2 DiureticsAgents that promote natriuresis (salt loss) and diuresis (water loss)Used to treat hypertension and fluid retention
3 Salt & Water Balance What causes edema? 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body¼ Plasma¾ Interstitium1/3 ECF2/3 ICF
4 Salt & Water Balance What causes edema? 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the bodyWhen water is added to the system, it distributes evenly: 2/3 to the ICF, 1/3 to the ECF¼ Plasma¾ InterstitiumIsotonic fluid, however, stays in the ECF1/3 ECF2/3 ICF
5 Salt & Water Balance What causes edema? 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the bodyISOTNCBP¼ Plasma¾ InterstitiumEdema1/3 ECF2/3 ICF
6 Salt & Water Balance What causes edema? 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the bodyISOTNC¼ Plasma¾ Interstitium1/3 ECF2/3 ICF
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 spaceIncreased Hydrostatic PressureDecreased Oncotic PressureIncreased Capillary Permeability
8 Diuretics Diuretics have profound clinical implications They allow physicians to manipulate salt and water excretion in impaired states of volume/solute regulationLike all great therapeutic interventions, they have the potential to make patients better, and, when not considered carefully, the potential to make patients worse
9 DiureticsAct primarily by inhibiting Na channels in the renal tubular systemTo reach the tubular lumen, these drugs must be…Ingested and absorbedEffectively circulatedSecreted into the renal tubular lumenBound to the target transporter
10 Question 1All of the following are potential obstacles in the diuretic’s migration from pill bottle to apical transporter EXCEPT:A. Low Albumin StatesB. Pt non complianceC. Renal FailureD. 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 retentionB. Are absorbed more efficiently in the gutC. May bind albumin in the urine instead of their targeted apical transportersD. Are unable to reach the apical transporters due to impaired glomerular permeability
14 Diuretics Are all diuretics pretty much the same? Well, they all cause people to peeBut recognize the difference based on the channels being blockedFavorite test questions focus on “Why is one diuretic better than another in a particular context?”
16 Diuretics LOOP DIURETICS Representative Example: Furosemide (Lasix) Onset of action: roughly 30 minutes with PO, 5 minutes with IVDuration: 6 hoursLASIX = “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 gradientThus…Impairs urine dilutionImpairs urine concentration
19 Regulation of Urine Content ADHNaK2Cl is necessary for:Dilution of Tubular FiltrateEstablishing the Hypertonic Medullary InterstitiumProviding the concentration gradient by which water is reabosrbed from the collecting duct (urinary concentration)
20 Effect of Lasix ADH LAS I X Blocking NaK2Cl causes: Impaired dilution No concentration gradientIncreased free water excretionImpaired dilution
26 Loop Diuretics Loop Diuretics: Increase excretion of Calcium Na Na K K ClCalcium
27 Loop DiureticsThe increase in Na delivery to the Collecting Duct causes an increase in the exchange of Na for secretion of K/H+Collecting DuctNaNaNaNaKH
28 Diuretics LASIX Quick onset of diuresis Good for acute volume overloadIncreases urinary calcium excretionUsed to treat hypercalcemia (Malignancy, Hyperparathyroidism)Increases urinary excretion of potassium and hydrogen ionsUsed to treat acute hyperkalemia3 Reasons to love your loop diuretic
29 DiureticsLASIXExcessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse3 Reasons to think twiceDiuresis
30 DiureticsLASIXExcessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse3 Reasons to think twiceDiuresis
31 DiureticsLASIXExcessive diuresis can lead to volume depletion and ARF/hypotension/CV collapseCan exacerbate calcium based kidney stonesCan cause hypokalemia, metabolic alkalosis3 Reasons to think twice
32 Diuretics Class Site Effect Use Side Fx Impairs dilution and concentrationAcute overload, edema, ↑Ca/K↓serum K, Met Alkalosis, Volume Depletion, ↑U CaTALNaK2ClLoopThiazidesK SparingOther
33 Diuretics THIAZIDE DIURETICS Representative Example: Hydrochlorothiazide (HCTZ)Onset of action: roughly 2 hoursDuration: 6-12 hoursFactoid: 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)Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the “most intimidating medication names.”Site of Action: Distal Convoluted TubuleEffect: HCTZ impairs urinary dilution, increases Na excretion in the urine
37 Regulation of Urine Content HCZTADHThiazide Diuretics:Impair Dilution, leading to excretion of salt and waterDo not disrupt the concentrating mechanism
38 Question 3Why are patients on thiazides more prone to hyponatremia than those on loop diuretics?A. Thiazides provide greater natriuretic effect than loop diureticsB. Trick question: They both equally predispose patients to hyponatremiaC. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilutionD. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia
39 DiureticsHow do I choose between a loop diuretic and a thiazide diuretic?Similarities:Both will make you peeBoth can be used for edema and HTNBoth can result in hypokalemia and metabolic alkalosis
40 Diuretics Loop Thiazide How do I choose between a loop diuretic and a thiazide diuretic?Differences:LoopThiazideImpairs both; greater free water excretionImpairs dilution only; more prone to ↓NaConcentration/DilutionGreater kaliuretic effect; better for Tx of ↑KLess kaliuresisPotassiumIncreases Ca excretion; better for Tx of ↑Ca↑Ca reabsorption; better for folks with Ca stonesCalciumBetter in renal failure; Relieves resp distressInexpensive; First line agent for HTNUnique Superpowers
41 Diuretics Class Site Effect Use Side Fx Impaired dilution and concentrationAcute overload, edema, ↑Ca/K↓serum K, Met Alkalosis, Volume Depletion, ↑U CaTALNaK2ClLoopImpaired dilutionHyponatremia, ↓serum K, Met Alkalosis, Volume DepletionDCTNa/Cl cotrnsprtEdema, HTN, Ca stonesThiazidesK SparingOther
42 K-Sparing Diuretics 1. Aldosterone Antagonists Factoid: If Peter Griffin (Family Guy) was on a diuretic it would probably be spironolactone, which would account for his gynecomastiaRepresentative Example: SpironolactoneSite of Action: Cortical Collecting DuctMechanism: Competes with aldosterone receptorPharmacokinetics: Can take between hours to reach maximal efficacy
43 K-Sparing Diuretics Collecting Duct 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 surfaceNaNaAldoNaNaK
44 K-Sparing Diuretics Collecting Duct 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 surfaceNaNaAldoNaNaSpironolactone is an aldosterone antagonist, thus preventing sodium reabsorption and K excretionK
45 K Sparing Diuretics There’s more to aldosterone than meets the eye… There are mineralocorticoid receptors in the heart as wellLocal production of aldosterone in the heart is proportional to degree of heart failureAldosterone 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 DiureticsDespite 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 Diuretics2. ENaC BlockersFactoid: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 CourtSpares potassium by decreasing the lumen-negative gradient that drives the exulsion of K/H into the lumenRepresentative Example: Amiloride, triamtereneSite of action: Corical collecting ductMechanism: Blocks ENaC channelsPharmacokinetics: Half-life = 3-5 hours
48 K-Sparing Diuretics Collecting Duct Amiloride and triamterene directly block the ENaC channelNaNaAldoNaNaThis 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 CCDKK
49 K-Sparing Diuretics Collecting Duct Li Li Factoid: Certain drugs (trimethoprim, pentamidine) may have mild diuretic effects due to their ability to block reduce the number of open ENaC channelsLiLiLi
50 Question 4A 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 DIB. The patient may have lithium-induced nephrogenic DI because Bactrim increases the open Na channels available for Li entry into cellsC. The patient may have psychogenic polydipsia and worsening mania due to decreased absorption of lithium during treatment with BactrimD. Amiloride my alleviate his symptoms.
52 Diuretics Class Site Effect Use Side Fx Impaired dilution and concentrationAcute overload, edema, ↑Ca/K↓serum K, Met Alkalosis, Volume Depletion, ↑U CaTALNaK2ClLoopImpaired dilutionHyponatremia, ↓serum K, Met Alkalosis, Volume DepletionDCTNa/Cl cotrnsprtEdema, HTN, Ca stonesThiazides↓K, CHF, ESLD; Li tox, LiddlesK SparingCCDDecreased distal Na reabsorption↑ serum K, gynecomastiaOther
53 “Other” Diuretics CAI Ex: Acetazolamide Blocks carbonic anhydrase Causes alkaline diuresisApplications:GlaucomaProphylaxis of Mountain Sickness
54 “Other” Diuretics Osmotic Diuretics Ex: Mannitol Non-reabsorbable polysaccharidePreferential water diuresisThe 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 In the absence of salt restriction, the kidney will adapt to the effect of the diureticAfter an initial diuresis, further natriuresis will be blunted by post-diuretic salt retentionSalt restriction is, thus, crucial to continued diuresis
56 Downstream Compensation Fortune Cookie:“To fool the kidney, you must think like the kidney”ADHThe addition of a “downstream” diuretic (in this case, something that blocks the distal tubule) will prevent the kidney from reclaiming Na and waterLAS I XAs 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
57 Clinical ScenariosFor each of the following clinical scenarios, pick the appropriate diuretic:A. LoopB. ThiazideC. Aldosterone AntagonistD. ENaC InhibitorE. The square root of Misler/(1.73x Kukla)
58 Clinical Scenarios LASIX 60 year old with history of myocardial infarction presents to ER with sudden onset shortness of breath after participating in regional pickle eating contestToo winded to speak in full sentencesCrackles/Rales on exam, 2+ LE edema, Oxygen Saturation 74% on 5L O2LASIXWhy? Rapid onset of diuresis, +Pulmonary edemaResult? Symptomatic relief, avoidance of intubation and mechanical ventilation
59 Clinical Scenarios Thiazide Why? HTN, Ca-based stone 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 153/80ThiazideWhy? HTN, Ca-based stoneResult? Decrease risk for future stone formation, reduce BP, decrease risk of cardiovascular complications/death due to HTN
60 Clinical Scenarios ENaC Inhibitor 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 InhibitorWhy? Suspicion of Liddle’s (family history, HTN, low K, metabolic alkalosis)Result? Reduced blood pressure, decrease in cardiovascular risk from HTN
61 Clinical Scenarios Aldosterone Antagonist Why? Class III-IV HF 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 AntagonistWhy? Class III-IV HFResult? Decreased mortality at months
62 Clinical Scenarios Lasix Why? Kaliuretic effect 62 year old woman with CKD complaining of generalized weakness, intermittent palpitations. Serum K level is 6.8 (normal )LasixWhy? Kaliuretic effectResult? Reduction of serum K, prevention of cardiac arrhythmia and death
63 Clinical Scenarios Lasix Why? Increase Ca excretion 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?LasixWhy? Increase Ca excretionResult? Reduce serum Ca, prevent cardiac, renal, neurologic, musculoskeletal complications of hypercalcemia.
64 Clinical Scenarios Thiazide Why? Essential HTN 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 153/87ThiazideWhy? Essential HTNResult? Reduction of future cardiovascular risk, many more years of dominance on “The Iron Chef.”
65 Clinical Scenarios Aldosterone Antagonist 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 AntagonistWhy? Hypokalemia, improved volume removal in a cirrhotic patientResult? Mild alleviation of volume retention, improvement in serum K.
66 Clinical ScenariosThe 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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