What is the working definition/common usage of diuretics?
Natriuretics indirectly increase water excretion, all these drugs are referred to as diuretics.
What are the carbonic anhydrase inhibitors?
Acetazolamide and Dorzolamide. (These are the "ZOLAMIDES")
What are the Osmotic Diuretics?
What are the Loop Diuretics?
Furosemide and Ethacrynic Acid
What are the Thiazides and congeners?
Hydrochlorothiazide and Indapamide
What are the potassium sparring diuretics?
Triamterene, Amiloride, and Spironolactone
What are the Vasopressin antagonists?
Conivaptan and Tolvaptan (The Vaptans!)
Where do the carbonic anhydrase work? What is the mechanism of action?
They work in the proximal tubule. They inhibit NaHCO3 reabsorption. They work both cytoplasmically and in lumen (membrane bound)
Where do the Osmotic Diuretics work? What is the mechanism of action?
They work at the Thin Descending Loop of Henle. They specifically increase the osmolarity of tubular fluid.
Where do the Loop Diuretics work? What is the mechanism of action?
They work at the Thick Ascending Loop of Henle. They inhibit the Na/K/CL tri symporters.
Where do the Thiazides and Congeners work? What is the mechanism of action?
They work at the Early Distal Tubule. They inhibit he Na/Cl symporters.
Where do the Potassium Sparing Diuretics work? What is their mechanism of action?
They work at the Late Distal Tubule and the Cortical Collecting Tubule. They inhibit the epithelial Na channels. They inhibit aldosterone receptors.
Outline how the Carbonic Anhydrase Inhibitors work:
1. The basolateral Na,K ATPse actively transports Na out of the cell into the interstitial space. This sets up a Na gradient as well as causing K to flow into the cell.
2. This gradient drives the inward Na movement and the H outward movement.
3. Luminal + reacts with HCO3 to form H2CO3.
4. Membrane bound CA catalyzes H2CO3 to form CO2 and H20.
4. CO2 rapidly diffuses cell membrane into the cell while water enters through the aquaporin channels.
5. Cytoplasmic CA catalyzes the formation of H2CO3 from H20 and CO2. This will dissociate to form H and HCO3 to start the cycle again (step 3).
What are the effects of Carbonic Anhydrase Inhibitors?
Increase in renal excretion of Na, K, and HCO3.
Decrease in renal excretion of NH4 and H.
There is an increase in urine pH (more alkaline)
Causes metabolic acidosis.
What are the effects of Carbonic Anhydrase inhibitors on other organs/systems?
It increases the production of aqueous humor which is rich in HCO3.
It inhibits the choroid plexus' production of CSF.
Given mostly IV and its oral bioavailability is 100%. The half-life is 6-9 hours.
Given as eye drops. This is undetectable in the blasma because it binds to CA in RBC on chronic administration where it is slowly eliminated.
What are the Adverse effects of CA inhibitors?
1. Frequent Parasthesias and Drowsiness
2. Nephrolithiasis (kidney stones)
3. Hypercholermic Metabolic Acidosis
4. Hyperuricemia and an exacerbation of gout
6. DORZOLAMIDE: bitter taste and localized reactions causing burning, stinging or discomfort
What are the contraindications and precautions of CA inhibitors?
Hepatic Cirrhosis, COPD, hypersensitivity to sulfa drugs and hypokalemic states
What are the therapeutic uses of CA inhibitors?
Open Angle Glaucoma
Acute Mountain Sickness
Edema from Heart Failure
Alkalosis due to Thiazides or Loop Diuretics
Familial Periodic Paralysis
What is the mechanism of action of Mannitol?
It is freely filtered by the glomerulus. It works by extracting water from the ICF. This causes greater increase of Water Diuresis than Salt Diuresis.
What are the effects on other organs/systems by Mannitol?
By extracting water from ICF it can lead to an initial increase in ECF. The ECF will decrease eventually. In this manner it can reduce both intracranial and intraocular pressure.
What are the adverse effects of Osmotic Diuretics?
ECF volume contraction which can lead to hypovolemia, dehydration and hypernatremia.
ECF volume expansion in patients with cardiac or renal disease which can cause hypervolemia, hyponatremia, and pulmonary edema.
What are the contraindications and precausions of Osmotic Diuretics such as Mannitol?
Severe Renal Failure, Heart Failure, Pulmonary Congestion/Edema, Severe Dehydration
What are the therapeutic uses of Osmotic Diuretics?
Cerebral Edema, Acute Angle-Closure Glaucoma, Reduced Intraocular Pressure, Prevention and/or treatment of oliguria or anuria in acute renal failure to promote diuresis.
What is the difference between Furosemide and Ethacrynic Acid?
Furosemide is a sulfonamide while Ethacrynic Acid is not a sulfanamide.
What is the site of action of the Loop Diuretics?
The Tri-N,K,CL-symporter inhibitor at the Thick Ascending Loop of Henle. The diuretics prevent the reabsorption of N, K, and Cl.
What is the ratio in which Na, K, and Cl are transported across a cell membrane?
What are the effects of Loop Diuretics?
1. Decreased Lumen-Positive Potential causing a reduction of Ca and mg.
2. Decreased Hypertonicity of the Medulla
3. Inhibition of the Macula Densa
4. Due to the Macula Dense inhibition there is an inhibition of the tubuloglomerular feedback and a stimulation of renin relase.
What are the renal effects of the Loop Diuretics?
1. Renal Excretion of Na, Cl, K, H, Ca. The Sulfanamides increase the excretion of HCO3.
2. Metabolic Alkalosis
3. Specifically causes a high increase of Na exretion.
What are the effects on other organs/systems due to Loop Diuretics?
Vasodilation mainly in the venous bed. There is a redistribution of blood flow within the renal cortex.
Discuss the adverse effects of Loop Diuretics:
Prolongued use can lead to a significant Na+ depletion.
1. Hypokalemic Metabolic Acidosis
2. Hyperuricemia (increase in uric acid reabsorption in the PCT)
What are the adverse effects of Loop Diuretics?
1. CNS- dizziness, parasthesias
2. Gastrointestinal- GI bleeding
3. Postural Hypotension
4. Ototoxicity leading to tinnitus and hearing loss (due to alteration of electrolyte composition of the endolymph)
5. Allergic Reactions to sulfonamide loop diuretics
Concerning Loop Diuretics, what suggests kidney failure?
Annuria unresponsive to a trial dose of loop diuretic.
What are the contraindications and precautions of Loop Diuretics?
Serious Hypovolemia or Hyponatremia. Also, hypersesitivity to sulfa drugs.
What are the therapeutic uses of Loop Diuretics?
Acute Pulmonary Edema, Heart Failure, Edema, Ascites, Hypertension, and Hypercalcemia
What is the site of action of Thiazides and Congeners?
The Na/Cl symporters in the early distal convoluted tubule. This is responsible for NaCl reabsorption from the lumen into early DCT epithelial.
What is the mechanism of action of Thiazides and Congeners?
They are responsible for the inhibition of NaCl reabsorption from the lumen into the early DCT.
What are the renal effects of Thiazides and Congeners?
Increased renal excretion of Na,K, H, Cl, ad HCO3
Decreased renal excretion of Ca, NH4, and urates
What are the organ/system effects of the Thiazides and Congeners?
What are the averse effects of Thiazides and Congeners?
Hypokalemic Metabolic Alkalosis
Impaired carbohydrte tolerance
Hypernatremia (rare but fatal)
Patasthesias and Dizziness
Hyperbilirubinemia and Jaundice
Postural Hypotension and Palpitations
Allergic Reactions because Thiazides are sulfonamides.
What are the adverse effects of Thiazides and Congenes?
Hypersensitivity, Anuria, Renal Decompensation, and Pregnancy
What are the therapeutc uses of Thiazides and Congeners?
Hypertension (first choice diuretic)
Edema of the heart, liver, and kidney
Calcium Nepholithiasis (kidney stones)
Meniere's Disease (prevents endolymphatic fluid buildip)
Nephrogenic Diabetes Insipidus
What are Thiazides given with nephrogenic Diabetes Insipidus?
Due to the ECF volume contraction that promotes proximal tubular Na+ and Water Reabsorption. Therefore a reduced volume is delivered to the distal tubule.
What are the two molecular targets of Potassium Sparring Diuretics?
1. ENaC- the epithelial sodium channels (triamterene and amiloride)
2. Aldosterone Receptor- spironolactone
What are the mechanisms of action of the Potassium Sparing Diuretics?
1. ENaC inhibition
2. Aldosterone receptor antagonism
Outline how ENaC inhibition works:
Normally ENaC mediates Na reabsorption in the late distal tubule. Inhibition of this by amiloride prevents Na+ reabsorption and increases diuresis.
Outline how Aldosterone Receptor antagonists work:
Receptor activation normally causes gene activation and the synthesis of Aldosterone-Induced Proteins AIPs.
AIPs have multiple effects such as regulating the ENaC channel and cuasing salt and water retention (K and H excretion).
Spironolactone is a receptor antagonist that blocks the effects of aldosterone. This reduces ENaC channel expression.
What are the renal effects of Potassium Sparing Diuretics?
Increased renal excretion of Na and Cl
Decreased renal excretion of K, Ca, H
What are the adverse effects of Potassium Sparing Diuretics?
Hyperkalemia, Metabolic Acidosis
Spironolactone can cause gynecomastia, prostatic hypertrophy, hirstutism, menstrual irregularities
What are the contraindications of Potassium Sparing Diuretics?
Chronic Renal Insufficiency
Severe Hepatic Disease
Beta-Blockers, ACE inhibitors
High Doses of NSAIDs
What are the therapeutic uses of Potassium Sparing Diuretics?
All drugs in this category treats and prevents hypokalemic states.
Amiloride is used for Lithium-induced nephrogenic diabetes insipidus.
Spironolactone is used for Primary Hyperaldosteronism, Secondary Hyperaldosteronism, and Heart Failure
What is the site of action of Vasopressin Antagonists?
The ADH receptor in the medullary collecting duct. It works on 3 different receptors all of which are the G-protein-coupled receptors.
What is the MOA of the Vasopressin Antagonists?
Of most relevance here is the V2 receptor found on the basolateral membrane of principal cells of the medullary collecting duct.
V2 receptors regulate the distribution of aquaporin channels between the basolateral and the apical membrane of these cells.
Activation of the V2 receptors promote the insertion of aquaporin channels.
What is the MOA of Conivaptan and Tolvaptan specifically?
They are non-peptide competitive antagonistsof V2. Inhibition of these cause a shift of the balance of water movement in favor of diuresis.
Conivaptan is a V1 antagonist for V1a receptors that effect renal blood flow and is a minor contributor to its diuretic properties
Tolvaptan is a V2 receptor specifically.
Discuss the diuretic effects of Vasopressin antagonists:
Increases water diresis more than salt diuresis. This is how it hlps with hyponatremia.
What are the adverse effects of Vasopressin Antagonists?
Nephrogenic Diabetes Insipidus, Postural Hypotension and Hypokalemia
What are the adverse effects of Vasopressin Antagonists?
Do NOT use with strong CYP3A4 inhibitors such as Clarithromycin.
What are the therapeutic uses of Vasopressin Antagonists?
SIADH and Chronic Euvolemic Hyponatremia
What is SIADH?
A syndrome of impaired water excretion with accompanying hyponatremia and hypo-osmolality that is caused by the inappropriate secretion of vasopressin.