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Integrated Drug Structure, Function, and Therapeutics Winter Term > Kidney and Renal Hormones - Dr.Delander > Flashcards

Kidney and Renal Hormones - Dr.Delander Flashcards

1
Q

What hormones are used in the kidneys and vasculature, and what do they do?

A 
Renal action hormones:
ANP - diuresis, naturesis
Prostaglandins - vasodilation, diuresis
ADH - water conservation
aldosterone - conserve Na, regulate K
angiotensin - conserves H2O and Na

Vascular actions hormones:
NO - vasodilation, diuresis
Bradykinin - vasodilation, diuresis
Endothelia - vasoconstriction

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2
Q

How many types of natriuretic factors are there?

A

At least 3: Atrial natriuretic peptide/factor produced by atrial tissue, BNP (released by ventricular tissue) and CNP.

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3
Q

What are the roles of ANP?

A 
Diuresis
Natriuresis
Increases GFR
Inhibits cardiac remodeling
Inhibits stimulated drinking of H2O
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4
Q

Where are natriuretic factors released?

A

From the heart. ANP from the atria, BNP from the ventricles.

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5
Q

What are two ways of terminating the actions of ANP?

A
  1. Binding to the clearance receptor, which internalizes

2. NEP (neutral endopeptidase, or neprilysin) binds and chops up ANP

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6
Q

Which hormone causes diuresis and natriuresis?
ANP
ADH

A

ANP

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7
Q

Which hormone causes water conservation?
ANP
ADH

A

ADH

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8
Q

If there is ANP, Ang II, NE, ADH, which effect will predominate?

A

The vasodilatory effects of ANP will predominate.

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9
Q

What does natriuresis of ANP cause?

A

Inhibits aldosterone synthesis
Inhibits renin release
Inhibits Na reabsorption in collecting ducts (there are multiple sites for Na reabsorption)

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10
Q

What causes cardiac remodeling? What inhibits this remodeling?

A

High concentrations of angiotensin II seem to cause cardiac remodeling. ANP seems to inhibit this remodeling either due to direct effects, or because of the effects on the renin release.

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11
Q

What is ANP a physiologic antagonist of?

A

Angiotensin II and aldosterone

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12
Q

What should increasing or mimicking ANP result in?

A

Decrease volume
Decrease sodium
Because ANP “wins” over other hormones, the body should not be able to compensate to constrict the vasculature again.

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13
Q

What is nesiritide?

A

ANP receptor agonist, rarely used. For acute decompensated congestive heart failure. Decreases pulmonary congestion. Very effective, hard to fine-tune.

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14
Q

What does sacubitril do?

A

Inhibits neprilisyn (usually involved in breaking down ANP naturally). This helps to maintain the life of ANP in the body.
prodrug
Only available in combination with valsartan. Alone, angioedema is a problem. 97mg is highest concentration available.
Effective in management of heart failure.

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15
Q

What is the difference in side effect profile between ACE inhibitors and ARBs? What does neprilysin have to do with bradykinin?

A

Bradykinin breakdown is inhibited in ACE inhibitors, and not in ARBs. Inhibitors of neprilysin also cause increased concentrations of bradykinin (although less than ACE inhibitors). Bradykinin seems to be responsible for the side effect of the risk of angioedema.

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16
Q

How do eicosanoids effect Angiotensin II?

A

They tend to oppose effects of angiotensin II. We are looking at PGI2 (glomerulus effects) and PGE2 (tubule effects).

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17
Q

What does PGE2 do?

A

Inhibits Na reabsorption in thick ascending limb (only place that solutes can be reabsorbed and water want follow). Contributes most of the ions to the gradient.

Decreases efficacy of ADH

Both cause diuresis.

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18
Q

What does PGI2 do?

A

Causes vasodilation as it comes into the glomerulus. Stimulates release of renin, and renin stimulates release of PGI2.

19
Q

What works together to regulate vascular tone and blood flow in the glomerulus?

A

PGI2 and angiotensin II

20
Q

What do NSAIDs interact with?

A

They inhibit production of prostaglandins, and allow Na to be reabsorbed (water follows). Water is retained.

Also inhibit PGI2 production possibly decreasing RBF.

21
Q

What hormones facilitate diuresis rather than water retention?

A

ANP

Prostaglandins (PGE2 and PGI2)

22
Q

What is the most potent vasoconstrictor we have in the body?

A

Vasopressin, also called ADH (formed in hypothalamus, released from the pituitary)

23
Q

What stimulates the release of ADH?

What is the only thing that decreases the release of ADH?

A

Angiotensin II
Increased osmolarity or increased blood concentration
Low blood volume
Low BP

ANP decreases release of ADH

24
Q

What does V1a do?

A

Gq mechanism. Ca dependent action, causing vasoconstriction.

Decrease medullary blood flow which increases medullary osmolality.

25
Q

What does V2 receptors do?

A

G-s coupled receptors, release cAMP.
Insert aquaporins into the cells lining the collecting ducts. Makes it easier for water to be reabsorbed out of the tubules and back into the body. Facilitate reabsorption of urea at the same time.

26
Q

What are the consequences of releasing ADH?

A

V1a receptors: When the medullary blood decreases, the osmolality increases (less movement = more salt accumulation)
V2 receptors = aquaporins get rid of water back into interstitial fluid.

This is the mechanism by which ADH conserves water.

27
Q

What is SIADH?

A

Too much (inappropriate) ADH secretion
Multiple reasons: tumors, head injuries, infections, drug induced (TCAs, carbamazepine, anti-tumor agents)
Have to ask if there are drugs present that may be triggering the ADH release.

Symptoms may include dilutional hyponatremia. Can restrict water, can give sodium (but compounds fluid that is being retained).
Old solution - demeclocycline: decreases efficacy of ADH.
New solution - vaptans. These block V2 receptors. Conivaptan. (causes increased loss of water, but not electrolytes. This is what we want to achieve).

28
Q

What can you treat with Conivaptan?
SE’s?
Selectivity?
Contraindications?

A

SIADH
Volume retention associated with congestive heart failure (not labeled use)

It is not selective for V2. Newer ones are more selective.
SE’s: rapid correction of electrolytes can cause neurologic disorders (demyelination of neurons)
Can see increased concentrations of K+ (because of decreased Na in the filtrate, K is used instead)
Don’t use in volume-depleted patients
Can cause hypernatremia (too much sodium)

29
Q

Diabetes insipidus?

A

Insensitivity to ADH
Two types
1. Neurogenic: inadequate amounts of ADH being released (genetic, drug-induced uncommonly). Manage using analogs of vasopressin that aren’t metabolized as quickly. Blanching, cramping, nausea, angina (SE that are from increased muscle contraction).
Noctiva is new one that is used to decrease nocturnal urination.
Typically ADF is used to diagnose when it causes a response.

  1. Nephrogenic: insensitivity to ADH (doesn’t do what it is supposed to do once it hits the receptors.
    Replacing water is not the best solution
    Thiazide: diuretic, but for some reason almost half of pts respond. Sodium efficiency is improved because some sodium is lost, possibly making people better at reabsorbing water.
    Vaptans - people possibly have dysfunctional V2 receptor. Vaptan presence possibly change conformation of receptor to make them functional again.
30
Q

Aldosterone role:

A

Regulate K by K/Na exchanger (excretes K and retains Na)
Triggered by increased K levels, angiotensin II, low Na, ACTH has to be present
Inhibited by ANP
Hydrogen ions and K ions are competing for positive ion spots in filtrate.
Concerned with acidosis when we see hyperkalemia.

31
Q

What is 11-B-HSD?

A

It breaks down cortisol and limits the binding of the cytosolic aldosterone receptor to aldosterone (and keeps cortisol from triggering the same chain of events since the steroid receptor is not specific). Aldosterone is mineral corticoid. The receptor is translocated to the nucleus.

32
Q

What should you look for with resistant hypertension?

A

There might be an adrenal tumor that is causing excessive release of aldosterone. This is often how the presence of an adrenal tumor is diagnosed; by the reaction of the body to an aldosterone antagonist.

33
Q

What is Addison’s disease?

A

Usually due to adrenal atrophy. There is insufficient release of aldosterone. Observed as hypotension, malaise, hyper pigmentation. Need to replace both the mineral corticoids, and glucocorticoids. Hydrocortisone is drug of choice. Start with 200-300mg of hydrocortisone a day. (This is a glucocorticoid, but can bind to the aldosterone receptor because it doesn’t have affinity for the 11-B-HSD and isn’t degraded)

34
Q

What does fludrocortisone?

A

Only a mineral corticoid. So could use this to treat aldosterone insufficiency.

35
Q

Angiotensin/Renin system:

  • primary functions
  • Receptors
A
  • Conserve water, sodium, and maintain GFR

- AT1 and AT2

36
Q

What receptors are we interested in for the angiotensin/renin system?

A

AT1- Couples to different G proteins at different places.

37
Q

Actions of angiotensin II

rapid pressor effects, slow pressor effects, or cardiac remodeling.

A

Anything the stimulates renal perfusion will stimulate angiotensin II
Anything where we need sympathetic stimulation will stimulate angiotensin II to help out

Effects:
Rapid pressor response: enhances sensitivity to NE, increases sympathetic outflow for CNS and adrenal. If you’ve lost a lot of fluid, angiotensin can be mustered very quickly.

Slow pressor response: instead of direct effect on vessels, have to increase the volume. Fill up the vessels. There is a direct effect on sodium reabsorption. There is an increase in the release of aldosterone, which causes an increase in the sodium that is reabsorbed into the body. Water passively follows it into the body. (Normally potassium is excreted). Constriction of afferent arteriole. Slow renal blood flow, which retains water. As you increase concentrations of angiotensin II, the efferent artery constricts. This maintains the pressure inside the glomerulus to maintain GFR. Constricts inside Bowman’s capsule. Leaky capillaries inside Bowman’s capsules cells. Angiotensin II conserves water by blocking as much of the water leakage. Angiotensin II stimulates water drinking and release of ADH.

Vascular and cardiac remodeling. It turns out that both by direct and indirect actions, angiotensin II can cause a change in the tissue structure of the heart. Indirect: filling system with water and Na, harder for heart to much. Get heart remodeling to build up muscle, but it is fibrotic. Hypertrophy of tissues. If we tried to block this system, what therapeutic value could be had in antagonizing angiotensin II? - Management of hypertension.
Big effect: Get decrease in total peripheral resistance. See this through different mechanisms. See a decrease in vascular tone. This has to do with the rapid pressor part. Directly decrease tone and smooth muscle. Decrease sodium load, decrease aldosterone formation (no sodium exchange). Can increase renal perfusion.
Indirectly help by decreasing sympathetic outflow from CNS or adrenal. Baroreceptors are intact. in general, a decrease in vascular tone.
In CHF, the heart is working too hard. Decreasing remodeling is helpful and can be done by direct and indirect effects.
After MI, can decrease remodeling. Can also delay or prevent nephropathy (maintain appropriate pressure w/i Bowman’s capsule, by inhibiting actions of angiotensin II in kidney).

38
Q

ACE Inhibitor SE’s

A

Prototype
Hyperkalemia - prevent angiotensin II formation. Don’t produce aldosterone, which get rid of potassium. Therefore are at risk for hyperkalemia, and acidosis.
First dose hypotension. Angiotensin is playing a larger role in setting up vascular tone than it should. Thiazide decreases blood volume, which causes the body to produce angiotensin II to compensate, but knock it out with ACE inhibitor. Then you have hypotension. Should start with ACE I and then start thiazide.
Acute renal failure - anything that compromises renal blood flow. If someone does not have adequate perfusion to kidney, they could lose all of their GFR pressure if given an ACE or ARB.
Contraindicated in pregnancy. Decreases the amount of amniotic fluid being formed. Absence of growth of appendages.
Cough- bradykinin is also metabolized by ACE. If you block this, you get increased risk for the cough and possibly angioedema.
Proteinuria - Angiotensin II slows down GFR and causes solutes to back up. When this is reversed, protein can leak out.

39
Q

ACE Inhibitor SE’s

A

Prototype
Hyperkalemia - prevent angiotensin II formation. Don’t produce aldosterone, which get rid of potassium. Therefore are at risk for hyperkalemia, and acidosis.
First dose hypotension. Angiotensin is playing a larger role in setting up vascular tone than it should. Thiazide decreases blood volume, which causes the body to produce angiotensin II to compensate, but knock it out with ACE inhibitor. Then you have hypotension. Should start with ACE I and then start thiazide.
Acute renal failure - anything that compromises renal blood flow. If someone does not have adequate perfusion to kidney, they could lose all of their GFR pressure if given an ACE or ARB.
Contraindicated in pregnancy. Decreases the amount of amniotic fluid being formed. Absence of growth of appendages.
Cough- bradykinin is also metabolized by ACE. If you block this, you get increased risk for the cough and possibly angioedema.
Proteinuria - Angiotensin II slows down GFR (holding cells tight to decrease leakiness) and causes solutes to back up. When this is released, protein can leak out.

40
Q

ARB side effects

A

Affecting the same system as the ACE inhibitors
Only difference is that with the ARBs are not changing bradykinin levels and typically don’t see the cough associated with bradykinin.

41
Q

Pro-renin

A

The ultimate step preventing formation of angiotensin II.
Pro-renin has action in itself. Enhances enzyme production of angiotensin II. It appears that pro-renin has its own receptor. When it binds to its receptor, appears to cause remodeling, fibrosis from kidneys. May have its own effects independent of angiotensin II.

42
Q

What is the antagonist of pro-renin?

A

Aliskiren. Only agent. High affinity competitive antagonist of renin that prevents activation of pro-renin receptor. prevents formation of angiotensin II. Appears to have additive effects.

Same kinds of side effects as with ARBs

43
Q

Angiotensin II agonists

A

Helpful in treatment of things like shock

Can’t really control enough to have a therapeutic benefit.

Integrated Drug Structure, Function, and Therapeutics Winter Term (18 decks)

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