Diuretics

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

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

Salt & Water Balance What causes edema? 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 ¼ Plasma ¾ Interstitium Isotonic fluid, however, stays in the ECF 1/3 ECF 2/3 ICF

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

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

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

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

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

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 B. Pt non compliance C. Renal Failure D. All of these are obstacles to effective diuresis

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 B. Are absorbed more efficiently in the gut 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

Regulation of Urine Content ADH

Diuretics

Diuretics Are all diuretics pretty much the same? Well, they all cause people to pee 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?”

Diuretics Class Site Effect Use Side Fx Loop Thiazides K Sparing Other

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]”

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

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

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

Effect of Lasix ADH LAS I X Blocking NaK2Cl causes: Impaired dilution No concentration gradient Increased free water excretion Impaired dilution

Lasix: Let’s see that one more time

Diluting and Concentrating

Diluting and Concentrating Distal Tubule TAL Collecting Duct TAL Medullary Interstitium

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

Loop Diuretics Na Na K K Cl Calcium

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

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

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

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

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

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

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

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

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 Tubule Effect: HCTZ impairs urinary dilution, increases Na excretion in the urine

Regulation of Urine Content

Regulation of Urine Content HCZT

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

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 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 D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia

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

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

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

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 gynecomastia Representative Example: Spironolactone Site of Action: Cortical Collecting Duct Mechanism: Competes with aldosterone receptor Pharmacokinetics: Can take between 10-48 hours to reach maximal efficacy

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 surface Na Na Aldo Na Na K

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 surface Na Na Aldo Na Na Spironolactone is an aldosterone antagonist, thus preventing sodium reabsorption and K excretion K

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

K Sparing Diuretics 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

K-sparing Diuretics 2. ENaC Blockers 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 Representative Example: Amiloride, triamterene Site of action: Corical collecting duct Mechanism: Blocks ENaC channels Pharmacokinetics: Half-life = 3-5 hours

K-Sparing Diuretics Collecting Duct Amiloride and triamterene directly block the ENaC channel Na Na Aldo Na Na 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

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 channels Li Li Li

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.

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 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 D. Amiloride my alleviate his symptoms.

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

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

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

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 diuretic After an initial diuresis, further natriuresis will be blunted by post-diuretic salt retention Salt restriction is, thus, crucial to continued diuresis

Downstream Compensation Fortune Cookie: “To fool the kidney, you must think like the kidney” ADH The addition of a “downstream” diuretic (in this case, something that blocks the distal tubule) will prevent the kidney from reclaiming Na and water LAS I X 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

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

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 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

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 153/80 Thiazide Why? HTN, Ca-based stone Result? Decrease risk for future stone formation, reduce BP, decrease risk of cardiovascular complications/death due to HTN

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 Inhibitor Why? Suspicion of Liddle’s (family history, HTN, low K, metabolic alkalosis) Result? Reduced blood pressure, decrease in cardiovascular risk from HTN

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 Antagonist Why? Class III-IV HF Result? Decreased mortality at 16-24 months

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 3.5-4.5) Lasix Why? Kaliuretic effect Result? Reduction of serum K, prevention of cardiac arrhythmia and death

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? Lasix Why? Increase Ca excretion Result? Reduce serum Ca, prevent cardiac, renal, neurologic, musculoskeletal complications of hypercalcemia.

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 153/87 Thiazide Why? Essential HTN Result? Reduction of future cardiovascular risk, many more years of dominance on “The Iron Chef.”

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 3.5-4.5) Aldosterone Antagonist Why? Hypokalemia, improved volume removal in a cirrhotic patient Result? Mild alleviation of volume retention, improvement in serum K.

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?