1
Q
Describe what happens in the proximal tubule
A
- Na and Cl are reabsorbed isosmotically: 50-70% of filtered load
- K is reabsorbed
- Bicarb is reabsorbed ( via CA)
2
Q
What happens in the ascending limb of the loop of henle
A
- Na and Cl are reabsorbed (20-30%): Active Cl is reabsorbed (remember the Na/K/2Cl transporter)
- impermeable to water so no water reabsorption
- Can compensate for increased Na delivery from proximal tubule by increasing reabsorption
- diuretic on cortical and medullary segments differ in response
3
Q
What happens in the Distal Tubule and Collecting Duct
A
- Na is reabsorbed (8-9%)
- K is secreted
- Aldosterone regulation of Na and K exchange
- Water permeability regulated by ADH
4
Q
Prototypes of Renal Vasodilators
A
**Dopamine
Fenoldapam
Caffeine
**Atriopeptins
5
Q
Characteristics of renal vasodilators
A
- some orally active
- limited clinically to hypertensive crisis and shock
- weak diruetics bc act on proximal tubule
6
Q
Mechanism of renal vasodilators
A
- *Selectively dilate the renal vasculature that modifies proximal tubular function **
- Increase renal blood flow (RBF) without changing GFR. SO Filtration Fraction decreases
7
Q
What is Filtration rate again and how is it impacted by renal vasodilators
A
FF=GFR/RBF
FF= GFR (unchanged) /RBF (increased) so FF must decrease with a renal vasodilator
8
Q
If you increase the filtration fraction what will happen to water and Na excretion
A
decrease
-if you increase filtration fraction, the protein left in the capillary will be at a high concentration trigger water and Na reabsorption and therefore decreasing excretion of water and Na
9
Q
If you decrease the Filtration Fraction what will happen to Na and water release
A
decreasing filtration fraction will decrease the concentration of protein in the capillary bc there will be water there. SO there will be less water reabsorption and therefore more water and Na excretion
10
Q
Prototypes of osmotic diuretics
A
Mannitol
11
Q
Characteristics of osmotic Diuretics
A
- Mannitol
- Freely Filtered
- Not reabsorbed
- Metabolically inert
- basically just sits in the lumen
12
Q
Mechanism of Osmotic Diuretics
A
- **Act in the tubular lumen as reabsorbable solute**
- given via IV
- urine volume and sodium excretion are proportional to the osmotic load
- increases excretion of Na, K, Cl, water, mannitol
13
Q
Uses for Osmotic Diuretics
A
- edema
- glaucoma to reduce intraocular pressure
- acute renal failure
14
Q
Prototype of Carbonic Anhydrase Inhibitors
A
Acetazolamide
15
Q
Characteristics of CA inhibitors
A
- Acetazolamide
- oral
- weak diuretic: bc working on proximal tubule
- they are inhibited by acidosis which inhibits clinical use
16
Q
Mechanism of CA inhibitors
A
- Acetazolamide
- inhibit CA in the proximal tubule
- CA normally provides H ions for bicarb reabsorption. so basically you don’t reabsorb the bicarb (or really excrete H )
- increase excretion of Na, K, bicarb, water
- Alkalinize the urine
17
Q
Side effects of Carbonic Anhydrase Inhibitors
A
- Acetazolamide
- metabolic acidosis
- Hypokalemia (bc you increase excretion of K )
18
Q
Uses of CA inhibitors
A
- Glaucoma
- Alkalinization of the urine to reduce drug toxicity
- Mountain or altitude sickness
- Anticonvulsant
19
Q
prototypes of loop diuretics
A
Furosemide, Bumetanide, Ethacrynic Acid
20
Q
Characteristics of Loop Diuretics
A
- oral or IV
- high efficacy (20-30% of filtered Na load excreted)
- rapid onset
- short duration of action
21
Q
Mechanism for loop diuretics
A
- inhibits the N/K/sCl/ symporter (reabsorption)
- Acts on the cortical and medullary segments of the ascending limb of the loop of henle
- increase excretion of Na, K, Cl, water
22
Q
Disadvantages of Loop Diuretics
A
****Hypokalemia (bc increased excretion)
***Alkalosis (bc increase H excretion)
***Hypovolemia ( bc large water loss)
23
Q
Uses for Loop Diuretics
A
- edema of cardiac, hepatic or renal origin
- acute pulmonary edema
- HYN
24
Q
Thiazide and Thiazide like diuretics prototypes
A
Hydrochlorothiazide, Metolazone
25
Thiazide and Thiazide like diuretics characteristics
- oral
- intermediate efficacy
- moderate onset
- long duration
26
Mechanism of action for thiazide like diuretics
* ****-Inhibits Na-Cl symporter
* ****-Acts of cortical segment of distal tubule
- increases excretion of Na, K, Cl, water
- Urine is hypertonic (unable to dilute)
27
Disadvantages of Thiazide diuretics
*****Hypokalemia-bc increase Na in the lumen (from decreased reabsorption) causes increased activity of the ENaC channel in the collecting duct and therefore increased K excretion
*****Alkalosis
28
uses of thiazide diuretics
- edema due to CHF
- HTN
- hypercalciuria
29
Prototype for K sparing diuretics
Aldosterone Antagonists: Spironolactone, Eplerenone
Sodium Channel Inhibitors: Amiloride, Triamterene
30
Characteristics of K SParing diuretics
```
-oral
low efficacy ( 2-3% of Na load excreted)
-weak diuretic
-increases Na excretion without K loss
-work on the collecting duct
```
31
Mechanism of the K sparing diuretics
****Mineralocorticoid receptor antagonists: Block the action of aldosterone on the collecting duct
*****Sodium channel inhibitors: Blocks sodium entry into principal cells of the collecting duct
* ***-increase Na excretion
* ***-decrease K excretion
increase excretion of Na, Cl, H2O
32
Disadvantages to K sparing diuretics
- low efficacy*****
| - hyperkalemia*******
33
Uses of K sparing diuretics
- edema
- HTN
- seldom used alone. usually in combination with a thiazide or loop diuretic-enhanced natriuresis without K loss
- Aldosterone anatagonists improve survival rate in heart failure
34
Factors in choosing a diuretic
1.Intrinsic Activity
2 Cost
3. Route of Administration: IV vs. oral
4. Speed of Onset: loop faster than thiazides
5. Risk to Benefit Ratio 6. Effects on Renal Hemodynamics
35
compare the intrinsic activity of the diuretics
HIGHEST
Loop
Thiazides
K sparing
36
Compare the cost of diuretics
HIGHEST
thiazides
loop
K sparing
37
Explain the concept of the diuretic ceiling
there reaches a dose of diuretic where the diuretic is doing its max potential. Increasing the dose after this point will no make the diuresis more or better, in fact it may lead to some adverse effects
38
What two things does the diuretic ceiling effect depend upon
- diuretic
| - disease
39
List things that decrease plasma oncotic pressure (and can cause edema)
- plasma oncotic pressure is the amount of protein in the blood and therefore it usually is a force that draws fluid in
- Decreased by:
* malaborption
* nephrotic syndrome
* liver failure
* malnutrition
40
List things that can increase capillary hydrotic pressure (an therefore lead to edema)
- an out pressure
* venous obstruction
* cirrhosis
* CHF
* constriction/restriction
* renal failure
* pregnancy
41
Explain the use of diuretic drugs in edema and the two point foundation of edema therapy
-you increase Na and water excretion by reducing renal tubular Na and water reabsorption ( so it is all excreted!!)
- Foundation of edema therapy
1. Reduce intravascular volume
2. Reduce ECF and edema
42
Prototypic diuretic drugs used for edema
hydrochlorothiazide, furosemide
43
List four things that the tissue compartment determines
1. Dictates rate of fluid mobilization (slow equilibrium between ECF and body compartment, but fast equilibrium between vasculature and ECF
2. Determines volume status
Diuresis: 1st – vascular; 2nd - edematous tissue; 3rd - compartments (peritoneal or
pleural spaces
4. Loculated Fluid Ascites: mobilize slowly 0.5 kg/d monitor diuretic effect (fluid in body leaves slowly bc of the slow equilibrium between body and ECF)
44
4 facts about electrolyte imbalance relating to K
- K loss parallels Na excretion ( bc as more Na is lost ENaC will try to compensate in collecting duct and will cause a lot of K loss)
- to overcome loss: increase intake with K supplements or decrease output with K sparing diuretics
- Hypokalemia: rarely life threatening
- Hyperkalemia: can be fatal
45
How do Carbonic Anhydrase Inhibitors influence acid-base balance
Metabolic Acidosis (dont reabsorb HCO3-)
46
How do Loop Diuretics influence acid-base balance
Metabolic Alkalosis
47
How do Thiazide Diuretics influence acid-base balance
Metabolic Alkalosis
48
How would a diuretic work to help with hypertension
it would increase salt and water excretion by reducing renal tubular sodium and water reabosporption
*increase excretion by reducing reabsorption
1. lower BP
2. Prevent salt and water retention and enhance blood pressure lowering by other antihypertensive drugs
Prototypic drugs: hydrochlorothiazide, furosemide
49
How is is thought that diuretics decrease BP according to looking at the CV system
they decrease the vascular volume which would decrease venous return which would decrease Cardiac Output which would decrease Blood Pressure
50
So what actually happens when you give someone a diuretic for a BP medication
it works at first exactly as you would like, but then it is no longer effective at decreasing the blood pressure
then the arteries dilate and the peripheral resistance resistance decreases, so the Cardiac output increases back to what it was before and all goes back to normal
51
How do diuretics decrease peripheral resistance/vasodilate
1. decreased Na/water in vessel wall
2. PGI2 and NO release
3. Vascular K channel activation
4. decreased sensitivity to NE
5. Increase Na-Ca exchange
52
Diuretic use in chronic heart failure
- mainstay of heart failure management
- reduce fluid volume and ventricular preload (stop the cylce of heart failure at fluid and sodium retention)
- reduction in heart size improves efficiency
- reduce edema (and its symptoms)
- not associated with a reduction in mortality
53
What do diuretics do to SV and LVEDP
they allow you in a failing heart to pump at the same SV, with a lower LVEDP
54
Actions of Angiotensin II on the heart
- stimulates vascular smooth muscle cells migration proliferation and hypertrophy
- increases vascular smooth muscle cell extracellular matrix production
- causes cardiac myocyte hypertrophy
- increases cardiac fibroblast extracellular matrix production
- stimulates growth factors (TGF-B, FGF, PDGF)
- Angiotensin II also alters extracellular matrix formation and degradation indirectly by increasing aldosterone
55
SO what happens to your heart when Angiotensin II is inappropriately elevated
- Cardiac Fibrosis-both ventricles
| - Left Ventricular Hypertrophy
56
Explain the effect of RAAS in heart failure in my own words
Increase in angiotensin II stimulates aldosterone release which causes Na and water retention which causes and increase in preload so the heart has to work harder
Also increase in AngII causes vasoconstriction which increases the after load (blood left in the heart) so the heart has to work harder
57
What are the Compensatory mechanisms in congestive heart failure
- expanded activation of the sympathetic system (increases HR, forcec and preload)
- Activation of the renin angiotensin aldosterone axis (increases preload, afterload, and causes hypertrophy)
58
If the compensatory mechanisms in heart failure make heart failure worse (aka are bad for the heart) what is their goal
to maintain perfusion of vital organs by increasing preload, stimulating contractility and increasing arterial tone
59
3 things Aldosterone does to CV system *****
- cardiac fibrosis
- LVH
- HTN
60
Aldosterone Antagonists and chronic heart failure
- weak diuretics: small effect on preload
- Reduce potassium loss and hypokalemia and enhance the natriuresis due to other diuretics (when used w others)
- Block cardiac effects of aldosterone- decrease fibrosis and hypertrophy and arrhythmias
- IMPROVE SURVIVAL
61
Prototypic aldosterone antagonists
Spironolactone, Eplerenone
62
Effects of spironolactone and eplerenone
```
Reduce edema, anti-
arrhythmic, and decrease
fibrosis in the myocardium
and vessels (i.e.,
counteracts adverse
remodeling)
```
63
What diuretics work in the proximal tubules cortex
CAI: Acetazolamide
64
What diuretics work in the proximal tubule medulla
osmotic diuretics: Mannitol
65
What diuretics work in the Thin ascending loop of henle
Loop Diuretics:
Furosemide
Bumetanide
66
What Diuretics work in the cortical segment of distal tubule
Thiazide:
- Indapamide
- Hydrochlorothiazide
- Chlorthalidone
67
What diuretics work in the collecting duct
K sparing
PDA Block 2
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