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Pharmacology Block 2 > 09 Renin-Angiotensin > Flashcards

09 Renin-Angiotensin Flashcards

1
Q

Where is angiotensinogen synthesized?

A

Liver

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2
Q

Where is Renin synthesized? What is it’s function?

A

Juxtaglomerular Cells of Kidney

An acid protease that splits leucine-leucine bond of angiotensinogen giving angiotensin I (biologically inactive decapeptide)

Leads to Vasoconstriction/Aldosterone Secretion/Sympathetic Activation

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3
Q

How is Angiotensin II made?

A

Angiotensin Converting Enzyme (ACE) converts Angiotensin I into Angiotensin II (biologically active octapeptide)

t1/2 = 4 mins

Leads to Vasoconstriction/Aldosterone Secretion/Sympathetic Activation

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4
Q

What is the function of Angiotensin Converting Enzyme (ACE)? Where is it found?

A

Removes C-Terminal His-Leu dipeptide from angiotensin I producing angiotensin II, the active peptide

Converts Bradykinin, Substance P, and Enkephalins into inactive fragments

Found in vascular endothelium, lung, kidney and plasma

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5
Q

Where are renin granules located?

A

Juxtaglomerular cell–modified smooth muscle found in the media of afferent arteriole

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6
Q

What are specialized epithelial cells found at point where distal tubule comes in contact with afferent arteriole of kidney?

A

Macula Densa

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7
Q

Where are sympathetic nerves found in the juxtaglomerular apparatus?

A

Found in media or afferent arteriole

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8
Q

What is the function of angiotensinases?

A

Nonspecific aminopeptidases and carboxypeptidases

Inactivate angiotensin I and II

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9
Q

Where is aldosterone synthesized? Why is it synthesized? What is its function?

A

Synthesized by zona glomerulosa cells of the adrenal cortex

Synthesis stimulated by potassium, ACTH and angiotensin II

Mineralocorticoid acts on distal tubule and collecting duct to enhance sodium reabsorption and potassium excretion

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10
Q

What is the rate limiting step in activation of the renin-angiotensin system?

A

Control of Renin Release

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11
Q

What is the function of intrarenal baroreceptors?

A

Sense changes in wall tension of afferent arteriole

Wall tension inversely related to renin release

Ex. ↑ vascular pressure or afferent arteriolar vasoconstriction will ↑ wall tension and ↓ renin release

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12
Q

↓ vascular pressure or afferent arteriolar vasodilation will __ wall tension and __ renin release

A

↓ vascular pressure or afferent arteriolar vasodilation will ↓ wall tension and ↑ renin release

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13
Q

What is the function of the macula densa?

A

Senses changes in sodium load (UNaV) presented to the macula densa segment of distal tubule

Sodium load is inversely related to renin release

Ex. ↓ salt intake, sodium deprivation, diuretic therapy or ↓ GFR will ↓ sodium load and ↑ renin release.

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14
Q

↑ salt intake or mineralocorticoids will __ sodium load and __ renin release.

A

↑ salt intake or mineralocorticoids will ↑ sodium load and ↓ renin release

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15
Q

What is the function of the renal sympathetic nervous system? What mediates its function?

A

Renin release is increased by direct or indirect activation of renal sympathetic nerves or beta-adrenergic agonists

Mediated by beta1 adrenergic receptors on JG cells

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16
Q

Renin release is ___ by reduction in sympathetic nerve activity

A

Renin release is decreased by reduction in sympathetic nerve activity

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17
Q

What is the function of Angiotensin II?

A

Angiotensin II causes feedback inhibition that suppresses renin release by direct action on JG cells

AT1 receptor antagonists and converting enzyme inhibitor stimulate renin release by blocking this feedback inhibition

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18
Q

Which receptor does angiotensin II prefer to bind?

A

AT1&raquo_space; AT2

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19
Q

AT1 vs AT2 receptor effects

A

Specific angiotensin receptors, AT1 and AT2

AT1:

  • vasoconstriction
  • vascular proliferation
  • aldosterone secretion
  • cardiac myocyte proliferation
  • inc sympathetic tone

AT2:

  • vasodilation
  • antiproliferation
  • apoptosis
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20
Q

What is the mechanism of action when AngII binds AT1? AT2?

A

AT1:
AT1 →Gq→PLC→IP3 →Ca2+→Response

AT2: Unclear

21
Q

What is the mechanism of action of AT1 on vascular smooth muscle?

A

Arteriolar vasoconstrictor–inc BP

Hypertrophy– inc in wall to lumen ratio

  • inc in migration, proliferation, and hypertrophy
  • inc EC matrix proteins like collagen
22
Q

What is the mechanism of action of AT2 on vascular smooth muscle?

A

Endothelium-dependent vasodilation – nitric oxide mediated

Inhibition of proliferation of smooth muscle

Promotes apoptosis

23
Q

What is the effect of AT1 on the sympathetic nervous system?

A

The sympathetic neuron releases NE that binds post-synaptic alpha1 receptors leading to vasoconstriction

Ang II blocks the NE reuptake into the pre-synaptic terminal, increasing the duration vasoconstriction

At adrenal medulla, promotes Epi secretion

24
Q

What is the effect of AngII on CNS?

A

Promotes thirst-dipsogenic

Promotes ADH release and positive water balance

25
Q

What is the effect of AngII on the heart?

A
  1. Hypertrophy of cardiac myocytes

2. Increase in extracellular matrix production by fibroblasts

26
Q

What is the action of aldosterone on kidney? Heart?

A

Specific mineralocorticoid receptor agonist

Activates expression of target genes involved in sodium reabsorption and potassium secretion

At kidney:

  • acts on principal cells of collecting duct
  • sodium reabsorption, potassium secretion

At heart:

  • fibrosis of both ventricles
  • LV hypertrophy
27
Q

What is the role of volume and vasoconstriction in hypertension?

A

High Renin = Lots of Vasoconstriction -> inc TVR -> inc BP

Low Renin = Lots of volume

28
Q

What is the role of Angiotensin II in Congestive Heart Failure?

A

Vasoconstrictor – increases afterload

Activates sympathetic nervous system

Arrhythmogenic– increased force and rate of contractions

Promotes myocardial hypertrophy and apoptosis

Releases aldosterone

29
Q

What is the role of Aldosterone in Congestive Heart Failure?

A

Promotes Na+ and H2O retention –increases preload

Cardiac Fibrosis
LV Hypertrophy

30
Q

During CHF, how is perfusion to the vital organs maintained?

A

Maintain perfusion of vital organs by increasing preload, stimulating contractility, and increasing arterial tone

31
Q

Renin-Angiotensin System Inhibitors–function, AEs, contraindications

A

Drugs that inhibit the RAS by different mechanisms

BP lowering related to plasma renin activity

Dec BP with no change in HR

AE: can cause hypotension

Contraindicated in pregnancy– fetal wasting

32
Q

Losartan

A

Angiotensin II Receptor Antagonist

selectively block AT1 receptors

Angiotensin II act on AT2 receptors unopposed

Reduce BP without increasing HR
- caution use in patients with volume depletion or on diuretics (additive effect)

Improves heart failure:

  • dec BP (afterload)
  • dec aldosterone, reducing Na+ retention (dec preload)

Tx:
- Essential Hypertension

Contraindicated in pregnancy

33
Q

What drug is a selective AT1 receptor blocker, which reduces BP without increasing HR?

A

Losartan

34
Q

Captopril, Enalapril, Lisinopril

A

Angiotensin converting enzyme (ACE) inhibitors – inhibit angiotensin II formation and bradykinin degradation

Reduce BP without increasing HR
- caution use in patients with volume depletion or on diuretics (additive effect)

Improves heart failure:

  • dec BP (afterload)
  • dec aldosterone reducing Na+ retention (dec preload)
  • inc CO

Enalapril and Lisinopril are prodrugs = long duration of action

Lowers aldosterone release so hyperkalemia may occur–reduces diuretic-induced hypokalemia

Tx: Essential Hypertension

Side effects:
Rash, taste disturbance, proteinuria, neutropenia, cough and angioedema may occur.

35
Q

What drugs are Angiotensin Converting Enzyme Inhibitors?

A

Captopril, Enalapril, Lisinopril

36
Q

Which ACE inhibitors are prodrugs? What does this mean for duration?

A

Enalapril and Lisinopril are prodrugs = long duration of action

37
Q

What drug reduces diuretic-induced hypokalemia because it lowers aldosterone release?

A

ACE inhibitors

Captopril, Enalapril, Lisinopril

38
Q

What drug decreases both afterload, preload, as well as increases cardiac output?

A

ACE inhibitors

Captopril, Enalapril, Lisinopril

39
Q

What side effects can occur with ACE inhibitors?

A

Rash, taste disturbance, proteinuria, neutropenia, cough and angioedema may occur.

40
Q

When looking to prescribe anti-hypertensive medication to blacks, what works best: ACE inhibitor or diuretic?

A

Diuretic works best on blacks who are non-responders to ACE inhibitors

All other races have equal effectiveness from both

41
Q

Which is superior in reducing mortality due to heart failure: ACE inhibitors or vasodilators?

A

ACE inhibitors

42
Q

Why are ACE inhibitors contraindicated in patients with renal artery stenosis?

A

With decreased efferent arteriolar pressure, GFR decreases

There is a compensatory vasoconstriction via AngII which increases efferent arteriolar pressure thereby increasing renal perfusion pressure and GFR

ACE Inhibitors would prevent the compensatory vasoconstriction resulting in decreased renal perfusion pressure and GFR in addition to increased serum creatinine

43
Q

Aliskiren

A

Direct Renin Inhibitors Sections

Potent active site, non-peptide inhibitor

Specific for renin; no inhibition of other aspartic proteases

Decreases plasma angiotensin II and aldosterone concentrations

Long acting (t 1⁄2 = 24h) – given once daily

Antihypertensive effect enhanced by diuretic, converting enzyme inhibitor or angiotensin antagonist

Tx: Hypertension (lowers BP with no change in HR–comparable to angiotensin receptor blocker)

Side effects:
- fatigue, headache, GI symptoms

44
Q

What drug is a direct renin inhibitor?

A

Aliskiren

45
Q

How often does Aliskiren need to be taken?

A

Long acting (t 1⁄2 = 24h) – given once daily

46
Q

What drugs can be used to inhibit beta1 adrenergic receptors to lower bp related to plasma renin?

A

Propranolol (beta1 and beta2)
Metoprolol (beta 1)

Drugs that inhibit beta drenergic receptors:

  1. Cardiac– dec HR
  2. Renal– dec renin release
47
Q

What is the effect of aldosterone antagonists on Angiotensin II ability to vasoconstrict?

A

Does not effect AngII

AngII still results in vasoconstriction

48
Q

Spironolactone, eplerenone

A

Competitive aldosterone antagonists at mineralocorticoid receptor

Inhibit the renal (Na and H2O retention) and extra-renal (fibrosis, inflammation, etc.) actions of aldosterone

Uses:

  • diuretic
  • hypertension
  • heart failure

Reduce mortality from heart failure – decreases cardiac hypertrophy, fibrosis, sodium retention

Used with thiazide or loop diuretic to treat hypertension or edema

49
Q

What drugs inhibit the renal (Na and H2O retention) and extra-renal (fibrosis, inflammation, etc.) actions of aldosterone?

A

Spironolactone, eplerenone

Pharmacology Block 2 (12 decks)

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