Renal Agents Flashcards
Filter approximately 1300 mL blood per min or 700 mL plasma
Kidneys
In the kidney, the peritubular capillary network surrounds the
Convoluted tubules
Passes close to the glomerulus between the afferent and efferent arterioles
Distal Convoluted Tubule
Osmotic diuretics that promote water retention in the tubular fluid
Mannitol or glucose
Water permeability in collecting duct is controlled by
ADH
Inhibits ADH secretion by the pituitary
Alcohol
A carbonic anhydride inhibitor that blocks sodium bicarbonate reabsorption, resulting in decrease in NaCl reabsorption
Acetazolamide
Acetazolamide functions on the
Proximal tubule
Osmotic agents act on the thin descending limb to promote
Water retention
Block the NKCC2 cotransporter
-Act on thick ascending limb
Loop diuretics (i.e. furosemide)
Relatively impermeable to water
DCT
Blocks the electrically neutral Na+/Cl- cotransporter NCC
Thiazides diuretics
Reabsorption in DCT is via parathyroid hormone regulated apical Ca2 channel and a basolateral Na+/Ca2+ exchanger
Ca2+
The site of mineralcorticoid and ADH action
Collecting tubule
The major site of K+ secretion
Collecting tubule
Sodium bicarbonate reabsorption by the PCT is initiated by the action of the
-Allows Na+ to enter the cell
Na+/H+ exchanger NHE3
Inhibits carbonic anhydride and acts predominantly in the proximal tubule by blocking sodium bicarbonate reabsorption
Acetazolamide
The bicarbonate loss from carbonic anhydride inhibitors can cause a
Hyperchloremic metabolic acidosis
The portion of acetazolamide that can cause allergic reactions, bone marrow depression, and skin toxicity
Sulfonamide group
Carbonic anhydride inhibitors should be avoided in patients with
Hepatic Cirrhosis
Used to treat glaucoma, acute mountain sickness, metabolic alkalosis, and to alkalinize the urine
C.A. Inhibitors
Raise CO2 content of tissues, which in turn stabilizes deoxyhemoglobin
-Useful for counteracting acute mountain sickness
C.A. Inhibitors
Osmotic diuretics such as mannitol act in the
-Where the cells are freely permeable to water
PT and Descending limb of Henle’s loop
Causes loss of water, reduced intracellular volume, and hypernatremia risk
Mannitol
Function to increase water excretion in preference to Na+ excretion
- Reduces intracranial and intraocular pressure
- Promotes prompt removal of renal toxins
Osmotic Diuretics
Water expansion into the extracellular compartment causing hyponatremia
-Effect of osmotic diuretic toxicity
Extracellular volume expansion
Can complicate congestive heart failure and may produce florid pulmonary edema
Extracellular Volume Expansion
Excessive use of osmotic diuretics w/out carefully monitoring serum ion composition and fluid balance can lead to
Dehydration and Hypernatremia
Loop diuretics act in the loop of Henle and block the
NKCC2 cotransporter
Loop diuretics cause an increase in the excretion of
Mg2+ and Ca2+
Furosemide, bumetanide, ethacrynic acid, and torsemide are the
Loop Diuretics
The most effective diuretics currently available
Loop diuretics
A phenoxyacetic acid derivative containing an adjacent ketone and methylene group
Ethacrynic Acid
What is the duration of effect for
- ) Furosemide
- ) Torsemide
- ) 2-3 hours
2. ) 4-6 hours
Block tubuloglomerular feedback by inhibiting salt transport into the macula densa
Loop Diuretics
Induce synthesis of renal prostaglandins by expressing COX-2
Loop Diuretics
Inhibit cyclooxygenase and can reduce prostaglandin synthesis in the kidney and interfere with loop diuretics
NSAIDs
Can both relieve pulmonary congestion and reduce LV filling pressures in CHF before a measurable increase in urinary output occurs
Furosemide and ethacrynic acid
Most important indications are acute pulmonary edema, other edematous conditions, and acute hypercalcemia
Loop Diuretics
A major adverse effect of loop diuretics is
Hypokalemic metabolic alkalosis
Can also cause impaired carbohydrate tolerance, hyperglycemia, dehydration, and hyponatremia
Loop diuretics
Both loop diuretics and thiazides can cause
Hypokalemic metabolic alkalosis
Is mostly just used for patients sensitive to sulfonamides
Ethacrynic acid
Furosemide, bumetanide, and torsemide may demonstrate cross reactivity in patients who are sensitive to other
Sulfonamides
Diuretics of the thiazides class block the electrically neutral
NCC transporter
NCC is the gene mutated in
Gitelman’s syndrome
Enhance Ca2+ reabsorption
Thiazides
Include hydrochlorothiazide, indapamide, chlorthalidone, and metolazone
Thiazides
Some members of the thiazides retain significant
CA inhibitor activity
Thiazides can be inhibited by
NSAIDS
Similar to CA inhibitors, thiazides has unsubstituted
Sulfonamide group
Thiazides that is less lipid soluble and must be given in relatively large doses
-Slowly absorbed and has longer duration of action
HCTZ
Indicated for hypertension, heart failure, nephrolithiasis, and nephrogenic DI
Thiazides
In nephrogenic DI, reduce plasma volume to lower GFR which enhances proximal tubule reabsorption of NaCl and water
-Causes decreased delivery of fluid to the diluting segments
Thiazides
Can cause hypokalemic metabolic alkalosis and hyperuricemia
Thiazides
Also cause impaired carbohydrate tolerance, hyperlipidemia, hyponatremia, and allergic reactions
Thiazides
Cause a 5-15% increase in serum cholesterol and increase LDLs
Thiazides
An important adverse effect of thiazides. Due to a combination of hypokalemic-induced elevation of ADH, reduction in diluting capacity of kidney, and increased thirst
Hyponatremia
Where we see 2-5% of NaCl reabsorption
-Determines the final Na+ concentration in the Urine
Late Distal Tubule and Collecting Duct
The late distal tubule and collecting duct is the site of action for
Aldosterone
Major site of K+ secretion and acidification of urine
Late distal tubule and collecting duct
Major sites of Na+, K+, and H2O (ADH-sensitive) transport
Principal cells
Diuretics that increase Na+ delivery to the late distal tubule and collecting duct will therefore increase secretion of
K+ and H+
Primary sites of proton secretion
Late distal tubule and collecting duct intercalated cells
Increases expression and delivery of apical membrane channels and the basolateral Na+/K+ ATPase
Aldosterone
Competitive antagonists of the aldosterone receptor
-“Potassium-sparing Diuretics”
Spironolactone and Eplerenone
More selective and has less side effects
Eplerenone
Block the ENaC Na+ channel in the apical cells of the collecting tubule
Triamterene and amiloride
Also can be inhibited by NSAIDs
Triamterene and Spironolactone
Promoted by hyperkalemia and high levels of AN-II
Aldosterone release
Has high levels in cirrhosis w/ ascites, renalvascular hypertension, adrenal tumors, and cardiac or nephrotic edema
Aldosterone
Most useful in states of mineralocorticoid excess, due either to primary hypersecretion or to secondary aldosteronism
Potassium sparing diuretics
Can be used to treat hypertension in Liddle’s Syndrome
Triamterene and amiloride
Can cause hyperkalemia
Potassium-sparing diuretics
The risk of this complication is greatly increased in the presence of renal disease or other drugs that reduce renin
Hyperkalemia from aldosterone
By inhibiting H+ secretion in parallel with K+ secretion, the K+-sparing diuretics can cause
Hyperchloremic metabolic acidosis
Synthetic steroids may cause endocrine abnormalities by effects on other steroid receptors. One of these effects is
Gynecomastia
These endocrine abnormalities can be avoided by using
Eplerenone
Patients with renal insufficiency are especially vulnerable and should rarely be treated with
Aldosterone antagonists
Patients with liver disease may have impaired metabolism of
Triamterene and spironolactone
Strong CYP3A4 inhibitors (ketoconazole and itraconazole) can markedly increase blood levels of
Eplerenone
Secreted by the posterior pituitary whenever the cardiovascular system is challenged by hypovolemia and/or hypotension
ADH
Increases the permeability of principal cells to water by binding to V2 receptors, thus increasing the number of water channels (AQP2) on apical surface
ADH
The cell that responds to ADH is the same cell that responds to aldosterone. This is the
Principal Cell
ADH receptor antagonists
Vaptans
Used to treat euvolemic hyponatremia
Vaptans
A non-selective antagonist at V1a and V2 receptors
Conivaptan
Oral agents selectively active against the V2 receptor
Lixivaptan and tolvaptan
Both appear to reduce the formation of cAMP in response to ADH and also interfere w/ cAMP in collecting tubule cells
Li+ and Demeclocyline
Are indicated to treat SIADH
ADH antagonists
If serum Na+ is not monitored closely, ADH antagonists can cause severe hypernatremia and
Nephrogenic DI
If Li+ is being used for an effective disorder, than we can treat the nephrogenic DI with
Thiazides diuretic or amiloride