Transcript Diuretica - GZA jaarverslag

Diuretica
Robert Rutsaert
Indicaties
• -hypertensie
• -hartfalen, longoedeem
• -oedeem (chronische nierinsufficiëntie, nefrotisch
syndroom, levercirrose)
• -idiopatisch cyclisch oedeem
• -urolithiase (renale hypercalciurie)
• -(Menière, hoogteziekte, glaucoom)
Nevenwerkingen
-hypokaliëmie
-hypomagnesemie
-(orthostatische) hypotensie
-hyperuricemie, jicht
-diabetes mellitus (~K+)
-hyperlipidemie
-impotentie
-hyponatremie
-pancreatitis
-allergische reacties: interstitiële nefritis, hematologische
afwijkingen, huidreacties,
-doofheid
-(cholecystitis?)
-(lithiumintoxicatie)
Nevenwerkingen
Kaliumsparende diuretica
Spironolactone
• hyperkaliëmie
• gynecomastie, pijnlijk (20%)
• impotentie
• cyclusstoornissen
• maaglast
Canrenoaat (Soldactone)
• metaboliet van spironolactone
• hyperkaliëmie
Eplerenon (Inspra)
• minder endocriene afwijkingen
• duur
• hyperkaliëmie
• CYP3A4 interferenties
Hypokaliëmie
-kaliuretisch, kaliumverlies uit myocardcel
-reduceert antihypertensief effect
-> diabetes, tubulusbeschadiging, ritmestoornissen, plotse dood (ook <betablokkers)
-dosisafhankelijk
-onderschat door staalartefact
-+hypomagnesemie
-QT (< quinolones, macroliden, psychotropica, ...) ; digitalis
-risico milde hypertensie vs. hypokaliëmie!
Hyperkaliëmie
• NI ; e-GFR <(30)-40ml/min/1,73m²
• Cave: NSAID, trimethoprim (cotrimoxazol), ACE-inhibitoren, sartanen of
renine-inhibitoren
Hyponatremie
• ouderen, lage BMI
• thiaziden > loopdiuretica
• euvolemisch (cfr. SIADH), geconcentreerde urine
• bij correctie hoog risico op osmotisch
demyelinisatiesyndroom
• beter niet bij bierdrinkers, psychogene polydipsie
• niet opnieuw
Nevenwerkingen
If a little is good more must be better
Hypertensie
• BD = CO x SVR
= (HRxSV) x (SVR)
Hypertensie
• BD = CO x SVR
= (HRxSV) x (SVR)
op korte termijn:
na 6-tal weken:
SV/CO
SVR
An interesting feature of the hemodynamic effects of thiazide diuretics is
that although the early reduction of BP is associated with a fall in cardiac
output, this becomes converted after approximately 1 month to a fall in total
peripheral resistance and a rise in cardiac output, back to pretreatment
levels
Shah S, Khatri I. Freis ED. Am Heart J 1978;95:611-618
Effects of treatment on morbidity in hypertension.
Results on patients with diastolic blood pressures
averaging 115 through 129mmHg.
JAMA 202, 1028-1034, 1967
ALLHAT
• >55j, hypertensie + 1 risicofactor
• N = 33357
JAMA, 288, 23:2981, 2002
ALLHAT
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chlortalidone (12,5-25mg), amlodipine (2,5-10mg), lisinopril (10-40mg/d)
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vergelijkbaar qua CIHL, niet-fataal AMI
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geen hogere cardiale sterfte met amlodipine
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minder hartfalen en CVA met chlortalidone
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meer nieuw hartfalen met amlodipine > chlortalidone
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meer gecombineerde cardiovasculaire eindpunten met lisinopril > chlortalidone
(CVA, hartfalen)
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chlortalidone ook beter bij diabetici
JAMA, 288, 23:2981, 2002
Should we prescribe diuretics for patients
with prediabetes and hypertension
ALLHAT
• normale basale glycemie
• na 4j, diabetes (nuchtere glycemie >123mg/dl):
• chlortalidone
• amlodipine
• lisinopril
11,6%
9,8%
8,1%
(niet K-sparend)
Arroll B, BMJ, 2008,337,13:1415
Hypertensie
NICE: cardiovasculaire eindpunten
diuretica vs ACEi: minder CVA
diuretica vs CEB: minder hartfalen
CV outcome beter ondanks diabetes
Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for
primary hypertension
Vijaya M Musini
Cochrane Hypertension Group
29 MAY 2014
Hydrochlorothiazide; dose-related blood pressure-lowering effect
• 6.25 mg
4/2 mmHg
• 12.5 mg
6/3 mmHg
• 25 mg
8/3 mmHg
• 50 mg/d
11/5 mmHg
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for other thiazide drugs, the lowest doses studied lowered blood
pressure maximally and higher doses did not lower it more
greater effect on systolic than on diastolic blood pressure
pulse pressure -4 to 6 mmHg
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> 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors
> 2 mmHg pulse pressure reduction with non-selective beta-blockers
thiazides did not increase withdrawals due to adverse effects in these
short-term trials but there is a high risk of bias for that outcome.
Thiaziden
• meerdere studies outcome chlortalidone > HCTZ
• bij dezelfde dosis is chlortalidone 1,5 to 2x krachtiger
dan HCTZ
• 12,5 to 25 mg HCTZ < 12,5-25mg chlortalidone
(ALLHAT)
• langer werkend, tragere renale excretie
• beschikbaarheid?
Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for
primary hypertension
Balraj S Heran
Cochrane Hypertension Group
14 NOV 2012
• amiloride and triamterene
• no trials when used alone
• 6 trials when added as a second drug at
low doses: no blood pressure lowering
effect
Blood pressure lowering efficacy of diuretics as second-line therapy for
primary hypertension
Jenny MH Chen
Cochrane Hypertension Group
7 OCT 2009
• thiazides as second-line drug = first-line
drug
• BP lowering effect of thiazides is additive
• loop diuretics similar blood pressure
lowering effect at 1 times the
recommended starting dose
Indapamide
• interessante molecule
• diureticum, natriuretisch, proximaal segment
van de distale tubulus convolutus
• vasculair effect, inhibitie cardiovasculaire
reactiviteit op pressor stimulus
• vrijwel onveranderlijk hypokaliëmie
• risico/baten?
ZOUT
• Cochrane review : "modest" reduction in salt intake on blood
pressure over four weeks or more.
• 22 trials, hypertension (n = 999)
• BP -5,39/2,82 mmHg
• baseline median 24-hour urine sodium excretion was 162 mmol
(9,5 g salt) and the mean reduction in the active arms was 75
mmol (4,4 g salt),
• target daily sodium intake of 87 mmol (equivalent to 2000 mg of
sodium or 5 g of salt) reasonable.
ZA dieet : 5-6g zout/d
cave zout in geneesmiddelen
Therapieresistente hypertensie
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dd: witte jas hypertensie, pseudohypertensie, slechte therapietrouw,
secundaire hypertensie, zout
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Systolische bloeddruk ≥ 140 mmHg
3 antihypertensiva van verschillende klassen inclusief een diureticum
In adequate dosering
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Toevoegen van furosemide of spironolactone
Blood pressure lowering efficacy of loop diuretics for primary hypertension
Vijaya M Musini
Cochrane Hypertension Group
15 AUG 2012
-limited number of published RCTs
-effect is modest (-8/-4 mmHg)
-no differences between different loop diuretics
-dose ranging effects could not be evaluated
-no good estimate of the incidence of harms associated with loop diuretics
because of the short duration of the trials and the lack of reporting of
adverse effects in many of the trials.
Diuretica bij hartfalen
Diuretics for heart failure
Rajaa F Faris
Cochrane Heart Group
15 FEB 2012
Chronic heart failure
• conventional diuretics reduce the risk of
death and worsening heart failure
compared to placebo (-80 deaths /1000 treated)
• compared to active control, diuretics appear
to improve exercise capacity (+28-33%)
Loopdiuretica
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krachtiger, sneller werkend, korter werkend
prolongatum (duurder)
sterk eiwitgebonden, tubulaire secretie
compensatoire mechanismen: RAAS, ADH
Loopdiuretica
• furosemide: bioavailability 50%
bumetamide: bioavailability 95%, piek
na 0,5-2u; eiwitbinding 95%; t1/2 11,5u; tubulaire excretie
• minder hyponatremie dan thiaziden
• U Na/K > thiaziden
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Rate of furosemide excretion vs increase in sodium excretion in normals (solid line)
and patients with heart failure (HF; dashed line).
Patients with HF show relative resistance at a given rate of diuretic excretion due
to increased sodium reabsorption in other nephron segments.
BraterDC, Kidney Int 1984; 26:183
Loopdiuretica
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normal renal function:
IV: diuresis begins with as little as 10 mg of furosemide; maximal effect with 40 mg
given intravenously
po: maximum dose is 80 mg since its bioavailability is only about 50 percent,
although there is substantial interpatient and intrapatient variability
equivalent maximal doses are 1 mg for bumetamide and 15 to 20 mg for either oral
or intravenous torasemide since these agents are almost completely absorbed
all of the loop diuretics produce the same response if given at equipotent doses
going above these maximum doses will produce little or no further diuresis but may
increase the risk of side effects
the maximum effective diuretic dose differs in patients with heart failure, advanced
cirrhosis, or renal failure.
Diureticaresistentie
• worsening renal function during diuresis with a
progressively reduced an inadequate
response to diuretic drugs
• diuretic resistance has been described as a
component of "cardio-renal syndrome"
• poorer outcomes (increased morbidity and
mortality) in both chronic and acute
decompensated heart failure
Acuut longoedeem
• -R/afterloadreductie (Cedocard 3mg IV)
• -furosemide IV 20-40-60mg
• -25% blijkt ondervuld
Diuretic strategies in patients with
acute decompensated heart failure
Felker MG,NEJM, 2011; 364/9: 797-805
• geen verschil tussen continu infuus en bolussen
alsook lage en hoge dosissen zowel voor effect als
veiligheid in primaire eindpunten
• in tegenstelling tot eerdere kleine studies: continue infusie
beter effect en minder nierfunctiedaling
• verklaring
• placebo continu infuus: langer plat liggen: op zich diurese zou
bevorderen
• bolusgroep hogere dosis gekregen dan continue groep
• hoge dosis:
• snellere verbetering dyspnoe
• meer vocht- en gewichtsverlies
• meer nierinsuffuciëntie
Nierinsufficiëntie
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klassiek thiaziden tot e-GFR 50 ml/min/1,73m²
try and error
kaliumsparende tot e-GFR (30)-40 ml/min/1,73m²
toevoegen loopdiureticum
in dialyse furosemide tot 2x500mg + chlortalidone
100mg/d (‘comfortdiurese’)
Zwangerschap
• -oedeem = cosmetisch probleem
• -diuretica af te raden
• methyldopa, labetalol, nifedipine
• postpartum is lage dosis thiazide geen
probleem voor borstvoeding
Diuretics for preventing pre-eclampsia
David Churchill
Cochrane Pregnancy and Childbirth Group
24 JAN 2007
• no clear benefits
• with the level of adverse effects found, the
use of diuretics for the prevention of preeclampsia and its complications cannot be
recommended.
Levercirrose
• cave hypokaliëmie
• spironolactone (ev. + loopdiureticum)
• cave hepatorenaal syndroom
Idiopatisch cyclisch oedeem
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-etiologie onbekend (capillair lek, hormonaal)
-klinisch weinig afwijkingen, CVD normaal
-eetstoornis? refeeding oeddem?
-diuretica-abusus (hypokaliëmie,nierinsufficiëntie)
-ZA dieet, diuretica stoppen 3-4 weken
-z.n. lage dosis spironolactone, continu
Zwarten
• low renin hypertensie
• calciumantagonisten >diuretica>
ACEi/sartanen-betablokkers
Urolithiase
• zoutarm dieet + thiazide
• toename Na-reabsorptie in proximale
tubulus
• gekoppeld aan Ca-reabsorptie
• cave hypercalcemie
• (bv. bij fruste hyperparathyreoïdie)
Besluit
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onmisbaar
ook bij hypertensie
laag gedoseerd
kaliumsparend tot e-GFR 40
+zoutbeperking
combinatietherapie
Acetazolamide - Diamox
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Proximal tubular diuretics decrease Na+ reabsorption.
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Drugs that work at the site (some of these agents work at other sites as well) include mannitol, an osmotic diuretic, acetazolamide (a carbonic anhydrase
inhibitor) and organomercurials.
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acetazolamide (a carbonic anhydrase inhibitor)
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The enzyme, carbonic anhydrase exhibits the following characteristics:
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Its major location is the luminal proximal tubule membrane.
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Carbonic anhydrase catalyzes dehydration of carbonic acid, H2CO3 , required for bicarbonate reabsorption
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Blockade of carbonic anhydrase activity induces a sodium bicarbonate diuresis, which reduces body bicarbonate levels
Carbonic anhydrase inhibitors are unsubstituted sulfonamides which are bacteriostatic. These agents promote alkaline diuresis and a hyperchloremic metabolic acidosis.
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Prototype drug: acetazolamide (Diamox)
Acetazolamide: (Diamox) is well absorbed orally and is excreted by tubular secretion, at the proximal tubule.
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In renal insufficiency a dose reduction is appropriate.
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At maximal carbonic anhydrase inhibition, a 45% inhibition of bicarbonate reabsorption is observed.
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This level of inhibition results in significant bicarbonate loss and a hyperchloremic metabolic acidosis.
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Acetazolamide (Diamox) administration causes a reduction in aqueous humor and cerebrospinal fluid production
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Clinical Application:
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Glaucoma:
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Because acetazolamide decreases the rate of aqueous humor production, a decline in intraocular pressure occurs.
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Management of glaucoma is the most common indication for use of carbonic anhydrase inhibitors.
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Dorzolamide (Trusopf), another carbonic anhydrase inhibitor exhibits no diuretic or systemic metabolic effect; however, administration of this agent
causes a reduction in intraocular pressure.
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Urinary Alkalinization:
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Increased uric acid and cystine solubility by alkalinizing the urine (by increasing bicarbonate excretion)
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For prophylaxis of uric acid renal stones, bicarbonate administration (baking soda) may be required
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Metabolic Alkalosis:
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Results from:
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Decreased total potassium with reduced vascular volume
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High mineralocorticoid levels
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These conditions are usually managed by treating the underlying causes; however, in certain clinical settings acetazolamide may
assist in correcting alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}
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Acute Mountain Sickness:
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Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of all of 3000 meters}; symptoms -- usually mild
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In serious cases: life-threatening cerebral or pulmonary edema
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Acetazolamide reduces the rate of CSF formation and decreases cerebral spinal fluid pH.
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Prophylaxis against acute mountain sickness may be appropriate
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Other Uses:
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Some role in management of epilepsy
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Hypokalemia periodic paralysis
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Increase urinary phosphate excretion during severe hyperphosphatemia.
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Toxicity:
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Hyperchloremic metabolic acidosis
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Due to reduction of body bicarbonate stores
DIURETICA
ZOUT
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This article summarizes the evidence behind updates to the 2013 and 2014 Canadian Hypertension Education
Program (CHEP) guidelines.
* We review the evidence leading to changes to the recommendations for sodium intake and the threshold for
starting pharmacotherapy in older adults.
* We also review the evidence behind two new recommendations regarding target blood pressure levels in patients
with coronary artery disease and the use of resistance exercise by patients with hypertension.
Summary of updated recommendations
* In older adult patients (age ≥ 80 yr) who do not have diabetes or end organ damage, the systolic blood pressure
threshold for starting drug therapy Is 160 mm Hg or higher (revised recommendation, 2014, grade C). The target for
systolic blood pressure should be less than 150 mm Hg (new recommendation, 2013, grade C).
* When decreasing systolic blood pressure to target levels in patients with established coronary artery disease
(especially if isolated systolic hypertension is present), be cautious when the diastolic blood pressure Is ≤ 60 mm Hg
because of concerns that myocardial Ischemia might be exacerbated (new recommendation, 2014, grade D).
* For patients who do not have hypertension or who have stage 1 hypertension (I.e., systolic pressure 140-159 mm
Hg, diastolic pressure 90-99 mm Hg), the use of resistance or weight training (such as free weight lifting, fixed-weight
lifting, or handgrip exercise) does not adversely Influence blood pressure (revised recommendation, 2013, grade D).
* To decrease blood pressure, consider reducing sodium Intake toward 2000 mg (5 g salt or 87 mmol sodium) per
day (revised recommendation, 2014, grade A).
Loop of Henle diuretics represent the most potent diuretic drugs and act by inhibiting active NaCl transport in the medullary ascending limb.
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The maximal diuretic effect corresponds to about 20%-25% of the filtered sodium load.
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Examples of loop diuretics include furosemide, torsemide, bumetanide, and ethacrynic acid.
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Because of their efficacy in blocking Na+ ion transport, these agents are routinely used for managing fluid retention/overload associated with heart failure.
Agents include:
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Mechanism of action:
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Acts rapidly
Eliminated by a renal secretion and glomerular filtration (half-life -- depend on renal function)
Co-administration of drugs that inhibit weak acid secretion (e.g. probenecid or indomethacin) may alter loop diuretic clearance.
Other effects:
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Furosemide: increases renal blood flow; blood flow redistribution within the renal cortex
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Furosemide decreases pulmonary congestion and the left ventricular filling pressure in congestive heart failure (CHF) -- prior to an increase in urine output.
Clinical uses:
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Major uses:
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Other uses:
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Loopdiuretica
Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle
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Inhibit the Na/K/2Cl transport system in the luminal membrane
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Reduction in sodium chloride reabsorption
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Decreases normal lumen-positive potential (secondary to potassium recycling)
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Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)
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Therefore, loop diuretics increase magnesium and calcium excretion.
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Hypomagnesemia may occur in some patients.
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Hypocalcemia does not usually develop because calcium is reabsorbed in the distal convoluted tubule.
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{in circumstances that result in hypercalcemia, calcium excretion can be enhanced by administration of loop diuretics with saline infusion}
Since a significant percentage of filtered NaCl is absorbed by the thick ascending limb of loop of Henle, diuretics acting at this site are highly effective
Loop diuretics--Properties: rapidly absorbed following oral administration (may be administered by IV)
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Furosemide (Lasix)
Bumetanide (Bumex)
Torsemide (Demadex)
Ethycrinic acid --no longer in use because of toxicity.
Acute pulmonary edema
Acute hypercalcemia
Management of edema
Hyperkalemia:
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Loop diuretics increase potassium excretion
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Effect increased by concurrent administration of NaCl and water.
Acute renal failure:
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May increase rate of urine flow and increase potassium excretion.
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May convert oligouric to non-oligouric failure {easier clinical management}
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Renal failure duration is not affected
Anion overload:
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Bromide, chloride, iodide: all reabsorbed by the thick ascending loop:
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Systemic toxicity may be reduced by decreasing reabsorption
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Concurrent administration of sodium chloride and fluid is required to prevent volume depletion
Toxicity:
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Hypokalemia metabolic alkalosis:
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Increased delivery of NaCl and water to the collecting duct increases potassium and proton secretion-- causing a hypokalemic metabolic alkalosis
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In managed by potassium replacement and by ensuring adequate fluid intake
Ototoxicity:
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Dose-related hearing loss (in usually reversible)
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Ototoxicity more common:
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With decreased renal function
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With concurrent administration of other ototoxic drugs such as aminoglycosides
Hyperuricemia:
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May cause gout
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Loop diuretics cause increased uric acid reabsorption in the proximal tubule, secondary to hypovolemic states.
Hypomagnesemia: loop diuretics cause:
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Reduction in sodium chloride reabsorption
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Decreases normal lumen-positive potential (secondary to potassium recycling)
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Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)
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Therefore, loop diuretics increase magnesium and calcium excretion.
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Hypomagnesemia may occur in some patients.
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Reversed by oral magnesium administration
Allergic reactions:
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Furosemide: skin rash, eosinophilia, interstitial nephritis(less often)
Other toxicities:
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Dehydration (may be severe)
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Hyponatremia (less common than with thiazides thought may occur in patients who increased water intake in response to a hypovolemic thirst)
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Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition {e.g. oat cell long carcinoma} is also present.
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Distal tubular diuretics include both K+ -sparing and K+ -non-sparing agents.308
Among the K+ -non-sparing drugs are thiazide diuretics, chlorthalidone (Hygroton), and metazolone (Mykrox).
These agents reduce Na+ absorption in the cortical segment of the ascending limb of the loop of Henle and distal convoluted tubule.
Since distal tubular diuretics act proximal to the distal site of K+ secretion, these drugs increase urinary K+excretion.
Resulting hypokalemia is an noteworthy clinical consequence and may require treatment.
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As noted earlier, hyperkalemia may precipitate life-threatened ventricular tachyarrhythmias, the likelihood of which is increased by cardiac
glycoside or other positive inotropic agent therapy.
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By contrast, there are a number of K+-sparing agents including triamterine, amiloride, and aldosterone antagonists such as spirolactone and
eplerenone.308
Triamterine and amiloride inhibit K+ secretion independent of adrenal function; however, spirolactone and eplerenone activity depend on both
circulating aldosterone and an intact adrenal cortex.
K+ -sparing agents lack sufficient potency to be used as monotherapy but can attenuate or eliminate K+ loss (and thus hypokalemia) associated
with diuretics acting more proximal locations.
Two major, common consequences of diuretic treatment are K+ loss and volume depletion.308
Frequently used agent such as thiazide diuretics, metazolone, and loop diuretics are associated with these adverse effects.
Volume depletion can cause hypotension and hypoperfusion.
With hypoperfusion, inadequate blood flow to critical organs may cause severe end-organ damage.
Reduced renal function may also occur even in the presence of hypervolemia.
Reduced kidney perfusion may manifest by an increase in both blood urea nitrogen (BUN) and serum creatinine levels.
Worsening of kidney function may be expected in about a third of patients exhibiting acute, decompensated heart failure.
Serious renal hypoperfusion itself can precipitate intrinsic renal failure associated with acute tubular necrosis, in addition to prerenal
azotemia.308
Prerenal azotemia is associated with high blood levels of nitrogen-containing chemicals such as urea, creatinine, etc. due to inadequate
glomerular filtration rates, specifically resulting from renal hypoperfusion.
The BUN: creatinine ratio in prerenal azotemia may be >20.
Heart failure patient should be evaluated and monitored for both hyperkalemia and hypokalemia. Either condition can precipitate cardiac
excitability and/or conduction changes which may lead to sudden death.329,330
In an effort to maintain organ perfusion during heart failure, activation of both sympathetic nervous system and renin-angiotensin system can
cause hypokalemia.329,331,332
As noted above, many drugs used in management of heart failure can change K+ serum levels.329,333
Serum potassium levels should be in the 4.0-5.0 mmol/L range.
Small decreases in serum K+ increase risk associated with antiarrhythmic drug and cardiac glycoside treatment330,334; furthermore, small
increases in serum K+ may prevent use of treatments known to extend life.335
In some patient subsets, low serum K+ may require supplementation of potassium and magnesium; whereas, in other patient subsets, especially
those taking angiotensin-converting enzyme inhibitors (ACE inhibitors), either as monotherapy or in combination with aldosterone antagonists,
potassium salts may be both unnecessary and potentially harmful.329
Hyponatremias can occur due to impaired water excretion, secondary to chronic heart failure.308
Increased NaCl excretion by commonly used diuretics in heart failure management can either cause or worsen hyponatremic in patients with
advanced heart failure, absent fluid intake restriction.
Water restriction may be used to manage symptomatic hyponatremia.
Carbonic anhydrase inhibitors, e.g. acetazolamide administration may result in a metabolic acidosis due to reduced H+ ion secretion.308
Authors' conclusions
• We found predominantly moderate quality
evidence that all-cause mortality is similar
when first-line RAS inhibitors are compared to
other first-line antihypertensive agents.
• First-line thiazides caused less HF and stroke
than first-line RAS inhibitors.
Dosis
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largest reduction in blood pressure at a half-standard dose
only modestly greater reductions in systolic and diastolic blood
pressures at standard or twice-standard doses
average fall in systolic blood pressure over 24 hours with half-standard,
standard, and twice-standard doses was 7.1, 9.1, and 10.9 mmHg with
data from all classes combined and 7.4, 8.8, and 10.3 mmHg with a
thiazide diuretic
with thiazide diuretics, calcium channel blockers, and beta blockers, the
rate of symptomatic and metabolic adverse effects increased
significantly with standard or twice-standard doses compared to halfstandard doses
after the initial dose, going to higher doses produced on average
relatively small further reductions in blood pressure at the price of an
increasing rate of adverse effects. As a result, we generally limit dose
titration to one step with a given antihypertensive drug (eg, 12,5 to 25
mg of chlortalidone)
Schematic representation of the transport mechanisms in the distal tubule. The Na-K-ATPase pump in the
basolateral (peritubular) membrane pumps sodium (Na) out of, and potassium (K) into, the cell. This creates
a low intracellular Na concentration which drives many of the cell's reabsorptive processes. The entry of
filtered Na and chloride (Cl) into the cell is mediated by a neutral Na-Cl cotransporter NCCT in the apical
(luminal) membrane. This cotransporter is inhibited by thiazide diuretics. The energy for this process is
provided by the favorable inward electrochemical gradient for Na (the intracellular Na concentration is very
low and the cell interior is electronegative). The reabsorbed Na which has entered the cell is pumped out by
the Na-K-ATPase pump. The reabsorbed Cl exits via a chloride channel. This is the ClC-Kb channel which
requires interaction with a small protein called barttin to function normally. The distal tubule is also a major
site of active calcium (Ca) reabsorption. Ca enters the cell via a Ca transporter that is probably a Ca channel.
Reabsorbed Ca combines with a vitamin D-induced Ca binding protein (Ca-BP), moves across the cell, and is
then extruded at the basolateral membrane by a Ca-ATPase (not shown) and a 3Na:1Ca exchanger that also
uses the energy provided by the favorable inward electrochemical gradient for Na.
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●Patients with generalized edema (due for example to heart
failure, the nephrotic syndrome, or renal disease) are typically
treated with daily therapy. At a given dose, net sodium loss
occurs for only one to two weeks before a new steady state is
achieved; in this setting, sodium intake and excretion are again
equal as the effect of the diuretic is balanced by activation of
counterregulatory factors that promote sodium retention, such
as the renin-angiotensin system. However, selected patients
with mild edema who comply with dietary sodium restriction can
be treated with intermittent therapy as needed.
Inleiding
• DOSE trial: Diuretic Optimization Strategies Evaluation
• National Heart, Lung and Blood Institute Heart Failure Clinical
Research Network
• Clinical trial
• Prospectief, gerandomiseerd, dubbel blind gecontroleerde
studie
• Exclusie:
• Systolische BD < 90 mmHg
• Serum creatinine > 3mg/dl
• Nood aan IV vasodilatators of inotropica (andere dan digoxine)
Studie
•
Inclusie:
• < 24uur presenteren mat acuut hartfalen
• Minstens 1 vd volgende symptomen:
• Dyspnoe
• Orthopnoe
• Oedeem
• En 1 vd volgende tekens:
• Ronchi
• Perifere oedemen
• Ascites
• Stuwing op rx thorax
Inleiding
•
Acuut hartfalen
•
•
•
Frequentste oorzaak van hospitalisatie pt > 65j
Standaard behandeling: diuretica
Gebreken ikv diuretische behandeling:
•
•
Guidelines zijn vooral expert opion => sterke variabiliteit zowel in dosage als
toedieningsvorm
Hoge dosages potentieel schadelijk:
•
•
•
•
Activatie RAAS en sympatisch ZS
Elektrolytstoornissen
Achteruitgang nierfunctie
Toedieningsvorm:
•
•
Farmacokinetische en dynamische data: continu > intermittent bolussen
MAAR studies hierover waren klein en hadden onvoldoende power
Studie
•
Opzet:
•
2 groepen
•
•
•
Lage dosis: totale dagelijkse IV dosis = eigen totale orale diuretica in
furosemide equivalente
Hoge dosis: totale dagelijkse IV dosis = 2,5 x eigen totale orale diuretica in
furosemide equivalente
IV therapie
•
•
•
•
•
Bolussen om de 12uur
Continue
Dubbelblind: alle pt krijgen zowel continu infuus en bolussen met
fysiologisch als placebo
follow up biomarkers: creatinine, BNP en cystatine C
Follow up gedurende 60dagen
• Eindpunten:
• Primaire:
Studie
• Globale assesment van symptomen ahv VAS tot 72uur
• serum creatinine tot 72uur
• Secundaire
•
•
•
•
•
•
•
Dyspnoe ahv VAS
Verandering in lichaamsgewicht
Netto vochtverlies
Ratio van pt vrij van congestie (CVS < 8cm, geen orthopnoe) op 72uur
Achteruitgang nf (toename crea > 0,3mg/dl)
Achteruitgang of aanhoudend hartfalen
Verandering in biomarkers op 72uur, op 7dagen of op moment van
ontslag en op dag 60
• Overlijden, rehospitalisatie, spoed consulten, aantal gehospitaliseerde
dagen.
Secondary End Points for Each Treatment Comparison.
Felker GM et al. N Engl J Med 2011;364:797-805.
Discussie
•
Eerdere studie: hoge dosis diuretica => achteruitgang nf =>
slechtere outcome
•
•
•
Hoge dosis: frequenter achteruitgang nf op korte termijn, op 60 dagen
geen verschil
Recent studies: transiënte achteruitgang nf geen effect zou hebben op
outcome na ontslag.
Beperkingen:
•
Chronische pt die ambulant reeds hoge dosissen
 Zegt niets over nieuwe diagnose
 Vele pt kregen reeds diuretica in periode voor randomisatie en
mogelijkheid tot aanpassen dosis na 48uur
Increase in urinary sodium excretion (UNa) after intravenous bumetanide, given as a continuous infusion
(solid line) or as a bolus (dashed line), in patients with stable chronic kidney disease. The continuous
infusion produced a 30 percent greater increase in sodium excretion than bolus therapy due to a more
favorable rate of diuretic excretion. In addition, the natriuretic response declined over time with both
regimens. With the bolus, for example, the peak natriuretic response to the second dose was 25 percent
less than that to the first.
Rudy DW,Ann Intern Med 1991; 115:360
•
acetazolamide
•
•
•
•
ethacrynezuur
furosemide, furosemide prolongatum
bumetamide
torasemide
•
•
chlortalidone
hydrochlorothiazide
•
•
•
•
•
triamterene
amiloride
spironolactone
canrenol
eplerone
•
vaptanen
•
combinaties:
•
•
•
•
•
amiloride 5mg + furosemide 40mg
amiloride 5mg + HCTZ 50mg (Moduretic)
spironolactone 25mg+HCTZ25mg
HCTZ 25mg + triamterene 50mg (Dytenzide)
amiloride 5mg+HCTZ50mg