Diuretics Flashcards
where are beta1 receptors located?
the heart and kidney
what do stimulated beta1 receptors lead to?
in heart: increased HR, increased contractility, and increased SV leading to increased CO
in kidneys: increase renin release
where are alpha1 receptors located?
blood vessels
what do stimulated alpha1 receptors lead to?
increased vasoconstriction, and increased peripheral resistance
equation for cardiac output
HR X SV
what does increased renin release imply?
increased conversion of angiotensinogen to angiotensin I
how is angiotensin I converted to angiotensin II?
ACE
how does angiotensin II impact the adrenal cortex?
increases aldosterone release
how does angiotensin II impact the posterior pituitary?
increases vasopressin or antidiuretic hormone
function of aldosterone
act on late distal tubule and collecting duct, directly impacts Na absorption and K excretion
what does increased Na channels and Na-K ATPase in the nephron imply?
increased passive diffusion of na into na channels on the luminal side (into the blood vessels), increased active transport of na into blood and K into cell via basolateral na-k atpase
NET EFFECT: sodium absorption into blood cells from lumen of nephron
function of vasopressin (ADH)?
act on V2 receptors of distal or collecting tubules, and generates aquaporin-2 (and encourages aquaporin-2 migration to luminal membrane of tubule cells), water then reabsorbed from urine to the blood stream.
end product of ADH?
water resorption, concentration of urine, reduces urine volume, increases blood volume
overall impact of aldosterone and ADH increase?
increased Na and H2O retention = increased blood pressure
site of action of carbonic anhydrase inhibitors?
proximal convoluted tubule
example of carbonic anhydrase inhibitor?
acetazolamide
site of action of osmotic diuretics?
thin descending limb, PCT, collecting duct (places where water is permeable)
class of mannitol?
osmotic diuretic
class of urea?
osmotic diuretic
class of glycerin?
osmotic diuretic
class of furosemide?
loop diuretic
class of bumetanide?
loop diuretic
class of torsemide?
loop diuretic
class of ethacrynic acid?
loop diuretic
site of action of loop diuretics?
thick ascending limb
class of metolazone?
thiazide
class of indapamide?
thiazide
site of action of thiazides?
distal convoluted tubule
class of triamterene
potassium sparing diuretic
class of eplerenone
potassium sparing diuretic
class of canrenone
potassium sparing diuretic
class of spironolactone
potassium sparing diuretic
class of amiloride
potassium sparing diuretic
site of action of potassium sparing diuretics
collecting ducts
class of demeclocycline
vasopressin antagonist
class of vaptans
vasopressin antagonist
site of action of vasopressin antagonists?
collecting ducts
what do most diuretics block in the renal tubules?
transporters on the luminal membrane of tubular cells
how do most diuretics reach the site of action?
secretion by the organic acid secretory system in the proximal convoluted tubule
do diuretics ever block na-k-ATPase?
NO
4 biological actions of most diuretics?
increased urine volume and flow, decreased na reabsorption (increased na in urine), decreased water reabsorption indirectly (increased water concentration in urine), changing urine and plasma concentration of ions
5 major ions affected by diuretics?
sodium, chloride, potassium, calcium, magnesium
what are diuretics majorly used to treat?
htn, heart failure
where is the organic acid secretory system located?
proximal convoluted tubule
reabsorption in the proximal convoluted tubule?
most reabsorption of na, k, and ions and water; nearly all glucose, AA; sodium bicarb
organic acid secretory system
secretes uric acid, antibiotics, and para-aminohippuric acid into lumen
reabsorption in thin descending tubule?
water (permeable) (urine increases in concentration), NO SALT
reabsorption in thick ascending tubule?
Na, Ca, Mg reabsorption, water impermeable (urine concentration decreased - losing ions but no water)
urine concentration in thin descending tubule?
increased concentration
urine concentration in thick ascending tubule?
decreased concentration
reabsorption in distal convoluted tubule?
Na and Ca, water impermeable
where in the nephron is water impermeable?
thick ascending tubule, distal convoluted tubule
where in the nephron is water permeable
PCT, thin descending, collecting duct
collecting duct reabsorption
Na, water if ADH and aldosterone
site of action of aldosterone and ADH
collecting ducts
where is Na NOT resabsorbed?
thin limb of loop of henle
what is the passive step of Na reabsorption?
passive movement of na from lumen into tubular cell mediated by transporter mechanisms
what is the active step of na resorption?
movement of na from the tubular cell through the ECF to the blood, mediated by Na/K ATPase in basolateral membrane
where is the basolateral membrane?
between the tubular cell and the interstitial fluid (extracellular fluid)
% of Na reabsorption in PCT?
67%
passive step of Na reabsorption in PCT?
Na/H exchanger
active step of Na reabsorption in PCT, thick ascending, DCT and collecting duct?
Na/K ATPase
Na reabsorption in thin descending limb?
NONE
%Na reabsorption in thick ascending limb?
25%
passive step of Na reabsorption in thick ascending limb?
Na/K/2Cl transporter
% Na reabsorption in DCT?
6%
passive step of na reabsorption in DCT?
NaCl transporter
% na reabsorption collecting tubule?
2%
passive step of na reabsorption in collecting tubule?
na ion channels
which step do diuretics block for Na reabsorption?
passive steps (Na/K/2Cl, NaCl transporters and Na ion channels)
2 routes that diuretics reach site of actions?
blood to site, tubular fluid to site
which is the only diuretic that utilizes blood transport?
aldosterone antagonists (spironolactone)
how do most diuretics travel from the tubular fluid to the site of action?
drug binds to OASS and is transported from the blood directly into the tubular lumen in the PCT
how do aldosterone antagonists (spironolactone) reach the site of action?
directly from blood to site
how do osmotic diuretics reach the site of action?
filtration of the substance at the glomerulus
what large or extensively bound molecules are transferred from the blood to the renal tubules through the OASS?
diuretics, penicillin, uric acid, NSAIDs
what is the effect of diuretics with frequent gout attacks?
diuretics compete with endogenous substances for transfer into tubular fluid and can lead to decreased uric acid secretion and increased uric acid concentrations in blood (increased uric acid in plasma, buildup of uric acid)
most potent loop diuretic
bumetanide
2 most notable characteristics of loop diuretics?
- most powerful diuretic that produce lots of urine (highest efficacy in producing na and water loss)
- very rapid onset of action
benefit of very rapid onset of action of loop diuretics?
can be used in emergency situations (edema from heart failure)
loop diuretic access to site of action?
to the tubular fluid via OASS in the PCT
nephron site of action of loop diuretic?
thick ascending limb
transporter site of action loop diuretics
Na/K/2Cl transporter on the luminal membrane of thick ascending limb
which ions can move directly from lumen to blood?
calcium and magnesium
5 major physiological events in thick ascending limb?
- increased Na reabsorption
- increased Cl reabsorption
- increased water reabsorption
- increased Ca reabsorption
- increased Mg reabsorption
explain K accumulation in the thick ascending limb CELL
Na/K/2Cl transporter increases the [K], Na-K ATPase increases [K] in cell, which then causes the concentration gradient to move back into the lumen. this buildup of +charge drives Ca and Mg out of the lumen and into the blood.
what is the major reason for Ca and Mg reabsorption at the thick ascending limb?
the buildup of + charge from K secretion into the lumen driving out the Ca and Mg
6 pharmacological effects of loop diuretics on thick ascending limb
- decreased na reabsorption (directly)
- decreased cl reabsorption (directly)
- decreased water reabsorption
- decreased Ca reabsorption (indirectly)
- decreased Mg (indirectly)
reabsorption - decreased K reabsorption (directly)(abolishes K back diffusion into the lumen, prevents + charge buildup in luminal side, removes driving force for Ca and Mg reabsorption)
pharmacology of loop diuretics on thick ascending limb
blocks Na/K/2Cl transporter
considerations for loop diuretics?
hypocalcemia, hypokalemia
drug interaction of loop diuretics?
NSAID decreases overall efficacy of diuretic, risk of kidney failure
why are NSAIDs and loop diuretics contraindicated?
NSAID blocks renal prostaglandins (PGE2), which contribute to the diuretic effects of loop diuretics
loop diuretic impact on prostaglandins?
loop diuretics increase PGE2, which decreases na and water reabsorption, decreasing blood volume and blood pressure
what adverse side effect can the loop diuretic action of decreasing K reabsorption have?
decreased K plasma concentration, increasing risk of hypokalemia
what adverse side effect can the loop diuretic action of decreasing Na and H2O reabsorption have?
decreases blood volume, therefore decreasing blood pressure, increasing risk of hypovalemia (orthostatic hypotension and lightheaded)and hyponatremia
what adverse side effect can the loop diuretic action of increasing uric acid reabsorption have?
increased plasma uric acid concentration, increases risk for hyperuricemia and gout
chlorthiazide classq
thiazide diuretic
HCTZ class
thiazide diuretic
chlorthalidone class
thiazide-like diuretic
metolazone class
thiazide like diuretic
indapamide class
thiazide like diuretic
onset of action speed?
slower than loop diuretics
which class is the most effective diuretic in lowering BP and is the first line HTN tx?
thiazide and thiazide-like diuretics
thiazide/TLD nephron side of action?
distal convoluted tubule
transporter targeted by thiazides?
NaCl transporter on luminal membrane of DCT
how do thiazides/TLD access the DCT?
tubular fluid via organic acid secretory system (OSS in the PCT)
4 major physiological events in the distal tubule?
- increased Na reabsorption
- increased Cl reabsorption
- increased water reabsorption (direct and indirect)
- increased Ca reabsorption
where does Ca reabsorption occur in the distal convoluted tubule?
Na/Ca exchanger, driven by energy derived from the steep Na gradient (high Na outside the cell makes high Ca outside the cell, optimizing reabsorption)
Thiazide diuretics and NaCl transporter relationship??
thiazide blocks NaCl channel, decreasing Na and Cl reabsorption directly, decreasing intracellular Na directly
thiazide NaCl transporter effect on Ca?
increases Ca reabsorption indirectly via reduction in intracellular Na (blocked NaCl) d/t increased movement of Na from blood to cell at the Na/Ca exchanger which equals more energy input to Ca transport )increase rate of Ca movement from cell into blood) = rise in blood Ca levels
Thiazide/TLD effect on arterioles?
work directly on smooth muscle cells, promote smooth muscle relaxation, most responsible for long term reduction in blood pressure
physiologic response to smooth muscle relaxation in the arterioles?
vasodilation, decreased peripheral resistance, decreased blood pressure
where is thiazide/TLD active?
orally
onset of action of thiazides?
1-3 weeks before stable BP reduction
duration of action of thiazides?
long duration (d/t vasodilation mostly and volume reduction)
5 main effects of thiazides/TLD?
- decreased Na and H2O reabsorption
- relaxation of smooth muscle in arterioles
- decreased K reabsorption
- increased Ca reabsorption
- uric acid reabsorption
risk of decreased K reabsorption?
decreased plasma K concentration, leading to increased risk of hypokalemia
risk of increased Ca reabsorption?
increased plasma Ca concentration, increasing bone mineral density and decreasing risk of hip fractures
risk of uric acid reabsorption?
increased plasma uric acid concentration, leading to hyperuricemia and increased gout risk
risk of the combination decreased Na, H2O absorption and decreased peripheral resistance?
decreased BP that could lead to hypovolemia, orthostatic hypotension and light headedness, and hyponatremia
what makes potassium sparing diuretics special?
actually increases K reabsorption, not decreased
what are the two classes of potassium sparing diuretics?
- Na channel blockers
2. aldosterone antagonists
amiloride class
K sparing, na channel blocker
triamterene class
na channel blocker, Ksparing diuretic
spironolactone class
aldosterone antagonist ,K sparing
canrenone class
aldosterone antagonist, K sparing
eplerenone class
aldosterone antagonist, K sparing
K sparing diuretic site of action?
collecting ducts
aldosterone antagonist transporter site of action
block aldosterone receptors in cytoplasm of collecting duct cells
Na channel blocker transporter site of action?
block Na channels on luminal membrane of collecting duct
aldosterone antagonist access to site of action?
transported through the blood and then directly through the lipid membrane of collecting duct cells to cytoplasmic aldosterone receptor
na channel antagonist access to site of action?
tubular fluid via OASS in the PCT
3 major aldosterone effects?
- decreased K reabsorption
- increased Na reabsorption
- increased water reabsorption (decreased water output) (passive and indirect)
what 2 things (genetically) occur when aldosterone is released?
- binds to and activates cytoplasmic aldosterone receptor
2. aldosterone-receptor complex migrates to nucleus and binds to DNA
what does aldosterone-receptor complex binding to DNA cause? (3)
- increased Na channel expression
- increased Na channel activity
- increased K channel expression
