Renal pharm – Diuretics HY points

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HY points followed by a quiz at the end

Mannitol

MOA of mannitol?

  • Osmotic diuretic; acts in the proximal convoluted tubule (PCT), proximal straight tubule (PST), and descending loop of Henle.
  • Osmotic diuretic means it functions to retain water in the lumen of the nephron by exerting an oncotic effect (i.e., the mere presence of more solute in the lumen means water is less likely to be reabsorbed –> more is micturated).

When is it used?

  • Can be used to treat increased intracranial pressure.
  • The sequence of treatment is: elevate head of the bed –> intubation + hyperventilation (decreased CO2 causes decreased cerebral perfusion) –> mannitol. In other words, mannitol is never the first answer for increased intracranial pressure; just know that it can be used for this purpose.

When is mannitol notably contraindicated?

  • Don’t give to patients with heart failure –> increased oncotic pressure occurs in the peripheral vasculature as well –> transient increase in plasma volume –> increased venous return –> increased oxygen demand on the myocardium –> increased risk of cardiac decompensation and ischemia.

Acetazolamide

MOA of acetazolamide?

  • Carbonic anhydrase inhibitor in the PCT of the kidney.
  • Carbonic anhydrase functions to facilitate CO2 and H2O combining to form H2CO3. Once H2CO3 is formed, it can equilibrate into bicarb and a proton. The bicarb is then reabsorbed by the PCT tubular cell.
  • In other words, if we inhibit carbonic anhydrase with acetazolamide, less bicarb is reabsorbed, thereby creating a metabolic acidosis for the patient.

When is it used?

  • Altitude sickness –> person goes to high altitude where there’s fractionally less O2 in the air –> breathes faster to compensate –> also results in blowing off more CO2 –> patient becomes transiently alkalotic because it takes time for the kidney to naturally excrete more bicarb to compensate for the reduced serum pCO2. The role of acetazolamide is to create a transient metabolic acidosis by forcing bicarb excretion; this compensates for the respiratory alkalosis faster than the kidney can naturally excrete bicarb.
  • Topical carbonic anhydrase inhibitors can be used for glaucoma by decreasing aqueous humor production.

Adverse effects?

  • Sulfa drug (contraindicated in sulfa allergy).
  • Because it increased the pH of the urine, it can theoretically increase the risk of calcium phosphate stones (which form at higher pH). Calcium oxalate stones, in contrast, form at lower pH, so risk of these would not be increased.

Loop diuretics

  • Be familiar with a few names –> furosemide, bumetanide, torsemide, ethacrynic acid

MOA of loops?

  • Inhibit the Na/K/2Cl (one sodium, one potassium, and two chloride) symporter on the apical membrane of the thick ascending limb of the loop of Henle.
  • When ions are reabsorbed, water follows, so inhibition of this four-ion symporter causes massive diuresis (increased urination).
  • This effect also decreases paracellular (between the cells, without a transporter) reabsorption of calcium and magnesium. That is, loops also cause hypercalciuria (and can cause hypocalcemia). The USMLE likes you to know the effect of loops on calcium.

When are they used?

  • Most effective agents for fluid unloading in patients with peripheral and pulmonary edema due to heart, liver, or renal failure.
  • Must be pointed out that they do not decrease mortality in heart failure; they are merely used for symptomatic patients (i.e., dyspnea from pulmonary edema, or peripheral edema) who need fluid unloading.
  • Ethacrynic acid is a non-sulfa loop – i.e., it can be used in patients with sulfa allergy. It carries the same adverse effects of other loops, including ototoxicity.

Adverse effects?

  • Ototoxicity –> need not be neurosensory hearing loss –> can be vertigo (room is spinning). This ototoxic effect is synergistic if the patient is simultaneously on aminoglycosides (e.g., gentamicin), as the latter are also ototoxic.
  • Hypokalemia –> due to a combination of the loop directly preventing potassium reabsorption + the effects of the renin-angiotensin-aldosterone system (RAAS) being upregulated to compensate for the drop in plasma volume –> increased distal secretion of potassium under the action of aldosterone.
    • Aldosterone causes sodium + water reabsorption, and potassium + proton secretion (excretion) in the distal kidney.
  • Dehydration with orthostatic hypotension (i.e., if you’re causing a high level of diuresis, you’re prone to fainting).
  • Contraction alkalosis –> since loops cause significant diuresis, the RAAS will upregulate and the late-DCT and collecting duct will attempt to reabsorb more fluid to compensate –> however the action of aldosterone leads to secretion of protons distally, resulting in increased serum pH and bicarb.
  • Hypocalcemia (due to hypocalciuria).
  • Loops are said to “abolish the effects of vasopressin (ADH).” –> ADH functions to insert aquaporins in the medullary collecting duct to promote free-water reabsorption –> the high ion concentrations in the renal interstitium due to the ion reabsorption in the thick ascending limb are what enable the free-water reabsorption to occur passively. If loops prevent ion reabsorption and in turn abolish the ion concentrations in the interstitium, less free-water reabsorption will occur due to ADH. Once again, just memorize: “loops abolish the effects of vasopressin.”
  • Sulfa allergy.

Thiazides

  • Be familiar with a few names –> hydrochlorothiazide (HCTZ), chlorthalidone, metolazone, indapamide

MOA of thiazides?

  • Block the Na/Cl symporter on the apical membrane of the early-DCT.
  • This results in increased calcium reabsorption in the DCT. That is, thiazides cause hypocalciuria and hypercalcemia. Note that this is the opposite effect of loop diuretics. The USMLE wants you to know this contrast of effect urinary and serum on calcium.

When are they used?

  • First-line treatment for essential hypertension in patients without pre-diabetes, diabetes, renal, or cardiovascular disease. In other words, thiazides or dihydropyridine calcium channel blockers (e.g., nifedipine) are used for otherwise healthy patients who have essential hypertension. This shows up on 2CK FM material (i.e., patient has HTN and hydrochlorothiazide is the answer).
    • If the patient has pre-diabetes, diabetes, renal, or cardiovascular disease, use an ACE inhibitor or angiotensin II receptor blocker (ARB). As an example, if the patient has elevated fasting glucose or evidence of protein in the urine, use an ACEi or ARB, not a thiazide or dCCB.
  • Used to prevent recurrent calcium urolithiasis (because they cause hypocalciuria).

Adverse effects?

  • HyperGLUC
    • HyperGlycemia –> can cause diabetes, or push pre-diabetics into diabetes; so never use in patients with elevated fasting glucose. Use with caution in overweight patients.
    • HyperLipidemia –> have never seen this on NBME material, but part of the mnemonic.
    • HyperUricemia –> can cause gout –> have also never seen this on NBME material, but part of the mnemonic.
    • HyperCalcemia –> due to increased reabsorption of calcium in the DCT; likewise, thiazides cause hypocalciuria; this effect on calcium is HY for Step.

Amiloride, triamterine

MOA of amiloride and triamterine?

  • ENaC inhibitors (inhibit sodium reabsorption in the late-DCT and cortical collecting duct).
  • Water follows sodium, so inhibition of ENaC promotes diuresis.
  • Potassium-sparing (i.e., do not cause a decrease in serum potassium).
    • Aldosterone normally promotes potassium secretion distally in the kidney. It accomplishes this by upregulating the basolateral Na/K-ATPase pump on the basolateral surface of the cortical collecting duct. This cause sodium to be reabsorbed from the tubular cell into the blood, and potassium to be secreted from the blood into the tubular cell. The reduction in intra-tubular cell sodium causes a favorable (high-to-low) gradient from the urine into the cell for sodium. ENaC, on the apical membrane, then opens to enable sodium to flow from the urine into the cell. The movement of sodium through ENaC is considered secondary active transport because sodium is able to move down its apical gradient only because energy was first utilized by the basolateral ATPase pump.
    • Inhibition of ENaC on the apical membrane means the basolateral ATPase pump can’t continue to function, since there’s less intracellular sodium to move across the basolateral membrane. In turn, this means less potassium can be secreted, so serum potassium is maintained (i.e., ENaC inhibitors are potassium-sparing).

When are they used?

  • Triamterine (and spironolactone, mentioned below) is also used as a second agent for fluid unloading when the patient is already on a loop diuretic (usually furosemide). Since furosemide can cause hypokalemia, if the patient needs more diuretic therapy, a potassium-sparing diuretic is chosen next, and triamterine or spironolactone are common answers on USMLE for this purpose.

Adverse effects?

  • Can cause hyperkalemia (since it’s possium-sparing).

Spironolactone, eplerenone

MOA of spironolactone and eplerenone?

  • Aldosterone receptor antagonists.
  • Potassium-sparing.
  • By blocking aldosterone receptors, there’s decreased activity of the Na/K-ATPase pumps on the basolateral membrane of the late-DCT and cortical collecting duct –> less Na reabsorption –> since water follows sodium, there’s less water reabsorption –> decreased plasma volume. Likewise, potassium and protons are not secreted –> serum potassium does not go down (potassium-sparing).

When are they used?

  • Spironolactone is classically used in heart failure after the patient is already on an ACEi/ARB and beta-blocker.
  • Hierarchy for drugs in heart failure (simplified but HY for USMLE):
    • Start with ACE inhibitor or an angiotensin II receptor blocker (ARB) to improve ejection fraction (normal is 55-70%).
    • If the patient is fluid overloaded (i.e., peripheral edema or pulmonary edema), attempt to achieve euvolemia by adding furosemide (loop diuretic).
    • If insufficient ejection fraction with the ACEi or ARB, add a beta-blocker (metoprolol XR, bisoprolol, carvedilol, or nebivolol).
    • If insufficient ejection fraction with ACEi/ARB + beta-blocker, add spironolactone (aldosterone receptor antagonist).
    • If insufficient ejection fraction, add the combination of hydralazine + nitrates. Only the combo decreases mortality in HF. It is especially efficacious in African Americans (tend to have stiffer vessels).
    • If insufficient ejection fraction when already on ACEi/ARB + beta-blocker + spironolactone + hydralazine + nitrates, add digoxin.
    • If pharmacologic therapy insufficient, use implantable device.

    • Spironolactone is also used as a second agent for fluid unloading when the patient is already on a loop diuretic (usually furosemide). Since furosemide can cause hypokalemia, if the patient needs more diuretic therapy, a potassium-sparing diuretic is chosen next, and spironolactone or triamterine are common answers on USMLE for this purpose.
    • Can be used for adrenal cortical hyperplasia where aldosterone is high, or for aldosteronoma prior to surgery.

Adverse effects?

  • Spironolactone causes gynecomastia (HY). It is anti-androgenic and can block androgen receptors. Eplerenone apparently doesn’t carry the same risk.
  • Both can cause hyperkalemia.

Angiotensin-converting enzyme inhibitors (ACEi)

  • Be familiar with a few names –> enalapril, lisinopril, captopril

MOA of ACEi?

  • Inhibit ACE, which normally converts angiotensin I to angiotensin II.
  • ACE acts in the lungs. Therefore ACEi act in the lungs.
  • By decreasing angiotensin II levels, ACEi intercept the RAAS and therefore decrease aldosterone production and effects (angiotensin II normally upregulates aldosterone synthase in the zona glomerulosa of the adrenal cortex).
  • Angiotensin II on its own is a potent vasoconstrictor. It acts on systemic arterioles and at the efferent arterioles of the kidney. So giving an ACEi causes a decrease in afterload (decreased constriction of systemic arterioles) and improves cardiac output and ejection fraction.
  • Potassium-sparing because they intercept RAAS (and therefore aldosterone-induced distal renal secretion of potassium is hindered).

When are they used?

  • First-line for essential hypertension in patients with pre-diabetes, diabetes, renal, or cardiovascular disease.
  • Also used in patients who don’t have hypertension if they have pre-diabetes or diabetes and evidence of proteinuria or increased creatinine.
  • First-line in heart failure.
  • Oral captopril can be used for hypertensive urgency (>180/110, either number; without evidence of end-organ damage; if retinopathy, nephropathy, etc., then it’s hypertensive emergency, and nitroprusside is used, among others).

Adverse effects?

  • Dry cough (HY) –> ACE is also known as bradykininase –> therefore ACEi can cause increased bradykinin in the lungs –> can cause cough.
  • Hyperkalemia (because they’re potassium-sparing).
  • Angioedema (avoid in patients with hereditary angioedema).
  • Can cause increased serum creatinine and renin in patients with renal artery stenosis or fibromuscular dysplasia.
    • 32F + HTN + given enalapril + now creatinine rises to 2.1 from 1.0; diagnosis? –> fibromuscular dysplasia.
    • In other words, if you observe in a vignette that creatinine or renin jumps in response to an ACEi or ARB, you know the answer is renal artery stenosis (patients 50s+ with cardiovascular disease) or fibromuscular dysplasia (women 20s-40s without cardiovascular disease).

Angiotensin II receptor blockers (ARBs)

  • Be familiar with a few names –> losartan, valsartan, candesartan

MOA of ARBs?

  • Block angiotensin II receptors.
  • Effects are the same as ACEi for all intents and purposes.

When are they used?

  • Same as ACEi.
  • If patient was given an ACEi and gets dry cough, switch to ARB.

Adverse effects?

  • Hyperkalemia (because they’re potassium-sparing).
  • Can cause increased serum creatinine and renin in patients with renal artery stenosis or fibromuscular dysplasia.
    • 32F + HTN + given enalapril + now creatinine rises to 2.1 from 1.0; diagnosis? –> fibromuscular dysplasia.
    • In other words, if you observe in a vignette that creatinine or renin jumps in response to an ACEi or ARB, you know the answer is renal artery stenosis or fibromuscular dysplasia.

Vasopressin (ADH) receptor antagonists (tolvaptan, conivaptan)

MOA of tolvaptan, conivaptan?

  • Block vasopressin receptors in the kidney.

When are they used?

  • SIADH (e.g., from small cell carcinoma of the lung, or post-head trauma).
    • Should be noted that demeclocycline (a tetracycline antibiotic) can cause nephrogenic diabetes insipidus and is also an answer on NBME for the treatment of SIADH.

Aliskiren

MOA of aliskiren?

  • Direct renin inhibitor.
  • Renin normally cleaves angiotensinogen into angiotensin I in the plasma. So aliskiren decreases angiotensin I production.
  • Can be used for hypertension.
  • Just know this drug’s MOA.

1. MOA of mannitol? / Where does it act in the nephron?

2. When is mannitol used?

3. When is mannitol notably contraindicated?

4. MOA of acetazolamide? / Where does it act in the nephron?

5. When is acetazolamide used?

6. What are two adverse effects of acetazolamide?

7. Which of the following are loop diuretics? (select all that apply)

 
 
 
 
 
 
 

8. MOA of loop diuretics? / Where do they act in the loop of Henle?

9. What’s the effect of loops and thiazides on calcium?

10. When are loop diuretics used?

11. Which of the following are adverse effects of loop diuretics? (select all that apply)

 
 
 
 
 
 
 
 
 

12. Which of the following are thiazides? (select all that apply)

 
 
 
 
 
 
 

13. MOA of thiazides? / Where do they act in the nephron?

14. When are thiazides used?

15. Adverse effects of thiazides?

16. MOA of amiloride and triamterine? / Where in the nephron do they act?

17. When are amiloride and triamterine used?

18. a) 42F + liver disease + peripheral edema; what drug should she be started on to help her edema?

b) Above patient needs a second drug to help her edema; what should be given?

19. MOA of spironolactone and eplerenone? / Where do they act in the nephron?

20. When is spironolactone or eplerenone used? (3)

21. a) Where do ACE inhibitors act?

b) Name three locations angiotensin II normally acts.

22. When are ACE inhibitors used in the treatment of hypertension?

23. When is oral captopril used?

24. Which of the following are ACE inhibitors? (select all that apply)

 
 
 
 
 
 

25. 32F + HTN + given enalapril + now creatinine rises to 2.1 from 1.0; diagnosis?

26. Name four adverse effects of ACE inhibitors.

27. a) MOA of tolvaptan, conivaptan?

b) When are they used?

28. MOA of aliskiren?

29. Name two drugs that antagonize aldosterone receptors.

30. Adverse effects of spironolactone and eplerenone?

31. Which diuretic is used in hypertensive urgency?

32. Which diuretics can cause dry cough?

33. Name four potassium-sparing diuretics.

34. Which diuretics can cause hyperGLUC?

35. Which diuretics can cause ototoxicity?

36. Which diuretic is a carbonic anhydrase inhibitor?

37. Which diuretic is a direct-renin inhibitor?