10 Pharmacology of Diuretics

Question 1

Diuretics

• Nephrons
• Diseases that disrupt this balance
• Diuretics

Answer 1

• 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

Question 2

Kidney

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

Answer 2

• 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

Question 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

Answer 3

• 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%

Question 4

Loop diuretics

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

Answer 4

• 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

Question 5

Thiazide diuretics

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

Answer 5

• 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

Question 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

Answer 6

• 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

Question 7

Mineralocorticoid receptors (MR) antagonists

• Aka
• Drugs
• Effects
• Mechanism

Answer 7

• 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

Question 8

Edema & diuretics

• Edema
• Local edema
• Generalized edema
• Edema pathophysiology

Answer 8

• 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

Question 9

Mechanism of edema formation

• Edema formation
• Starling forces
• Hydrostatic capillary pressure (P_cap) & oncotic interstitial pressure (π_IT)
• Hydrostatic interstitial pressure (P_IT) & oncotic capillary pressure (π_cap)
• Net driving force for fluid filtration across the capillary wall
• Effect of lymphatics

Answer 9

• 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) * [(P_cap - P_IT) - (π_cap - π_IT)]
• Hydrostatic capillary pressure (P_cap) & oncotic interstitial pressure (π_IT)
  
  • Drive fluid into the IT space
• Hydrostatic interstitial pressure (P_IT) & oncotic capillary pressure (π_cap)
  
  • 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

Question 10

Edema

• Renal Na retention
  
  • Primary
  • Secondary
• Common causes

Answer 10

• 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

Question 11

Cardiac edema

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

Answer 11

• 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

Question 12

Hepatic edema

• Due to…
• Risk factors
• Mechanism
• Pathophysiology

Answer 12

• 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

Question 13

Renal edema

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

Answer 13

• 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 π_cap
    
    • 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

Question 14

Idiopathic edema

• General
• Pathophysiology
• Treatment

Answer 14

• 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

Question 15

Pharmacological effects of diuretics

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

Answer 15

• 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

Question 16

Na/K/2Cl symptort inhibitors

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

Answer 16

• 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

Question 17

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

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

Answer 17

• 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

Question 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

Answer 18

• 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

Question 19

Na/Cl symport inhibitors

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

Answer 19

• 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)

Question 20

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

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

Answer 20

• 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

Question 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

Answer 21

• 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

Question 22

Na channel inhibitors

• Type of diuretics
• Effects

Answer 22

• 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

Question 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

Answer 23

• 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

Question 24

Adverse effects of K sparing diuretics (Na channel inhibitors)

• Most dangerous
• Contraindications
• Triamterene

Answer 24

• 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

Question 25

Mineralocorticoid receptor antagonists

• Efficacy
• Effects

Answer 25

• 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

Question 26

Therapeutic effects of mineralocorticoid receptor antagonists

• Spironolactone + thiazide & loop diuretics
• Spironolactone
• Eplerenone

Answer 26

• 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

Question 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

Answer 27

• 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

Question 28

Diuretics: molecular targets

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

Answer 28

• 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

Question 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

Answer 29

• 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

Question 30

Diuretic resistance

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

Answer 30

• 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

Question 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

Answer 31

• 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

Question 32

Summary

Answer 32

• 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

Question 33

Vasopressin receptor locations & functions

• V1a
• V1b
• V2

Answer 33

• 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