Lecture - Pharmacology (Diuretics)

Question 1

Okay so you need to know about 4 types of drugs but actually only 3 - where do they sorta fit in the nephron?

Answer 1

So osmotic (which we dont need to know a heap about) affect the PCT, descending arm of LoH, the distal part of DCT and also the collecting duct

Loop diuretics sit in the ascending arm of LoH

Thiazaides sit in the proximal part of DCT

K sparing sit in the distal part of DCT

Question 2

Physiology recap

Explain what the kidney does and include NaCl, H2O in your answer

Answer 2

-So the kidneys control the extracellular fluid volume by adjusting NaCl and H2O excretion (where NaCl goes, water goes). But we do reabsorb the Na that we filter because if we filtered it all, we’d; die. The body also maintains blood pressure at the expense of extracellular fluid volume. Also, if NaCl intake is greater than output eg in renal failure, you’ll get odema.

Question 3

Physiological bases of diuretic action

1. How is Na+ absorbed?
2. What does the Na+/K+ exchanger do?
3. How does Na+ get from the lumen into the cell?
4. Water accompanies what?
5. Where does the Na+ mostly get reabsorbed?
6. What do diuretics do the Na+ reabsorption?

Answer 3

5. In the PCT

Question 4

Site of diurteic 1: PCT (and remainder of tubule)

1. What drug works here, what’s an example of this type of drug and how is it delivered?
2. It’s pharmacologically inert but osmotically active - what does that mean?
3. It’s freely f_____ in the glomerulus but poorly ______ in the PCT
4. So what does it limit? And where?
5. Greatest effect is where? Why?
   - what happens to urine?

Therapeutic Uses:

1. Primarily used for what?

Toxcitiy of osmotic diuretics:

1. There’s two bolded ones, what are they?

Answer 4

-

Question 5

So how do diuretics get into the tubule?

1. How does mannitol get into the tubules? How is it excreted?
2. Other drugs are protein-bound and ______ filtered through the glomerules
3. Proximal tubule mediates _____ and _____ of weak acids/bases (aka most ____) - tell me about OATs

Answer 5

2. Aren’t

Question 6

High ceiling loop diuretics

1. What’s the site of action?
2. Give me an exmaple of this drug
3. These are the most potent diuretics availble and the most chemically diverse range diuretics. What do they primarily inhibit by…..? What does this channel do?
4. This channel has the capacity to reabsorb how much of the filtered Na+? Does the downstream nephron have the reabsorptive capacity to recover this level of filtrate?
5. Loop diuretics also do more at TAL - what do they do?

Frusemide PK:

1. If you give it orally, is the abs rapid or nah? With IV - when is the onset? So what do you do in emergencies?
2. Extensively (90%) bound to p____ p_____
3. Does not pass directly into what? So how does it get into the proximial tubule? What’s the remainder metabolised by?
4. What do loop diuretics profoundly increase?
5. Okay, so what will #4 do at the distal and collecting ducts?
6. Is frusemide a drug you give for constant?
7. What does glucuronidation mean?

Therapeutic uses of Loop Diuretics

1. H_____ - is this even effective in pateints with low GFR?
2. What does it cause o_____ of?
3. What else? (think logically - what does it get rid of so who will it be useful for?)

Loop diuretics - side effects and interactions

1. What does it do? SO what if that goes overboard? What’s that called?
2. What does it get rid of? So you can get depletion of…..
3. You know how it leads to loss of H+ and K+ at the distal and collecting ducts, what will that mean?
4. How does it get in? So what can it lead to? What condition can you get with this?
5. What will you get with prolonged use? - So should you be taking this long term?

Answer 6

4. No, they can only absorb 5-10%
5. They will disrupt the positive transepithelial potential by loop diuretics so you’ll not get the reabs of Ca++, Mg+, Na+
6. Nope, you lose the effect

Question 7

Thiazide site: _____ _____

1. What’s the site of thiazide diuretics?
2. What’s an example of a thiazide diuretic?
3. Where are they secreted?
4. What do they competitively bind to?
5. It’s a main to moderate diuretic - why? Leads to what?

PK:

6. What is the administration of the thiazide diuretic? What’s the abs like?
7. How is it eliminated? What about its half life?
8. How is it excreted into the PCT? So will it be affected by other drugs?
9. Eliminated mostly by what route orrrrr?
10. What are it’s therapeutic uses?
    - delivery method
    - h___ - use in association with what?
    - is there effective monotherapy in elderly hypertensive pateints? Butttttt….
    - can it be used in renal disease if GFR is lost?
11. On slide 26, there is a graph of the various effects of thiazide during the therapy - do and cover it up and try to redraw it
12. Adverse effects of thiazide diuretics (they are maybe’s - depends on the dose, renal and metabolic function of the pateint aka dont produce these effects in every patient)
    - they usually occur with ____ doses
    - whats’s an effect that’s particularly evident in elderly? So this is why you shouldnt use it as monotherpay in elderly for hypertension
    - what’s hyponatremia? What do you get with this in elderly?
    - Increased Na+ loss can also lead to what accumulation in treated pateints?
    - Why get metabolic alkalosis and hypokalaemia?
    - Why do you get uric acid retention? What condition can you get with this?
    - what does the K+ loss prolong? So what arrthymia is produced?
    - But they’re often the first-line treatment for hypertension, why?
    - why hyperglycaemic?

Answer 7

3. Probably only because cortical diluting segment of distal tubule only reabsorbs 5%

4, 5, 6 = So basically, it binds comeptitively to eNCC-1 channel and that’s the Na/Cl co-transporter. it will inhibit Na+ coming in so increase (modestly) the excretion of Na. Modest because this channel in the DCT only absorbs ~5% of the filtered Na. Downstream, there is a Na/K exchanger (which will reabsorb Na and excrete K+ in return) and when you have high Na+ load in the tubule, it will promote more reabs of the Na+ at the expense of K+ and H+ (the same mechanism follows with loop diuretics)

CAN’T USE THIAZIDE IF GFR IS NOT MAINTAINED in renal disease

Question 8

K+ Sparing Diuretics; Mineralocorticoid receptor inhibitors

1. What site do they work on? And on the pumps that are regualted by a_____)
2. Okay, background: what are the renal effects of aldosterone? How does it affect CO?
3. Go read over slide 31 carefully to see aldosterone’s effects
4. So a drug that is an aldosterone antagonist issssss? What does it ______ bind to and prevent?
   - does it need to cross the lumen to act? So where does it comeptetively bind?
   - How does it still conserve K+?
   - what is the action of this drug depdendent on?
5. Pharmacokinetics of spironolactone
   - what delivery method is used?
   - how much is absorbed in the GI tract?
   - what can you say about first pass?
   - extensively bound to _____ _____
   - what is it turned into to get ot urine?
   - what can you say about it’s toxcitiy? (be logical….what does it retain so if pateint aldready has that, should you give this?)
6. There’s another K-sparing dicuretic - what is it?
   - how does it work?
   - but it has relatively weak effects on overall ____ balance
   - action of amiloride is complementary to what? It augments ____ ______ but limits _____ _____
   - how is it transported to from lumen and into PCT?
7. What’re the main therapeutic uses of K sparing diuretics?

Answer 8

Ohhhhh so it conserves K+ because it will not let Na+ be reabs (so water stays out = diuretic) and it also won’t let K+ get out. So antagonist of aldosterone (the more aldosterone = the more effect it has as a diuretic)

Question 9

Pharmacological summary

1. What’s the primary therapeutic goal of a diuretic? (2)
2. Diuretics primarily prevent entry of what into what?
3. Once a diuretic enters the tubule fluid, the _____ _____ at which it acts determines its effect
   - in addition, the site of action also determines what?
4. All diureitcs excpet ______ exert effects from the luminal side of the nehphron
5. Diuretics must get into _____ _____ in order to be effective
6. How does mannitol get into the tubule fluid? Why dont the others? So how do they get across?
7. What can reduce the diuretics’s effectiveness?
   - As do drugs which compete for the…..

Answer 9

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