DiureticsStephen Duden, P4

Family Medicine Morning ReportUniversity of Tennessee Medical Center

July 15, 2016

Objectives• Understand the basic 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.

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

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)⬇

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)

Types of Diuretics continued

• 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)

Types of Diuretics continued

• Osmotic diuretics• Mannitol (Resectisol)- Initially increases plasma volume

and blood pressue followed by osmotic diuresis

• Carbonic anhydrase inhibitor• Acetazolamide (Diamox)

http://pharmacologycorner.com/video-animation-on-renal-physiology-and-diuretics-mechanism-of-action/

HTN -ALLHAT• In patients 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.

JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427.

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%)

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.

Renal Threshold• Patient’s with 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.

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

Pharmacokinetics – Loop diuretics

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

Sulfa allergy?

• All common 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?”

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?

Practice Question #1 Answer• 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

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)

Practice Question #2 Answer• 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.

Adverse Effects• Hypotension and Dehydration• Renal insufficiency• Ototoxicity

• Primarily with bumetanide or ethacrynic acid• Electrolyte disturbances

• Loops • Hyponatremia, Hypokalemia, Hypocalcemia, Hypomagnesemia,

Hyperuricemia• Thiazides

• Hyponatremia, Hypokalemia, Hypercalcemia, Hyperglycemia

Clinical Pearls

• Triamterene has 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

Important Take Home Points• 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.

References• ALLHAT Officers and 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.

DiureticsStephen Duden, P4

Family Medicine Morning ReportUniversity of Tennessee Medical Center

July 15, 2016