Diuretics - Bahouth Flashcards
What is the main idea of diuretics?
To mobilize sodium, leading to urination
What is Aquaporin-1 found? Aquaporin-2
In the PCT and the descending loop of henle
In the CD
What makes the interstitium hyperosmotic and how does this affect the collecting duct?
The TALH makes the interstitium hyperosmotic by secreting Na. This makes the CD want to reabsorb water.
What percent of Carbonic Anyhydrase is found in the PCT and what percent in the DCT?
90% and 10%
What is the mechanism of action of Carbonic Anhydrase Inhibitors?
Inhibit CA, resulting in HCO3 loss in the urine
What is the net effect of CAinh?
Alkaline urine, due to Na-Bicarb loss in the urine. Systemic acidosis because of the HCO3 loss. Enhance Cl reabsorption resulting in acidosis.
What are the clinical uses of CAinh?
Diuretics: limited use (1-2 days) Alkalinize urine Reduce intraocular pressure (in glaucoma surgery) Management of seizues (unk) Given prophylactically for mtn sickness
What is the only diuretic we need to know?
Acetazolamide (oral 500 mig BID)
What are the side effects of CAinh?
Metabolic Acidosis
Markedly increases K loss in the urine
Explain the normal pathway of HCO3 and H due to CA?
HC03 and H are in the lumen urine, where they combine to form H2C03. CA then acts to convert the acid to water and carbon dioxide, which can freely cross the membrane and reenter the cell. Once in the cell, CA turns C02 and H20 into carbonic acid again. This then turns to H and HC03, with the H excreted to bring in Na. The secreted H then goes to bind with bicarb in the urine.
What are the minor effects of osmotic diuretics? Where is this happening?
In the PCT, osmotically inh Na and H20 reabsorption
What are the characteristics of osmotic diuretics?
Small molecules that are filtered but not reabsorbed by the kidney
What is the major use of osmotic diuretics and where does this occur?
LOH
They increase osmolarity of plasma
Extract water from peripheral tissues and decrease blood viscosiy
increase medullary renal blood flow and reduce its tonicity
impair water reabsorption by thin descending loop of henle
impair nacl and urea extraction by thin ascending loop of henle
interfere with transport processes in the TALH
How do osmotic diuretics work?
They impair water reabsorption in the descending loop of henle and na reabsorption in the TALH. This increases the amount of h20 in the tubular system
What are the clinical uses of osmotic diuretics?
tx of dialysis disequilibrium syndrome
reduce intracranial pressure
reduce intraocular pressur
what is an example of osmotic diuretics?
mannitol
what are the side effects of osmotic diuretics?
volume overload (what does this mean...? how?) contraindicated in cardiac failure
What are the mechanisms of loop diuretics?
inhibit NaK2Cl symporter in TALH
inhibit the ability of the macula densa to sense NaCl
Stimulate biosynthesis of prostaglandins
increase total renal blood flow
maintain gfr
POTENTLY INCREASE RENIN RELEASE BY:
inh macula densa
reflexely activating the sympathetic NS
stimulating intrarenal baroreceptor mechanisms
What does the Macula Densa want to normally do? Why is it important that the loop diuretics inh the macula densa?
MD wants to shut afferent arteriole so that they can reabsorb more Na. So these drugs prevent MD from sensing NaCl, so it cannot close afferent arteriole. This leads to more urine.
What percentage of Na is reabsorbed in the TALH by the NaK2Cl?
25%
Why do we give loop diuretics
They give the maximum amount of response for a drug
What are the net effects of loop diuretics?
Most potent class of diuretics in mobilizing NaCl
Copious diuresis and significant NaCl loss
Increase urinary excretion of K/H
Increase excretion of Ca and Mg
Impair the ability of the kidney to concentrate urine
Of the three ions involved in the NaK2Cl , which is the driving force? Which is the one that is filtering into and out of the cell?
Na is the driving force (Na is being pumped into interstitium, lowering the cellular concentration so sodium wants to freely come through
K is cycling into and out of the cell and lumen
What are the therapeutic uses of loop diuretics?
Edema of cardiac, hepatic or renal origin (GFR <30)
Pulmonary Edema
Hypercalcemia to mobilize Ca
Protect against renal failure
Washout of toxins by increasing urine flow
Antihypertensive diuretics used with other drugs
What are the examples of loop diuretics?
Furosemide, Bumetanide, Torsemide,
What is important about the administration of furosemide?
Has to be taken in and then SECRETED, to affect the NaK2Cl transporter from inside the lumen
What are the pharmacological effects of furosemide?
Copious diuresis with significant NaCl losses Increased urinary excretion of K/H Urinary excretion of Ca and Mg Increased renal prostaglandins Increased venous capacitance
What are the side effects of furosemide?
Hypokalemia and disorders in pH, mostly alkalosis (because of H excretion)
Elevated BUN, hyperglycemia or hyperuricemia
kidney stones
Ototoxicity(!!!!), sialadentitis
What are drug intrx of furosemide?
Interactions with Li (bipolar)
Indomethacin (pg inh)
probenecid
warfarin (competes with warfarin so could double warfarin concentration)
When do you use bumetanide?
Furosemide substitute in pts receiving warfarin
What is significant about torsemide?
Loop diuretic that also lowers bp
What two types of Na channels are expressed in IMCD
amiloride-sensitive cylce nucleotide gated cation CNG channel
Low conductance highly-selective Na ENaC channel
What is the most popular diuretic?
Thiazide diuretics
What is the mechanism of action of thiazide diuretics
Inhibit NaCl reabsorption in the Na-K aldosterone-independent segment of the DCT
What are the pharmacological effects of THiazide Diuretics?
Moderate loss of Na, K and Cl, cause 3x increase in urine flow
Sodium loss results in reduced GFR
Elevation of excreted urinary potassium (hypokalemia)
Increase excretion of titratable acid, due to increased delivery of Na to distal tubule
Decresae urinary excretion of Ca (DIFFERENCE WITH LOOP DIURETICS)
Increase the urinary excretion of Mg
What are the therapeutic uses of thiazide diuretics?
diuretic to reduce edema with CHF, cirrhosis, and nephrotic syndrome hypercalciurea and renal calcium stones reduce bp in essential htn osteoporosis nephrogenic diabetes insipidus
What is a similarity in adminstration efx of thiazide diuretics and loop diuretics?
both must be taken into the nephron and attack channels from the inside
Whats the difference between class I and class II thiazide diuretics?
Class I used when gfr > 50ml/min
Class II when GFR 30
What is the most common thiazide diuretic?
Class I and hydrochlorothiazide
What is the big class II thiazide diuretic?
Metolazone (10X more potent than hydrochlorothiazide
What are all the class I thiazide diuretics?
hydrochlorothiazide
chlorthalidone
quinethazone
What are all the class II thiazide diuretics?
metolazone
indapamide
What are the adverse reactions of thiazides?
From Depletion:
hypoK, hypoCL alkalosis, hypoMg
From retention:
hyperuricemia, hyperCal,
Metabolic Changes:
hyperglycemia
What type of cells are found in the late DCT and CD?
Principal cells
What is the difference between two types of principal cells?
Type A hormonally responsive
Type B load responsive
Which type, A or B, of principal cell is involved in Na reabsorption and K secretion?
Type A, hormonally regulated by aldosterone
What are considered the holy grail of diuretics?
aldosterone antagonists
What are the mechanisms of action of aldosterone antagonists?
bind to aldosterone receptor in the cytoplasm and prevent its translaocation to the nucleus
reduce ENaC channels that are involved in Na reabsorption
What are the net effects of aldosterone antagonists?
increase urinary excretino of Na and inhibit secretion of K (k-sparring)
What is the major aldosterone antagonist?
spironolactone
What is spironolactone metabolized to?
canrenone
What are the side effects of aldosterone antagonists?
hyperkalemia gynecomastia (has intxn with androgen receptor as well)
Why do you use eplenerone instead of spironolactone?
Expected to have less side effects because it has very low affinity from androgen receptors compared to spironolactone
What are the clinical uses of spironolactone/aldosterone antagonists?
diuretic, usually in combo with HCTZ
tx of chf cirrhosis
What are additional k-sparing diuretics?
triametrene and amiloride
What are the moa of triametrene & amiloride?
inhibit na reabsorption in the late distal tubule
what are the pharmacological efx o k-sparing diuretics?
increase urinary excretion of na and decreased secretion of k and h
what hematologic disorder do you see with k-sparing diuretics?
megaloblastic anemia in pts with cirrhosis
What are Atrial Natriuretic Peptides?
Inhibitors of the nonspecific Na Channel
What is the mechanism of ANP?
ANP produced in response to stretch.it binds to NP receptor, and increases cGMP. BNP is produced by the ventricle, BNP also binds to NPRA and acts like ANP, CNP binds to NPRB in vasclar smooth muscle cells and mediates relaxation
What are examples of ANP?
nesiritide recombinant b-type NP
what are the clinical effects of anp?
increase Na excretion by iNH CNG-nonspecific cation channel in IMCD
Renin-angiotensin system and endothelin production
The rest of the cards are from his summary slides
yes
Diuretics with what two things have been shown to be useful in management of hypertension?
Beta-blockers and ACEis
Patients with edematous conditions such as ________ frequently require the use of a diuretic for optimal control of BP
heart failure and renal insufficiency
What are thiazides widely used to treat?
mild or moderate HTN
What is the most popular drug for therapy for high BP?
HCTz
What are two drugs that may help with impaired renal function when thiazides are not?
metolazone and indapamide, usually not effective when gfr lower than 30
A poor response to thiazides may reflect what about their htn?
they may have an overwhelming load of dietary sodium or an impaired renal capacity to excrete the sodium
Are loop diuretics more or less efficient than thiazides?
more efficient
When do you use loop diuretics?
severe hypertension
Do loop diuretics have more or less side efx than thiazides?
more because they are also more effective, so you ahve to worry about extreme natriuresis
What is a very common preventable side effect of loop diuretics and what do you ahve to avoid?
Avoid coadministration with NSAIDs because it can lead to diuretic resistance.
1) PGs reduce Na reabsorp
2) antagonize ADH
3) distribute renal blood from the cortex to the juxtaglomerulus
What is the only diuretic that does not cause increased uric acid?
aldosterone antagonists
Are k-sparing diuretics helpful in patients with hyperuricemia?
yes
What is the drug of choice in cirrhosis?
spironolactone
Are K-sparing diuretics stronger than, equal to or weaker than thiazides as an antihypertensive?
equal to
