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Renal Week 2 > ICL 1.8: Renal Pharmacology > Flashcards

ICL 1.8: Renal Pharmacology Flashcards

1
Q

what are diuretics?

A

agent that increases urine volume

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2
Q

what are natriuretics?

A

they increases renal Na+ excretion

this increases urine volume; these agents are usually called “diuretics”

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3
Q

what are aquatics?

A

increases excretion of water without electrolyte loss

also often called “diuretics”

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4
Q

what are diuretics mainly used for?

A
  1. HTN

2. edema/fluid retention conditions like CHF, liver cirrhosis and nephrotic syndrome

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5
Q

what part of the nephron do osmotic diuretics work on?

A
  1. PCT

2. descending limb of loop of Henle

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6
Q

what part of the nephron do carbonic anhydrase inhibitors work on?

A
  1. PCT

2. thick descending limb

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7
Q

what part of the nephron do loop diuretics work on?

A

thick ascending limb

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8
Q

what part of the nephron do thiazide diuretics work on?

A

DCT

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9
Q

what part of the nephron do K+ sparing diuretics work on?

A

collecting duct

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10
Q

what part of the nephron do ADH antagonists work on?

A

collecting duct

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11
Q

how do natriuretics work?

A

they diminish Na+ reabsorption at different sites along the nephron, increasing urinary Na+

since water follows Na+, urine output is increased.

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12
Q

how does Na+ get reabsorbed into blood?

A

all the Na+ transporting cells have Na/K/ATPase pumps on the basolateral (blood) side which:

  1. return Na+ to the blood
  2. keep cellular Na+ levels low (lets filtered Na+ move down gradient into cells via carriers)
  3. raise K+ levels to polarize the cell
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13
Q

why do diuretics act at different sites of the nephron?

A

since Na+ can’t freely enter cells, each segment of the nephron has a different way of moving Na+ from filtrate into the cells

different drugs specifically target these different Na+ carriers/channels on the apical (urine) side

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14
Q

what is the general MOA of most diuretics?

A

most diuretics act by blocking membrane transport channels along the nephron, to prevent Na+ reabsorption and alter ionic and water content of urine

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15
Q

do diuretics cause loss of K+?

A

most diuretics (all except the K-sparing diuretics) cause loss of K+ as part of the sodium-water diuresis

  1. any agent that increases flow through the tubule increases K+ excretion
  2. loop diuretics inhibit a pump that reabsorbs K+
  3. diuretics decrease BP and Na+ delivery to the distal tubule –> both stimulate the RAAS to make aldosterone, which increases K+ and H+ excretion in urine in exchange for reabsorption of Na+ and water

a potential side effect from H+ loss is alkalosis and loss of K+ causes hypokalemia

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16
Q

how does hypokalemia clinically manifest?

A
  1. muscle weakness
  2. cardiac arrhythmias
  3. renal abnormalities
  4. glucose intolerance
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17
Q

which drug classes are natriuretics?

A
  1. carbonic anhydrase inhibitors
  2. loop diuretics
  3. thiazide diuretics
  4. K-spacing diuretics
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18
Q

which drug classes are aquaretics?

A
  1. osmotic diuretics

2. vasopressin antagonists

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19
Q

which drugs are K sparing diuretics?

A
  1. aldosterone antagonists

2. ENaC channel blockers

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20
Q

which substances get reabsorbed in the PCT?

A
  1. HCO3-
  2. sugars
  3. amino acids
  4. Na+

carbonic anhydrase inhibitors work here! they work on enzymes

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21
Q

which drugs are carbonic anhydrase inhibitors?

A
  1. acetazolamide

2. methazolamide

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22
Q

what is the MOA of carbonic anhydrase inhibitors

A

they work at the PCT and target carbonic anhydrase enzymes

they reversibly inhibit CA enzymes which blocks HCO3- reabsorption (and thus intracellular H+ generation), decreases apical Na+/H+ exchanger (NHE3) activity so Na+ stays in urine

without CA, CO2 + H2O moves into the cell but you can’t generate H+ or HCO3- inside the cells to power the H+/Na+ pump on the luminal side or the HCO3- and Na/K/ATPase pumps on the basolateral side

it’s a weak diuretic though because Na+ gets reabsorbed downstream

other effects include pH changes; urine alkalinization / blood acidification (CA is key in acid-base homeostasis)

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23
Q

what are the uses of carbonic anhydrase inhibitors?

A

they’re the first class of diuretics but now they aren’t really used as diuretics and instead they’re used based on their ability to alter fluid transport at non-kidney sites and to alter pH

  1. centrencephalic epilepsy
  2. glaucoma treatment
  3. intracranial HTN
  4. altitude sickness
  5. off table uses: sleep apnea and hypercapnia, metabolic alkalosis, prevention of renal calculi
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24
Q

how do carbonic anhydrase inhibitors treat glaucoma?

A

Ciliary body secretes HCO3- from blood into aqueous humor

CAIs reduce IO fluid production

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25
Q

how do carbonic anhydrase inhibitors treat intracranial HTN?

A

CAIs reduce CSF production

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26
Q

how do carbonic anhydrase inhibitors treat altitude sickness

A

pulmonary edema can happen at high altitudes

CAIs can ↓CSF production & ↑pH which increases ventilation rate above normal which helps with altitude sickness!

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27
Q

what are the side effects of carbonic anhydrase inhibitors?

A
  1. metabolic acidosis from reduction in body stores of HCO3-
  2. may promote nephrolithiasis since calcium salts are less soluble in alkaline urine
  3. hypokalemia
  4. drowsiness and paresthesia with large doses

1 and 2 are related to altered pH

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28
Q

what are the contraindications of carbonic anhydrase inhibitors?

A
  1. sulfa allergy since CAIs are structural similarity to sulfa antibiotics –> skin rash is common, anaphylaxis rare

patients with sulfa allergies are much more likely to have a reaction to a sulfa antimicrobial vs. other sulfa agents so the current guidance: use sulfa diuretics cautiously or avoid

  1. renal/hepatic dysfunction
  2. cirrhosis because the alkaline urine impairs NH4+ excretion (hyperammonemia, hepatic encephalopathy)
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29
Q

which drugs are loop diuretics?

A
  1. furosemide (lasix)

2. ethacrynic acid

30
Q

what is the MOA of loop diuretics?

A

site of action is the thick ascending limb

they target the luminal Na+/K+/2Cl transporter (NKCC2) and competitively inhibits NKCC2 transporter

the NKCC2 transporter is on the luminal side and transports all of these ions into the cell to reabsorb them

the net effect is that they block reabsorption of 20-25% of filtered Na+

31
Q

what are the effects of loop diuretics?

A
  1. they block reabsorption of 20-25% of filtered Na+
  2. induces COX-2 expression which increases PGE2, causing some vasodilation in kidney, periphery
  3. many electrolyte changes due to increased urinary excretion of Na+, K+, Cl-, Mg2+, Ca2+

Ca2+ and Mg2+ are passively reabsorbed paracellularly in the TAL which is driven by the positive lumen potential from K+ recycling –> when you Inhibit NKCC2 transporter it reduces the positive lumen potential so Ca2+ and Mg2+ are retained in urine and don’t get reabsorbed as much…

32
Q

what are the uses of loop diuretics?

A
  1. they are really powerful diuretics and their most important use is the treatment of edema!!!

they move interstitial fluid into urine and have a really rapid effect and therefore are useful in acute edema –> furosemide has a short half-life (90 min) and rapid onset of effect

they’re good for edema associated with CHF, cirrhosis, nephrotic syndrome, pulmonary edema etc.

ethacrynic acid is used in patients with sulfonamide hypersensitivity

  1. they’re used in severe HTN since they’re such powerful diuretics
  2. hyperkalemia –> they enhance urniary excretion of K+ but only in patients with normal renal function
  3. hypercalcemia (formerly)
33
Q

what are the side effects of loop diuretics?

A
  1. ototoxicity
  2. hyperuricemia/precipitation of gout
  3. hypomagnesemia
  4. photosensitivity
  5. nephrotoxicity
  6. thyroid effects
  7. profound fluid/electrolyte loss** (boxed warning)
34
Q

why are loop diuretics associated with ototoxicity?

A

due to inhibition of NKCC1 in the inner ear

this is rare, dose-related

35
Q

why are loop diuretics associated with hyperuricemia/precipitation of gout?

A

hypovolemia triggers uric acid reabsorption in the PCT

treat this by backing off dose to reduce hypovolemia since it’s reversible

36
Q

what are the contraindications of loop diuretics?

A
  1. anuria

2. sulfa allergy

37
Q

do all diuretics have sulfa allergy contraindication?

A

yes

EXCEPT ethacrynic acid because it’s not a sulfonamide derivative

38
Q

which drugs are thiazide diuretics?

A
  1. hydrochlorothiazide

2. chlorthalidone

39
Q

what is the MOA of thiazide diuretics?

A

they act mainly in the DCT and target the luminal Na/Cl co-transporter (NCC) and competitively inhibits NaCl co-transporter

in the DCT, water is not reabsorbed so when Na+ and Cl- are reabsorbed (via NCC) the urine gets diluted –> thiazides block the reabsorption of Na+ and Cl- and effectively decreases the diluting capacity of the nephron

40
Q

what are the effects of thiazide diuretics?

A
  1. they block reabsorption of ~5% of filtered Na+ which decreases the diluting capacity of the nephron
  2. increased reabsorption of Ca2+ (more Ca2+ into blood)

when thiazide diuretics inhibit NCC, the resulting decrease in intracellular Na+ causes the Na/Ca exchanger on the basolateral side to let more Na flow into cells in exchange for Ca2+ moving in opposite direction from the cell –> blood) which puts more calcium in blood/less in urine

  1. many electrolyte changes due to increased urinary excretion of Na+, Cl-, K+
41
Q

what are the uses of thiazide diuretics?

A

this is the most commonly used diuretic class and are very effective at reducing BP buttttt they aren’t as effective in treating edema

  1. reducing BP –> they decrease blood volume and have a mild vasodilating effect
  2. calcium nephrolithiasis and hypercalciuria are an issue because there’s too much Ca+ in the urine so since thiazides move Ca+ out of the urine into the blood, they’re great for treating this
  3. refractory edema (loop diuretics are first line)
  4. mild CHF
  5. nephrogenic diabetes insipidus treatment –> in this condition, kidney can’t concentrate urine in response to ADH aka they aren’t responding to ADH so they get treated with thiazide or K-sparing diuretics, NSAIDS, changes in diet since thiazides decrease urine dilution
42
Q

what are the side effects of thiazides?

A
  1. increased blood sugar –> beware in DM patients
  2. increased cholesterol/LDL –> beware in high cholesterol patients
  3. hypercalcemia and hyperuricemia –> beware in gout or hypercalcemia
  4. photosensitivity
  5. electrolyte disturbances = hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia, metabolic alkalosis –> electrolyte disturbances can be minimized when used in combination with electrolyte-sparing agents
43
Q

what are the contraindications of thiazides?

A
  1. anuria

2. sulfa allergy

44
Q

what are the pharmacokinetics associated with thiazides?

A
  1. substantial potency differences across class; doses are hugely different within the class
  2. renal clearance which means they compete with uric acid secretion which leads to hyperuricemia
45
Q

which drugs are K+ sparing aldosterone antagonists?

A
  1. spironolactone

2. eplerenone

46
Q

what is the MOA of K+ sparing aldosterone antagonists?

A

they act on the principal cells of the collecting duct and target the aldosterone receptor

the aldosterone receptor is also called the mineralocorticoid receptor and is a nuclear receptor

aldosterone stimulates the Na/K ATPase on the basolateral surface and it increases density of ENaC and K +channels

so these steroid derivatives are antagonists at aldosterone receptors and they reduce expression of ENaC and K+ channels and ATP-dependent K+ pumps on the luminal surface

Na+ is re-absorbed via aldosterone-sensitive sodium channels (ENaC). Reabsorption of cationic Na+ (no anion) creates electrical gradient that favors secretion of K+ and H+ into urine

47
Q

what are the effects of K+ sparing aldosterone antagonists?

A
  1. block reabsorption of 1-2% of filtered Na+
  2. decreases K+ and H+ excretion keeping more in blood which causes hyperkalemia and metabolic acidosis
  3. off-target effects at estrogen and progesterone receptors (mainly spironolactone)
48
Q

what are the uses of aldosterone antagonists?

A
  1. adjunct to K-wasting diuretics
  2. primary hyperaldosteronism because they contract the effects of aldosterone in the renal tubule
  3. heart failure and post-MI because they prevent cardiac remodeling
  4. HTN (alternative)
  5. ascites due to cirrhosis
49
Q

why do aldosterone antagonists have a slow onset of action?

A

they change transcription so it takes a while!

50
Q

what are the off table uses of spironolactone?

A
  1. acne
  2. hirsutism
  3. transgender therapy

these are due to their antiandrogenic effects!

51
Q

what are the side effects of aldosterone antagonists?

A

K-sparing effects
1. hyperkalemia

  1. acidosis

androgen-blocking effects (spironolactone only)
1. gynecomastia

  1. impotence
  2. menstrual irregularities
52
Q

what are the contraindications of aldosterone antagonists?

A
  1. hyperkalemia

2. Addison disease (adrenal insufficiency_

53
Q

what are the drug interactions associated with aldosterone antagonists?

A
  1. ACE inhibitors, ARBs, NSAIDS (hyperkalemia)
  2. digoxin (they interfere with digoxin excretion)
  3. CYP3A4 inhibitors increase eplerenone levels
54
Q

which drugs are K+ sparking ENaC blockers?

A
  1. amiloride

2. triamterene

55
Q

what is the MOA of K+ sparing ENaC blockers?

A

they work at the DCT and target ENAC sodium channels and directly block the ENaC sodium channels without having any effect on the aldosterone receptors

Na+ is re-absorbed via aldosterone-sensitive sodium channels (ENaC) –> reabsorption of cationic Na+ (no anion) creates electrical gradient that favors secretion of K+ and H+ into urine

56
Q

what are the effects of K+ sparing ENaC blockers?

A
  1. blocks reabsorption of Na+ into the blood

2. shifts electrochemical gradient to reduce secretion of K+ into urine (retains K+ in blood)

57
Q

what are the uses of ENaC blockers?

A

many of the same uses as aldosterone antagonists:

  1. primary hyperaldosteronism
  2. adjust to K-wsting diuretics
  3. nephrogenic diabetes inspidisu
  4. CHF and post-MI
  5. HTN alternative
58
Q

what are the side effects of ENaC blockers?

A
  1. hyperkalemia
  2. nephrolithiasis

contraindicated in elevated K+ levels, anuria, renal insufficiency, diabetes mellitus

59
Q

what are the pharmacokinetics associated with ENaC blockers?

A

amiloride is primarily eliminated renally; patients with renal impairment are at greater risk for toxicity

60
Q

which drugs are vasopressin antagonists?

A
  1. tolvaptan

2. conivaptan

61
Q

what is the MOA of vasopressin antagonists?

A

they work on the collecting duct and target V2 vasopressin (ADH) receptors and have a competitive antagonists effect

GPCR Gs-coupled V2 receptors mediate antidiuretic response by directing aquaporin 2 (AQP)-containing vesicles to apical membrane; moves water toward blood

62
Q

what are the effects of vasopressin antagonists?

A
  1. excretion of water into urine without accompanying Na+ (aquaresis)
  2. hypernatremia (loss of electrolyte-free water tends to raise serum Na+)
63
Q

what are the uses of vasopressin antagonists?

A
  1. useful for treating conditions of water retention and hyponatremia due to excess ADH
  2. hyponatremia in HF and cirrhosis
  3. syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  4. polycystic kidney disease –> tolvaptan is used to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)
64
Q

what are the side effects of vasopressin antagonists?

A
  1. liver injury –> tolvaptan should not be used for longer than 30 days and not in people with liver disease
  2. osmotic demyelination syndrome when hyponatremia correction is too rapid
    expensive: $300-600/day
65
Q

which drugs are osmotic diuretics?

A
  1. mannitol

2. glycerin

66
Q

what is the MOA of osmotic diuretics?

A

they act in the PCT and descending limb of the loop of hence

they increase the osmolarity of filtrate, inhibiting reabsorption of water and electrolytes

mannitol is freely filtered by the glomerulus and is not reabsorbed or secreted – the PCT and descending limb of the loop of Henle are both freely permeable to water which causes water to be retained in urine

by extracting water from intracellular compartments there is expansion of extracellular fluid volume and decreased blood viscosity

67
Q

what are the uses of osmotic diuretics?

A
  1. increased intraocular pressure
  2. intracranial HTN
  3. diagnosis of bronchial hyperreactivity (powder form)
  4. used for irrigation in genitourinary surgery (topical form)
68
Q

why is mannitol not given orally?

A

poorly absorbed by GI tract; causes osmotic diarrhea rather than diuresis

it’s IV only! you don’t prescribe it or people to take at home

69
Q

what are the side effects of osmotic diuretics?

A

low/normal doses

  1. hypovolemia
  2. hypernatremia

high doses or CKD
1. volume expansion; acute edema

  1. hyponatremia = headache and nausea
  2. hyperkalemia
  3. metabolic acidosis

mannitol is retained in systemic circulation, causing rise in plasma osmolality; results in osmotic movement of water and K+ out of cells, expanding extracellular fluid volume

70
Q

what are the contraindications of osmotic diuretics?

A
  1. anuria
  2. severe hypovolemia
  3. vascular congestion
  4. pulmonary edema

it’s a vesicant so it can damage tissue if there’s extravagazation!

Renal Week 2 (10 decks)

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