8. Diuretics Flashcards
The issue in brief
• The sodium concentration in normal people is 154 mEq/L (140 mEq in plasma)
• In health, the kidneys filter ____ mL of plasma per minute
• Doing the math, each minute the kidneys filter 18 mEq of sodium; each hour (6018=) 1080 mEq; and each day (24*1080=) more than ____ mEq of asodium. The normal human has less than ____ mEq sodium in their entire body.
* Na is important to the human body - principle cation that keeps plasma vol where it is * Reason why it's 140 > draw blood tube and measure it on that > measuring it in 930 mL of blood, but 7% of blood is \_\_\_\_> then brings you to 154
120
25000
2200
The average American
- Consumes 3400 mg of sodium per day (that’s about 150 mEq)
- This is (150/25000) about ____% of what the kidneys filter each day• Kidneys need to be ____% efficient in recovery of Na
- 6
99. 4
• Everyday you retain 1 meq of Na > for a year, at the end of the year you’ll have 360+ extra meq of Na > 2+ L of normal saline
○ 1 meq = <1% of daily intake
1
- Kidney do a balancing job of keeping us at straight and narrow at what we take in
- When something throws hormones out of whack > ____ retention becomes a problem
- Na loss - ____ loss, don’t live to adulthood
Na
pediatric
• Diuretic ○ Running through \_\_\_\_ish • Natruresis ○ Running through \_\_\_\_ • Kaliuresis ○ Running through \_\_\_\_ • Chloruresis ○ Running through \_\_\_\_ • Aquaresis ○ Running through \_\_\_\_ • Natruietic diuretic > more \_\_\_\_ loss • Kalireutic diuretic > more \_\_\_\_ loss
water sodium potassium chloride water sodium potassium
Therapeutic Uses of Diuretics • Volume excess states* – \_\_\_\_ – Cirrhosis – \_\_\_\_ • \_\_\_\_ • Electrolyte disorders • Glaucoma, Kidney stones, Altitude sickness
• Most common is in HTN ○ Avg 20-30: 5% prevlence ○ 70: 70% ○ Most common drug to maintain HTN are \_\_\_\_ § Cheap (costs more for pharmacist to put label on bottle) • Kidney stones ○ Some diuretics are good, and some are bad ○ Some diuretics affect urine \_\_\_\_ in a good way, and some in a bad way
HF edema HTN diuretics calcium
• Kidney has a cortex and medulla
○ Cortex = ____ of blood
§ And for diuretic to work - has to get into the ____
§ If it doesn’t get into the urine, it won’t block Na reabsorption
§ Most diuretics are targeted towards sodium
filtration
urine
• Everything starts at BC
• Glomerulus allows ____ of water, some electrolytes/AA/glucose, but not proteins or cells
• 200k-2m nephrons per kidney
○ Thought one of casues of HTN is a ____ number of nephrons, so they work harder and wear out more quickly
○ ____ of numbers among population
filitration
low
variation
- After plasma is filtered and ultrafiltrate begins in bowman’s space > proximal section, and a loop of henle, and distal segment (each one ____ to input and output of input and output of glomerulus so it can adjust the filtration based on that); then urine joins other segments from many collecting ducts
- Na, H2O absorbed with a variety of pumps
feedsback
• Proximal tubule ○ Responsible for \_\_\_\_% of reabsorbing what was filtered ○ Biggest structure in \_\_\_\_ of the kidney • Loop of henle ○ Urine is cxn or diluted ○ \_\_\_\_% of Na reabsorbed • DT ○ \_\_\_\_ what comes out • CD ○ Everything goes ○ \_\_\_\_ diuretics work here
70 cortex 20-25 fine tune water
Mechanism of Diuretic Action
• Active
• Passive
• Most diuretics are \_\_\_\_ ○ Sit and block
passive
Diuretic Basics
• highly ____ bound
• interact with specific ____
• inhibit ____+ transport
• most receptors are on the ____ of the tubule (luminal or apical)
• delivery to active site is by two pathways – ____ and secretion
• Highly protein bound ○ Issue: has to get it in the urine, has to get past glomerulus, but if highly protein bound and the glom is picky (doesn't let albumin through) then diuretics go to liver to be metabolized ○ There's another mechanism! ○ Limits delivery by filtration • Specific receptors ○ Typically on luminal side of tubule (not \_\_\_\_, that's the blood side)
protein receptor Na inside filtration basolateral
• Secretion
○ Past glom and in the blood through the kidney, once the blood comes back up along tubule cells > ____ is able to strip a loop diuretic or a DCT diuretic from the protein and slip it into the cell > ____ transfers the diuretic into the lumen > travels along the nephron
○ A lot of delivery is through here
○ ____ tubule cells > harder to get the diuretics in the urine
OAT
MRP
sick
Size of Urine Volume Response 1
• The magnitude of the response (as measured by increase in urine volume and sodium loss) is determined by
– ____ transported by that segment
– “____” the site has to the drug
• How much urine you make for how much drug you expose the research participant
sodium
exposure
• PT > 70% of Na reabsorption
○ Lousy diuretics > if block on that scale person will disappear into urine
• LH > 25% during the thick limb
○ Loop diuretics are most ____ > bc they can block a portion of 25% recovered Na
• DCT > thiazides; 5%
• Gonna see a bigger response effect on blocking the ____
potent
LH
• FENa
○ Fractional excretion of Na
○ Can do a FE of ____ (anything that can filter and measure)
○ If kidney is filtering plasma > and you know the kidney filters 100 ml of urine (via creatinine measurement) > base filtration, and then the ____ of Na > can tell how much you excreted
○ Can calc what portion of Na that was filtered actually makes it into the urine
○ When drug works on active part of the nephron > 20% of what is excreted is in a short amount of time
• Thiazide
○ 5% excretion rate
○ Wimpier drug - but more useful bc get into less ____ with them on the long haul (volume depltion, etc.)
• Only shows magnitude - loop diuretics is very ____
anything
plasma cxn
trouble
potent
• HF > diurese quickly > IV loop diuretics, but don’t know how much Bumex to give
○ IV push (6 now and 6 later)
○ Or 12 mg and drip continuously
○ Depends on how to do it > continuous > more ____ but durable response compared to the mountaintop of the bolus
○ Measure area under curve > colelct urine > measure the Na that came out > you get more than 1 1/4 times the amount of Na excreted > get it closer with ____ infusion
§ Continuous infusion > straight amount of drug to the ____
§ Bolus > ____ more quickly
§ Actual exposure of drug to nephron is greater when infuse ____ versus giving as a bolus
blunted continuous kidney cleared continuously
Size of Urine Volume Response 2
• Delivery of the drug – \_\_\_\_ – GFR – \_\_\_\_ secretion • Nature of volume excess (if present) – \_\_\_\_ – Abdominal ascites • Braking phenomena
• Use drug that's oral; most diuretics are PO (esp thiazides) ○ Must be able to absorb via \_\_\_\_ ○ A lot of people have swollen intestine • A lot of problems can be bc they didn't absorb it bc of \_\_\_\_ • GFR falls > marker of how well kidney works ○ If it's 1/5 of normal > amount you filter is 1/5 compared to a normal person • Tubulointerstitial diseases ○ Damages the ability of the tubules to do \_\_\_\_ so tubular secretion is impaired ○ May give drugs that \_\_\_\_ with the OAT > and if get there first > diuretic goes right by • Ascites > no blood supply, just a wall of fluid • Braking phenomena ○ When give diuretics and threaten volume > \_\_\_\_ back
absorption tubular peripheral edema intestines edema OAT compete pushes
• When have diseases > shifts everything down
• FENa in a healthy individual, and one with disease
○ In HF > the ____ is low
§ Or wall of gut is impaired
○ Cirrhosis
§ Aldo ____
○ Nephrotic syndrome
§ Little ____
§ Affects the secretion across cells via ____ side
GFR
excess
albumin
basolateral
• If use multiple diuretics:
○ More sense to use diuretic that works on a diff ____ then it gives to a larger dose of diuretic on same segment
○ Treat with furoesmide and give them more > you don’t get more in terms of urine Na excretion
○ Have furosemide and give a thiazide > more ____
segement
effect
• Proximal tubule
○ Can absorb bc it has a huge ____ > bc of all the villi
○ Have some ____
○ A lot of reabsorption
surface area
mito
• Most important pump in PCT: ____
○ Highest michaelis menton numbers in human physiology
○ Speaks with forked tongue
§ When filter blood > Na, K, Cl and bicarb > you have no mechanism to recover filtered bicarb > we recover via secreting ____ (Na H antiporter) from proximal tubule cell lumen where there’s a little bit of H ion courtesy of CA in the cell and cytoplasm > makes this available > shot out, Na gets resorbed of the Na-bicarb that we filter > H+ attacks the carbonic anion until it sits to CA > breaks into H2O and CO2 > easily absorb these, and diffuse down equilibrium into the cell > CA in cell picks up > strips ____ and creates carbonic anion and that with Na is jettisoned into the basolateral side
§ No ____ in healthy urine
• Inhibit the Ca > bicarb comes out in the urine
carbonic anhydrase
H+
H+
bicarb
Carbonic Anhydrase Inhibitor
• CO2+H2O H2CO3 H++HCO3- • Reduces luminal \_\_\_\_ production • Reduces \_\_\_\_ in the cytosol • Reduces HCO3- extrusion in \_\_\_\_ space • What’s lost in urine: – \_\_\_\_, \_\_\_\_, \_\_\_\_ • Serum Consequences: Low HCO3-, Low \_\_\_\_
• Reduce bicarb reabsorption • Bicarbonatruei, natureitic, and kalioretic • CA inhibitors - only class of diuretics that'll elevate urine bicarb cxn chronically ○ Consequence: if keep losing bicarb > liver will try to generate more but it can't keep up > develop low bicarb > \_\_\_\_ • Lose a cation with this ○ Bicarb out in urine, the thing that's in cell that's jettisoned to match is K (lots of K+ in cell, little sodium in cell) ○ Cause \_\_\_\_ § Low K+ levels in cardiac disease > determines potential on membrane; small fall outside cell > depolarizes cell > don't repoloraize well > \_\_\_\_ fibrillation
CO2 HCO3- basolateral Na+ HCO3- K+ K+
metabolic acidosis
hypokalemia
vent
Carbonic Anhydrase Inhibitors
• Clinical uses of acetazolamide (DIAMOX):
– Treating states of HCO3- excess (____ )
– **Treating ____
– ____
• Generating too much bicarb • Glaucoma ○ CA is important for forces that cause filtration of fluid in chambers of eye ○ Reduce \_\_\_\_ pressure • Altitude sickness ○ Climb quickly > O2 fall > breather harder > generate an acidosis in response to the respiratory alkalosis > brain \_\_\_\_ and get sick ○ But if know going into that environment, and prep them and reduce bicarb before they begin the climb > generate \_\_\_\_ that they need to generate on the fly (3 days naturally vs \_\_\_\_ day chemically)
alkalosis
glaucoma
altitude sickness
ocular
swelling
metabolic acidosis
1
Toxicity of CAI
• Metabolic Acidosis
– (Low serum ____ level)
• Hypokalemia
– (Reduced ____ levels)
• Hypokalemia ○ Muscle weakness ○ But with vent tachy or v fib > lethal
bicarbonate
potassium
Loop Diuretics
• Mechanism of action:
– Inhibition of the Na+:K+::Cl-:Cl- transporter
– This pump is very active, located in the LOOP of Henle (many ____)
– Depends on ____ cycling
– Depends on ____ extrusion
• Block \_\_\_\_ ○ Active pump ○ Passive way to block • Characteristc of LH > lots of mitochondria • Reason loop diuretics continue to work is bc of K cycling
mitochondria
K+
Cl-
NKCC2
