01/25/16

Question 1

Renal Physiology

Answer 1

• Nephron: basic structural unit of the kidney

Question 2

Renal Epithelial Cells

Answer 2

• “polarized” cells
• apical membrane: nephron lumen
• basolateral membrane: interstitium, capillaries

Question 3

Kidney Physiology: Segment, Function, H₂O, Drugs, Target

Answer 3

Question 4

Kidney: Sites of Action

Answer 4

Question 5

Osmotic Diuretics

Answer 5

• Do not interact with receptors or directly block renal transport
• Actively dependent on development of osmotic pressure
• Drugs:
  
  • Mannitol (Osmitrol)
  • Urea
  • Glycerol
  • Isosorbide

Question 6

Osmotic Diuretics: MOA

Answer 6

• Osmotic diuretics are freely filtered, not reabsorbed
• Increase osmotic pressure in PT and TDLOH
• Decrease passive reabsorption of H₂O
• Osmotic force lumen>osmotic force interstitium
• Increase H₂O and Na⁺ excretion

Question 7

Osmotic Diuretics: Pharmacokinetics

Answer 7

• Freely filtered through glomerulus
• Not reabsorbed or secreted
• Poorly absorbed in the GI tract→diarrhea
• Excreted unchanged in 30-60 min

Question 8

Osmotic Diuretics: Clinical Uses

Answer 8

• Decreases intracranial pressure
• Decreases intraocular pressure
• Increases urine volume→prevent hemolysis, rhabdomyolysis during surgical procedures

Question 9

Osmotic Diuretics: Toxicity

Answer 9

• Pulmonary edema
• Headache, nausea,vomiting
• Dehydration

Question 10

Carbonic Anhydrase Inhibitors

Answer 10

• Acetazolamide (Diamox)
  
  • protype
  • developed from sulfanomide
  • replaced mercurial diuretics in 1950’s
• Dorzolamide
• Brinzolamide

Question 11

Carbonic Anhydrase Inhibitors: MOA

Answer 11

• Active in proximal tubule
• Inhibits the enzyme carbonic anhydrase
• HCO₃^- + H⁺→H₂CO₃→ H₂O + CO₂

Question 12

Electrolyte effects of CA administration

Answer 12

• Decreases HCO₃^- reabsorption and whole body HCO₃^-
  
  • Urine alkalinization
  • Metabolic acidiosis
• Increases Cl^- reabsorption
  
  • hyperchloremia

Question 13

Carbonic Anhydrase Inhibitors: Clinical Uses

Answer 13

• Glaucoma: topical brinzolamide or dorzolamide
• Uric acid stones
• Metabolic alkalosis
• Acute mountain sickness

Question 14

Carbonic Anhydrase Inhibitors: Pharmacokinetics

Answer 14

• Oral, IV, topical
• well absorbed
• 0.5-2 hours onset of action
• 3-9 hour of duration

Question 15

Carbonic Anhydrase Inhibitors: Toxicity

Answer 15

• hyperchloremic metabolic acidosis
• Ca²⁺ renal stones
• Fatigue, drowsiness
• Parasthesias (pins and needles under skin)
• sulfa allergy
• fever, rash, bone marrow suppression

Question 16

Loop Diuretics

Answer 16

• Furosemide
• Bumetanide
• Torsemide
• Ethacrynic acid

Question 17

Loop Diuretics: MOA

Answer 17

• Active in Thick Ascending Limb of Henle
• Inhibits Na⁺/K⁺/2Cl transporter (NKCC2)
• Compete with Cl^- binding sites

Question 18

Electrolyte effects of loop diuretic administration

Answer 18

• Decreases reabsorption of GFR filtrate by ~25%
  
  • Rapid diuresis
• Increases Mg²⁺ excretion
  
  • hypmagnesemia
• Increases Ca²⁺ excretion
  
  • hypercalciuria
• Increases K⁺ excretion
  
  • hypokalemia
• Increases H⁺ excretion
  
  • metabolic alkalosis

Question 19

Loop Diuretics: Pharmacokinetics

Answer 19

• Oral or IV injection
• Rapid absorption, onset of action (minutes)
• duration 2-4 hours
• Enter nephron lumen via organic acid transporter in PCT
• Inhibitors of organic acid ion transport decrease potency (i.e. probenecid, NSAIDs)

Question 20

Loop Diuretics: Clinical Uses

Answer 20

• Edema: cardiac, pulmonary, renal
• Hypertension
• Acute hypercalcemia
• Acute and chronic hyperkalemia
• Anion overdose

Question 21

Loop Diuretics: Toxicity

Answer 21

• hypokalemic metabolic alkalosis
• ototoxicity
• hyperuricemia
• hyponatremia
• hypmagnesemia
• allergic reactions

Question 22

Thiazides

Answer 22

• Chlorothiazide (Diuril)
• Bendroflumethiazide
• Chlorthalidone
• Hydrocholorthiazide (Microzide)
• Hydroflumethazide
• Methylclothiazide
• Polythiazide
• Trichlormethiazide

Question 23

Thiazides: MOA

Answer 23

• Active in distal convoluted tubule
• inhibit Na⁺/Cl^- co-transporter (NCC)

Question 24

Electrolyte effects of thiazide administration

Answer 24

• Decreases Na⁺ reabsorption
  
  • hyponatremia
• Decreases Cl^- reabsorption
  
  • hypochloremia
• Increases Ca²⁺ reabsorption
  
  • hypocalciuria
• Increases K⁺ excretion
  
  • hypokalemia

Question 25

Thiazides: Pharmacokinetics/Dosing

Answer 25

• oral, IV
• Slowly absorbed, moderate duration (~5-12 hours)
• Secreted by organic acid transporter in PT
• many combination therapies

Question 26

Thiazides: Clinical Uses

Answer 26

• Hypertension
• Congestive heart failure
• Hypercalcuria
• Nephrogenic diabetes insipidus
• Osteoporosis
• Li⁺ toxicity

Question 27

Thiazides: Toxicity

Answer 27

• Hypokalemic metabolic alkalosis
• hyponatremia
• hyperglycemia
• hyperlipidemia
• hyperuricemia
• allergic reactions

Question 28

K⁺ sparing diuretics

Answer 28

1. Na⁺ channel (ENaC) blockers
   
   • Triamterene (Dyrenium)
   • Amiloride
2. Aldosterone receptor antagonists
   
   • Eplerenone (Inspra)
   • Spironolactone (Aldactone)

Question 29

Effects of Aldosterone and Blocking ENaC

Answer 29

Question 30

Na⁺ channel blocker and Aldosterone antagonist: MOA

Answer 30

• Na⁺ channel blockers:
  
  • Amiloride
  • Inhibit Na⁺ (ENaC) in CCD
• Aldosterone antagonists:
  
  • Spironolactone
  • Inhibit aldosterone receptor in CD
  • Decrease Na⁺ pump expression/activity

Question 31

Electrolyte effects of potassium sparing diuretics adminstration

Answer 31

• Decreases exchange of Na⁺ for K⁺ in CCD
• Increases Na⁺ excretion
  
  • hyponatremia
• Decreases K⁺ excretion
  
  • prevent hypokalemia

Question 32

Na+ channel blocker and Aldosterone antagonist: Clinical Uses

Answer 32

• Counter K⁺ wasting effects of thiazides/diuretics
• Inhibit effects of excessive aldosterone production
  
  • Conn’s syndrome
  • Secondary hyperaldosteronism
• Hypertension, congestive heart failure, cirrhosis
• Potency: loops>thiazides>aldosterone

Question 33

Na+ channel blocker and Aldosterone antagonist: Toxicity

Answer 33

• Antiandrogen effects with spironolactone
  
  • Gynecomastia, hypogonadism
• Eplereone lacks anti-androgen effects
• Aldosterone antagonsists have slow onset of action (weeks)
• hyperkalemia with Na⁺ channel blockers and aldosterone receptor antagonists

Question 34

V2 vasopressor receptor antagonists

Answer 34

• Tolvaptan (Samsca)
• Lixivaptan (VPA-985)
• Mozavaptan
• Satavaptan

Question 35

V2 vasopressor receptor antagonists: MOA

Answer 35

• Inihibit V2 vasopressin receptor in DCT and CCD
• Decrease aquaporin-2 insertion into apical membrane
• Increase H₂O excretion

Question 36

V2 vasopressor receptor antagonists: clinical uses

Answer 36

• Hyponatremia
• CHF
• Cirrhosis
• SIADH

Question 37

V2 vasopressor receptor antagonists: Toxicity

Answer 37

• nephrogenic diabetes insipidus
• liver damage with prolonged use (>30 days)

Question 38

Mannitol: Drug Card

Answer 38

• Brand Name:
  
  • Osmitrol
• MOA:
  
  • Increases nephron osmolarity in proximal tubule and thin descending limb of Henle
• Clinical Uses:
  
  • Decrease intraocular/intracranial pressure
  • Drug overdose
• Toxicities:
  
  • Pulmonary edema
  • Dehydration
• Extra Info:
  
  • Freely filtered through glomerulus
  • Excreted unchanged in 30-60 min

Question 39

Acetazolamide: Drug Card

Answer 39

• Brand Name:
  
  • Diamox
• MOA:
  
  • Carbonic anhydrase inhibitor
• Clinical Uses:
  
  • glaucoma
  • metabolic alkalosis
  • acute mountain sickness
• Toxicities:
  
  • hyperchloremic metabolic acidosis
  • paresthesias
  • sulfa allergy
• Extra Info:
  
  • Active in proximal tubule
  • HCO₃^- + H⁺→H₂CO₃→H₂O + CO₂

Question 40

Furosemide: Drug card

Answer 40

• Brand name:
  
  • Lasix
• MOA:
  
  • inhibit NKCC2 in thick ascending limb of Henle
• Clinical Uses:
  
  • Edema in CHF, cirrhosis, nephrotic syndrome
  • hypertension
  • hypercalcemia
• Toxicities:
  
  • hypokalemia
  • ototoxicity
  • dehydration
• Extra info:
  
  • “high ceiling diuretic”
  • rapid onset of action (minutes)

Question 41

Hydrochlorothiazide: Drug card

Answer 41

• Drug name:
  
  • Microzide
• MOA:
  
  • inhibit NCC in distal convoluted tubule
• Clinical Uses:
  
  • hypertension
  • CHF
  • idiopathic hypercalcuria
• Toxcities:
  
  • hypokalemic metabolic alkalosis
  • hyponatremia
  • hyper-lipidemia, uricemia, calcemia
• Extra Info:
  
  • “low ceiling diuretic”
  • component of many combination therapies

Question 42

Amiloride: Drug Card

Answer 42

• Brand Name:
  
  • Midamor
• MOA:
  
  • Inhibit ENaC in cortical collecting duct
• Clinical uses:
  
  • CHF
  • Hypertension
  • Hypokalemia
• Toxicity:
  
  • hyperkalemia
• Extra Info:
  
  • “K⁺ sparing diuretic”
  • used in combination with loop and thiazide diuretics

Question 43

Spironolactone: Drug Card

Answer 43

• Brand Name:
  
  • Aldactone
• MOA:
  
  • Competitive antagonist of aldosterone receptor
• Clinical uses:
  
  • hyperaldosteronism
  • CHF
  • HTN
• Toxicities:
  
  • Hyperkalemia
  • endocrine effects (gynecomastia)
• Extra Info:
  
  • Used in combination with loop diuretics to prevent hyperkalemia
  • eplerenone lacks anti-androgen effects

Question 44

Tolvaptan: Drug Card

Answer 44

• Brand Name:
  
  • Samsca
• MOA:
  
  • V2 vasopressin receptor antagonist
• Clincal Uses:
  
  • symptoms of inappropriate anti-diuretic hormone (SIADH)
  • hyponatremia
• Toxicities:
  
  • nephrogenic diabetes insipidus
  • hepatotoxicity
• Extra Info:
  
  • In clinical trials for CHF, polycystic kidney disease