Edematous states & Diuretics
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2 basic steps in edema formation
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Alteration in capillary haemodynamics that favors the movement of fluid from the vascular
space to the interstitium
Dietary Na & water are retained by the kidney
Major causes of edematous states
Increased capillary hydrolic pressure
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Increased plasma volume due to renal Na retention:
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heart failure
Primary Na retention
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Protein loss: nephrotic syndrome, protein losing enteropathyu
Reduced albumin synthesis: liver disease, malnutrition
Increased capillary permeability
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CCB, idiopathic edema
Decreased oncotic pressure (alb<1.5-2mg/dl)
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Hepatic venous obstruction, hepatic cirrhosis,
Acute pulmonary edema, Local venous obstruction
Decreased arteriolar resistance
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Pregnancy
Idiopathic edema, when diuretic induced
Venous obstruction
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Renal ds incl. NS
Drugs: minoxidil, CCB, diazoxide, NSAIDS, fludrocortisone, estrogen
Refeeeding edema
Early hepatic cirrhosis
Idiopathic edema, burns, trauma, inflammation / sepsis, allergic reactions, ARDS, DM,
IL2-therapy, malignant ascites
Lymphatic obstruction / increased interstitial oncotic pressure
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Nodal enlargement due to malignancy
Hypothyroidism, malignant ascites
• Renal sodium retention
– Inability to excrete the Na & water that has
been ingested – patients with renal disease.
– Appropriate compensatory response to
effective circulating volume depletion, with
urine [Na]<25 meq/L
• The compensated state
– Initial fluid retention has increased venous
return to the heart, allowing systemic
hemodynamics to be stabilized, and removing
the stimulus for continued renin release –
noremalization of BP, renin, aldosterone, urine
[Na] secretion
Intrarenal factors
• Reflex activation of the sympathetic
nervous system
• Activation of RAAS and ADH
• Resistance to the action of natriuretic
peptides
• Altered glomerular haemodynamics
• Peritubular forces in PT
General principles of treatment
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When must edema be treated?
– Pulmonary edema is life threatening and demands immediate treatment
– Other edematous states, removal of fluid can proceed more slowly
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What are the consequences of the removal of edema fluid?
– Is the retention of Na & water a compensatory response or inappropriate primary
Na retention?
– If retention of edema fluid is compensatory then removal of this fluid with
diuretics should diminish the effective circulating volume.- decrease in venous
return to the heart, and cardiac filling pressures – fall in cardiac output
– Leads to increased secretion of the hypovolemic hormones: renin,
norepinephrine, ADH.
– Most patients will benefit from the appropriate use of diuretics
– Adequacy of tissue perfusion can be estimated by monitoring BUN & plasma [Cr]
– as long as these parameters remain constant, it can be assumed that diuretic
therapy has not led to a significant impairment in perfusion to the kidney or,
therefore, to other organs.
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How rapidly should edema fluid be removed?
– Fluid that is lost initially comes from the plasma; restoration of plasma volume is
by mobilization of edema luid into the vascular space
– In patients with generalized edema due t heart failure, nephrotic syndrome, or
primary Na retention, the edema fluid can be mobilized rapidly, since most
capillary beds are involved
– Important exception is hepatic cirrhosis with ascites but no peripheral edema –
only 500-750 ml/d can only be removed safely.
• Congestive heart failure
Cardiac dysfunction
Cardiac output
Renal Na & water
Retention
Blood volume
venous pressure
EDEMA
HEPATIC CIRRHOSIS & ASCITES
HEPATIC DISEASE
UNDERFILLING
Hypoalbuminemia
Peripheral
vasodilatation
sinusoidal
pressure
Splanchnic
pooling
ASCITES
Effective Circ
Volume
Renal Na &
Water retention
FURTHER ASCITES
OVERFLOW
Renal Na &
Water retention
Plasma volume
ASCITES
Primary renal Na retention
RENAL Na RETENTION
Plasma volume
Capillary hydraulic pressure
EDEMA
Pathogenesis of edema in primary renal Na
retention, which is most often due to
glomerular disease, advanced renal failure,
Or the use of potent vasodilators in the
treatment of hypertension.
• Drugs;
– direct vasodilators, minoxidil, diazoxide
– CCB, dehydropyridines
• Pregnancy;
– normal pregnancy is associated with retention of 1000meq Na
and 6-8L water
• Refeeding edema
– Insulin directly stimulates Na reabsorption in PT & perhaps in the
loop of Henle & DT
• Nephrotic syndrome
• Idiopathic edema;
– in young menstruating women
– May represent a capillary leak syndrome
– Dopamine deficiency & impaired hypothalamic function
• Diuretic induced edema
– Chronic use of diuretics activates Na retaining mechanisms
DIURETICS
Site of action
Carrier/channel inhibited
mechanism
% filtered Na
excreted
Proximal Tubule
Acetazolamide
inhibits Enz. Carbonic Anhydrase
prevent NaHCO3 reabsorption
modest
Loop of Henle
Furosemide
Bumetamide
Ethacrinic acid
Na – K - 2Cl carrier
up to 25%
Distal tubule &
Connecting segment
Thiazides
Chlortalidon
Metalazone
Na – Cl Carrier
up to 3 – 5%
Cortical collecting tubule
Spironolactone
Amiloride
Triamterene
Na Channel
up to 1 – 2%
blocks aldosterone receptor in cytoplasm
especially with thiazides
Other effects
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Loop diuretics
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Thiazide type diuretic
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Aldosterone sensitive Na – channel
Can lead to hyperkalemia and metabolic acidosis
Trimetoprim at very high doses
Amiloride in the treatment of lithium induced nephrogenic DI
Triamterene is a potential nephotoxin; crystalluria, cast formation, triamterene stones
Acetazolamide
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DT is major site of active Ca reabsorption, independent of Na transport
Increase reabsorption of Ca, similar response occurs in the cortical collecting tubule with
amiloride
Useful in treatment of kidney stones due to hypercalciuria
K-sparing diuretics
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Ca reabsorption in the loop of henle is primarily passive, driven by gradient created by NaCl
transport
Increase Ca excretion
Treatment of hypercalcemia; NaCl solution & loop diuretic
Net diuresis is modest; reclaimed in the more distal segments, diuretic action limited by the
metabolic acidosis
Major indication: as a diuretic in edematous patients with metabolic alkalosis
Mannitol
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Osmotic diuretic, inhibiting Na & water reabsorption in PT, loop of Henle
Produces a relative water diuresis, water is lost > Na & K
Can cause increase in plasma osmolality;- can lead to water deficit and hypernatremia,
hypertonic mannitol may be retained in patients with renal failure
Determinants of diuretic response
• Site of action of the diuretic
• Presence of counterbalancing antinatriuretic
forces, AII, hypotension.
• Rate of drug excretion
– Most diuretics, particularly the loop diuretics, are
highly protein bound
– Are poorly filtered, and enter the urine primarily via
the organic – anion/cation secretory pump in PT
– Their ability to inhibit Na reabsorption is in part dose dependent
• The natriuretic response tends to plateau at
higher rates of diuretic secretion
General guidelines
• Use the minimum effective dose
• Use for as short a period of time as
necessary
• Monitor regularly for adverse effects
• Use only for appropriate conditions