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DIURETICS: (know those used to Tx hypertension and HF) Thiazide diuretics: hydrochlorothiazide - PowerPoint PPT Presentation


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Normal renal function:. urine output (pressure diuresis). MAP  renal perfusion. salt output (pressure natriuresis). Davidoff ‘09. DIURETICS: (know those used to Tx hypertension and HF) Thiazide diuretics: hydrochlorothiazide Loop diuretics: furosemide, ethacrynic acid

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Normal renal function:

urine output

(pressure diuresis)

MAP  renal perfusion

salt output

(pressure natriuresis)

Davidoff ‘09

  • DIURETICS:

  • (know those used to Tx hypertension and HF)

  • Thiazide diuretics: hydrochlorothiazide

  • Loop diuretics: furosemide, ethacrynic acid

  • Potassium-sparing diuretics:

    • spironolactone, eplerenone, amiloride

  • Osmotic diuretics: mannitol

  • Carbonic anhydrase inhibitors: acetazolamide


Rationale for using diuretics

For heart failure:

Blood volume  preload (cardiac work)

congestion (edema)

For hypertension:

 Blood volume and peripheral resistance 

 preload (ventricular filling)   CO   BP

  • Diuretics promote natriuresis (Na+ excretion)

  • Water tends to follow Na+ (diuresis)

  • Relative potencies of diuretics:

  • Loops >> Thiazides >>>>>> K+ sparing


Na+

Ca2+

reabsorption

Thiaz

filtration

K+

sparing

Na+

secretion

Na+

+ALD

Loops

K+

H+

+ADH

Katzung Fig 15-1


  • Thiazides: hydrochlorothiazide

  • Most commonly used class of diuretics

  • Differ in their pharmacokinetics

  • Indicated for mild hypertension

  • short-term effects  blood volume

  • long-term effects TPR (lose their diuretic effects)

  • For moderate or severe hypertension,

  • used in combination with other antihypertensive drugs

  • Flat dose-response curve

  • (i.e., increasing dose does not make them more effective)


loss of diuresis is fast

Brenner Fig 10-2


With whom should care be taken?

  • Thiazides: (con’t)

  • Na+ reabsorption by inhibiting Na/Cl co-transport in the distal

  • convoluted tubule

  • Modest effect because only 5-10% of Na+ is reabsorbed there

  • Must be filtered or secreted to work, therefore ineffective

  • in patients with renal insufficiency/failure

  • Require renal prostaglandins to work, therefore NSAIDs can

  • interfere with diuresis

  • Side effects:

  • Hypokalemic metabolic alkalosis

  • Blood glucose, lipids, and uric acid

Bonus:

Blood Ca2+ (via Ca2+ reabsorption) useful for osteoporosis

 Urine Ca2+ useful for kidney stones


How do thiazides

(and loops) promote

K+ loss?

Na+

K+ H Loss

Na+

tubular Na+

collecting

duct

Na+

K+ H loss

Na+/K+ exchange

urine

urine


Loop diuretics: furosemide, ethacrynic acid

  • “High ceiling diuretics” - work in a dose-dependent manner

  • Ethacrynic acid is an alternative if patient has sulfonamide allergy

  • Extremely effective, rapid onset

  • Indicated for severe edema (e.g., pulmonary edema, CHF)

    • not typically used for hypertension

  • Inhibit Na/K/2Cl transport in ascending loop of Henle

  • normally responsible for ~35% Na+ reabsorption

  • Are filtered and secreted

  • Directly increase renal blood flow, therefore effective with renal insufficiency


'high ceiling diuretics'

Diuresis

'flat D-R curve'

Dose of diuretic

Brenner Fig 13-3


Like Thiazides:

Loops require renal prostaglandins to work,

therefore NSAIDs can interfere with diuresis

  • Side effects include:

  • Hypokalemic metabolic alkalosis and hyperuricemia

  • Hypovolemia

  • Ototoxicity

Loops greater incidence of adverse side effects than thiazides


Na+

Ca2+

reabsorption

Thiaz

filtration

K+

sparing

Na+

secretion

Na+

+ALD

Loops

K+

H+

+ADH

Katzung Fig 15-1


Potassium sparing ‘diuretics’

Spironolactone, Eplerenone, Amiloride

  • Weak diuretics

    • used in combination with other diuretics

  • Antagonize aldosterone effects

  • Aldosterone is a steroid

  • binds to mineralocorticoid receptors in tubular epithelial cells

  • stimulates the synthesis of Na/K/H pumps

  • promotes Na+ reabsorption, K+/H+ secretion

  • Prevents hypokalemia from thiazide and loop diuretics

  • Must be cautious of hyperkalemia


  • Spironolactone

  • Competitively binds to aldosterone receptors - nonselective

  • (mineralocorticoid, androgenic and progesterone receptors)

  • Inhibits aldosterone-induced synthesis of pumps

  • Slow onset (WHY?), long duration (active metabolites)

  • Weak naturiuretic effects, but lowers BP in some patients with mild/moderate hypertension

  • Also indicated for hyperaldosteronemia

  • Shown to improve morbidity and mortality in patients with end-staged heart failure (Pitt et al., NEJM, 1999)

  • Side effects include:

    • Men: gynecomastia and erectile dysfunction because of anti-androgenic actions

    • Women: menstrual irregularities, hirsutism


  • Eplerenone

  • More specific for aldosterone receptors than spironolactone therefore avoids side effects

    • (but really expensive)

  • Currently approved hypertension and post-MI LV dysfunction

  • CYP450 3A4 inhibitors (e.g., erythromycin, verapamil, and grapefruit juice) can elevate blood levels of eplerenone

  • Aldosterone is also associated with endothelial dysfunction and fibrotic effects in hypertension, HF and atherosclerosis

  • (mechanism underlying ACE-I cardioprotection???)

  • Cardioprotective effects appear similar to spironolactone

  • http://www.jaapa.com/issues/j20040201/articles/0204wcardiomeds.html


    • Amiloride

    • Directly inhibits pumps in distal tubules and collecting ducts

    • therefore independent of aldosterone

    • (blocks Na+ selective channels in apical membrane)

    • Onset of action much faster than spironolactone

    • does not involve gene expression

    • Relatively few side effects (caution about hyperkalemia)


    JNC VII Compelling Indications for Drug Classes

    Clinical-Trial Basis

    Compelling Indication

    Initial Therapy Options

    MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES

    Heart Failure

    Diuretic, BB, ACEI,ARB, Aldo Ant

    ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

    BB, ACEI, Aldo Ant

    Post-MI

    ALLHAT, HOPE, ANBP2,LIFE, CONVINCE

    High CAD Risk

    Diuretic, BB, ACEI, CCB

    NKF-ADA Guideline,UKPDS, ALLHAT

    Diuretic, BB, ACEI,ARB, CCB

    Diabetes Mellitus

    NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

    Chronic Kidney Disease

    ACEI, ARB

    Recurrent Stroke Prevention

    Diuretic, ACEI

    PROGRESS

    ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction

    Chobanian AV et al. JAMA. 2003;289:2560-2572


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