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Final Draft Diuretics Presentation
- 1. Diuretics Stephen Duden, P4 FamilyMedicine Morning Report University of Tennessee Medical Center July 15, 2016
- 2. Objectives • Understand thebasic pharmacology of the different diuretic agents • Evaluate what diuretic class is appropriate for the clinical vignette of a patient. • Be able to recall the correct dosing of diuretic agents for treating hypertension and edema. • Apply pharmacokinetic parameters to convert doses from oral loop diuretics to IV loop diuretics. • Apply pharmacokinetic parameters to convert doses between the various IV loop diuretics. • Recognize the adverse effects of diuretics in patients at UTMC.
- 3. Introduction and Pharmacology •What are diuretics? • Medications to reduce blood pressure and edema. • Most inhibit electrolyte transporters in the nephron. • Some have osmotic effects • Can be hazardous or C/I in certain patients • AKI • Dehydration • Electrolyte disturbances • Oliguria and anuria
- 4. Indications for Diuretics •HTN (Thiazide/K sparing diuretics, some loops) • Chronic or acute edema (Thiazides, Loops) • Hypercalcemia (Loops), prevention of Kidney stones/osteoporosis (Thiazides) • AKI, acute closed angle glaucoma, brain edema, drug overdose (Osmotic) • Altitude sickness, Hypercapnic COPD (CA inhibitors) ⬇
- 5. Types of Diuretics •Thiazide diuretics-inhibit sodium and chloride reabsorption in the distal tubule • Hydrochlorothiazide (Microzide) • Chlorthalidone (Thalitone) • Metolazone (Mykrox) • Loop diuretics-inhibit chloride reabsorption in the thick ascending loop of Henle • Furosemide (Lasix) • Bumetanide (Bumex) • Torsemide (Demadex) • Ethacrynic acid (Edecrin)
- 6. Types of Diureticscontinued • Potassium sparing diuretics – Work on the DCT to increase Na excretion and decrease K secretion. • Amiloride (Midamor) • Triamterene (Dyrenium) • Aldosterone antagonists – Block aldosterone’s action in RAAS system, preventing fluid retention. • Spironolactone (Aldactone) • Eplerenone (Inspra)
- 7. Types of Diureticscontinued • Osmotic diuretics • Mannitol (Resectisol)- Initially increases plasma volume and blood pressue followed by osmotic diuresis • Carbonic anhydrase inhibitor • Acetazolamide (Diamox)
- 8.
- 9. HTN -ALLHAT • Inpatients with hypertension, what is the efficacy and safety of alpha blockers, calcium channel blockers, ACE inhibitors, or thiazide diuretics in lowering the incidence of CV events? • No difference in primary outcome between CCBs, ACEI, or thiazides. • Thiazides shown to have stroke benefit. (ALLHAT) • Chlorthalidone had 15% less incidence of stroke than Lisinopril arm • Alpha blocker arm stopped early due to increased CHF. • Thiazides became the first line agent for treatment of HTN JAMA 2002: 288-2981-97.
- 10. JAMA. 2014 Feb5;311(5):507-20. doi: 10.1001/jama.2013.284427.
- 11. Dosing – HTN •HCTZ: 12.5-50 mg/day – 1st line therapy • Chlorthalidone: 12.5-25 mg/day – 1st line therapy • Metolazone: 2.5-5 mg/day • Amiloride: 5-10 mg/day • Eplerenone: 50-100 mg/day • Triamterene: 50-100 mg/day • Spironolactone: 25-50 mg/day • Furosemide: 40 mg twice daily – Loops may be used in ESRD with resistant HTN • Torsemide: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks Consider in resistant HTN or HTN w/HF (EF <35-40%)
- 12. Dosing - Edema •For edema, there is no target dose, each patient is different • Each patient has a different renal threshold for diuresis • Start with double the patient’s home dose and double that dose until diuresis occurs. • Once patient has achieved diuresis, there is no further efficacy from higher doses. • Treatment of edema confers a symptomatic benefit only.
- 13. Renal Threshold • Patient’swith worse renal function will have high thresholds, requiring higher doses. • Thiazides may not work in ESRD, loop diuretics will be more efficacious. • CrCl <30, thiazides will not work at all. • Other strategies if refractory • thiazide+loop • inotrope+loop • Last line therapies J Am Coll Cardiol. 2012;59(24):2145-2153.
- 14. Dosing - Edema •Furosemide: 20-80 mg PO qday-bid, 20-200 mg IV per dose. Max 600 mg daily. • Can repeat in 1-2 hours • Bumetanide: 0.5-5 mg PO qday-bid, 0.5 mg-1 mg IV per dose. Max 10 mg daily • Can repeat in 4-5 hours for up to 2 doses • CIVI • 1 mg IV load then 0.5-2 mg/hour; repeat loading dose before increasing infusion rate • Torsemide: 10-100 mg PO qday-bid, 10-20 mg IV per dose. Max 200 mg daily. • Can repeat every 2 hours • Ethacrynic Acid 50-200 mg PO qday, 0.5-1 mg/kg IV per dose. Max 100 mg/dose • Can repeat in 8-12 hours, usually only one dose is given • Mannitol: 0.25-1 g/kg dose q6-8 hours (cerebral) keep serum osmol <320
- 15. Pharmacokinetics – Loopdiuretics Drug IV Potency Bioavailability Oral: IV Metabolism Affected by Food? Furosemide 40 50% 2:1 Renal Yes, ⬇ Torsemide 20 ~100% 1:1 Hepatic No Bumetanide 1 ~100% 1:1 Hepatic Yes, ⬇ *NSAIDs and food can diminish diuretic effects
- 16. Sulfa allergy? • Allcommon loop diuretics, acetazolamide, and thiazides have a sulfonamide group in them. • However, very few patients have a true type one allergic reaction to the sulfonamide moiety. • Most patients have allergy to sulfates or sulfites, which would not prevent a patient from receiving these medications. • “What loop diuretic can be used in a true type 1 allergy to sulfonamides?”
- 17. Practice Question #1 •HS is a 67 yo WM with CC of SOB secondary to pulmonary edema. Pt’s BP is 136/80 with HR of 80. SCr is 1.8, K+: 4.3, all other labs within normal. PMH includes HFrEF (35%), HTN, HLD, GERD, and T2DM. NKDA. • TBW: 89 kg, was 82 kg last week. IBW: 50 kg. BMI: 35. • His home dose of Lasix is 40 mg qday with food. The decision is made to initiate IV Bumetanide for inpatient diuresis. • What dose of IV bumetanide is appropriate?
- 18. Practice Question #1Answer • Home dose: furosemide 40 mg po qday with food • Food decreases absorption • Assessment of renal threshold. Warm/wet HF exacerbation. Give 2-2.5 times his home dose to manage (DOSE trial) • 40 mg po x 2: 80 mg • Convert 80 mg PO furosemide to IV furosemide • 80 mg PO= 40 mg IV push qday • Convert IV furosemide to IV bumetanide • 40 mg IV furosemide qday = 1 mg IV bumetanide qday
- 19. Practice Question #2 •You give HS the appropriate diuretic dose, but his I/O are still positive at 1030:500 with no resolution of pulmonary edema. Renal function still reduced but stable with SCr 1.82. Albumin 1.8. BP 128/76 and HR: 80. What are appropriate interventions for HS to improve his diuresis? (Multiple correct answers)
- 20. Practice Question #2Answer • Option 1: Add a Thiazide or Thiazide like diuretic before next dose of bumetanide (if po). If using IV chlorthalidone, give at same time. • Option 2: Add Dobutamine (if patient goes from warm and wet to cold and wet with hypoperfusion) • Option 3: Transition patient to dialysis if you feel kidney function is heading towards ESRD and above interventions will not be effective. (clinical judgement) • Option 4: Administer 6.25 mg Albumin 5% with next dose of bumetanide • Controversial, last line.
- 21. Adverse Effects • Hypotensionand Dehydration • Renal insufficiency • Ototoxicity • Primarily with bumetanide or ethacrynic acid • Electrolyte disturbances • Loops • Hyponatremia, Hypokalemia, Hypocalcemia, Hypomagnesemia, Hyperuricemia • Thiazides • Hyponatremia, Hypokalemia, Hypercalcemia, Hyperglycemia
- 22. Clinical Pearls • Triamterenehas a BBW for hyperkalemia • Septra’s trimethoprim component is structurally similar to triamterene • Metolazone is preferred in ESRD to enhance loop diuretic effects in refractory edema. It has a once daily dosing frequency. • Hypotension from diuretics can lead to falls, especially in the elderly
- 23. Important Take HomePoints • For edema, diuretics confer a symptomatic benefit only • There are no target doses for diuretics • There are goal BP ranges for HTN • Thiazides are a first line treatment for HTN and have low efficacy w/CrCl<30 • Monitor electrolytes, renal function, and hydration status. • NSAIDs and food can reduce loop diuretic efficacy. • Loop diuretics have different potencies and require dose conversion.
- 24. References • ALLHAT Officersand Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288 : 2981 –2997, 2002, JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981. • DiPiro, Joseph; Talbert, Robert L.; Yee, Gary; Wells, Barbara; Posey, L. Michael (2014-02-26). Pharmacotherapy A Pathophysiologic Approach 9/E (Pharmacotherapy : a Pathophysiologic Approach) • Felker G, Mentz RJ. Diuretics and Ultrafiltration in Acute Decompensated Heart Failure. J Am Coll Cardiol. 2012;59(24):2145-2153. doi:10.1016/j.jacc.2011.10.910. • http://pharmacologycorner.com/video-animation-on-renal-physiology-and-diuretics-mechanism-of-action/ • Ohtani T, Felker GM, McNulty SE, LeWinter MM, Braunwald E, Redfield MM. Plasma Renin Activity (PRA) Predicts Diuretic Resis- tance in Acute Heart Failure Patients: An Ancillary Study of the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF). J Card Fail 2011;17:S25–6. • Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; January 29, 2015. • James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809. PubMed PMID: 24352797.
- 25. Diuretics Stephen Duden, P4 FamilyMedicine Morning Report University of Tennessee Medical Center July 15, 2016
Editor's Notes
- #4 Primarily affect sodium transport. Na=water Affect sodium at different sites! some have osmotic effects by increasing osmolality of the filtrate, drawing more fluid in. Obstructive uropathy, don’t want to give in patients with no urine output, MONITOR I/O’s
- #5 Read up on Hypercapnic COPD and altitude sickness! Sometimes can use loops for hyperkalemia (not really) Read up on hypercalciuria Thiazides can treat kidney stones Data from a randomized, double-blind, placebo-controlled study supports the use of hydrochlorothiazide for the prevention of recurrent calcium nephrolithiasis (Laerum 1984). Additional trials may be necessary to further define the role of hydrochlorothiazide in the treatment of this condition. Based on the American Urologic Association (AUA) guidelines for the medical management of kidney stones, hydrochlorothiazide is effective and recommended for the prevention of recurrent calcium stones in patients with high or relatively high urine calcium concentrations. THINK ABOUT IT, THIS MAKES SENSE. In kidney stones, calcium deposits are in the FILTRATE, thiazides decrease calcium in the filtrate and increase it in the blood, which helps osteoporosis.
- #6 Na+/2Cl−/K+ cotransporter- loops Thiazide diuretics such as hydrochlorothiazide block sodium reabsorption in the distal convoluted tubule (approximately 5% to 8% of filtered sodium). Chlorothiazide is the only thiazide diuretic that can be given intravenously (500 to 1000 mg once or twice daily) Metolazone is actually a thiazide like diuretic. These drugs are called benzothiadiazides, or thiazides for short. Chemically, metolazone is not a substituted benzothiadiazine, and therefore is not technically a thiazide. However, since metolazone, as well as other drugs like indapamide, act on the same target as thiazides and behave in a similar pharmacologic fashion, they are considered "thiazide-like diuretics".
- #7 Additional C/I for Potassium sparing. acute renal insufficiency; significant impairment of renal excretory function; hyperkalemia; Addison’s disease eGFR should be >30 mL/minute/1.73 m2 or creatinine should be ≤2.5 mg/dL (men) or ≤2 mg/dL (women) OR K+ >5 for initiation Discontinue if serum potassium >5.5 or serum creatinine >4 mg/dL. Avoid routine triple therapy with the combined use of an ACE inhibitor, ARB, and spironolactone. Instruct patients with heart failure to discontinue use during an episode of diarrhea or dehydration or when loop diuretic therapy is interrupted (ACCF/AHA [Yancy 2013]). -worsening hyperkalemia or renal dysfunction
- #10 Bring up the fact that they studied chlorthalidone and not HCTZ. MR.FIT saw a nonsignificant trend of worse outcomes with HCTZ and then included chlorthalidone.
- #12 Chlorthalidone was the actual drug studied in the ALLHAT study. We do not have HARD data for HCTZ, and it was trending poorly in Mr. FIT. Can’t go into detail in that one today. Can do aldosterone antags if EF <40% IF they have T2DM or symptomatic HF while already on an ACEI and BB. If not, wait until <35%. Resistant HTN= combination of at least three antihypertensive medications of different classes, optimally dosed and usually includ- ing a diuretic AND the patient is ADHERENT to them! No white coat HTN either chronic kidney disease, obstructive sleep apnea, or hyperaldosteronism, all of which can lead to fluid retention. Higher doses of diuretics (or a change to a loop diuretic) are usually needed.
- #14 -Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function, although higher doses may be necessary to obtain adequate delivery of the drug to the site of action -loop diuretics are highly bound to plasma proteins, they are not highly filtered at the glomerulus. Adding ALBUMIN to Bumex…Few patients with severe hypoalbuminemia (plasma albumin <2.0 g/dL) have been studied. It is possible that infusion of furosemide or other loop diuretic plus albumin would be effective in patients with refractory edema and severe hypoalbuminemia. However, if attempted, sodium excretion should be monitored after addition of albumin infusions, and infusions should be discontinued if they do not result in a net increase in sodium excretion. General issues related to the management of edema in patients with nephrotic syndrome are discussed in detail elsewhere. Administer 6.25 mg Albumin 5% with next dose of bumetanide --They reach the tubular lumen by active transport via the organic acid transport pathway. Competitors for this pathway (probenecid or organic by-products of uremia) can inhibit delivery of loop diuretics to their site of action and decrease effectiveness. -Loop diuretics also induce a prostaglandin-mediated increase in renal blood flow, which contributes to their natriuretic effect. -Coadministration of NSAIDs blocks this prostaglandin-mediated effect and can diminish diuretic efficacy. -Excessive dietary sodium intake may also reduce the efficacy of loop diuretics.
- #15 You can also use Hydrochlorothiazide for Edema Oral: 25 to 100 mg daily in 1 to 2 divided doses; may administer intermittently on alternate days or on 3 to 5 days each week. Furosemide Continuous IV infusion (ACCF/AHA [Yancy, 2013]); Brater, 1998; Howard, 2001): Initial: IV bolus dose 40-100 mg over 1-2 minutes, followed by continuous IV infusion rate of 10-40 mg/hour; repeat loading dose before increasing infusion rate. Note: With lower baseline CrCl (eg, CrCl <25 mL/minute), the upper end of the initial infusion dosage range should be considered. If urine output is <1 mL/kg/hour, double as necessary to a maximum of 80-160 mg/hour (Howard, 2001; Schuller, 1997). The risk associated with higher infusion rates (80-160 mg/hour) must be weighed against alternative strategies.
- #16 Average duration of effect for oral intake is ~ 6 hours for all agents, Bumex is the shortest, Torsemide is the longest Bumetanide 1 mg = furosemide 40 mg = torsemide 20 mg = ethacrynic acid 50 mg Half life and expected duration of action can be increased in renal or hepatic dysfunction Furosemide also comes as a sublingual tablet as well Bumex and Cirrhosis: Use caution in patients with cirrhosis; initiate bumetanide therapy with conservative dosing and close monitoring of electrolytes; avoid sudden changes in fluid and electrolyte balance and acid/base status which may lead to hepatic encephalopathy.
- #17 Answer: Ethacrynic acid, less potent than furosemide (50:1 bumex) Has high potential for ottotoxicity Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes. The nonsulfonamide diuretic ethacrynic acid may be used in patients who are allergic to sulfonamide-based diuretics, but is not considered a first-line agent because it may be more ototoxic than the sulfonamide diuretics in high doses and its relative insolubility makes it difficult to administer intravenously.
- #18 CrCL w/ IBW is <30 HF exacerbations in patient’s with ESRD are usually admitted as inpatient. Inpatient management is IV loop therapy. His renal threshold will be very high, bumex is appropriate HF increases threshold With renal insufficiency, as seen in >50% of ADHF patients (15), organic anions compete with receptor sites for tubular transporters (16) and further increase dose requirements.
- #19 DOSE trial randomized 308 ADHF patients to IV furo- semide given as twice-daily boluses or continuous infusion and to either a low dose (IV dose numerically equivalent to the patient’s oral dose) or a high dose (2.5 times oral dose given intravenously) strategy. There was no significant difference in either of the co-primary endpoints of global assessment of symptoms There was no significant difference in either of the co-primary endpoints of global assessment of symptoms the higher dose group had fewer serious adverse events and no evidence of worse 60-day outcomes. Taken as a whole, the data suggest that higher doses of diuretics are likely to be more efficacious in relieving congestion than a low-dose strategy,
- #21 Thiazides or thiazide like diuretics may be added before loop diuretics Positive inotropes may be added to loop diuretics to promote renal perfusion Decreases threshold for diuresis. Sodium reabsorption can be blocked in the distal tubule by the concurrent administration of a thiazide diuretic [4,31-33]. The distal tubule reabsorbs about 75 to 80 percent of the sodium delivered out of the loop of Henle. Administration of a loop diuretic increases distal sodium delivery and therefore sodium reabsorption in the distal tubule, an effect mediated in part by increased activity of the thiazide-sensitive sodium-chloride cotransporter in the luminal membrane of the distal tubule cells Loop diuretics are highly (≥95 percent) protein bound. As a result, they primarily enter the tubular lumen by secretion in the proximal tubule, not by glomerular filtration. Patients who do not respond to usual loop diuretic therapy may be resistant because of decreased diuretic secretion into the tubular lumen. As examples, decreased renal perfusion in heart failure (due to the reduced cardiac output) and cirrhosis (due to renal vasoconstriction) and competitive inhibition of tubular secretion in renal failure may contribute to impaired diuretic secretion Patients with nephrotic syndrome may also be unresponsive to diuretics because of decreased tubular secretion. Because loop diuretics are highly protein bound, hypoalbuminemia associated with the nephrotic syndrome may reduce the delivery of diuretic to the renal tubule. In addition, filtered albumin in nephrotic patients may bind loop diuretics in the tubular lumen, thereby interfering with their function. HOWEVER THIS STUDY WAS DONE IN RATS However, a subsequent study in patients with nephrotic syndrome (mean plasma albumin 3.0 g/dL) found that a mixture of loop diuretic and albumin (60 mg of furosemide infused in 200 mL of a 20 percent albumin solution) produced only a modest increase in sodium excretion compared with furosemide alone without an increase in the rate of furosemide excretion Coadministration of HA potentiates the action of FU in patients with the nephrotic syndrome, but only modestly. This effect is mediated by changes in renal hemodynamics. Increase in sodium excretion was due to the salt in the bag, no increase in sodium excretion! Few patients with severe hypoalbuminemia (plasma albumin <2.0 g/dL) with refractory edema have been studied. It MAY work in these patients but no evidence.
- #22 Ototoxicity: Bumetanide-induced ototoxicity (usually transient) may occur with rapid IV administration, renal impairment, excessive doses, and concurrent use of other ototoxins (eg, aminoglycosides). In the setting of ESRD or hepatic disease (depends on agent) Electrolyte disturbances can manifest as mental status change, cardiac arrythmias MAKE SURE TO REPLENISH ELECTROLYTES Patients can be given potassium for supplementation to offset hypokalemia from loop diuretics. Thiazides can help in osteoporosis but also worsen gout.
- #23 which is why Septra can also cause hyperkalemia
- #24 Ensure patient has urine output after administration -If not, dose may need to be increased or investigate AKI/urinary blockage