Diuretics Flashcards
CA inhibitors
Acetazolamide
Brinzolamide (topical opthalmic)
Dorxolamide (topical opthalmic)
Methazolamide
Loop diuretics
Ethacrynic acid
Furosemide (Lasiz)
Bumetanide
Torsemide
Thiazide diuretics
Hydocholorthiazide -thiazide chlorothalidone indapamide metolazone
K sparring
mineralcorticoid (aldosterone) antagonists
spironolactone (adactone)
eplerenone
K sparring
inhibitors of renal NaCh
Amiloride
triamterene
osmotic diuretics
mannitol
isoorbide
hormone antagonists
conivaptan
tolvaptan
PCT fnx
resorption of
65% Na/K/Ca/Mg
85% NaHCO3
100% glucose, aa
PCT drugs and their targets
CA inhibitors
CA
DCT fnx
secretion and reabsoprtion of organic acids, bases, including uric acid and most diuretics
DCT drug targets
none
PCT transporters
Na/H exchanger (NHE3)
DCT transporters
acid and base transporters
tDL fnx
passive reabsorption of water
tDL transporters
aquaporins
tDL drugs/targets
none
TAL fnx
active reabsorption of
15-25% Na/K/Cl
secondary reabsoption of Ca and Mg
TAL transporters
Na/K/Cl cotransporter (NKCC2)
TAL drugs and their targets
Loop diuretics
Na/K/Cl cotransporter
DCT fnx
active reabsorption of
4-8% Na, Cl
Ca under PTH control
DCT transporters
Na/Cl cotransporter (NCC)
DCT drugs and their targets
Thiazides
NCC
CCT fnx
Na resorption coupled to K and H excretion
CCT transporters
ENaC
KCh
H transporters
aquaporins
CCT drugs
K sparring diuretics
MCT fnx
water reabsorption under vassopressin control
MCT transporters
aquaporins
MCT drugs
vassopressin antagonists
CA inhibitor prototype
Acetazolamide
Acetazolamide pharmacokinetics
well absorbed orally
excretion of drug is by secretion thru PCT (dosing must be adjusted for renal failure)
excreted druge is unchanged
Acetazolamide MOA
inhibit membrane bound and cytoplasmic CA -> abolition of NaHCO3 reabsorption in PCT -> decreased H in cells -> decreased NHE3 -> increased Na and HCO3 in lumen -> diuresis
Acetazolamide and pH
urine pH increased and body pH decreased
Acetazolamide and tolerance
w/in a few days become tollerant
Acetazolamide toxicity
metabolic acidosis and bicarbonaturia
renal stones due to increased Na in CCT which increased K secretion
drowsiness and paresthesias
rare hypersensitivity reactions
Acetazolamide contraindications
cirrhosis -> hyperammonia and hepatic encephalopathy
hypercholremic acidosis or COPD
Acetazolamide clinical indications
diuretics- rarely used
glaucoma- most indicated use, reduces aqueous humor and decreases pressure, topical
urinary alkalization- excretion of uric acid or cystine, metabolic acidosis, acute mountain sickness, adjuvants in epilepsy
loop diurectic prototypes
furosemide and ethacrynic acid
loop diuretics pharmacokinetics
- rapidly absobed PO
- IV also utilized
- eliminated by kidney via glomerular filtration and tubular secretion
- act on luminal side after secretion so activity correlates w/kidney fnx
- coadministration w/other weak acids (NSAIDs) may result in reduced loop diuretic secretion
loop diuretic MOA
inhibit NKCC2 in TAL -> no NA, CL, K, transport -> no lumen postive charge -> no Mg Ca transport -> increased delivery of Na and H to DCT and CCT -> increased excretion of K -> induce PG synth -> increase RPF
Loop diuretic toxcicty
-depletion of total body Na -> hyponatremia, reduced GFR, circulatory collapse, thrombohemolytic episodes, and hepatic encephalopathy in liver disease patients
-hypokalemic metabolic alkalosis
- hyperuricemia -> gout
dose-related hearing loss
-hypomagnesemia
allergic reactions
-dehydration
loop diuretics contraindications
- fuosemide, bumetanide, and torsemide and sulfonamides
- deleterious to hepatic cirrhosis, borderline renal failure, or heart failure
- avoid in postmenopausal osteopenic women due to hypocalcemic effects
loop diuretic drug interactions
aminoglycosides (enhanced ototoxicity)
lithium (decrease or increase serum levels of lithium)
digoxin (increased toxicity due to electrolyte disturbances
loop diuretics clinical indications
among most efficacious diuretics acute pulmonary edema hypertension and heart failure mild hyperkalemia acute renal failure anion overdose (bromide, fluorise, iodide) hypercalcemic states
thiazide diuretics prototype
hydocholorothiazide
thiazide diuretics pharmacokinetics
PO
not lipid soluble, so large dose
chlorthalidone longest acting t1/2=47hours
secreted by PCT
thiazide diuretics MOA
inhibits NCC ->inhibits NaCl reabsoption -> enhanced Ca reabsorption in PCT and DCT
rarely causes hypocalcemia, but can maskhypercalcemia
thiazide diuretics toxicity
- Hypokalemic metabolic alkalosis and hyperuricemia
- impaired carbohydrate tolerance -> hyperglycemia -> unmask latent diabeties
- hyperlipidemia: increased total serum cholesterol and LDL, may normalize w/time (indapamide does not have this effect)
- hyponatremia due to hypovolemia induced ADH
- weakness, fatigue, paresthesias, impotence
- sulfonamide hypersensitivity
thiazide contraindications
diabetics
efficacy may be reduced when combined w/NSAIDs
excessive use dangerous in hepatic cirrhosis, borderline renal failure, heart failure
thiazide clinical indications
HTN and heart failure
nephrolithiasis due to idiopathic hypercalciuria
DI
thiazide w/DI
inhibits Na/Cl transporter in DCT -> increase diuresis -> reduce ECF -> less volume filtered at glomerulus and decreased GFR -> increase PCT Na and water reabsorption -> less Na and water delivery to CDs and decrease urine output
K sparring diuretics MR antagonist prototype
spironolactone
K sparring diuretic NaCh inhibitor prototype
amiloride
Pharmacokinetics spironolactone and eplerenone
PO
inactivation in liver and several days needed before effect is seen
eplerenone
spirnolactone analog w/greater sensitivity for MR
amiloride and triamterene
PO
triamterene is metablized extensivly in liver and has shorter half life then amiloride
spirnolactone and eplernone MOA
Synthetic steroids act as competitive inhibiotrs of aldosterone binding MR -> reduce Na reabsorption in CCT -> reduce K secretion
only diuretic that does not need access to tubular lumen to work
MR
nuclear hormone receptor
regulated expression of ENaC and Na/K ATPase pumps in DCT and CCT
amiloride and triamterene MOA
directly inhibit Na entry by blocking ENaC in CCT
therefore reduce K secretion
K sparring toxicity
mild, moderate, or even life threatening hyperkalemia (higher risk w/renal disease, B-blockers, NSAIDs, ACEIs, ARBs)
metabolic acidosis due to reduced H secretion
gynecomastia, impotence, BPH
triamterene precipitates -> stones
Triamterene drug interactions
indomethacin -> acute renal failure
K sparring contraindications
chronic renal insufficiency
concomitant use of K sparring diuretics w/beta blockers, NSAIDS, ACEIs, or ARBs
patients w/liver disease
strong inhibitors of CUP3A4 and can increase eplerenone
K sparring indications
states of mineralcorticoid excess or hyperaldosteronism
thiazides and loop diuretics can cause hyperaldosteronism, which increases K wasting so can be combined w/K sparring
MR antagonists are used to treat heart failure
Osmotic agents prototype
mannitol
mannitol pharmacokinetics
poorly absorbed and must be given parenterally
not metabolized, excreted in glomerular filter w/in 30-60min
mannitol MOA
increases osmotic pressure pulling water into PCT and descending limb
oppose ADH effects in CCT
increase in water diuresis increased flow rate also reduces Na reabsorption
natriuresis < diuresis therefore leads to hypernatremia
mannitol toxcicity
prior to diuresis -> ECF expansion and hyponatremia
dehydation, hyperkalemia, hypernatremia
mannitol contraindications
severe renal disease, severe dehydration, severe pulmonary edema or congestion
mannitol clinical indications
promoting urinary excretion of toxic substances
reduction of intracranial and intraoccular pressure
use for prevention of acute renal failure/promote diuresis not recommended
antidiuretic hormone agonists
- increased water reabsorption
- vasopressin and desmopressin mediate vasoconstriction of vascular smooth m and increase water permeability and reabsorption in CCT
antidiuretic hormone agonists indications
-treatment of choice for cDI, polyuria, polydipsia, hypernatremia, nocturnal enuresis
antidiuretic hormone antagonists
Conicaptan and tolvaptan ADHR antagonists
- Conivaptan parenteral t1/2 5-10hrs
- tolbaptan PO
- MOA: conicaptan V1a and V2 in CCT, tolvaptan selective for V2
- variety of medical conditions cause water retention as result of ADH excess -> hyponatremia
- Toxicity: can cause hypernatremia, nDI
loop agents + thiazides
if patients fail or become refractory to usual dose of loop
effective bc:
-salt and water reabsorption in TAL (blocked by loop) or DCT (blocked by thiazides) leads to overactivity of the other, therefore combining them has a more then additive affect
-thiazides often produce mild naturesis in PCT that is usually masked by increased absorption in TAL, but blocked by loop
-metolazone (thiazide) is popular choice for combo
NOT recommended for outpatient b/c secer hypokalemia common
K sparring w/loop or thiazides
- hypokalemia common side effect of loop agents and thiazide
- if hypokalemia unmanagable via diet and supplementation can be combined w/K sparring diuretic
- generally safe, but avoided in patients w/renal insufficiency and those receiving angiotensin antagonisits
edematous states treated w/diuretics
heart failure
kidney disease
hepatic cirrhosis
heart failure
reduces CO -> decreased BP and blood flow to kidney -> sensed as hypvolemia -> RAAS -> retention of salt and water -> pulmonary interstitial edema occurs when plasma volume increases and kidney continues to retain salt and water
kidney disease
- renal diseases usually cause water and Na retention
- insufficient GFR to sustain natriuretic response and diuretics are of little benefit
- patients w/mild cases of renal disease may benefit
- diuretics are beneficial in glomerular disease such as SLE or SM
- loop and thiazide diuretics are beneficial w/hyperkalemia in early stage renal disease
hepatic cirrhosis
- diuretics are useful with edema and ascites
- aggressive use of diuretics can be disastrous in patients w/liver disease
edematous states that are treated w/diuretics
HTN
Nephrolithiasis
hypercalcemia
DI
HTN
thiazides are often used b/c of their mild diuretic and mild vasodilator activity
loop often reserved for patients w/mild renal insufficiency or heart failure
diuretics are often used in combo w/vasodilators b/c vasodilators cause significant salt and water retention
nephrolithiasis
2/3 of kidney stones contain Ca phosphate or Ca oxalate
thiazides enhance Ca reabsorption in DCT and reduce urinary Ca
hypercalcemia
loops reduce Ca reabsoption and promote Ca excretion, can cause marked volume contraction when used alone
saline can be administered simultaneously
DI
thiazides can reduce polyuria and polydipsia in both types of DI
