Diuretics I & II

Question 1

what are the ions reabsorbed/secreted in the

proximal tubule?

thick ascending loop of henle?

distal convluted tubule?

collected tubule?

Answer 1

• reabsorbed: (note Na, Cl- reabsorbed at each segment)
  
  • proximal tubule: Na+, Cl- HCO3
  • thick ascending loop of henle: Na, Cl-, Ca+, Mg
  • distal convoluted tubule: Na-, CL- Ca
  • collecting tubule: Na, Cl-
• secreted:
  
  • proximal tubule: H+
  • collecting tubule: H+, K+

Question 2

carbonic anhydrase inhibitor diuretics act on what renal tubular segment?

Answer 2

proximal tubule

Question 3

loop diuretics act on what tubular segment?

Answer 3

thick ascending loop of henle

Question 4

thiazide diuretics act on what tubular segment?

Answer 4

distal convoluted tubule

Question 5

K+ sparing diuretics act on what part of the tubular segment?

Answer 5

the collecting tubule

Question 6

Answer 6

Question 7

Answer 7

Question 8

carbonic anhydrase inhibitors

• renal MOA

Answer 8

• MOA: multiple
  
  • renal: diuresis by acting on the proximal convoluted tubule
    
    • inhibits reabsorption of Na+, HCO3 and HCl-
      
      • recall from phys:
        
        • Na+/H antiporter takes up Na+ in exchange for H+
          
          • Na+ reabsorbed into blood by Na/K transporter
        • the secreted H+ combinates with bicarb to make H₂CO₃
        • H2CO₃ dissociates back into back into H₂O + CO₂ via carbonic anhydrase
        • these products are reabsorbed into the cell and ultimately break down to release HCO₃ (which is reabsorbed into the blood) and H+, which drives Na+/H antiport
          
          • (antiport necessary to drive Na+ reabsorption)
    • thus, inhibition of carbonic anhydrase impedes both Na+ and HCO3 reabsorption
      
      • since HCO_3- starts the accumulate in the filtrate, the filtrate becomes basic.
      • the Cl-/base exchanger, which pumps base into the blood in exchange for sodium reabsorption, is now slowed
        
        • this slows Cl- reabsorption

Question 9

net effects of carbonic anhydrase inhibitors

Answer 9

• decreased reaborption Na, HCO3 and Cl
  
  • net effect:
    
    • reduced NaHCO3 and NaCl reabosprtion
    • increased tubular concentration of NaHCO3 and NaCl, which results in.
      
      • 1. DIURESIS (due to NaCl)
           * water follows NaCl into tubule
           * increased urine volume –> pee it out
      • 2. INCREASED URINE pH (due to NaHCO3)

Question 10

why is tolerance to carbonic anhydrase inhibitor diuretics so common?

Answer 10

• in response to basic urine pH resulting from CAIs, the body compensates with metabolic acidosis
  
  • the body provides H+ for the plasma
  • the plasma H+ diffuses into the cell, then drives the Na+/H+ antiporter, promoting Na+ reabsoprtion and H+ secretion (which then combines with HCO_3-) to ultimately pull it back into the cell
    
    • though carbonic anhydrase can still inhibit CAIs, the Na+/H+ antiporter now works, Na+ enters the blood, followed by water –> high blood pressure

Question 11

non-renal indications and MOAs of carbonic anhydrase inhibitors

Answer 11

• CAIs used to treat high pressure in the eye and cerospinal system
  
  • glaucoma
    
    • in eye - carbonic anhydrase generates HCO3- that draws Na+ and fluid into the aqueous humor
      
      • _​_this increases the introocular pressure/
      • CAIs inhibit this process to lower introular pressure
  • cerebrospinal pressure
    
    • in brain - carbonic anhydrase generates HCO3- that draws inNa+ and fluid into the cerbrospinal fluid
      
      • increases cerobrospinal fluid pressure
      • CAIs inhibit this process

_(_dont fully understand the mechanisms here)

Question 12

clinical uses of CAI

Answer 12

• glaucoma
• high cerobrospinal pressure
  
  • can also treat acute mountain sickness resulting from high cerocrospinal pressure:
    
    • sickness caused when high cranial pressure impedes oxygen extraction
      
      • CAIs lower pressure and allow for improved O2 intake/CO2 removed
• urinary acidosis - CAIs increase urinary HCO3
• compensatory metabolic alkalosis (resulting from excessive use of diuretics or respiratory acidosis)
  
  • CAIs increase urinary HCO3, neutralizing acidic urine so the body doesn’t have to

Question 13

AEs of CAIs

Answer 13

• metabolic acidosis (CAIs correct urinary acidosis, but resulting urinary alkalosis could induce compensatory metabolic alkalosis)
• renal K+ wasting
• renal stones (rarely)
  
  • due to K+, Ca+ excretion, these ions forms stones in tubules
• parathesia
• drowsiness
• hypersensitivity reactions

Question 14

name of CAI

Answer 14

acetazolamine (a sulfonamide)

Question 15

loop diuretics MOA

Answer 15

loop diuretics act on the thick ascending loop of henle

• here, they inhibit reabsoprtion of Na+, Cl-, Mg+, Ca+
  
  • recall from phys:
    
    • the NKCC2 transporter pumps Na+, K+ and 2Cl- into cell from filtrate
    • on basolateral side, the reabsorbed Na+ moves into the blood in exchange for K+ thru Na/K ATPase
    • the combined K+ increase in the cell drives K+ out of the cell into the filtrate
      
      • this increases the (+) charge in the filtrate
      • this drives cations Mg2+ and Ca2+ out of filtrate into cell –> into blood
        
        • combined reabsorption Na, CL-, Mg and Ca creates medullary hypertonicity
        • K+ secreted after initial reabsorption so does not contribute to this
  • loop diuretics work by:
    
    • inhibiting the NKCC2 transporter - inhibits all absorption resulting from that transporter (Na, Cl, Mg, Ca)
      
      • reduces medullary tonicity

Question 16

overall effects of loop diuretics

Answer 16

• decrease tonicity of medulla
  
  • this diminshes the the osmotic gradient that goes from the cortex to the medulla: typically, the solute reabsorbsion that occurs at the thick ascending limb establishes a interstitial concentration that increases from the cortex down into the medulla and promotes water reabsoprtion in the thin descending limb and collecting tubules
    
    • ​since loop diruetics inhibit reabsorption at TAL, they disrupt this gradient and impede water reabsorption at the thick descending limb at collecting tuubles

Question 17

what are the loop diuretics?

Answer 17

• furosemide
• bumetanide
• torsemide
• ethacrynic acid

Question 18

MOA of thiazide diuretics

Answer 18

thiazide diuretics act at the DCT (distal convoluted tubule)

• at the DCT: Na, Cl, Ca++ reabsorbed
  
  • recall from phys:
    
    • a Na/K ATPase establishes a Na+ gradient that drives NCC, a NaCl cotransporter
      
      • NCC moves Na+ and Cl- from filtrate into cell for reaborption
• thiazide diuretics block the NCC channel:
  
  • _​_this decreases Na+ and Cl- reabsorption
    
    • the decrease in intracellular [Na+] drives a Ca++/Na+ exchanger to move Na+ from the blood into the cell in exchange fro Ca++
      
      • –> increasing Ca++ reabsoprtion
  • they also may increase Ca++ reabsorption at the PCT as a result of volume depletion

Question 19

net effects of thiazide diuretics

Answer 19

• increased excretion of NaCl, water, and K+ (?)
• increased reabsorption of of Ca++

Question 20

contrast the effects of loop diuretics and thiazide diuretics on Ca++ movement and what this means in terms of their clinical uses

Answer 20

have opposite effects:

• loop diuretics: decrease Ca++ reabsorption, increase tubular Ca++
  
  • thus can be used to treat with patients with hypercalcemia [high blood Ca++]
• thiazide diuretics: increase Ca++ reabsorption, lower tubular Ca++
  
  • thus can be used to treat patients hyperuricemia
    
    • this can reduce the risk of gallstones

Question 21

contrast loop and thiazide diuretics in terms of potency

Answer 21

loop diuretics more potent

Question 22

describe how loop and thiazide diuretics can be used to treat “edematous status”

Answer 22

both drugs can be used to lower edema caused by the two following conditions:

• chronic heart failure (HF)
  
  • HF leads to edema because: lowered CO leads to –> renal hyperperfursion –> riggering RAAS activation –> causing Na+/water reabsorption –> f_luid retention_ –> edema
    
    • both drugs inhibit fluid rention, lowering edema as well as pulmonary and systemic congestion
  • loop vs thiazide:
    
    • ​loop diuretics best for severe HF and first choice for rapid relief of congestive symptoms
    • thiazide diruetics: best for mild HF
• acute pulmonary edema
  
  • ​both durgs promote Na+ and water excretion –> lowering ventricular feeling pressure –> decreasing pulmonary edema
  • loop vs thiazide:
    
    • both drugs can be used, loop diuretics are better - “drug of choice” for acute pulmonary edema

Question 23

describe how loop and thiazide diuretics can be used to manage hypertension.

Answer 23

• Thiazide diuretics: all patients with essential hypertension and normal renal function
• Loop diuretics: hypertensive patients with renal insufficiency or heart failure

Question 24

discuss use of loop and thiazide diuretics in the treatment of diabetes

Answer 24

only thiazide diuretics are use dto treat diabetes. they can be used to treat

• diabetes insipidus (DI):
  
  • diabetes inspidus is characterize by an inability of ADH to induce water reabsorption, either due to 1. impaired ADH synthesis (neurogenic DI) or 2. inadeuqate response of kidney to ADH
  • use of thiazides:
    
    • thiazides relieve polyuria and polydipsia secondary to DI by increasing urine flow (dont really get this, picture attached)
    • they are indicated in the treatment of lithium induced nephrogenic DI
      
      • ​they work by increasing expression of Na+ transporters in the DCT and CCT –> increasing water reabsorption

Question 25

discuss the clinical uses of thiazide diuretics pertaining to its effect on Ca++ movement

Answer 25

• thiazide diuretics increase Ca++ reabsorption in the DCT and PCT, and can thus be used to treat:
  
  • nephrolithiasis (caused by a defect of Ca++ reaborption in PCT)
  • osteoporosis
  • hyperuricemia

Question 26

discuss the clinical use of loop diuretics pertaining to their effect on calcium reabsorption

Answer 26

• loop diuretics decrease Ca++ reabsorption
  
  • they are combined with saline to treat hypercalcemia in patients with:
    
    • renal failure
    • HF

Question 27

thiazide-like duiretics

• what are they?
• what are their clinical uses and how do they work?

Answer 27

• indapamide, metaolazone, chlorthalidone
• can be combined with loop diuretics to treat patients with edema who:
  
  • have a GFR < 20 ml/min
  • are refractory to loop diuretics
• how this works:
  
  • since these thiazide like diuretics decrease Na++ reabsorption in the PCT/DCT, they i_ncrease the load of Na++_ in the tubular filtrate in the thick ascending limb. this is Na++ that would have otherwise been reabsorbed, but will now be excreted due to loop diuretics

Question 28

adverse effects of both loop and thiazide diuretics

Answer 28

hypos:

• hyponatremia
• hypomagnesemia (especially loop diuretics)
• hypokalemic metabolic acidosis: both diuretics increase tubular Na++ that arives to the collecting ducts
  
  • this may induce aldosterone mediated activativation of the Na/K exchanger, which would promote Na+ uptake in exchange for K+ secretion

hypers:

• hyperuiciemia: this is because the diuretics themselves are secreted via an organic acid transporter that secretes uric acid.
  
  • the diuretics can compete for this transporter, leading to buildup or uric acid in the blood
• hyperglycemia
  
  • ​hypokalemia can cause can decrease insulin secretion from pancreas B-cells
  • this doesn’t apply to thiazide-like diuretics
• possibly hyperlipidemia
• allergic reactions

Question 29

what are the unique AEs of loop diuetics?

Answer 29

otoxicity: reversible, stria vascularis edema that damages the ears

Question 30

what are the unique adverse effects of thiazide diuretics?

Answer 30

hypercalcemia

Question 31

drug drug interactions of loop & thiazide diuretics

Answer 31

• dofelitide: prolonged QT interval
• digoxin: hypokalemia
• NSAIDS: decrease diuretic effect
• anti-hypertensives: can cause hypotension

Question 32

what are the unique functions of the collecting tubule?

Answer 32

• the collecting tubule is:
  
  • the final site of NaCl reabsorption
  • action site of ADH and aldosterone
  • site of K+ secretion
    
    • ​and thus the site of diruetic induced K+ changes

Question 33

discuss the movement of solutes at the collecting tubule

Answer 33

• reabsorption of Na+ in principle cells causes a negative intraluminal charge that drives:
  
  • K+ secretion from principle cells
  • paracellular Cl- reabsorption
  • H+ secretion from adjacent intercalated cells

Question 34

what are the classes of K+ sparing diuretics and their MOAs?

Answer 34

• they act on the collecting tubules to
  
  • increase excretion of Na+ and Cl-
  • decrease excretion of K+ and H+
• classes: both block reabsorption at Na+ channel
  
  • aldosterone antagonists
  • Na+ blockers

Question 35

list the drugs in each class of K+ sparing diuretics.

Answer 35

• aldosterone receptors antagonists
  
  • spironolactone
  • epleronone
• Na+ channel blockers:
  
  • amiloride
  • triamterine

Question 36

what are the clinical uses shared by all K+ sparing diuretics?

Answer 36

• both aldosterone antgonists and Na+ blockers: can be used to treat
  
  • edema and hypertension - in combo w/other diuretics
  • nephrogenic DI - in combination with thiazide diuretics

Question 37

what are the clinical uses of aldosterone receptor antagonists?

Answer 37

spironolactone, epleronone

• hypertension, edema, nephrogenic DI (along with Na+ blockers)
• specific to aldosterone antagonists:
  
  • hyperolderstonemia
    
    • ​primary hypersecretion: increased aldosterone secretion
    • secondary hypersecretion: caused by reduced intravascular volume
  • chronic heart failure with reduced ejection fraction
  • edema due to cirrhosis

Question 38

what are the adverse effects of both aldsterone antagonists and Na+ blocker potassium diuretics?

Answer 38

• hyperkalemia
• metabolic acidosis

Question 39

what are the adverse effects of aldosterone receptor antagonists?

Answer 39

• hyperkalemia, metabolic acidosis (applies to all K+ sparing diuretics)
• gynecomastia
• mentstural irregularities
• decreased libido

these AEs seen mostly in spironolactone

Question 40

AEs of triamterine

Answer 40

triamterine = Na+ channel blocke

• hyperkalemia, metabolic acidosis (all k+ sparing diuretics)
• megoblastic anemia
• kidney stones
• acute renal failure

Question 41

AEs of amiloride?

Answer 41

amiloride = Na+ channel blocker (potassium sparing diuretic)

• hyperkalemia, metabolic acidosis (all K+ sparing diuretics)
• nausea, vomitting, diarrhea
• headache

Question 42

what are the contraindications of K+ sparing diuretics?

Answer 42

• oral K+ administration
• hyperkalemia
• renal insufficiency

Question 43

what are the drug drug interactions of K+ sparing diuretics?

Answer 43

• coadministration with the following drugs increases the risk of hyperkalemia:
  
  • _​_ACE inhibitors/ARBs:
    
    • block RAAS –> decrease aldosterone secretion and thus increase K+ retention
  • K+ supplements
  • trimethoprine - behaves like an Na+ blocker (sounds like triameterene)
  • cyclosporine & tacrolimus - impair K+ excretion

Question 44

potassium binding agents?

• what are they?
• what is their MOA?
• what are their clinical uses?
• drug drug interactions?

Answer 44

• potassium binding agents:
  
  • paritromer (an oral suspension)
  • sodium polystyrene sulfonate
• MOA: binds excess K+ in the intestinal lumen –> promotes its excretion
• clinical uses: non life-threatening hyperkalemia
• drug-drug interaction:
  
  • effects absorption of other drugs from the GI tract.
  • should be a 3 hr time gap between K+ binding agents and administration of other drugs

Question 45

mannitol

• how does it work as a diuretic?
• how is it admistered?
• pharmokinetics

Answer 45

• mannitol is an osmotic diuretic
• MOA:
  
  • mannitol is easily filtered through the glomeruli
  • is restricted to the extracellular fluid compartment
  • thus, is NOT reabsorbed from the tubules
  • locally, by increasing osmolality of rental tubular fluid, mananitol
    
    • prevents water reabsorption in the PCT and the descending loop of Henle
    • opposes the action of ADH in the collecting tubule
• pharmokinetics:
  
  • not metabolized
  • nontoxic
• uses:

Question 46

clinical uses of mannitol as a diuretic.

Answer 46

• CNS uses:
  
  • cerebral edema
  • intracranial hematoma
• glaucoma
  
  • reduces intraocular pressure in patients requiring ocular surgery
    
    • administered pre-and post operation
• prevents anuria (failure of the kidney to produced urine) caused by hemolysis (lysed RBCs) or ryabdomyolysis (muscle breakdown)

Question 47

adverse effects of mannitol

Answer 47

• can expand the ECF volume to the point of:
  
  • worsening heart failure
  • producing pulmonary edema
  • causing
    
    • headache
    • nausea
    • vomitting
  • dehydration
  • hyperkalemia, hypernatrmia

Question 48

contraindications of osmotic diuretics

Answer 48

• Pulmonary edema
• Poor cardiac reserve
• Severely dehydrated patient
• Active cranial bleeding (though it can be used to treat intracrnial hemotoma)
• Anuria (though it can be used to prevent anuria)

Question 49

summarize the drugs within each class of diuretics

Answer 49