Renal I-III Flashcards
single nephron glomerular filtration rate
K(change in pressure - pi)
k = ultrafiltration coefficient
pi is difference in osmotic pressure
proximal tubule
-What absorbed?
65% H20; most K; 65% Na+, 65% bicarb
urine here is iso-osmotic w blood
organic acids and bases are secreted actively into urine, esp highly PRO bound small molecules–2nd point of entry. Imp for renal elim of drugs
-driving force is the Na/K ATPase in basolateral surface of membranes
loop of Henle
-What is absorbed?
H20 25%; no NaCl, no urea = thin descending limb
no H20, no urea, NaCl out = ascending limb
vasa recta
descending absorbs NaCl from ascending loop of Henle
ascending absorbs H20 from descending loop of Henle
macula
-specialized epithelial cells at the distal end of the ascending thick limb
-sense osmolality of urine
-if NaCl is too high, sends signal to afferent arteriole to reduce BF, drops GFR (tubuloglomerular feedback)
Na diuresis is self-limiting due to TGF
distal convoluted tubule
actively transports out NaCl but not H20
fluid here is hypotonic urine, even when dehydrated
collecting tubules
H20 out only if ADH present, highly dependent on NaCl concentration in medulla.
-urea out of distal collecting duct only, adds to medullary salt gradient
diuretic
increases solute excretion to increase volume of urine
aquaretic
increases excretion of h20 but not of solutes (dilute urine)
natriuretic
inc. excretion of Na and CL ions
saluretic
increases excretion of Na and Cl iones
Kaliurietic
incr excretion of potassium
acetazolamide
- carbonic anhydrase inhibitor
- acts on CA in lumen and cells of prox tubule (distal collecting duct is a secondary site of ax where acid secretion in inhibited)
- proximal tubule is the major site of bicarb reabsorption and acidification (net result: drives sodium bicarb out of urine, inhibitors leave na bicarb in urine)
- luminal pH increases, less H+ delivery to lumen.
- sulfanilamide drug
- K wasting due to high Na delivery to distal nephron
acetazolamide effects on excretion: Na K H Ca/Mg Cl HCO3 H2P04
Na: inc (5%) K: incr x 2 H+: decrease Ca/Mg no effect Cl: NA HCo3/h2po4: increased x 2
any mechanism that increases ______ to distal tubules increases K excretion
Na delivery
indications for rx with acetazolamide
CA inhibitor
- open angle glaucomea
- pre surg relief of glaucoma pressure
- altitude sickness relieved temporarily by lower Co2 in blood/brain and metabolic acidosis
- counteracting diuretic induced metabolic alkalosis (low eff as a single agent diuretic)
adverse reactions to acetazolamide
CA inhibitor
- allergies (sulta drugs)
- metabolic acidosis
- diversion of renal ammonia into cirulation that can worsen hepatic encephalopathy (d/t alkaline urine, ammonia not secreted)
- kidney stones from alkaline urine
- BM depression, paresthesias, tingling
gylerin action
- act on tissues by drawing water into blood
- act on kidney by inc renal BF (by decreasing viscosity, inc rate passing through glomerulus) and washing out medullary salt gradient
- primary site of action in loop of henle
- secondary site is prox convoluted tubule where water efflux is inhibited by osmotic gradient
- K wasting diurectics
osmotic diuretic effect on: Na K Ca Mg H Cl HC03 h2p04 uric acid
glycerin effect on: Na incr x 2 K increased Ca inc Mg inc x 2 H NA Cl inc HC03 inc h2p04 inc uric acid inc
mannitol action
- act on tissues by drawing water into blood
- act on kidney by inc renal BF (by decreasing viscosity, inc rate passing through glomerulus) and washing out medullary salt gradient
- primary site of action in loop of henle
- secondary site is prox convoluted tubule where water efflux is inhibited by osmotic gradient
- K wasting diurectics
indications for osmotic diuretics
(mannitol, glycerin)
- ARF
- ATN
- dialysis disequilibrium syndrome resulting from too rapid removal of solutes during dialysis
- acute glaucoma to reduce IOP
- mannitol and urea are used pre-op and post op for neurosur to reduce brain swelling (contraindicated in bleed, will worsen swelling)
osmotic diuretics adverse reactions
glycerin, mannitol
- can convert pulmonary congestion to pulm edema
- hyponatremia
- hyponatremia and dehydration
- contraindicated in anuria, impaired liver fxn (can’t get rid of it)
- mannitol/urea contraindicated in active intracranial bleed
- glycerin is metabolized and could cause hyperglycemia
furosemide action
- inhibits Na/K/2Cl symporter in ascending loop of henle
- enters urine via organic ion transporters in proximal tubules (anything that interferes with process with inhibit efficacy)
- K wasting
- Na, Cl, K stay in the thick ascending limb tubule, h20 stays with ions, medullary ion gradient diminishes
- urine flow is increased and urine is more concentrated bc salts are not removed
- furosemide is also a weak CA inhibitor and sulfa moiety
- furosemide acutely incr systemic venous capacitance (relaxes vasculature)
- glucuronidated in kidney, not liver
- all are high ceiling diuretics
- block Na transport into macula, not limited by TGF
bumetanide action
- inhibits Na/K/2Cl symporter in ascending loop of henle
- enters urine via organic ion transporters in proximal tubules (anything that interferes with process with inhibit efficacy)
- K wasting
- Na, Cl, K stay in the thick ascending limb tubule, h20 stays with ions, medullary ion gradient diminishes
- urine flow is increased and urine is more concentrated bc salts are not removed
- all are high ceiling diuretics
- block Na transport into macula, not limited by TGF
- mostly renal excretion, rest is metabolized
ethacrynic acid action
- inhibits Na/K/2Cl symporter in ascending loop of henle
- enters urine via organic ion transporters in proximal tubules (anything that interferes with process with inhibit efficacy)
- K wasting
- Na, Cl, K stay in the thick ascending limb tubule, h20 stays with ions, medullary ion gradient diminishes
- urine flow is increased and urine is more concentrated bc salts are not removed
- all are high ceiling diuretics
- block Na transport into macula, not limited by TGF
- mostly renal excretion, rest is metabolized
torsemide action
- inhibits Na/K/2Cl symporter in ascending loop of henle
- enters urine via organic ion transporters in proximal tubules (anything that interferes with process with inhibit efficacy)
- K wasting
- Na, Cl, K stay in the thick ascending limb tubule, h20 stays with ions, medullary ion gradient diminishes
- urine flow is increased and urine is more concentrated bc salts are not removed
- all are high ceiling diuretics
- block Na transport into macula, not limited by TGF
- mostly metabolizes, small amt renal excretion
effect of loop diuretics on: Na K H Ca/Mg Cl bicarb phos uric acid
torsemide, furosemide, bumetanide, ethacrynic acid na inc x 2 K inc x 2 H inc ca/mg inc x 2 cl inc x 2 bicarb inc phos inc uric increased acutely, decreased chronic d/t decr circulating volume
indications for loop diuretics
- tosemide, furosemide, bumatanide, ethacrynic acid
- acute pulm edema
- CHF
- HTN (thiazides preferred)
- nephrotic syndrome
- edema and ascites of cirrhosis (may induce hepatorenal syndrome)
- CRF
loop diuretics adverse effects
furosemide, torsemide, bumetanide, ethacrynic acid
-few unrelated
to diuretic activity
-hyponatremia
-hypokalemia (arrhythmias)
-volume depletion (contraindicated with hypovolemia)
-ADH will not work
-metabolic alkalosis
-hyperuricemia (bad for gouty types)
-ototoxicity d/t inhibitiion of same symporter in the inner ear
-contraindicated with sulfonamide sensitivity
-NSAIDs reduce diuretic response
-probenecid may increase effective dose (blocks ion channels)
-interacts with anticoags, propanolol, lithium, sulonylurea, cisplatin, amphotericin B
hydrochlorothiazide action
-sulfonamide analog but not CA inhib
-blocks Na/Cl symport but not K
-enter urine via organic ion transporters in porximal tubules, like loop diuretics-act on distal convoluted tubule-commonly used
-potassium wasting
-different transporter than loop diuretics, but energy is still from basolateral NaK antiporter
shorter 1/2 life, better for acute diuresis
chlorothiazide action
-sulfonamide analog but not CA inhib
-blocks Na/Cl symport but not K
-enter urine via organic ion transporters in porximal tubules, like loop diuretics-act on distal convoluted tubule-commonly used
-potassium wasting
-different transporter than loop diuretics, but energy is still from basolateral NaK antiporter
-only moderately efficacious bc 90% of na already absorbed before DCT
-but, acti distal to the macula, so not limited by TGF
-secondary effect of some thiazides on CA
-inc Ca with chornic use
-medullary salt conc not affected so h20 retention during dehydration is preserved
shorter 1/2 life, better for acute diuresis
metolazone action
- sulfonamide analog but not CA inhib; thiazide LIKE diuretic
- blocks Na/Cl symport but not K
- enter urine via organic ion transporters in porximal tubules, like loop diuretics-act on distal convoluted tubule-commonly used
- potassium wasting
- different transporter than loop diuretics, but energy is still from basolateral NaK antiporter
- only moderately efficacious bc 90% of na already absorbed before DCT
- but, acti distal to the macula, so not limited by TGF
- secondary effect of some thiazides on CA
- inc Ca with chornic use
- medullary salt conc not affected so h20 retention during dehydration is preserved
- longer 1/2 life, good for HTN
thiazide effects of: Na K H Ca Mg Cl bicarb phos uric acid
metolaxone, chlorothiazide, hydrochlorothiazide
Na inc
K incr x 2
H inc
Ca dec
mag inc
cl inc
bicarb inc (bc of weak ca inihib, doesn’t inhib H elimination)
phos inc
uric acid inc acutely, decreased chronically
indications for thiazide diuretics
HTN bc do not risk hypovolemia
- edema from CHF
- daily dosing
- considering safe although there is a small risk of sudden death and renal ca
- bc ca reabsorption in increased, these can be used to treat calcium nephrolithiasis and aid in rx of osteoporosis
- treats nephrogenic DI, reducing urine volume 50%. unknown mech
adverse effects of thiazide diuretics
chlorothiazide, hydrochlorothiazide, metolazone
- hypotension, hypokalemia, hyponatremia, metabolic alkalosis
- corticosteroids and amphotericin B inc risk of hypokalemia and arrhythmias
- hypercalcemia, hyperuricemia
- contraindicated with sulfa allergy
- NSAID reduce diuresis
- probenecid may increase effective dose
- may decrease glucose tolerace and unmask latent diabetes
- rare CNS and GI effects, erectile dysfxn
amiloride
in the late distal tubule, Na channel depolarizes the luminal membrane but not he basolateral membrane, thus driving K secretion, blocking Na channel drops K secretion, inhibits proton secretion by raising intra luminal positive potential
- block uptake of lithium by na channels in collecting duc
- used for lithium induced DI (reverse lithium OD)
triamterene
in the late distal tubule, Na channel depolarizes the luminal membrane but not he basolateral membrane, thus driving K secretion, blocking Na channel drops K secretion, inhibits proton secretion by raising intra luminal positive potential
inhibitors of renal Na channels effects on excretion Na K H Ca Mg Cl
amiloride (renal excretion) triamterene (metabolized) Na inc K dec ca dec (chronic) mg dec (chronic) Cl inc
indications for renal na Channel inhibitors
amiloride, triamterene
-only slighly increased na excretion as most na is reabsorbed proximally
strongly increases K reabsorbtion, can result in hyperkalemia
-typically co admin w thiazide or loop diuretics to enhance effects and reduce K loss
-rx for liddle’s syndrom (genetic d/o w stabilization of Na channel)
-%5 AA have a polymorphism in the ENaC beta subunit (target for drug), makes them potent for reducing HTN in this group
-used as aerosol in cystic fibrosis to clear mucous
adverse reactions of renal Na inhibitors
amiloride, triamterene
-hyperkalemia (arrhythmias/death)
-will interact with other potassium sparing diuretics (spironolactone), ACE inhib, NSAIDs, K dietary supplements
-AIDS patients with pneumocystis carinii rx w pantamidine and trimethoprim wich are also ENaC inhib will get hyperkalemia
-triamterene is a folate antagonist and may lead to megaloblastic anemia in cirrhosis
-some diffuse CNS, GI, derm, hematological effects
NSAIDS may decrease efficiency
spironolactone action
competitiely binds mineralocorticoid receptor, blocks fxn
-mineralocorticoids are secreted by the adrenal glands and cuase retention of salt/water, while increasing excretion of K and protons
sites of activity are mineralocorticoid receptors in the distal convoluted tubule and collecting duct
eplerenone action
competitiely binds mineralocorticoid receptor, blocks fxn
-mineralocorticoids are secreted by the adrenal glands and cuase retention of salt/water, while increasing excretion of K and protons
sites of activity are mineralocorticoid receptors in the distal convoluted tubule and collecting duct
action of aldosterone
acts in the nucleus to change DNA expression of aldosterone induced proteins, which activate previously silent Na channels and pumps, promoting increased Na and water reabsorption
- induced in response to dehydration
- Na channels increase rep on membrane, Na/K atpase increases in activity
effects of mileralocoritcoid antagonists on secretion: Na K H Ca Mg Cl
eplerenone, spironolactone na inc k dec H decrease ca dec mg dec cl inc
mineralocorticoid antagonists indications
eplerenone, spironolactone
- coadmin w thiazides or loops diuretics for K sparing action
- spironolactone used to rx primary hyperaldosteronism in adrenal adeomas/hyperplasia
- spironolactone used w secondary hyperaldosteronism from cardiac failure, cirrhosis, nephrotic syndrome, severe ascities
- spironolactone is rx o choice for ascites and edema assoc w cirrosis (primarily driven by inc in aldosterone)
adverse effects of mineralocorticoid antagonists
eplerenone, spironolactone
kyperkalemia
NSAIDs may decrease diuretic efficiency
cross rxn w other steroid receptors (antiandrogen = feminization, antiprogesterone = menstrual irreg)
diarrhea, gastritis, gastric bleeding, contraindicated with peptic ulcers
CNS symp and rash
eplerenone clearance rate sig decreased by inhibitors of CYP3A4
possible malignancies from spironolactone chronic use
vasopressin
antidiuretic morphone
-binds V1/V2 receptors, increases H20 reabsorption from collecting ducts via aquaporins
desmopressin action, indication
synthetic analog of vasopressin
little V1 activity, primary effeccts via V2 receptors
indication: DI (not nephrogenic DI)
V1 effects
in vasculature
-reduce medullary BF, thus increasing medullary salt gradient and reabsorption of h20
v2 effects
stimulate water reab in distal tubule and collecting duct by stimulating production of aquaporins in epithelim, more aquaporins in apical membrane due to increased recycling
- more perm of distal duct to urea
- incr activity of Na/K/2Cl symporter in thick ascending limb
adverse effects of desmopressin
coronary artery constriction, water intox
chlorpropamide action
sulfonylurea previously used for DM II. increase adh section
gout
painful inflammatory response to the presence of urate crystal in tissues and joints, precipitated by hyperuricemia
allopurinol
inhibits xanthine oxidase (converts xanthine to uric acid)
colchicine
reduces neutrophil activity (not understood by works for gout)
probenecid
uricosuric agent, increases renal excretion of uric acid
- biphasic effect: 1) causes decreased excretion of UA by blocking acid transport into the tubular lumen (proximal tubule)
2) once in the lumen, urance reabsoprtion is inhibited, resulting in increaed urate excretion
adverse effects of probenecid
well tolerated
increased risk for renal stones
interferes with renal excretion of many drugs
interfere with diuretics (loop/thiazide) by preventing transport into the tubular lumen
