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Six classes of Renal Diuretics

Carbonic Anhydrase Inhibitors
Loop Diuretics
ADH Agonists
ADH ANtagonists
Thiazides
Sufonamides (similar to Thiazides)
Potassium Sparing Diuretics
Osmotic Diuretics

Carbonic Anhydrase Inhibitors (4)

Acetazolamide
Dorzolamide
Dichlorphenamide
Methazolamide

MOA of Carbonic Anhydrase Drugs?

Carbonic Anhydrase Drugs block HCO3- reabsorption
= Alkalizes the urine, BUT can acidify the blood (toxicity)

Carbonic Anhydrase:

catalyzes the dehydration f H2CO3

H2CO3 <--> H2O + CO2
-occurs in the luminal membrane of the proximal tubule

Inhibition of renal carbonic anhydrase causes:

Inhibition of renal carbonic anhydrase causes:
-Sodium bicarbonate diuresis
-Reduction in total body bicarbonate stores
-Alkaline diuresis, hyperchloremic metabolic acidosis

Effects of inhibition on eye and cerebrospinal fluid:
-Dramatic reduction in the volume and pH of fluid

Acetazolamide
Kinetics:
Use:

Kinetics: orally well absorbed, secreted by kidney, effects last 12h
Use: Glaucoma -reduces intraocular pressure
Acute Mountain Sickness
To achieve urinary alkalization (increases the solubility AND excretion of uric acid, aspirin, and weak acid, short term)
To correct metabolic acidosis:

Acetazolamide
Toxicity:
Contraindications:

Acetazolamide
Toxicity
Hyperchloremic metabolic acidosis
Renal stones
Renal potassium wasting (administer KCl)

Contraindicated in hepatic cirrhosis
(basic urine decreases NH4+ excretion
→ hyperammonemia and hepatic encephalopathy.)

Loop Diuretics (4)

Furosemide
Ethacrynic acid
Butmetanide
Torsemide

Loop Diuretics MOA:

Loop Diuretics MOA: Selectively inhibit NaCl reabsorption in the ascending limb of the Loop of Henle

Loop Diuretucs
Kinetics:

Loop diuretics
Kinetics: rapid absorbption, excreted by glomerular filtration and tubular secretion
-act on the luminal side of the loop
(probenacid and indomethacin inhibit secretion)

Loop Diuretics
Pharmacodynamics:

Pharmacodynamics
-Inhibit Na+/K+/2Cl- transport system
-decrease K+ recycling
-decrease paracellular Ca2+ and Mg2+ reabsorption
Causes hypomagnesemia and direct effects on blood flow. (relieves pulmonary congestion, reduces left ventricular filling pressure in CHF, increases renal blood flow)

Loop Diuretics- Clinical Indications

Loop Diuretics- Clinical Indications
-Acute pulmonary edema, other edema conditions, hypercalcemia (see Clin. Pharm. below )
-Hyperkalemia: in mild hyperkalemia loop diuretics enhance K+ excretion
-Acute renal failure: increase urine flow, enhance K+ excretion
"flush out" intratubular cast (myoglobin), but may worsen cast formation in myeloma or light chain nephropathy
-Anion overdose: bromide, fluoride, iodide
reabsorption is prevented in ascending limb
-NaCl should be administered to replace urinary loss of ions, replace volume.

Loop Diuretics - Toxicity

Loop Diuretics - Toxicity

-Hypokalemic metabolic alkalosis
(increased volume in collecting duct --> enhanced secretion of K+ and H+
can be reversed by replacement of K+, volume)
-Ototoxicity
(dose-related, reversible: most common in weak renal function, or w/aminoglycoside antibiotics (also ototoxic))
-Hyperuricemia (decrease dose!)
-Hypomagnesemia
(correct the diet, add Mg++)
Allergy- Skin rash

Loop Diuretics - Toxicity
Contraindications

Contraindications:
-caution in cirrhosis, congestive heart failure
(in chf, cardiac output is maintained by high filling pressure - excessive use of diuretics may diminish venous return, impair CO)
Sulfonamide sensitivity is rare (use ethacrynic acid)

Loop Diuretics- Note

Note: NSAIDS may interfere with the action of loop and thiazide diuretics.

Thiazides
MOA:
Prototype:

MOA: Inhibit NaCl reabsorption in the distal convoluted tubule (on the luminal side)

-Increase Ca2+ resorption (because of low intracellular Na+)
-Increases Uric Acid in serum
-Loss of serum K+

Prototype = Hydrochlorothiazide.

Thiazides- Use

Hypertension
Heart failure
Nephrolithiasis due to idiopathic calciuria
Nephrogenic diabetes insipidus.

Thiazides
Toxicity

Thiazides
Toxicity
-Hypokalemic metabolic alkalosis
(increased volume in collecting duct --> enhanced secretion of K+ and H+
can be reversed by replacement of K+, volume)
-Hyperuricemia
-Impaired carbohydrate tolerance
-Hyperlipidemia: 10% increase in cholesterol and LDL
-Hyponatremia: can be dangerous! Is due to elevated ADH because of hypovolemia (causes increased water resorption)
increased thirst
Remedy: reduce dose, limit water intake

Allergic reactions: sulfonamides!(rarely severe)
Rarely: hemolytic anemia, thrombocytopenia

Thiazides
ContraIndications

Contraindications: (well, not exactly, but...)
Caution needed in cirrhosis, borderline renal failure, congestive heart failure

Sulfonimides SIMILAR to Thiazides (4)

Sulfonamides similar to Thiazides
Chlorthalidone
Indapamide
Metolazone
Quinethazone

K+ Sparing Diuretics
2 Classes, 4 drugs

K+ Sparing Diuretics
Aldosterone antagonists
Eplerenone
Spironolactone

Na+ channel blockers
Amiloride
Triamterene

K+ Sparing Diuretics
MOA:

K+ Sparing Diuretics
MOA: Act in the collecting tubule and late distal tubule.
Aldosterone antagonists --> decrease Na+ absorption and K+ secretion

Na+ Channel Blockers directly inhibit Na+ channels (K+ couples) --> decreases Na+ absorption and K+ secretion

K+ Sparing Diuretics
Triamterene & Amiloride:

Directly inhibit Na+ channels in luminal membrane

K+ Sparing Diuretics
Spironolactone:

Spironolactone: a synthetic steroid that is a c ompetitive antagonist to aldosterone at thee mineral corticoid receptor
-onset is several days

K+ Sparing Diuretics
Eplereone:

Eplerenone: a amore selective for Mineralocorticoid R, fewer side effects

K+ Sparing Diuretics
Use?

K+ Sparing Diuretics
Use: most useful in mineralocorticoid excess:
-prevent the depletion of K+ stores
primary hypersecretion (Conn's syndrome)
-secondary aldosteronism from salt retention (in heart failure, cirrhosis, nephrosis)
(*Note: Other diuretics would cause or exacerbate hypovolemia, thus aggravating secondary aldosteronism.)

K+ Sparing Diuretics
Toxicity

K+ Sparing Diuretics
Toxicity
-Hyperchloremic metabolic acidosis: due to inhibition of H+ secretion (in parallel with K+ secretion)
-Hyperkalemia: can be dangerous
Increased risk in: renal disease if renin is decreased (by beta-blockers, NSAIDs, ACE inhibitors, angiotensin-receptor inhibitors)
(*Note: Combination with other diuretics reduces risks: Thiazide-induced hypokalemia and metabolic alkalosis balances potassium-sparing drug effects.)

Other:
Spironolactone (steroid!) may cause gynecomastia, impotence, benign prostatic hyperplasia
Triamterene: poorly soluble, may precipitate in urine and form kidney stones

K+ Sparing Diuretics
Contraindications:

Fatal hyperkalemia can develop in case of
oral K+ administration
chronic renal insufficiency
use of beta-blockers, ACE inhibitors
Liver disease: impaired drug metabolism; adjust dose.

Agents Enhancing Water Excretion:
Osmotic Diuretics (1)

Agents Enhancing Water Excretion:
Osmotic Diuretics
-Mannitol

Agents Enhancing Water Excretion:
Osmotic Diuretics
MOA:

MOA Mannitol: Enhances excretion in the water in proximal tubule and descending loop of Henle

-Non-permeable solutes retain water in lumen by countering the osmotic force.
Increased flow rate also decreases Na+ reabsorption

Agents Enhancing Water Excretion:
Osmotic Diuretics
Mannitol Kinetics:

Mannitol:
-must be given parenterally
(poor intestinal absorption: oral administration causes osmotic diarrhea)
-not metabolized
-excreted by glomerular filtration in 30-60 min
-no reabsorption or secretion.

Agents Enhancing Water Excretion:
Osmotic Diuretics
Use?

-Used to increase urine volume (water)
when unresponsive to other diuretics because of:
1) compromised renal hemodynamics
2) avid Na+ retention
3) to prevent anuria that may result from pigment load (hemolysis,rhabdomyolysis)
-To reduce intracranial or intraocular pressure: by reduction of intracellular volume.

Agents Enhancing Water Excretion:
Osmotic Diuretics
Toxicity

-Extracellular volume expansion -> Circulatory Overload, or Acute water Intoxication(in its with inaeqduate urine flow)
( due to extraction of intracellular water may enhance congestive heart failure, or may cause pulmonary edema
headache, nausea, vomiting)

-Dehydration and hypernatremia:
(Due to excessive use of mannitol without water replacement)

MUST Monitor ions &fluid balance!!

Agents Enhancing Water Excretion
ADH Antagonists (3)

Agents Enhancing Water Excretion
ADH Antagonists
Lithium
Demeclocycline
Conivaptan (IV only)

Agents Enhancing Water Excretion
ADH Antagonists MOA:

ADH Antagonists MOA: Inhibit the effect of ADH AT the collecting duct

Agents Enhancing Water Excretion
ADH Antagonists
Use?
Tox?

Agents Enhancing Water Excretion
ADH Antagonists
Use:
-Syndrome of Inappropriate ADH Secretion (SIADH),
if water restriction is not applicable
(demeclocycline effect more predictable than Li+)

-Other causes of elevated ADH:
diminished effective circulating blood volume (can use when volume replacement is not possible because of heart failure or liver disease (demeclocycline))

Toxicity:
nephrogenic diabetes insipidus, renal failure.

ADH Agonists (2)

ADH Agonists
Vasopressin
Desmopressin

Diuretic Combinations =

Diuretic Combinations = Loop agents AND Thiazides or K+ sparing AND Loop agents OR Thiazides

Diuretic Combinations =
Why use them in combo??

-2 drugs acting at 2 different sites show synergy, because compensatory salt and water reabsorption at the "other site" is blocked
-Significant mobilization of fluids (diuresis) even if the patient is refractory to either agent
-Monitoring necessary; outpatient use is not recommended
-Potassium wasting is common; parenteral K+ is often necessary.

K+ sparing AND Loop agents OR Thiazides
Why this combination?
Contraindications?

K+-sparing AND loop agents or thiazides
-Many patients on loop agents or thiazides develop hypokalemia
~dietary salt restriction often helps (less Na+ reaches the collecting tubule)
~dietary KCl supplement can also be used

If the above measures are not successful,
Potassium-sparing diuretics can be used to lower K+ excretion

This combination is generally safe, but
Contraindicated in renal insufficiency (hyperkalemia may develop).

Reasons TO Rx diuretics?

Edematous States
-Heart Failure
-Kidney Disease and Renal Failure
-Hepatic Cirrhosis
-Idiopathic Edema

Non-Edematous States
-Hypertension
-Nephrolithiasis
-Hypercalcemia
-Diabetes Insipidus.

Caution in CHF use?

Caution:
in heart failure, high filling pressure ensures cardiac output
excessive use of diuretics may decrease venous return, (especially in right ventricular failure w/systemic congestion!) -->cardiac output will decrease!
Can cause
-Diuretic-induced Metabolic alkalosis
-Diuretic-induced Hypokalemia

Use in Renal patients??

Kidney Disease
-Sufficient glomerular filtration is essential for diuretics to be effective (work from inside!)
-Retention of salt and water occurs in most kidney diseases
Glomerular diseases (e.g. in diabetes mellitus, systemic lupus, others)
The cause of sodium retention is not precisely known (impaired microcirculation? mediators?)
If patients get edema and hypertension: diuretics are effective
-Hyperkalemia (esp. in diabetic nephropathy): treat with loop agents and thiazides.

Choosing an agent for a renal patient?

Choosing a diuretic for the patient with kidney disease:
-Loop agents are often the best choice to treat edema

Caution:
-avoid acetazolamide - it may exacerbate acidosis
-K+ sparing drug may exacerbate hyperkalemia
-Thiazides are ineffective when GFR < 30 mL/min, but can be used to decrease dose of loop agents

Overzealous use of diuretics:
causes decline of renal function in all patients, but more so in renal disease.

Diuretic use in HTN

Hypertension
Thiazides have well-documented, beneficial effects in essential hypertension ;
- similar or better than ACE inhibitors or Ca2+-blockers - cheap and effective!

Restriction of dietary Na+ potentiates the anti-hypertensive effect of diuretics, lessen K+ wasting

In combinations, diuretics
enhance the effects of ACE inhibitors
are needed to correct salt and water retention caused by vasodilators (hydralazine, minoxidil).

Use with Nephrolithiasis:

Nephrolithiasis

-Most kidney stones contain calcium (phosphate or oxalate)
renal "Ca2+ leak" can be treated with thiazides which enhance Ca2+ reabsorption in the distal convoluted tubule
NaCl intake has to be limited.

Hypercalcemia and diuretics:

Hypercalcemia

Can be life-threatening
Loop diuretics promote calcium diuresis, but may cause volume contraction,which leads to increased Ca2+ reabsorption in the proximal tubule

Loop diuretics + saline, both IV, is effective.
-should match saline with urine flow rate.

Diuretics and Diabetes Insipidus:
Caution:

Diabetes insipidus
-if deficient ADH production: give ADH or analogue
-if patients not responding to ADH: Thiazides are beneficial (a paradox effect):
~plasma volume reduction decreases glomerular filtration rate
~enhances proximal Na+ reabsorption
decreases fluid delivery to distal segments
~Dietary Na+ restriction potentiates the thiazides

Caution:
Lithium may cause diabetes insipidus;
thiazides (or amiloride) are indicated
Caution: diuretics may reduce renal Li+ clearance!

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