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Diuretics. Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention.

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Presentation on theme: "Diuretics. Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention."— Presentation transcript:

1 Diuretics

2 Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention

3 Salt & Water Balance 2/3 ICF 1/3 ECF What causes edema? ¼ Plasma ¾ Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body

4 Salt & Water Balance 2/3 ICF 1/3 ECF What causes edema? ¼ Plasma ¾ Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body When water is added to the system, it distributes evenly: 2/3 to the ICF, 1/3 to the ECF Isotonic fluid, however, stays in the ECF

5 Salt & Water Balance 2/3 ICF 1/3 ECF ISOTONICISOTONIC What causes edema? ¼ Plasma ¾ Interstitium BP Edema 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body

6 Salt & Water Balance 2/3 ICF 1/3 ECF ISOTONICISOTONIC What causes edema? ¼ Plasma ¾ Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body

7 Salt & Water Balance What causes edema? 1. There is a change in capillary hemodynamics favoring the movement of fluid from the vascular to interstitial space Increased Hydrostatic Pressure Decreased Oncotic Pressure Increased Capillary Permeability

8 Diuretics Diuretics have profound clinical implications They allow physicians to manipulate salt and water excretion in impaired states of volume/solute regulation Like all great therapeutic interventions, they have the potential to make patients better, and, when not considered carefully, the potential to make patients worse

9 Diuretics Act primarily by inhibiting Na channels in the renal tubular system To reach the tubular lumen, these drugs must be… Ingested and absorbed Ingested and absorbed Effectively circulated Effectively circulated Secreted into the renal tubular lumen Secreted into the renal tubular lumen Bound to the target transporter Bound to the target transporter

10 Question 1 All of the following are potential obstacles in the diuretic’s migration from pill bottle to apical transporter EXCEPT: A. Low Albumin States A. Low Albumin States B. Pt non compliance B. Pt non compliance C. Renal Failure C. Renal Failure D. All of these are obstacles to effective diuresis D. All of these are obstacles to effective diuresis

11 Question 2 In patients with nephrotic syndrome, oral diuretics: A. Are not effective, since these patients have volume retention due to low albumin states and not salt retention A. Are not effective, since these patients have volume retention due to low albumin states and not salt retention B. Are absorbed more efficiently in the gut B. Are absorbed more efficiently in the gut C. May bind albumin in the urine instead of their targeted apical transporters C. May bind albumin in the urine instead of their targeted apical transporters D. Are unable to reach the apical transporters due to impaired glomerular permeability D. Are unable to reach the apical transporters due to impaired glomerular permeability

12 Regulation of Urine Content ADH

13 Diuretics

14 Diuretics Are all diuretics pretty much the same? Well, they all cause people to pee Well, they all cause people to pee But recognize the difference based on the channels being blocked But recognize the difference based on the channels being blocked Favorite test questions focus on “Why is one diuretic better than another in a particular context?” Favorite test questions focus on “Why is one diuretic better than another in a particular context?”

15 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other

16 Diuretics LOOP DIURETICS Representative Example: Furosemide (Lasix) Onset of action: roughly 30 minutes with PO, 5 minutes with IV Duration: 6 hours LASIX = “Lasts Six [Hours]”

17 Diuretics LOOP DIURETICS Representative Example: Furosemide (Lasix) Site of Action: NaK2Cl transporter in the Thick Ascending Limb

18 Loop Diuretics Decrease sodium reabsorption Impairs the generation of a medullary gradient Thus… Impairs urine dilution Impairs urine dilution Impairs urine concentration Impairs urine concentration

19 Regulation of Urine Content ADH NaK2Cl is necessary for: 1.Dilution of Tubular Filtrate 2.Establishing the Hypertonic Medullary Interstitium 3.Providing the concentration gradient by which water is reabosrbed from the collecting duct (urinary concentration)

20 Effect of Lasix ADH Blocking NaK2Cl causes: 1.Impaired dilution 2.No concentration gradient 3.Increased free water excretion LASIXLASIX Impaired dilution

21 Lasix: Let’s see that one more time

22 Diluting and Concentrating

23 TAL Distal Tubule Collecting Duct Medullary Interstitium

24 Loop Diuretics Decrease sodium reabsorption Impairs the generation of a medullary gradient Thus… Impairs urine dilution Impairs urine dilution Impairs urine concentration Impairs urine concentration

25 Loop Diuretics Na K Cl Na K Calcium

26 Loop Diuretics Na K Cl Na K Calcium Loop Diuretics: Increase excretion of Calcium

27 Loop Diuretics Collecting Duct Na K The increase in Na delivery to the Collecting Duct causes an increase in the exchange of Na for secretion of K/H+ H

28 Diuretics LASIX Quick onset of diuresis Quick onset of diuresis Good for acute volume overload Increases urinary calcium excretion Increases urinary calcium excretion Used to treat hypercalcemia (Malignancy, Hyperparathyroidism) Increases urinary excretion of potassium and hydrogen ions Increases urinary excretion of potassium and hydrogen ions Used to treat acute hyperkalemia 3 Reasons to love your loop diuretic

29 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice Diuresis

30 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice Diuresis

31 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Can exacerbate calcium based kidney stones Can exacerbate calcium based kidney stones Can cause hypokalemia, metabolic alkalosis Can cause hypokalemia, metabolic alkalosis 3 Reasons to think twice

32 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other TAL NaK2Cl Impairs dilution and concentration Acute overload, edema, ↑Ca/K ↓serum K, Met Alkalosis, Volume Depletion, ↑U Ca

33 Diuretics THIAZIDE DIURETICS Representative Example: Hydrochlorothiazide (HCTZ) Onset of action: roughly 2 hours Duration: 6-12 hours Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the “most intimidating medication names.” Less effective at GFR < 40

34 Diuretics THIAZIDE DIURETICS Representative Example: Hydrochlorothiazide (HCTZ) Site of Action: Distal Convoluted Tubule Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the “most intimidating medication names.” Effect: HCTZ impairs urinary dilution, increases Na excretion in the urine

35 Regulation of Urine Content

36 HCZT

37 Regulation of Urine Content ADH HCZT Thiazide Diuretics: 1.Impair Dilution, leading to excretion of salt and water 2.Do not disrupt the concentrating mechanism

38 Question 3 Why are patients on thiazides more prone to hyponatremia than those on loop diuretics? A. Thiazides provide greater natriuretic effect than loop diuretics A. Thiazides provide greater natriuretic effect than loop diuretics B. Trick question: They both equally predispose patients to hyponatremia B. Trick question: They both equally predispose patients to hyponatremia C. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilution C. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilution D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia

39 Diuretics How do I choose between a loop diuretic and a thiazide diuretic? Similarities: Both will make you pee Both can result in hypokalemia and metabolic alkalosis Both can be used for edema and HTN

40 Diuretics How do I choose between a loop diuretic and a thiazide diuretic? Differences: LoopThiazide Concentration/Dilution Impairs both; greater free water excretion Impairs dilution only; more prone to ↓Na Potassium Greater kaliuretic effect; better for Tx of ↑K Less kaliuresis Calcium Increases Ca excretion; better for Tx of ↑Ca ↑Ca reabsorption; better for folks with Ca stones Unique Superpowers Better in renal failure; Relieves resp distress Inexpensive; First line agent for HTN

41 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other TAL NaK2Cl Impaired dilution and concentration Acute overload, edema, ↑Ca/K ↓serum K, Met Alkalosis, Volume Depletion, ↑U Ca DCT Na/Cl cotrnsprt Impaired dilution Edema, HTN, Ca stones Hyponatremia, ↓serum K, Met Alkalosis, Volume Depletion

42 K-Sparing Diuretics 1. Aldosterone Antagonists Representative Example: Spironolactone Site of Action: Cortical Collecting Duct Mechanism: Competes with aldosterone receptor Pharmacokinetics: Can take between hours to reach maximal efficacy Factoid: If Peter Griffin (Family Guy) was on a diuretic it would probably be spironolactone, which would account for his gynecomastia

43 K-Sparing Diuretics Collecting Duct Na K Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface Aldo

44 K-Sparing Diuretics Collecting Duct Na Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface Aldo Spironolactone is an aldosterone antagonist, thus preventing sodium reabsorption and K excretion K

45 K Sparing Diuretics There’s more to aldosterone than meets the eye… There are mineralocorticoid receptors in the heart as well Local production of aldosterone in the heart is proportional to degree of heart failure Aldosterone may stimulate cardiac fibrosis and hypertrophy (Bad) Aldosterone Antagonists may be particularly beneficial in the long term management of certain patients with heart failure

46 K Sparing Diuretics Despite being a weaker diuretic, aldosterone antagonists have a greater effect in cirrhotics than lasix! Despite being a weaker diuretic, aldosterone antagonists have a greater effect in cirrhotics than lasix! Cirrhotic patients have a poor response to lasix due to their low albumin state and reduced tubular secretion. Aldosterone antagonists do not require secretion into the tubular lumen, and thus may remain effective despite marginal renal perfusion in the context of cirrhosis

47 K-sparing Diuretics 2. ENaC Blockers Representative Example: Amiloride, triamterene Site of action: Corical collecting duct Mechanism: Blocks ENaC channels Pharmacokinetics: Half-life = 3-5 hours Factoid: Amiloride was first approved for use in 1967, the same year that Thurgood Marshall was sworn in as the first African American justice of the Supreme Court Spares potassium by decreasing the lumen- negative gradient that drives the exulsion of K/H into the lumen

48 K-Sparing Diuretics Collecting Duct Na Amiloride and triamterene directly block the ENaC channel Aldo This makes amiloride an ideal agent for the treatment of patient’s with Liddles Syndrome, in which there is an abundance of “active” ENaC channels expressed in the CCD K K

49 K-Sparing Diuretics Collecting Duct Li Factoid: Certain drugs (trimethoprim, pentamidine) may have mild diuretic effects due to their ability to block reduce the number of open ENaC channels

50 Question 4 A young bipolar patient with AIDS is seen in clinic. He was recently hospitalized and treated for PCP pneumonia with high doses of Bactrim (trimethoprim sulfamethoxazole). He also takes lithium and a cocktail of antiretroviral drugs. Since the completion of his antibiotic, the patient states that his breathing has improved dramatically, but he notes that he is always thirsty and has urine output of Gaussian proportions.

51 Question 4 (cont) The intern blows this off, but since you’ve read this syllabus you hypothesize that… A. Accumulation of TMX has led to nephrogenic DI A. Accumulation of TMX has led to nephrogenic DI B. The patient may have lithium-induced nephrogenic DI because Bactrim increases the open Na channels available for Li entry into cells B. The patient may have lithium-induced nephrogenic DI because Bactrim increases the open Na channels available for Li entry into cells C. The patient may have psychogenic polydipsia and worsening mania due to decreased absorption of lithium during treatment with Bactrim C. The patient may have psychogenic polydipsia and worsening mania due to decreased absorption of lithium during treatment with Bactrim D. Amiloride my alleviate his symptoms. D. Amiloride my alleviate his symptoms.

52 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other TAL NaK2Cl Impaired dilution and concentration Acute overload, edema, ↑Ca/K ↓serum K, Met Alkalosis, Volume Depletion, ↑U Ca DCT Na/Cl cotrnsprt Impaired dilution Edema, HTN, Ca stones Hyponatremia, ↓serum K, Met Alkalosis, Volume Depletion CCDDecreased distal Na reabsorption ↓K, CHF, ESLD; Li tox, Liddles ↑ serum K, gynecomastia

53 “Other” Diuretics CAI Ex: Acetazolamide Ex: Acetazolamide Blocks carbonic anhydrase Blocks carbonic anhydrase Causes alkaline diuresis Causes alkaline diuresis Applications: Glaucoma Prophylaxis of Mountain Sickness

54 “Other” Diuretics Osmotic Diuretics Ex: Mannitol Ex: Mannitol Non-reabsorbable polysaccharide Non-reabsorbable polysaccharide Preferential water diuresis Preferential water diuresis The net effect is akin to putting SpongeBob Squarepants in the lumen of the renal tubule.

55 Final thoughts Rebound The kidney is a master at compensation The kidney is a master at compensation In the absence of salt restriction, the kidney will adapt to the effect of the diuretic In the absence of salt restriction, the kidney will adapt to the effect of the diuretic After an initial diuresis, further natriuresis will be blunted by post-diuretic salt retention After an initial diuresis, further natriuresis will be blunted by post-diuretic salt retention Salt restriction is, thus, crucial to continued diuresis Salt restriction is, thus, crucial to continued diuresis

56 Downstream Compensation ADH LASIXLASIX As the kidney is an awfully smart fellow, it may try to restore steady-state Na status by increasing reabsorption distal to the site of diuretic action The addition of a “downstream” diuretic (in this case, something that blocks the distal tubule) will prevent the kidney from reclaiming Na and water Fortune Cookie: “To fool the kidney, you must think like the kidney”

57 Clinical Scenarios For each of the following clinical scenarios, pick the appropriate diuretic: A. Loop A. Loop B. Thiazide B. Thiazide C. Aldosterone Antagonist C. Aldosterone Antagonist D. ENaC Inhibitor D. ENaC Inhibitor E. The square root of Misler/(1.73x Kukla) E. The square root of Misler/(1.73x Kukla)

58 Clinical Scenarios 60 year old with history of myocardial infarction presents to ER with sudden onset shortness of breath after participating in regional pickle eating contest Too winded to speak in full sentences Crackles/Rales on exam, 2+ LE edema, Oxygen Saturation 74% on 5L O2 LASIX Why? Rapid onset of diuresis, +Pulmonary edema Result? Symptomatic relief, avoidance of intubation and mechanical ventilation

59 Clinical Scenarios 48 year old man seen in clinic after experiencing exquisite pain in groin last week. Passed the following Ca-based stone with urination. Noted to have BP 153/80 Thiazide Why? HTN, Ca-based stone Result? Decrease risk for future stone formation, reduce BP, decrease risk of cardiovascular complications/death due to HTN

60 Clinical Scenarios 12 year old with a strong family history of HTN, noted to have a BP of 188/60. Has been treated with thiazides, beta-blockers, ACE-inhibitors without BP control. Labs show a serum K of 3.1, bicarb of 32. ENaC Inhibitor Why? Suspicion of Liddle’s (family history, HTN, low K, metabolic alkalosis) Result? Reduced blood pressure, decrease in cardiovascular risk from HTN

61 Clinical Scenarios 63 year old with a history of CHF. Edema is managed with dietary restriction of Na and a loop diuretic, but patient still occasionally short of breath with minimal exertion. Is in clinic for follow up and management of his heart failure. Aldosterone Antagonist Why? Class III-IV HF Result? Decreased mortality at months

62 Clinical Scenarios 62 year old woman with CKD complaining of generalized weakness, intermittent palpitations. Serum K level is 6.8 (normal ) Lasix Why? Kaliuretic effect Result? Reduction of serum K, prevention of cardiac arrhythmia and death

63 Clinical Scenarios 69 year old man presents with back pain and anemia. Is found to have Ca 11.6 mg/dL. In addition to hydration with NS and the diagnosis of Multiple Myeloma, what diuretic should be given? Lasix Why? Increase Ca excretion Result? Reduce serum Ca, prevent cardiac, renal, neurologic, musculoskeletal complications of hypercalcemia.

64 Clinical Scenarios Iron Chef Morimoto shows up in your clinic for a routine check up. He has no significant past medical history. His renal function in intact. Electrolytes are stable. BP is 153/87 Thiazide Why? Essential HTN Result? Reduction of future cardiovascular risk, many more years of dominance on “The Iron Chef.”

65 Clinical Scenarios 47 year old with chronic hepatitis and cirrhosis. Has noted increasing abdominal girth over the last several days despite treatment with Lasix. Serum K is 3.2 (normal ) Aldosterone Antagonist Why? Hypokalemia, improved volume removal in a cirrhotic patient Result? Mild alleviation of volume retention, improvement in serum K.

66 Clinical Scenarios The previous patient has a slight improvement in edema and ascites. However, after three days she develops worsening renal function. What could have happened?


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