1. Clinical pharmacology of diuretic agents
Domina Petric, MD

2. Edematous states I.

3. Edematous states
Common diuretic use is reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal or vascular disease, that reduce blood flow to the kidney.
This reduction is sensed as insufficient effective arterial blood volume, which leads to salt and water retention.
Excessive diuretic therapy may compromise the effective arterial blood volume and reduce the perfusion of vital organs.
The use of diuretics to mobilize edema requires careful monitoring of the patient´s hemodynamic status.

4. Heart failure
When cardiac output is reduced by heart failure, the resultant changes in blood pressure and blood flow to the kidney are sensed as hypovolemia.
This leads to renal retention of salt and water, which initially increases intravascular volume and venous return to the heart.
This may partially restore the cardiac output toward normal.

5. Heart failure
If the underlying disease causes cardiac output to deteriorate despite expansion of plasma volume, the kidney continues to retain salt and water.
Water then leaks from the vasculature and becomes interstitial or pulmonary edema.
Diuretic use is now necessary to reduce the accumulation of edema, particularly in the lungs.
Reduction of pulmonary vascular congestion with diuretics may improve oxygenation and myocardial function.

6. Heart failure Reduction of preload can reduce the size of the heart.
Edema associated with heart failure is generally managed with loop diuretics.
Salt and water retention may become so severe that a combination of thiazides and loop diuretics is necessary.
Cardiac output in patients with heart failure is maintained in part by high filling pressures.
Excessive use of diuretics may diminish venous return and further impair cardiac output.

7. Heart failure
Diuretic-induced volume contraction reduces venous return and can severly compromise cardiac output if left ventricular filling pressure is reduced below 15 mmHg.
Reduction in cardiac output eventually leads to renal dysfunction resulting from reduced perfusion pressures.
Increased delivery of salt to the thick ascending limb leads to activation of the macula densa and a reduction in glomerular filtration rate (GFR) by tubuloglomerular feedback.

8. Heart failure
Adenosine is secreted by macula densa cells, which causes afferent arteriolar vasoconstriction through activation of A1 adenosine receptors on the afferent arteriole.
This vasoconstriction reduces GFR.
Tubuloglomerular feedback-mediated reduction in GFR exacerbates the reduction that was initially caused by decreased cardiac output.

9. Heart failure
Diuretic-induced metabolic alkalosis is exacerbated by hypokalemia.
It is another adverse effect that may further compromise cardiac function.
This complication can be treated with replacement of potassium and restoration of intravascular volume with saline.
Severe heart failure may preclude the use of saline even in patients who have received excessive diuretic therapy.

10. Heart failure
Adjunctive use of acetazolamide helps to correct the alkalosis.
Diuretics-induced hypokalemia can exacerbate underlying cardiac arrhythmias and contribute to digitalis toxicity.
This can usually be avoided by having the patient reduce sodium intake while taking diuretics.
Patients who are noncompliant with a low sodium diet must take oral KCl supplements or a potassium-sparing diuretics.

11. Kidney disease and renal failure
When renal failure is severe (GFR<5 mL/min), diuretic agents are of little benefit, because glomerular filtration is insufficient to generate or sustain a natriuretic response.
A large number of patients, even dialysis patients, with milder degrees of renal insufficiency (GFR 5-15 mL/min), can be treated with diuretics.
Many glomerular diseases (associated with diabetes mellitus or systemic lupus erythematosus) exhibit renal retention of salt and water.

12. Kidney disease and renal failure
Diabetic nephropathy is associated with development of hyperkalemia at a relatively early stage of renal failure.
Thiazide or loop diuretic enhance potassium excretion by increasing delivery of salt to the potasssium-secreting collecting tubule.

13. Kidney disease and renal failure
Patients with nephrotic syndrome may exhibit fluid retention in the form of ascites or edema.
In patients with minimal change nephropathy diuretic use may cause further reductions in plasma volume that can impair GFR and may lead to orthostatic hypotension.

14. Kidney disease and renal failure
High-dose loop diuretics (up to 500 mg of furosemide/day) or a combination of metolazone (5-10 mg/day) and mg/day of furosemide may be useful in treating volume overload in dialysis or predialysis patients.
Mannitol may be useful in the management of hemoglobinuria or myoglobinuria.

15. Hepatic cirrhosis
Liver disease is often associated with edema and ascites in conjunction with elevated portal hydrostatic pressures and reduced plasma oncotic pressures.
Mechanisms for retention of sodium by the kidney:
diminished renal perfusion (from systemic vascular alterations)
diminished plasma volume (due to ascites formation)
diminished oncotic pressure (hypoalbuminemia)

16. Hepatic cirrhosis
There may be primary sodium retention due to elevated plasma aldosterone levels.
When ascites and edema become severe, diuretic therapy can be very useful.
Cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels.
Cirrhotic edema is responsive to spironolactone and eplerenone.

17. Hepatic cirrhosis
The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients.
Caution is necessary in the use of aldosterone antagonists in cirrhotic patients with even mild renal insufficiency because of the potential for causing serious hyperkalemia.
Excessive use of diuretic therapy can cause marked depletion of intravascular volume, hypokalemia and metabolic alkalosis.
Hepatorenal syndrome and hepatic encephalopathy are consequences of excessive diuretic use in the cirrhotic patients.

18. Idiopathic edema
Idiopathic edema (fluctuating salt retention and edema) is a syndrome found most often in year-old women.
Spironolactone is sometimes used.
Moderate salt restriction alone is often enough.
Compression stockings may also be useful.

19. Nonedematous states
II.

20. Hypertension
The diuretic and mild vasodilator actions of the thiazides are useful for treating essential hypertension.
Hydrochlorothiazide is the most widely used diuretic for hypertension.
Chlorthalidone may be more effective because of its much longer half-life.
Loop diuretics are usually reserved for patients with mild renal insufficiency (GFR<30-40 mL/min) or heart failure.

21. Hypertension
Moderate restriction of dietary sodium intake ( mEq/day) has been shown to potentiate the effects of diuretics in essential hypertension.
Low sodium diet also lessens renal potassium wasting.
Potassium-sparing diuretics can be added to reduce potassium wasting.
Diuretics enhance the efficacy of many agents, especially ACE-inhibitors.
Patients that are treated with hydralazine or minoxidil usually require simultaneous diuretics because vasodilators cause significant salt and water retention.

22. Nephrolithiasis
Two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate.
Medical conditions that cause hypercalciuria are hyperparathyroidism, hypervitaminosis D, sarcoidosis, malignancies…
Many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption.
This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the distal convoluted tubule and reduce urinary Ca2+ concentration.

23. Nephrolithiasis
Fluid intake should be increased and salt intake reduced.
Excess dietary NaCl will overhelm the hypocalciuric effect of thiazides.
Dietary Ca2+ should not be restricted.
Calcium stones may also be caused by increased intestinal absorption of Ca2+ or they may be idiopathic.
Thiazides are also effective as adjunctive therapy with other measures for these patients.

24. Hypercalcemia Hypercalcemia can be a medical emergency.
Loop diuretics reduce Ca2+ reabsorption significantly and can be effective in promoting Ca2+ diuresis.
Loop diuretics alone can cause marked volume contraction.
Saline must be administered simultaneously with loop diuretics if an effective Ca2+ diuresis is to be maintained: normal saline and furosemide mg iv.

25. Diabetes insipidus (DI)
DI can be central or neurogenic DI (deficient production of ADH) or nephrogenic DI (inadequate responsiveness to ADH).
Administration of supplementary ADH or one of its analogs is effective only in central DI.
Thiazide diuretics can reduce polyuria and polydipsia in both central and nephrogenic DI.
Dietary sodium restriction can potentiate the beneficial effects of thiazides on urine volume.
Thiazides are also useful in treatment of lithium-induced nephrogenic DI.

26. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature:
Katzung, Masters, Trevor. Basic and clinical pharmacology.