Edematous states & Diuretics

2 basic steps in edema formation

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

Increased plasma volume due to renal Na retention:
heart failure Primary Na retention
Renal ds incl. NS Drugs: minoxidil, CCB, diazoxide, NSAIDS, fludrocortisone, estrogen Refeeeding edema Early hepatic cirrhosis

Pregnancy Idiopathic edema, when diuretic induced Hepatic venous obstruction, hepatic cirrhosis, Acute pulmonary edema, Local venous obstruction CCB, idiopathic edema

Venous obstruction

Decreased arteriolar resistance

Decreased oncotic pressure (alb<1.5-2mg/dl)

Protein loss: nephrotic syndrome, protein losing enteropathyu Reduced albumin synthesis: liver disease, malnutrition Idiopathic edema, burns, trauma, inflammation / sepsis, allergic reactions, ARDS, DM, IL2-therapy, malignant ascites Nodal enlargement due to malignancy Hypothyroidism, malignant ascites

Increased capillary permeability Lymphatic obstruction / increased interstitial oncotic pressure

 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

When must edema be treated?
Pulmonary edema is life threatening and demands immediate treatment Other edematous states, removal of fluid can proceed more slowly

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.

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

Depressed ventricular contractility, induced by the underlying cardiac disease, leads to neurohumoral activation (moving clockwise) that is initially adaptive in that it maintains blood pressure and tissue perfusion. Over the long-term, however, the increase in outflow resistance (afterload) hastens the rate of myocardial deterioration and worsens ventricular performance. This leads to a vicious cycle of increasing release of norepinephrine, angiotensin II, and ADH that further increases afterload.

HEPATIC CIRRHOSIS & ASCITES

HEPATIC DISEASE UNDERFILLING OVERFLOW

Hypoalbuminemia

Peripheral vasodilatation

sinusoidal pressure

Renal Na & Water retention Plasma volume

Splanchnic pooling

ASCITES Effective Circ Volume

Renal Na & Water retention

ASCITES

FURTHER ASCITES

Circulatory, vascular, functional, and biochemical abnormalities in patients with cirrhosis and ascites

Circulatory
Reduced systemic vascular resistance Reduced arterial pressure Increased heart rate Increased cardiac index Increased plasma volume Reduced renal blood flow Increased portal blood flow

Vascular
Splanchnic vasodilation Renal artery vasoconstriction Pulmonary vasodilation

Functional
Activation of systemic vasodilator factors Activation of systemic vasoconstrictor factors Activation of renal vasodilator factors Reduced glomerular filtration rate

Biochemical
Sodium retention

Water retention
Increased systemic nitric oxide Increased systemic prostaglandins Increased renal nitric oxide and prostaglandins

Pathogenic mechanisms responsible for the activation of vasoactive systems and hyperdynamic circulation in cirrhosis

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
Proximal Tubule Acetazolamide Loop of Henle Furosemide Bumetamide Ethacrinic acid Distal tubule & Connecting segment Thiazides Chlortalidon Metalazone Cortical collecting tubule Spironolactone Amiloride Triamterene

Carrier/channel inhibited mechanism

inhibits Enz. Carbonic Anhydrase prevent NaHCO3 reabsorption Na K - 2Cl carrier

% filtered Na excreted
modest

up to 25%

Na Cl Carrier

up to 3 5%

Na Channel up to 1 2% blocks aldosterone receptor in cytoplasm

especially with thiazides

Other effects
Loop diuretics
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 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

Thiazide type diuretic

K-sparing diuretics
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
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 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

Acetazolamide

Mannitol

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