: nephritic pathway

  • Due to kidney disease
  • Risk factors
    • Hx of kidney disease
    • Urinalysis
      • Proteinuria
      • Hematuria
      • Cellular casts
    • Renal imaging
      • Enlarged kidneys due to nephrotic syndrome, glomerulonephritis, diabetes, or multiple myeloma
      • Shrunked kidneys due to CKD
    • Frequent kidney steons or UTIs
  • Mechanism: nephrotic pathway
    • Loss of albumin in urine
    • Undelrying renal disease alters the glomerular sieving coefficient
      • Large molecules are inappropriately filtered rather than retained in the blood
    • Hypoalbuminemia lowers πcap
      • Drives fluid into the interstitial space
    • --> systemic edema
  • Mechanism: nephritic pathway
    • Loss of filtration in the glomeruli
      • Due to inflammation, abnormal proliferation of mesangial cells, increased production of extracellular matrix, etc.
    • Decreased GFR
      • Increased Na retention
    • --> systemic edema

14

Idiopathic edema

  • General
  • Pathophysiology
  • Treatment

  • General
    • Pts experience episodes of fluid retention (edema) w/ 5-15 lbs of water weight for no aparent reason
    • Leads pts to restrict calorie intake --> eating disorders
  • Pathophysiology
    • Dysregulation of precapillary vessels
    • --> higher transmission of ydrostatic pressure to capillaries &/or increased capillayr permeability
  • Treatment
    • Idiopathic edema will respond to diuretics
      • Diuretic abuse --> electrolte disturbances
    • Preferred treatment: pt counseling

15

Pharmacological effects of diuretics

  • Diuretics
  • Natriuretic agents
  • Aquaretic agents
  • Treatment of edematous states
    • Edematous states
    • Main effect
    • Common mech

  • Diuretics
    • Substances that increase urine production
  • Natriuretic agents
    • Clinically relevant diuretics
    • Increased diuresis is associated w/ increased Na excretion + concomitant loss of water
  • Aquaretic agents
    • Increased diuresis is associated w/ increased water excretion
    • Ex. osmotic agents (manitol) & ADH inhibitors
    • ADH receptor antagonists --> selective water diuresis
      • Na/K excretion isn't affected
      • Na & K loss are features of chronic SIADH
  • Treatment of edematous states
    • Edematous states: CHF, liver cirrhosis, nephrotic syndrome, renal failure, etc.
    • Main effect: decrease plasma volume by increasing Na & water excretion
    • Common mech: inhbiit Na reabsorption in dif sites in the nephron

16

Na/K/2Cl symptort inhibitors

  • Type of diuretics
  • Effects
  • Chronic administration of these drugs -->
  • Vascular effects
  • Effect on electrolyte transport

  • Type of diuretics
    • Loop diuretics
  • Effects
    • Increase urinray Na & Cl excretion
    • Decrease transepithelial potential differene --> increase Ca & Mg excretion
    • Increase urinary K & titratable acid excretion
  • Chronic administration of these drugs -->
    • Volume depletion 
      • --> increased uric acid reabsorptoin
      • --> competition b/n diuretic & uric acid for organic acid secretory mechs
    • --> enhanced uric acid transported in the PT
    • --> reduced uric acid excretion
  • Vascular effects (esp furosemide)
    • Increase systemic venous capacitance
      • --> decrease LV filling pressure
    • Mediated by prostaglandins
      • Requires intact kidneys
    • Benefits pts w/ pulm edema
  • Effect on electrolyte transport
    • High doses inhibit electrolyte transport
    • Important in the inner ear where altered electrolyte composition of endolymph --> drug-induced toxicity

17

Therapeutic effects of loop diuretics (Na/K/2Cl symport inhibitors)

  • Na
  • Urine volume
  • Ca
  • Free water reabsorption
  • Venous capacitance
  • ECFV

  • Increase Na excretion
    • --> treat severe edema & ascites in liver cirrhosis
  • Increase urine volume
    • --> treat oliguric ARF
  • Increase Ca excretion
    • --> treat hypercalcemia
  • Impair free water reabsorption + dilute urine
    • --> treat hyponatremia
  • Increase venous capacitance + natriuresis --> decrease LV filling pressures
    • --> treat acute pulm edema
  • Decrease ECFV
    • --> decrease venous & pulm confestion
    • --> treat chronic CHF

18

Adverse effects of loop diuretics (Na/K/2Cl symport inhibitors)

  • Most due to...
  • Overuse
  • Na delivery & RAAS
  • K
  • Mg & Ca
  • Menopause & osteopenia
  • Rapid IV administration
  • Other

  • Most due to abnormalities of fluid & electrolyte balance
  • Overuse --> Na depletion
    • --> hyponatremia
    • --> ECFV depletion
      • --> HoTN
      • --> decreased GFR
      • --> circulatory collapse
      • --> thromboembolic episodes
      • --> hepatic encephalopathy (w/ liver disease)
  • Increase Na delivery to distal tubule + RAAS activation
    • --> increased urinray K & H excretion
    • --> hypochloremic alkalosis
  • Insufficienct K intake
    • --> hypokalemia
    • --> cardiac arrhythmias (esp in pts taking cardiac glycosides)
  • Increase Mg & Ca excretion
    • --> hypomagnesemia
      • Risk factor for cardiac arrhythmias
    • --> hypocalcemia
      • Rarely --> tetany
  • Postmenopausal osteopenic women --> increased Ca excretion
    • --> deleteroius effects on bone metabolism
  • Rapid IV administration (& sometimes oral administration) & ethacrynic acid
    • --> ototoxicity
    • Tinnitus, hearing impairment, deafness, vertigo, & sense of fullness in ears
    • Hearing impairment & deafness are usulaly reversible
  • Other
    • Hyperuricemia --> gout
    • Hyperglycemia --> diabetes mellitus

19

Na/Cl symport inhibitors

  • Type of diuretics
  • Efficacy
  • Acute effects
  • Chronic effects

  • Type of diuretics
    • Thiazide diuretics
  • Efficacy
    • Moderate b/c 90% of filterd Na is reabsorbed before reaching the DCT
  • Acute effects
    • Increase Na & Cl excretion in teh DCT
    • Increase K & titratable acid excretion
    • Dilute urine (but don't interfere w/ ability to concentrate it)
  • Chronic effects
    • Decrease urica cid excretion
    • Decrease Ca excretion
      • Indirectly increase PT reabsorption from volume depletion
      • Directly increase reabsorption in the DCT
    • Magnesuria & Mg deficiency (esp in elderly)

20

Therapeutic effects of thiazide diuretics (Na/Cl symport inhibitors)

  • Edema
  • BP
  • Ca
  • Urine volume
  • Free water
  • Beneficial characteristics
  • Effect of GFR

  • Treat edema
    • Due to CHF, hepatic cirrhosis, & renal disease (nephrotic syndrome, chronic renal failure, & acute glomerulonephritis
  • Decrease BP in pts w/ HTN
    • Increase slope of renal pressure / natriuresis rltnshp
    • Used alone or w/ other anti-HTN drugs to treat HTN
      • Aditive/synergistic effects when combined w/ anti-HTN agents
    • Common dose for HTN: 25 mg/day of hydrochlorothiazide
  • Decrease Ca excretion
    • Treat Ca nephrolithiasis & osteoporosis
  • Decrease urine volume
    • Treat nephrogenic diabetes insipidus
  • Decrease free water excretion
    • By increasing PT water reabsorption & blocking DCT's ability to form dilute urine
    • Increases urine osmolality
  • Beneficial characteristics
    • Inexpensive & efficacious
    • Administered 1x/day & don't require dose titration
    • Well tolerated w/ few contraindications
  • Effect of GFR
    • Thiazide diuretics are ineffective when GFR < 30-40 ml/min

21

Adverse effects of thiazide diuretics (Na/Cl symport inhibitors)

  • Most serious are due to...
  • Volume
  • BP
  • K
  • Na
  • Cl
  • Acid/base
  • Mg
  • Ca
  • Uric acid
  • Glucose
  • LDL

  • Most serious are due to abnormal fluid & electrolyte balance
  • EC volume depletion
  • HoTN --> increased type II diabetes mellitus
  • Hypokalemia --> hyperglycemia
  • Hyponatremia
  • Hypochloremia
  • Metabolic alkalosis
  • Hypomagnesemia
  • Hypercalcemia
  • Hyperuricemia
  • Hyperglycemia
    • Decrease glucose intolerance --> diabetes mellitus
    • Due to decreased insulin secretion & altered glucose metabolism
  • Increase plasma LDL

22

Na channel inhibitors

  • Type of diuretics
  • Effects

  • Type of diuretics
    • K sparing diuretics
    • Triamterene, amiloride
  • Effects
    • Blocks ENAC
      • Blocks Na flow from tubular lumen into principal cells
    • Mildly increase Na & Cl excretion
      • DT & CD have a limited capacity to reabsorb solutes
    • Hyperpolarize luminal membrane
      • --> decrease lumen-negative transepithelial voltage
      • --> decrease K, H, Ca, & Mg excretion
    • Volume contraction --> increase uric acid reabsorption in the PT
      • Chronic Na channel inhibitors --> decrease uric acid excretion

23

Therapeutic effects of K sparing diuretics (Na channel inhibitors)

  • Co-administration
  • Na-channel inhibitors + thiazide & loop diuretics
  • Syndrome trated effectively w/ Na channel inhibitors
  • Amiloride

  • Co-administration
    • Rarely used alone to treat edema or HTN due to mild natriuresis
    • Major utility is in combo w/ other diuretics
  • Na-channel inhibitors + thiazide & loop diuretics
    • Increases diuretic & anti-HTN response
    • Reduces K excretion to offset kaliuretic effects --> normal plasma K
  • Syndrome trated effectively w/ Na channel inhibitors
    • Liddle's syndrome
  • Amiloride
    • Blocks Li transport into CD cells
    • Useful for Li-induced nephrogenic diabetes insipidus

24

Adverse effects of K sparing diuretics (Na channel inhibitors)

  • Most dangerous
  • Contraindications
  • Triamterene

  • Most dangerous
    • Hyperkalemia (life-threatening)
  • Contraindications
    • Pts w/ or at risk for hyperkalemia
    • Older, high dose therapy, renal impairment, hypoaldosteronism, & treatment w/ other drugs that impair renal K excretion (NSAIDs & ACE-Is)
  • Triamterene
    • Weak folic acid --> folic acid deficiency --> megaloblastosis
    • Interstitial nephritis
    • Renal stones

25

Mineralocorticoid receptor antagonists

  • Efficacy
  • Effects

  • Efficacy
    • Function of endogenous aldo levels
    • Higher endogenous aldo --> greater MR antagonist effects on urinary excretion
  • Effects
    • Similar to Na channel inhibitors
    • Reduces amt of Na coming into the cell --> increases Na in urine
    • Blocks excretion --> K sparing

26

Therapeutic effects of mineralocorticoid receptor antagonists

  • Spironolactone + thiazide & loop diuretics
  • Spironolactone
  • Eplerenone

  • Spironolactone + thiazide & loop diuretics
    • Increased mobilization of edema fluid + decreased K perturbations --> treat edema
    • Treat HTN
    • Reduces morbidity, mortality, & ventricular arrhythmias in pts w/ heart failure
  • Spironolactone
    • Treats primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia)
    • Treats refractory edema w/ secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, & severe ascites)
    • Diuretic of choice for hepatic cirrhosis
  • Eplerenone
    • Less used clinically than spironolactone
    • Safe & effective for HTN
    • Added to standard therapy for MI w/ LV systolic dysfunction

27

Adverse effects of mineralocorticoid receptor antagonists

  • Most serious
  • Contradinications
  • Due to affinity for other steroid receptors, spironolactone may cause...
  • Other adverse effects of spironolactone
  • Chronic or high dose adverse effects of spironolactone
  • Adverse CNS effects

  • Most serious
    • Hyperkalemia (life-threatening)
    • Metabolic acidosis in pts w/ cirrhosis
  • Contradinications
    • Pts w/ or at risk for hyperkalemia due to disease or other meds
  • Due to affinity for other steroid receptors, spironolactone may cause...
    • Gynecomastia
    • Impotence
    • Decreased libido
    • Hirsutism
    • Deepening of the voice
    • Menstrual irregularities
  • Other adverse effects of spironolactone
    • Diarrhea
    • Gastritis
    • Gastric bleeding
    • Peptic ulcers
  • Chronic or high dose adverse effects of spironolactone
    • Breast cancer
    • Malignant tumors (rats)
  • Adverse CNS effects
    • Drowsiness
    • Lethargy
    • Ataxia
    • Confusion
    • Headache

28

Diuretics: molecular targets

  • Loop diuretics
    • Nephron site
    • Molecular target
  • Thiazide-type diuretics
    • Nephron site
    • Molecular target
  • Potassium-sparing diuretics
    • Nephron site
    • Molecular target

  • Loop diuretics
    • Nephron site: TkAL
    • Molecular target: competition for the Cl site on the Na/K/2Cl cotransporter
  • Thiazide-type diuretics
    • Nephron site: distal tubule
    • Molecular target: competition for the Cl site on the Na/Cl cotransporter in the luminal membrane
  • Potassium-sparing diuretics
    • Nephron site: collecting tubule
    • Molecular target: affects the open probability and/or number of the epithelial cell apical Na channel

29

Celing dose

  • Diuretic potency
  • Dose response curve
  • Ceiling dose
  • Ceiling dose depends on...
  • Factors that determine the ceiling dose
  • Converting IV dosing to oral dosing
    • Furosemide
    • Bumetanide
    • Torsemide

  • Diuretic potency
    • Quantity of Na normally reabsorbed at the diuretic target area
    • Ability fo the more distal segments to reabsorb the excess Na
  • Dose response curve
    • Increase in Na excretion is related to rate of diuretic excretion (availability of the diuretic at the luminal site)
  • Ceiling dose
    • Dose that provides concs of diuretic in the tubular lumen that yield a near max ("ceiling") effect
      • Most diuretics (except MR antagonists) must gain access to the tubular lumen to be effective
    • Doses > ceiling dose: increased risk of adverse effects w/o increased therapeutic response
  • Ceiling dose depends on...
    • Diuretic
      • Loop > thiazide > K-sparing
    • Disease
      • Diminished nephron response in nephrotic syndrome, cirrhosis, & heart failure
  • Factors that determine the ceiling dose
    • Potency: increase potency --> decreaes dose
    • Tubular transport (ex. ARF/CRF): decrease tubular transport --> increase dose
    • Binding urinray proteins (ex. nephrotic syndrome): increaes binding urinary proteins --> increase dose
  • Converting IV dosing to oral dosing
    • Furosemide: bioavailability = 50% --> conversion factor > 2
    • Bumetanide: bioavailability = 100% --> conversion factor = 1
    • Torsemide: bioavailability = 100% --> conversion factor = 1

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Diuretic resistance

  • Diuretic resistance
  • Mechanisms of diuretic resistance
  • Frequent cause
  • Most popular sequential blockade
  • Frequent dosing or continuous infusion to overcome diuretic resistance

  • Diuretic resistance
    • The response to a diuretic is inadequate to provide the desired level of therapeutic response (edema resolution)
  • Mechanisms of diuretic resistance
    • Noncompliance --> pt counseling
    • NSAIDs --> pt counseling
    • Decreased tubular transport (ex. ARF, CRF) --> push to ceiling dose
    • Decreased RBF --> bed rest
    • Changes in volume hormones (SNS, RAS, ADH, ANF) --> bed rest
    • Compensation by distal nephron --> combination therapy (sequential blockade)
    • Diminished nephron response (CHF, cirrhosis, nephrotic syndrome) --> more frquent dosing or continuous infusion
  • Frequent cause: compensation by distal epithelial cells when proximal transport is inhibited
    • Ex. urinary excretion of Na may be adequate initially w/ a loop diuretic
      • Eventually the distal epitehlial cells undergo hypertrophy & express more transporters
      • Epithelial cells caputre more proximal "rejectate"
      • Na excretion becomes inadequate
    • Overcome by sequential blockade (combination therapy)
      • Use of >2 diuretics to inhibit transport in >1 nephron sit
  • Most popular sequential blockade
    • Loop diuretic (blocks LOH) + thiazide diuretic (blocks DT)
  • Frequent dosing or continuous infusion to overcome diuretic resistance
    • More frequent dosing provides ceiling concs in the tubular lumen for a higher % of the day
    • Continuous infusion provides ceiling concs of diuretic throughout the day

31

Postdiuresis Na retention

  • Postdiuresis Na retention
  • High salt diet
  • Low salt diet
  • Take home
  • Drug interactions
    • NSADS, salt decongestants, & probenecid
    • ACE-Is, beta-blockers, K supplements, K sparing diuretics, & heparin
    • Ototoxic drugs

  • Postdiuresis Na retention
    • Limits diuretic efficacy
    • Occurs after a high dose of diuretic during the time that transport is sub-maximally inhibited
    • Loss of Na --> kidneys retain Na
  • High salt diet
    • Increase in Na excretion during first 6 hours after diuretic administration is completely offset by a reduction in Na excretion during the next 18 hours
  • Low salt diet
    • Postdiuresis Na retention is blocked
  • Take home
    • Diuretics are more effective in reducing bodoy Na when pts are on a los-salt diet
    • Salt restriction attenuates the postdiuretic Na retention phenomenon
  • Drug interactions
    • NSADS, salt decongestants, & probenecid
      • Diminished diuretic response
    • ACE-Is, beta-blockers, K supplements, K sparing diuretics, & heparin
      • Hyperkalemia
    • Ototoxic drugs
      • Enhanced ototoxicity of loop diuretics

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Summary

  • Edema
    • Palpable swelling caused by expansion of the interstitial fluid volume
  • Two basic mechanisms responsible for edema formation
    • An alteration in capillary hemodynamics favoring movement of fluid from the vascular space into the interstitium
    • Compensatory renal sodium and water retention to expand the decreasing extracellular fluid volume
  • Diuretics
    • Promote lowering of the plasma volume mainly by increasing the excretion of Na and water
    • Work mainly by inhibiting Na reabsorption in different segments of the nephron
  • Common side effects of diuretics
    • Volume depletion from excess fluid removal
    • Disturbances in K balance

33

Vasopressin receptor locations & functions

  • V1a
  • V1b
  • V2

  • V1a
    • Vascular smooth msucle
      • Vasoconstriction
      • Myocardial hypertrophy
    • Platelets
      • Platelet aggregation
    • Hepatocytes
      • Glycogenolysis
    • Myometrium
      • Uterine contraction
  • V1b
    • Anterior pituitary
      • ACTH release
  • V2
    • Basolateral membrane collecting tubule
      • Insert AQP2 water channels into apical membrane
      • Induce AQP2 synthesis
    • Vascular endothelium
      • vWF & factor 8 release
    • Vascular smooth muscle
      • Vasodilation