Clinical pharmacology of diuretic agents

1. Domina Petric, MD
Clinical pharmacology
of diuretic agents

2. I.
Edematous states

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. • 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.
Heart failure

5. • 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.
Heart failure

6. • 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.
Heart failure

7. 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.
Heart failure

8. • 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.
Heart failure

9. 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.
Heart failure

10. 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.
Heart failure

11. • 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.
Kidney disease and renal failure

12. 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.
Kidney disease and renal failure

13. 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.
Kidney disease and renal failure

14. • High-dose loop diuretics (up to 500 mg of
furosemide/day) or a combination of
metolazone (5-10 mg/day) and 40-80 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.
Kidney disease and renal failure

15. • 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)
Hepatic cirrhosis

16. • 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.
Hepatic cirrhosis

17. • 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.
Hepatic cirrhosis

18. Idiopathic edema (fluctuating salt retention and edema) is a
syndrome found most often in 20-30 year-old women.
Spironolactone is sometimes used.
Moderate salt restriction alone is often enough.
Compression stockings may also be useful.
Idiopathic edema

19. II.
Nonedematous states

20. • 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.
Hypertension

21. • Moderate restriction of dietary sodium intake (60-100 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.
Hypertension

22. • 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.
Nephrolithiasis

23. • 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.
Nephrolithiasis

24. • 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 80-120 mg iv.
Hypercalcemia

25. • 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.
Diabetes insipidus (DI)

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