DRUGS ACTING ON

THE RENAL SYSTEM

diuretics
Diuretics ― also known as water pills ― are medicines that help
you move extra fluid and salt out of your body. They make you pee
more frequently, which is why you should take them in the morning
if you can. You may need to take diuretics once or twice a day at
the same time each day.
Water pills make your kidneys take away your body’s extra salt
and water by putting them into your urine (pee). By clearing out
extra fluids from your body, diuretics lower the amount of fluid in
your blood that your heart has to pump. This helps people whose
kidneys aren’t working well or who have swelling (edema), heart
failure or high blood pressure.
 What do diuretics treat?

 Diuretic medications can help with:

• High blood pressure
• Heart failure
• Cardiomyopathy (heart muscle disease)
• Pulmonary edema (fluid buildup in your lungs)
• Ascites (fluid buildup in your belly)
• Kidney failure
• Nephrotic syndrome (too much protein in your pee)
• High intraocular pressure (fluid buildup in your eye)
• Increased intracranial pressure (fluid buildup in your brain)
 What are the side effects?

 Possible side effects of diuretics include:

• Upset stomach, gas or diarrhea
• Loss of appetite
• Hair loss
• Fatigue
• Headache
• Gout
• Difficulty getting an erection
• Low potassium (for some types)
• Muscle cramps
• Higher blood sugar in people with diabetes
• Unbalanced electrolytes
Classification of diurdetics:

 loop diuretics
 Potasium-sparring diuretics
 Osmotic diuretics thiazide diuretics
 thiazide diuretics
2. Loop Diuretics

 Loopdiuretics selectively inhibit NaCl

reabsorption in the TAL.
 Loopdiuretics are the most efficacious
diuretic agents currently available
because of the large NaCl absorptive
capacity of the TAL and, unlike CAIs, they
are not limited by development of
acidosis.
Examples

Sulfonamide loop diuretics

 Furosemide
 Bumetanide
 Torsemide.
 Ethacrynic
acid, a non
sulphonamide
Pharmacokinetics

 The loop diuretics are rapidly absorbed.

 Eliminated by the kidney by glomerular
filtration and tubular secretion.
 Absorption of oral torsemide is more rapid (1
hour) than that of furosemide (2–3 hours) and
is nearly as complete as with intravenous
administration.
Kinetics contd.

 DoA for furosemide is usually 2–3 hours and that of

torsemide is 4–6 hours.
 Half-life depends on renal function.
 Reduction in the secretion of loop diuretics may result
from simultaneous administration of agents such as
NSAIDs or probenecid, which compete for weak acid
secretion in the proximal tubule
Pharmacodynamics

 Loop diuretics inhibit NKCC2, the luminal

Na+/K+/2Cl– transporter in the TAL of Henle's
loop.
 By inhibiting this transporter, the loop diuretics
reduce the reabsorption of NaCl.
 They cause an increase in Mg2+ and Ca2+
excretion.
 Prolonged use can cause significant
hypomagnesemia in some patients.
 Loop agents have direct effects on blood flow
through several vascular beds.
 Furosemide increases renal blood flow.
 Both furosemide and ethacrynic acid have
also been shown to reduce pulmonary
congestion and left ventricular filling
pressures in heart failure before a measurable
increase in urinary output occurs.
Clinical Indications

1. Edema
2. Heart failure
3. hypertension
4. Hyperkalemia
 loop diuretics can significantly enhance urinary
excretion of K+.
 This is enhanced by simultaneous NaCl and water
administration.
5. Acute Renal Failure

 Loop agents can increase the rate of

urine flow and enhance K+ excretion in
acute renal failure.
 However, they do not shorten the
duration of renal failure.
 Loop agents may help flush out
intratubular casts and ameliorate
intratubular obstruction.
6. Anion Overdose

 Loop diuretics are useful in treating

toxic ingestions of bromide,
fluoride, and iodide, which are
reabsorbed in the TAL.
 Saline solution must be
administered so as to avoid
extracellular fluid volume
depletion.
Hypokalemic Metabolic Alkalosis

 They inhibit salt reabsorption in the TAL thus

increasing delivery to the collecting duct.
 This leads to increased secretion of K+ and H+
by the duct, causing hypokalemic metabolic
alkalosis.
 This toxicity depends on the magnitude of the
diuresis and can be reversed by K+ replacement
and correction of hypovolemia.
Ototoxicity

 Loop diuretics occasionally cause reversible

dose-related hearing loss .
 This is common in patients with diminished
renal function or those on other ototoxic
agents such as aminoglycosides
Hyperuricemia

 Loop diuretics can cause hyperuricemia

and precipitate attacks of gout.
 Caused by enhanced uric acid
reabsorption in the PCT due to
hypovolemia.
 Preventedby using lower doses to avoid
development of hypovolemia
Hypomagnesemia

 A predictable consequence of the chronic use

of loop agents
 Occurs most often in patients with dietary
magnesium deficiency.
 Can be reversed by administration of oral
magnesium preparations.
Allergic & Other Reactions

 All loop diuretics, with the exception of

ethacrynic acid, are sulfonamides.
 Therefore, they may cause skin rash,
eosinophilia, and less often, interstitial
nephritis.
 This toxicity usually resolves rapidly after drug
withdrawal.
 Loop
diuretics can cause severe
dehydration.
 Hyponatremia (less common than with the
thiazides)
 However, patients who increase water
intake in response to hypovolemia-induced
thirst can become severely hyponatremic
with loop agents.
Contraindications

 Allergic cross-reactivity is seen in patients who

are sensitive to other sulfonamides and are put
on Furosemide, Bumetanide, or Torsemide.
Use judiciously in;
 Hepatic cirrhosis,
 Borderline renal failure, or
 Heart failure.
Potasium-sparring
diuretics
introduction

 Potassium-sparing diuretics reduce fluid levels in your body without

causing you to lose potassium, an important nutrient.
 The other types of diuretics cause you to lose potassium, which can
lead to health problems such as arrhythmia. Potassium-sparing
diuretics may be prescribed for people at risk of low potassium levels,
such as those who take other medications that deplete potassium.
Examples of potassium-sparing
diuretics include

• amiloride
• triamterene (Dyrenium)
• spironolactone (Aldactone)
• eplerenone (Inspra)
Side effects

• low sodium levels

• headache
• dizziness
• thirst
• increased blood sugar
• muscle cramps
• increased cholesterol
• skin rash
• gout
• diarrhea
Pharmacokinetics

• Absorption: Variable oral absorption.

• Distribution: Limited distribution; some are protein-
bound.
• Metabolism: Liver metabolism for some agents like
spironolactone.
• Excretion: Primarily renal excretion.
Clinical use

1. Hypokalemia: To prevent or treat low potassium

levels.
2. Heart Failure: Often used in combination with other
diuretics.
3. Ascites: In liver disease to prevent hypokalemia.
4. Hyperaldosteronism: To counteract the effects of
high aldosterone levels.
Mechanism of Action

 : Act on the collecting ducts and distal tubules.

Spironolactone and Eplerenone are aldosterone
antagonists, whereas Amiloride and
Triamterene inhibit sodium channels.
Adverse reations

 on their own this group of drugs may raise potassium levels beyond the normal
range, termed hyperkalemia, which risks potentially fatal arrhythmias.
 Triamterene, specifically, is a potential nephrotoxin and up to half of the patients
on it can have crystalluria or urinary casts.
 Due to its activity as an androgen receptor antagonist and progesterone receptor
agonist, spironolactone causes adverse effects, including gynecomastia or
decreased libido in males and menstrual abnormalities in females.[14]
 Spironolactone also causes hyperkalemia and renal insufficiency
Thiazide Diuretics
Introduction

 The thiazide diuretics were developed from

efforts to synthesize more potent carbonic
anhydrase inhibitors.
 They inhibit NaCl transport mainly in the DCT.
 However, some of them retain significant
carbonic anhydrase inhibitory activity.
 The prototype thiazide is hydrochlorothiazide.
Chemistry & Pharmacokinetics

 All have a sulfonamide group

 All thiazides can be administered orally.
 Chlorothiazide, the parent compound, is
not very lipid-soluble and must be given in
relatively large doses.
 It is the only thiazide available for
parenteral administration.
 Chlorthalidone is slowly absorbed and has
a longer duration of action.
Kinetics contd.

 Indapamide is excreted primarily by the biliary

system.
 However, some of its active form is cleared by the
kidney to exert its diuretic effect in the DCT.
 All thiazides are secreted at the PCT and compete
with the secretion of uric acid.
 Thiazide use may thus elevate serum uric acid
level.
Pharmacodynamics

 Thiazides inhibit NaCl reabsorption from the DCT by

blocking the Na+/Cl– transporter (NCC).
 They enhance Ca2+ reabsorption due to effects in
both the PCT and DCT.
 They can unmask hypercalcemia due to other causes
(e.g., hyperparathyroidism, carcinoma, sarcoidosis).
P’ dynamics contd.

 Useful in the treatment of kidney stones caused by

hypercalciuria.
 Their action depends in part on renal prostaglandin
production.
 The actions of thiazides can also be inhibited by
NSAIDs
Clinical Indications

 The major indications for thiazide diuretics are;

(1) Hypertension,
(2) Heart failure,
(3) Nephrolithiasis due to idiopathic hypercalciuria, and
(4) Nephrogenic diabetes insipidus.
Toxicity

 Hypokalemic Metabolic Alkalosis and Hyperuricemia

 Impaired Carbohydrate Tolerance
 Hyperlipidemia
 Hyponatremia
 Allergic Reactions
 Other Toxicities include Weakness, fatigability, and
paresthesias.
 Impotence has been reported but is probably related to
volume depletion
Potassium-Sparing Diuretics

 They may be inhibited by direct

pharmacologic antagonism of miMOA – They
prevent K+ secretion by antagonizing the
effects of aldosterone at the late distal and
cortical collecting tubules.
 neralocorticoid receptors ( spironolactone,
eplerenone ) or inhibition of Na+ influx
through (amiloride, triamterene ).
Chemistry & Pharmacokinetics

 Spironolactone is a synthetic steroid that acts as a

competitive antagonist to aldosterone.
 It is inactivated mainly in the liver.
 It has a slow onset of action, requiring several days
before full therapeutic effect is achieved.
 Eplerenone is a spironolactone analog which is more
selective for the mineralocorticoid receptor.
 It therefore has fewer adverse effects.
 Triamterene is metabolized in the liver, and
eliminated renally.
 Triamterene is extensively metabolised hence has a
shorter t1/2.
Pharmacodynamics

 They reduce Na+ absorption in the collecting tubules

and ducts.
 Na+ absorption (and K+ secretion) at this site is
regulated by aldosterone. Aldosterone antagonists
interfere with this process.
 Spironolactone and eplerenone bind to
mineralocorticoid receptors and blunt aldosterone
activity.
 Amiloride and triamterene do not block
aldosterone, but interfere with Na+ entry in the
CT.
 Since K+ secretion is coupled with Na+ entry in
this segment, these agents are also effective
potassium-sparing diuretics.
 The actions of the aldosterone antagonists
depend on renal prostaglandin production.
 The actions of K+-sparing diuretics can thus be
inhibited by NSAIDs
Clinical Indications

 Potassium-sparing diuretics are most useful in states

of primary or secondary hyperaldosteronism.
 Eplerenone is currently approved for use only in
hypertension
 Low doses of eplerenone (25–50 mg/d) may interfere
with inflammatory effects of aldosterone thus
reducing the progression of albuminuria in diabetic
patients.
 Eplerenone reduces myocardial perfusion defects
after myocardial infarction.
 In one clinical study, eplerenone reduced mortality
rate by 15% (compared with placebo) in patients with
mild to moderate heart failure after myocardial
infarction.
Toxicity

 Hyperkalemia
 Hyperchloremic Metabolic Acidosis
 Acute Renal Failure
 Kidney Stones
DIs and Contraindications
 Chronic renal insufficiency.
 Liver disease may cause impaired metabolism of
triamterene and spironolactone,
 CYP3A4 inhibitors (eg, ketoconazole, itraconazole) can
markedly increase blood levels of eplerenone.
Osmotic Diuretics

 The PCT and DL of Henle's loop are freely permeable

to water.
 Any osmotically active agent that is filtered by the
glomerulus but not reabsorbed promotes water
diuresis.
 Such agents can reduce ICP and promote prompt
removal of renal toxins.
 The prototypic osmotic diuretic is mannitol.
 Pharmacokinetics

 Mannitol is poorly absorbed by the GIT and when

administered orally it causes osmotic diarrhea.
 For systemic effect, mannitol must be given
parenterally.
 Mannitol is not metabolized and is excreted by
glomerular filtration within 30–60 minutes,
without any important tubular reabsorption or
secretion.
Pharmacodynamics

 Osmotic diuretics have their major effect in the

proximal tubule and the descending limb of Henle's
loop.
 Through osmotic effects, they also oppose the action
of ADH in the collecting tubule.
 The presence of a nonreabsorbable solute such as
mannitol prevents the normal absorption of water by
interposing a countervailing osmotic force.
Clinical Indications

 Increase of Urine Volume

 Reduction of Intracranial and
 Reduction of Intraocular Pressure
Toxicity

Extracellular
Volume Expansion
Dehydration, Hyperkalemia, and
Hypernatremia
Hyponatremia
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