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PCT
- Luminal carbonic anhydrase dehydration of H2CO3 to CO2 and H2O (MAJOR)
- Intracellular carbonic anhydrase rehydration back to H2CO3
- @ late PCT luminal fluid contains high NaCl
- Principle: water is reabsorbed in direct proportion to salt reabsorption constant osmolality, increase
concentration of impermeant solute inhibition by mannitol (osmotic forces)
- Secretory systems (middle third, S2) secrete organic acids (diureteics, NSAIDs, uric acid, antibiotics etc); blood
to lumen
- S1 and S2 secretion of organic base (creatinine, choline)
Loop of Henle
- Remember hypertonic medulla
- H2O reabsorption inhibition by mannitol (osmotic forces)
- TAL = diluting segment
- Na/K/2Cl (NKCC2) transporter causes postassium inside driving force for other ions to be reabsorbed:
divalent cations (Ca, Mg) via paracellular pathway
DCT
- K+ does not recycle across the apical membrane no lumen positive potential
- Ca and Mg not driven out of tubular lumen by electrical forces
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- Ca is actively reabsorbed via apical channel and basolateral Na/Ca exchanger regulated by PTH
Collecting tubule
- Final site of NaCl reabsorption
- Acted upon by mineralocorticoid
- K+ secretion
- All diuretic changes in K+ balance occur
- Principal cells major site of K, Na, and water transport (separate transport of Na and K, no cotransport)
- Intercalated cells primary sites of H+ secretion
- Cl transported back to the blood by luminal negative-electrical potential via paracellular pathway then K goes
out of the cell
- Principle: Na delivery to the CCT results to K secretion; Na + Cl- (anion that cannot be reabsorbed, HCO3- )
results to lumen negative potential and K secretion
- Aldosterone stimulates Na/K ATPase pump and ENaC potassium wasting, Na reabsorption
- ADH controls permeability to water by insertions of aquaporin, AQP2 @ apical membrane no ADH = dilute
urine is produces; also stimulates insertion of urea transporter (UTI) @ medullary collecting duct
Secretion is regulated by serum osmolality and volume status
- Urea concentration osmolality of medulla, concentration of urine
Prostaglandins
- PGE, PGI, PGD, PGF, and thromboxanes
- PGE regulation of salt reabsorption, influence activity of certain diuretics
PGE2 reduces both Na reabsorption in the TAL of LOH and ADH-mediated water transport in CCT
Inhibited prostaglandin synthesis block loop diuretic activity
The cells of the MACULA DENSA are sensitive to the concentration of sodium chloride in the distal convoluted
tubule:
- DECREASE in NaCl concentration initiates a signal from the macula densa that has two effects:
(1) resistance to blood flow in the afferent arterioles (dilation), which glomerular hydrostatic
pressure (blood flow) and helps return glomerulus filtration rate (GFR) toward normal, and
(2) renin release from the juxtaglomerular cells of the afferent and efferent arterioles, which are the major
storage sites for renin
Remember: DECREASE in NaCl concentration is due to decreased blood flow, GFR, rate of flow to the
tubule time for tubules to reabsorb solutes Na in the distal tubule thus interpreted as decreased blood
flow by the macula densa.
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DIURETICS
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Classification Pharmacokinetic Pharmacodynamic Important drug Clinical uses Adverse effects
- Drugs interactions
THIAZIDES - ALL thiazide can be - Inhibit NaCl transport NSAIDs inhibit action of - Hypertension - Excretion competes
- also sulfonamides administered PO predominantly in the thiazide - Heart failure with uric acid in
Prototype: - ALL thiazide are DCT - Nephrolithiasis - organic acid secretory
Hydrochlorothiazide secreted by organic - Enhance Ca Digoxin toxicity Kidney stones in hyper system elevation of
acid secretory system reabsorption (2) secondary to calciuria serum uric acid level
- Depends in part in hypokalemia - Nephrogenic diabetes (hyperuricemia)
renal prostaglandin insipidus - Hypokalemic metabolic
Chlorothiazide - Parent compound function Decreased effect of acidosis
- Not very lipid soluble hypoglycemic agents - Impaired CHO
- Given in large doses due to decreased Avoid in patients with: tolerance
- Only thiazide given pancreatic insulin hepatic cirrhosis, - Hyperlipidemia
parenteral release and diminished borderline renal failure or - Hyponatremia
tissue utilization of heart failure - Allergic Reactions
Chlorthalidone - Longer duration of glucose
action Others:
- Slowly absorbed Promotes lithium Weakness, fatigability,
toxicity due to paresthesias
Idapamide - Excreted mainly by increased Na in the
biliary system CCT, likewise increases
Others (1) its absorption 2o to
hypokalemia.
POTASSIUM-SPARING - @the CCT: NSAIDs - Mineralocorticoid - Hyperchloremic
DIURETICS Competitive antagonist action of k sparing excess Metabolic acidosis
Direct inhibition to effects of diuretics Primary: Conns - Hyperkalemia
Spironolactone - Onset and duration of aldosterone @ Syndrome - Gynecomastia
(synthetic steroids) action is determined by a) Mineralocorticoid Risk of hyperkalemia Secondary: - Acute renal failure
the kinetics of receptor when used with: Conditions associated - Kidney stones
aldosterone response in b) Na channel - -blockers with diminished (triamterene)
the target tissue (ENaC) - aliskiren intravascular volume
- Inactivation: Liver - NSAIDs
- Slow onset K exit is coupled with Na - ACEIs
entry so it is spared. - ARBs
Eplerenone - Spironolactone analog - Or when used solely - Eplerenone
(Synthetic steroids) - Greater selectivity for Dependent on renal Diabetic patients:
mineralocorticoid prostaglandin Acute renal failure reduce progression of
receptor production. triamterene and albuminuria
- 100x LESS ACTIVE in indomethacin Myocardial infarction:
androgen and combination (as of now) reduced myocardial
progesterone receptors perfusion defects
- Few adverse effect Oral K administration ( Reduced mortality
Inhibitors of Na influx from failure
Triamterene - Metabolized in the liver
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Classification Pharmacokinetic Pharmacodynamic Important drug Clinical uses Adverse effects
- Drugs interactions
- RENAL: Major route of
elimination
- Shorter half-life
- Given more frequently
compared with
Amiloride amiloride
AGENTS THAT ALTER - Effects is on PCT and - Increase in urine - Extracellular volume
WATER EXCRETION descending limb of volume expansion
Osmotic diuretics loop of Henle - Reduction of - Dehydration
Prototype: - Indirectly oppose intracranial and - Hyperkalemia
Mannitol - poorly absorbed in the action of ADH in the intraocular pressure - Hypernatremia
GI tract collecting tubule
OSMOTIC DIURETICS - oral: osmotic diarrhea - Principle:
alter STARLING - parenteral: not nonreabsorbable
FORCES metabolized; excreted solute (tubular lumen)
by glomerular filtration
(30-60 min); no impt water reabsorption
absorption or secretion
urine volume
urine flow
contact time
Na and water
reabsorption
Water loss >
Natriuresis
Hypernatremia and
water depletion
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Antidiuretic hormone agonist (1)
Vassopressin Drug Total daily oral Frequency of
Desmopressin dose administration
Renal action is mediated primarily via V2 Bendroflumethiazide 2.5 10 mg Single dose
receptors although V1a receptors may also be Chlorothiazide 0.5 2 g 2 divided doses
involved Chlorthalidone 25 50 mg Single dose
Diabetes insipidus Hydrochlorothiazide 25 100 mg Single dose
Hydroflumethiazide 12.5 5 mg 2 divided doses
Antidiuretic hormone antagonist Idapamide 2.5 10 mg Single dose
(-) ADH in the CCT Methychlothiazide 2.5 10 mg Single dose
1/2
Conivaptan and Demeclocyclin - T = 5-10 hours; (-) V2 Metolazone* 2.5 10 mg Single dose
receptors and V1a receptors Polythiazide 1 4 mg Single dose
Quinethazone 25 100 mg Single dose
Demeclocyclin and Lithium (-) cAMP formation
Trichlormethiazide 1 4 mg Single dose
Lixivaptan and Tolvaptan - (-) selective V2 receptor * Metolazone thiazide-like drug usually used in
antagonist patients refractory to loop agents alone
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