Flashcards in Renal Pharmacology Deck (67):
What is the main reason for using a Diuretic?
To mobilize Sodium (Na+)
What are carbonic anhydrase inhibitors?
Diuretics that inhibit the action of Carbonic Anhydrase.
Where is Carbonic Anhydrase found in the kidney?
1.90% of the Carbonic Anhydrase in the kidney is found in the Proximal tubule
2.10% found in the distal tubule..
What does Carbonic Anhydrase do in the PCT?
Converts carbonic acid to water and CO2
What is the mechanism of action of the Carbonic Anhydrase inhibitors?
These drugs block the action of the enzyme carbonic anydrase particularly in the PCT decreasing production of protons inside the cells of the PCT and thus Bicarbonate appears in the urine.
What are the effects of Carbonic Anhydrase inhibitors?
1.Increased Na+-bicarbonate loss in urine
2.Enhanced chloride absorption resulting in acidosis
What are the main uses of Carbonic anhydrase inhibitors?
2.Alkalinize urine (Cysteinure)
3.Reduce intra occular pressure
4.Prophylaxis for mountain sickness
5.Management of seizures
What is the chief Carbonic Anhydraze in use?
What is the self limiting side effect of Acetazolamide?
Hyperchlorimic systemic acidosis. Due to the fact that Sodium is now being reabsorbed with Cl-
What are the chief practical uses of Acetazolamide?
1.Alkalinize the urine in children with Cysteinurea
2.Prophylactic for glaucoma surgery (reduce intra-occular pressure)
What is the mechanism of action of Acetazolamide?
Inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium.
What are the effects of Acetazolamide?
The decreased ability to exchange Na+ for H+ in the presence of acetazolamide
results in a mild diuresis. Additionally, HCO3– is retained in the lumen, with marked elevation in urinary pH. The loss of HCO3– causes a hyperchloremic metabolic acidosis and decreased diuretic efficacy following several days of therapy
What is the most common use of Acetazolamide?
Treatment of glaucoma: The most common use of acetazolamide is to reduce the elevated intraocular pressure of open-angle
glaucoma. Acetazolamide decreases the production of aqueous humor, probably by blocking carbonic anhydrase in the ciliary
body of the eye. It is useful in the chronic treatment of glaucoma but should not be used for an acute attack. Topical carbonic
anhydrase inhibitors, such as dorzolamide and brinzolamide, have the advantage of not causing any systemic effects.
What is another mainstream use of Acetazolamide?
Mountain sickness: Less commonly, Acetazolamide can be used in the prophylaxis of acute mountain sickness among healthy, physically active individuals who rapidly ascend above 10,000 feet. Acetazolamide given nightly for 5 days before the ascent prevents the weakness, breathlessness, dizziness, nausea,
and cerebral as well as pulmonary edema characteristic of the syndrome.
What are the side effects of Acetazolamide?
Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and paresthesia may occur. The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a decreased excretion of NH4+.
Carbonic Anhydrase inhibitors are derivatives of what class of drug?
How long does it take for the diuretic effect of Azetazolamide to be reduced??
2-3 days,(after bicarbonate is depleted.)
What are the osmotic diuretics?
Small molecules that are filtered but not reabsorbed by the kidney
How do the osmotic diuretics work?
A number of simple, hydrophilic chemical substances that are filtered through the glomerulus, such as mannitol and urea,
result in some degree of diuresis. This is due to their ability to carry water with them into the tubular fluid. If the substance that is filtered subsequently undergoes little or no reabsorption, then the filtered substance
will cause an increase in urinary output. Only a small amount of additional
salt may also be excreted. Because osmotic diuretics are used to effect
increased water excretion rather than Na+ excretion, they are not useful for treating conditions in which Na+ retention occurs.
What are the chief uses of Osmotic diuretics?
They are used to maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure. Osmotic diuretics are a mainstay of treatment for patients with increased intracranial pressure or acute renal failure due to shock, drug toxicities, and trauma. Maintaining urine flow preserves longterm kidney function and may save the patient from dialysis.
How should Mannitol be administered?
Mannitol is not absorbed when given orally and should only be given intravenously.
What is the minor location for the action of osmotic diuretics?
The PCT. Osmotically inhibits Na+ and H2O reabsorption.
What are the other locations of action for the Osmotic diuretics?
Reabsorption of water is also decreased in the descending limb of the loop of Henle and the collecting tube.
What are the major actions of Mannitol in the Loop of Henle?
1.In large doses it increases the osmolarity of the plasma.
2.Extract water from peripheral tissues and decrase blood viscosity.
3.Increases medullary renal blood flow and reduce tonicity
4.Impair water reabsorption by thin descending limb of Henle's loop
5.Impair NaCl & Urea extraction by thin ascending limb of Henle's loop
6.Interfere with transport processes in the TALH (weak effect)
What is the net effect of the osmotic diuretics?
1.Significantly increase the volume of urine.
2.Increase the excretion of other filtered substances (unless actively reabsorbed)
What are the clinical uses of The osmotic diuretics?
1.Treatment of dialysis disequilibrium syndrome (over dialysed patient)
2.Reduce intracranial pressure
3.Reduce intraocular pressure
What are the side effects of Osmotic diuretics?
2.Contraindicated in cardiac failure
What are the loop diaretics?
4.Ethacrynic [eth-a-KRIN-ik] acid
What are the mechanisms of action of the loop diuretics?
1.Inhibit Na-K-2Cl- symporter in TALH
2.Inhibit the ability of the Macula Densa to sense NaCl
3.Stimulate biosythesis of prostaglandins
4.Increase renal blood flow
6.Potently increase RENIN release by
-inhibiting the macula densa
-reflexely activating the sympathetic NS
-stimulating intrarenal baroreceptor mechanisms
How do the loop diretics work?
Loop diuretics inhibit the cotransport of Na+/K+/2Cl– in the luminal membrane in the ascending limb of the loop of Henle. Therefore, reabsorption of these ions is decreased. The loop diuretics are the most efficacious of the diuretic drugs, because the ascending limb accounts for the reabsorption of 25 to 30 percent of filtered NaCl, and downstream sites are not able to compensate for this increased Na+ load.
Where do the loop diuretics ranck in terms of potency?
Most potent class of diuretics efficacious even in those with poor renal function.
However relatively short acting.
What is the net eefect of the loop diuretics?
1.Copious diuresis and significant NaCl loss
2.Increase urinary excretion of K+/H+
3.Increase excretion of Ca2+ and Mg2+
4.Impairment of the kidney's ability to concentrate urine
5.There is also loss of the lumen positive potential which reduces reabsorption of divalent cations
How does use of NSAIDs affect kidney function and effect of diuretics?
Prostaglandins are important in maintaining Glomerular filtration, NSAIDS interfere with prostaglandin synthesis and decreases the efficacy of most diuretics
What are the major uses of Loop Diuretics?
1.Edema of Cardiac, hepatic or renal origin (oral) (GFR <30ml/min)
3.Hypercalcemia to mobilize Ca2+
4.Protect against renal failure related to Prostaglandins and GFR
5.Washout of toxins by increasing urine flow
What is Furosemide?
1.Loop diuretic that inhibits NaCl reabsorption in the TALH (Sulfonamide derivative)
How is Furosemide administered?
Orally and IV/IM.
How is Furosemide secrted in the kidney?
Secreted by organic acid transporter to inhibit the luminal symporter.
What are the side effects of Furosemide?
1.Abnormalities of Fluid and electrolytes
-Hypokalemia and disorders in pH (mostly alkalosis)
-requires initial monitoring
2.Elevated BUN, hyperglycemia, hyperuricemia
3.Ototoxicity, sialadentitis (inflammation of salivary glands)
What are the possible drug interactions with Furosemide?
What is Bumetanide?
Loop diuretic (sulfonamide derivative)
How does Bumetanide compare to Furosemide?
Forty times (40x) more potent than Furosemide
When is Bumetanide used?
Substituted in patients also on Warfarin therapy.
What is Torsemide?
Loop diuretic that also lowers blood pressure
What are the advantages of Tosemide?
Has a longer half-life than the other loop diuretics (can be given once a day)
What is the normal dosing for Furosemide?
Orally at 20-40mg OD or BID
How soon is the response to Lasix?
30 minutes lasting ~8hr
What is the half-life of Lasix?
How is Lasix excreted?
In the Urine
Where in the Nephron is Lasix (and other Loops) secreted?
Proximal convoluted Tubule
Where does Furosimide work?
TALH works on symporter from the inside after being secreted into the nephron at the PCT
When is the dose of Furosemide increased?
In patients with rena disease who have significantly reduced GFR. These patients have reduced secretion and dosses can be up to 200-300mg per day
What must patients taking Furosemide also do?
Remember to stay well hydrated to prevent kidney stones due to the increased excretion of Calcium in urine
What is a major advantage of Furosemide?
WIDE MARGIN OF SAFETY.
Where do the Thiazide diuretics work?
Distal convoluted Tubule
What happens in the DCT?
This segment actively pumps out Na+ and Cl- out of the lumen of the nephron via the Na=/Cl- carrier (NCC).
What is the target of the Thiazide drugs?
(NCC) Sodium and Chloride cotransporter.
What is reabsorbed in the DCT?
What controls the reabsorption of calcium in the DCT?
(PTH) Parathyroid hormone
What happens in the SCT?
Fine tunning of Urine.
What portion of the DCT is most sensitive to the Thiazide diuretics?
The early part of the DCT.
What is an advantage of the Thiazide diuretics of the Loop diuretics?
They have a longer duration of action.
What is the precise mechanism of the Thiazide diuretics?
Inhibit NaCl reabsorption in the Na+-K+ aldosterone-independent segment of the distal tubule
What are the effects of the Thiazide diuretics?
1.Moderate loss of Na+, K+ and Cl-, cause 3X increase in urine flow
2.Sodium loss results in reduced GFR (chronic)
3.Elevation of Excreted urinary potassium
4.Increased excretion of titratable acid, due to increased delivery of Na+ to the distal tubule
5.Decrease the urinary excretion of Ca2+
6.Increase the urinary excretion of Mg2+
What are the therapeutic uses of the Thiazide diuretics?
1.Diuretic to reduce edema associated with CHF, cirrhosis, and nephrotic syndrome
2.Hypercalciurea and renal calcium stones
3.To reduce blood pressure in essential hypertension
4.To augment the action of other antihypertensives
6.Nephrogenic Diabetes insipidus
What do the Thiazides require similar to Loop diuretics to be effective?
Secretion into the tubular fluid to exert their effect.
Which 2 Thiazides are effect at GFR <30-40 mL/min
Metolazone and Indapamide.