Upload
ellen-stone
View
230
Download
3
Tags:
Embed Size (px)
Citation preview
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
MAP renal perfusion
urine output(pressure diuresis)
salt output(pressure natriuresis)
Normal renal function:
Davidoff ‘09
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
For heart failure:Blood volume preload (cardiac work)
congestion (edema)
Rationale for using diuretics
Katzung Fig 15-1
filtration
secretion
reabsorption
+ADH
+ALDLoops
ThiazK+
sparing
K+
H+
Na+
Ca2+Na+
Na+
Thiazides: hydrochlorothiazide
•Most commonly used class of diuretics
•Differ in their pharmacokinetics
•Indicated for mild hypertensionshort-term effects blood volumelong-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)
Brenner Fig 10-2
loss of diuresis is fast
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 alkalosisBlood glucose, lipids, and uric acid With whom
should care be taken?Bonus:
Blood Ca2+ (via Ca2+ reabsorption) useful for osteoporosis Urine Ca2+ useful for kidney stones
Na+
K+ H loss
tubular Na+
urine
K+ H Loss
Na+ Na+
urine
How do thiazides(and loops) promoteK+ loss?
Na+/K+ exchange
collectingduct
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 Henlenormally responsible for ~35% Na+ reabsorption
• Are filtered and secreted
• Directly increase renal blood flow, therefore effective with renal insufficiency
Brenner Fig 13-3
'high ceiling diuretics'
Dose of diuretic
Diu
resi
s
'flat D-R curve'
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
Katzung Fig 15-1
filtration
secretion
reabsorption
+ADH
+ALDLoops
ThiazK+
sparing
K+
H+
Na+
Ca2+Na+
Na+
•Weak diureticsused in combination with other diuretics
•Antagonize aldosterone effects
•Aldosterone is a steroidbinds to mineralocorticoid receptors in tubular
epithelial cellsstimulates the synthesis of Na/K/H pumpspromotes Na+ reabsorption, K+/H+ secretion
•Prevents hypokalemia from thiazide and loop diuretics
•Must be cautious of hyperkalemia
Potassium sparing ‘diuretics’ Spironolactone, Eplerenone, Amiloride
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 actionsWomen: 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 spironolactonehttp://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 spironolactonedoes not involve gene expression
•Relatively few side effects (caution about hyperkalemia)
ALLHAT, HOPE, ANBP2,LIFE, CONVINCE
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
NKF-ADA Guideline,UKPDS, ALLHAT
Diabetes Mellitus
Clinical-Trial BasisCompelling Indication
High CAD Risk
ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
Post-MI
MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT,
RALES
Initial Therapy Options
Diuretic, BB, ACEI, CCB
BB, ACEI, Aldo Ant
Diuretic, BB, ACEI,ARB, Aldo Ant
Heart Failure
JNC VII Compelling Indications for Drug Classes
Recurrent Stroke Prevention PROGRESSDiuretic, ACEI
NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Diuretic, BB, ACEI,ARB, CCB
ACEI, ARBChronic Kidney Disease