Block A Lecture 2 - The RAAS System and Diuretics Flashcards by Ryan Murray

What does the RAAS system regulate?

BP and fluid balance (blood volume)

(Slide 3)

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What are 3 triggers for the RAAS system?

An increase in renal sympathetic activity

A decrease in glomerular filtration (blood flow to kidneys)

Decrease in blood pressure

(Slide 3)

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What happens when the RAAS system is activated?

Renin is produced which ultimately results in production of angiotensin II, which increases BP and stimulates release of aldosterone, which increases sodium and water resorption into the blood, which also increases BP

(Slide 3)

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What is angiotensinogen?

A molecule produced by the liver which acts as a precursor for all angiotensin variants

(Slide 4)

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What does renin convert angiotensinogen into?

Angiotensin I

(Slide 4)

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What enzyme converts angiotensin I into angiotensin II?

ACE

(Slide 4)

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What enzyme converts angiotensin II into angiotensin I-7?

ACE2

(Slide 4)

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What does aminopeptidase do?

It converts angiotensin II to angiotensin III

(Slide 4)

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What is angiotensin I-7?

It counteracts the RAAS system by acting as a vasodilator, and reducing blood pressure, opposing angiotensin II’s effects

(Slide 4)

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What organ is renin secreted from?

The kidneys

(Slide 5)

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What are the 2 different types of renin and how do they differ?

Tissue renin - Found in tissues such as the heart, blood vessels, brain, adipose tissue, and kidneys, and acts locally and is triggered by local stimuli such as oxidative stress, inflammation or tissue damage and leads to localised effects such as vascular remodelling or fibrosis

Circulating Renin - Secreted by the juxtaglomerular cells of the kidney into the bloodstream and is triggered by typical RAAS system triggers. Leads to systemic effects such as an increased BP and stimulation of aldosterone leading to increased sodium and water retention

(Slide 5)

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What are 3 different ways in which renin secretion can be stimulated?

Sympathetic nerves can stimulate β1 receptors on juxtaglomerular cells to secrete renin

Sodium chloride levels of ultra-filtrate of the nephron are measured with prostaglandins being released if renal perfusion pressure is low, and these activate kidney cells.

Macula densa cells can measure sodium chloride levels and release prostaglandins if renal perfusion level is low, with these activating kidney cells.

(Slide 6)

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What can sodium depletion lead to concerning the RAAS system?

It can lead to sympathetic nerve stimulation, leading to activation of the RAAS system

(Slide 7)

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What can ACE2 convert angiotensin I into?

Angiotensin I-9

(Slide 7)

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What acts on mineralocorticoid receptors and what does this result in?

Aldosterone acts on these receptors which leads to sodium and water retention and an increase in blood volume and an increase in blood pressure

(Slide 7)

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What 2 receptors can angiotensin II act on?

AT1 and AT2 receptors

(Slide 7)

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What other than angiotensin II can act on AT1 receptors, and what effects do these receptors lead to?

Angiotensin IV can also act on these receptors, and they cause vasoconstriction, hypertension, inflammation, cardiac hypertrophy, oxidative stress, fibrosis and arrythmia

(Slide 7)

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Other than angiotensin II, what 2 things can act on AT2 (Mas) receptors, and what effects do these receptors cause?

Angiotensin III and angiotensin I-7 can act on these receptors and they cause vasodilation, anti-inflammatory and anti-proliferative effects, a decrease in cell growth, oxidative stress and fibrosis while causing an increase in natriuresis (kidneys removing excess sodium via urine)

(Slide 7)

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What are 4 effects of angiotensin II?

Answers Include:

Vasoconstriction

Stimulation of aldosterone secretion

Direct effect on the kidney to cause sodium and water retention (increases blood volume and pressure)

Feedback inhibition of renin secretion

Increases sympathetic nerve activity

Stimulation of secretion of ADH/ vasopressin (also leads to increased BP)

(Slide 8)

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Does angiotensin II favour interaction with the AT1 or AT2 receptors?

AT1

(Slide 9)

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What can sustained activity of the AT1 receptor lead to?

Vascular remodelling

(Slide 9)

What do ACE inhibitors do?

They block the ACE enzyme, preventing angiotensin I to be converted into angiotensin II, decreasing circulating angiotensin II (leading to a decreased pulmonary vascular resistance and BP) and aldosterone secretion, (leading to an increase in sodium and water excretion, which leads to a decreased blood volume, leading to a decreased BP)

Their diuretic effects also help to “unload” the heart, improving heart function

They prevent development of hypertrophy due to blocking angiotensin II

Inhibition of bradykinin breakdown may also be relevant to vasodilatory properties
(Slides 13 - 15)

What do ACE inhibitors promote the formation of?

Angiotensin I-7

(Slide 15)

What are 3 examples of adverse effects which ACE inhibitors can cause?

Answers Include:

Hypotension

Renal failure

Adverse effects on foetus (renal failure, hypotension pulmonary hypoplasia, oligohydramnios)

Coughing (due to accumulation of bradykinin in the lungs)

Angio-oedema (due to accumulation of bradykinin and substance P increasing vascular permeability and releasing things into the skin causing swelling)

(Slide 16)

Other than angiotensin I, what are 3 other substrates of ACE?

Bradykinin Enkephalins Substance P (Slide 17)

What is substance P?

A neuropeptide involved in processes such as pain perception, inflammation, and stress responses (Slide 17)

What are 2 examples of angiotensin II receptor blockers (ARBs)?

Answers Include: Losartan Candesartan Valsartan Irbesartan (Slide 18)

What do ARBs selectively block?

AT1 receptors (Slide 18)

How do the consequences of ARBs differ to those of ACE inhibitors?

They don't lower angiotensin II levels and do not cause the cough that is associated with ACE inhibitors (Slide 18)

What is the only renin inhibitor on the market (as of june 2020)?

Aliskiren (Slide 20)

What are the consequences of renin inhibitors (compared to other hypertension drugs)?

They lower angiotensin I level (rather than angiotensin II) and shouldn't cause cough associated with ACE inhibitors (Slide 21)

What can the combination of Aliskiren (a renin inhibitor) with ACE inhibitors or ARBs lead to?

Potential adverse effects in patients with kidney impairment or diabetes (Slide 21)

What are aldosterone / mineralocorticoid receptor antagonists?

Drugs which competitively bind to, and inhibit mineralocorticoid receptors and are used in resistant hypertension or heart failure Note: Aldosterone receptors and mineralcorticoid receptors are the same. The lecture does not say this. I hate this course sometimes I thought they were different for months I was so confused (Slide 22)

What is an example of an adverse effect of aldosterone receptor antagonists?

Hyperkalaemia (high potassium levels) (Slide 22)

In what patients should aldosterone receptor antagonists not be used?

In patients with renal impairment or hyperkalaemia (high potassium levels), as aldosterone promotes the excretion of potassium into the urine (Slide 22)

How can bradykinin result in vasodilation?

They can bind to B2 receptors, leading to the release of prostaglandins, which act on smooth muscle cells, leading to smooth muscle relaxation and vasodilation (Slide 23)

What kind of drug is sacubitril?

It's a NEP inhibitor (Slide 24)

What do NEP inhibitors do?

They inhibit neprilysin (NEP) , preventing it from degrading bradykinin (which interacts with B2 receptors, causing vasodilative effects) and preventing it from breaking down natriuretic peptides, which cause vasodilation, natriuresis and diuresis, decreasing BP preload and afterload, allowing them to act longer, however clinical trials failed to show a decreased BP (Slide 24)

What is entresto?

A drug which combines sacubitril (NEP inhibitor) and valsartan (angiotensin II receptor blocker). It is used for heart failure, but not for hypertension It can actually reduce blood pressure too much in unresistant hypertension, leading to dangerous hypotension (Slide 25)

What are 4 functions of the kidneys?

Regulation of water and inorganic ion balance (Most important) Removal of metabolic waste products from blood and excrete them via urine Removal of foreign chemicals in the blood and excretion via urine Endocrine functions (e.g via renin and aldosterone) (Slide 27)

What does an increase in renal pressure lead to?

Intrarenal redistribution of pressure which leads to increased absorption of salt and water (Slide 28)

What can decreased pressure in renal arterioles and decreased sympathetic activity lead to?

Renin production leading to angiotensin II production (Slide 28)

What do all diuretics indirectly do?

Prevent reabsorption of water in the kidneys, most of which do so by preventing the reabsorption of sodium (Slide 29)

What are the 3 classes of diuretics and what is an example of each?

Loop Diuretics - Furosemide supplemented with either spironolactone or amiloride Thiazides - Bendroflumethiazide Potassium Sparing - Eplerenone or Spironolactone (Slide 29)

Where do loop diuretics act?

They inhibit the Na+/K+/2Cl-co-transporter in the loop of Henle (Slide 30)

Where do thiazide diuretics act?

They inhibit the Na+/2Cl-transporter in the distal tubule (Slide 30)

Why are thiazide diuretics the most commonly used diuretrics?

as the Na+/2CL-transporter only reabsrobs about 5% of filtered Na+, meaning they are less potent and they have a less severe side effect profile (Slide 30)

How does aldosterone exert indirect negative feedback on the RAAS system?

By increasing effective circulating volume and lowering plasma potassium concentration (Slide 31)

What are 2 mechanisms of actions of potassium sparing diuretics?

They can either inhibit the distal tubule Na+-channel or they can inhibit the aldosterone receptor (Slide 31)

How do potassium sparing diuretics which inhibit the mineralocorticoid receptor promote sodium and water excretion in the collecting tubule and duct?

As aldosterone can stimulate sodium reabsorption and potassium excretion, so blocking its receptor produces the opposite effect (Slide 31)