CVPR Week 8: RAAS Flashcards
Objectives
The conversion of angiotensinogen into angiotensin I
How large is the angiotensinogen protein?
57 kDa
What happens in the conversion of angiotensinogen to angiotensin I?
14 amino acids in amino-terminal are cleaved by renin
Where is angiotensinogen produced?
It is synthesized by the liver
What determines the rate of angiotensin I formation?
concentration is important
What increases the concentration of angiotensinogen?
4 listed
- Corticosteroids
- Estrogens
- Thyroid hormone
- Pregnancy
Identify
Identify
Where is Renin produced?
synthesized by the granular juxtaglomerular cells of the kidney
What releases Renin?
Granular Juxtaglomerular cells
What controls the release of Renin?
Macula densa cells in the distal tubule control the release of Renin
Factors that control active Renin release from granular juxtaglomerular cells
5 listed
- Macula densa mediators
- β1-adrenergic receptor activation by NE or Epi
- granular juxtaglomerular cell stretch
- Angiotensin II negative feedback effect:
- ANP-BNP
Macula densa mediators of renin release
- decreased Na+ = increased PGE2 release = increased cAMP = increased Renin
β1-adrenergic receptor activation mediators of renin release
increased cAMP = increased renin
Granule juxtaglomerular cell stretch control of renin release
- mediated by increased Ca2+ permeable stretch receptor
- decreased stretch (vasodilation through α1 block, vasodilators, diuretics, anesthetics) = increased renin
- Increased stretch (vasoconstriction through α1 receptor activation, angiotensin II = decreased renin
Angiotensin II negative feedback effect control of renin release
angiotensin II receptor - increased [Ca2+] = decreased renin
ANP-BNP control of renin release
increased cGMP = decreased renin
Describe the conversion of angiotensin I to angiotensin II
ACE AKA
Angiotensin-converting enzyme
ACE functions
- converts angiotensin I to angiotensin II
- breaks down bradykinin
Effects of angiotensin II
Angiotensin II potency in vasoconstriction
40 times more potent than norepinephrine
Angiotensin II vasoconstriction mechanism
- Direct effect via angiotensin II receptor activation of Gq and PLC increasing IP3 levels and release of Ca2+ from intracellular stores.
- Rho kinase is also activated decreasing myosin light chain phosphatase activity
- Angiotensin II can also increase peripheral resistance via effects on the CNS by increasing sympathetic tone
Angiotensin II reflex bradycardia
there is little to no bradycardia because angiotensin II rests the baroreceptor reflex
Angiotensin II effect on the renal circulation
constricts the efferent glomerular arteriole maintaining glomerular filtration rate
Effects of angiotensin II
Drug classes that inhibit the renin-angiotensin-aldosterone system
5 listed
- Renin release blockers
- Renin inhibitors
- ACE inhibitors
- Angiotensin II receptor blockers
- Aldosterone antagonists
Renin release blockers
2 listed
- β-blockers
- centrally acting α2 agonists
Renin inhibitors
Aliskiren
ACE inhibitors
Captopril
Angiotensin II receptor blockers
Losartan
Aldosterone antagonists
- spironolactone
- eplerenone
β-blockers and RAAS
counteract the harmful effects of sympathetic and RAAS over-activation
β-blockers uses and mechanisms of improving outcomes
They are particularly useful in heart failure, cardiomyopathy and coronary artery disease
- decrease remodeling
- improve survival
- decreased incidence of sudden death/arrhythmias
- use in stable heart failure patients without substantial fluid retention
Prototype β-blocker
Metoprolol
Metoprolol clinical uses
- heart failure
- cardiomyopathy
- coronary diseases
β-blockers side effects
- bronchospasm
- bradycardia
- heart block
- heart failure (uncompensated patients)
- sedation
- sleep disturbances
- depression
- impotence
- mask hypoglycemia
- dyslipidemia
- rebound hypertension
- aggravate peripheral vascular disease
Renin inhibitor prototype
Aliskiren
Aliskiren uses
hypertension
Aliskiren side effects
- teratogen
- increased creatinine
- hyperkalemia
- hypotension
Aliskiren interactions
- prevents increases in plasma renin activity caused by other agents, including diuretics, Ca2+ channel blockers and vasodilators
- renal impairment, hyperkalemia, hypotension in combination with ARBs or ACEIs
- renal impairment with NSAID diuretics
ACE inhibitors mechanism
Mechanisms of cardiac benefits of ACE inhibitors
- Hemodynamic actions (i.e. vasodilation and decrease in intravascular volume)
- decrease in remodeling
Indications for ACE inhibitors
- Heart failure
- hypertension monotherapy
- hypertension associated with CHF or diabetes
- Cardioprotective after acute myocardial infarction
- Delay the progression of kidney disease, including diabetic nephropathy
ACE inhibitors adverse effects and mechanisms
- Cough
- Angioedema
- Teratogen
- Increased creatinine
- Hyperkalemia
- Hypotension
ACE inhibitors and renal vascular autoregulation
ACE inhibitors drug interactions
- K+ sparing diuretics, K+ supplements and K+ iodide = risk of hyperkalemia
- Increase effects of other anti-hypertensive meds (e.g. hypovolemic patients taking diuretics, also be careful with patients on NaCL restricted diets or with GI disorders)
ACE inhibitors prototype
Captopril
Captopril uses
- heart failure
- hypertension
- chronic kidney disease
- diabetic nephropathy
Captopril side effects
- cough
- angioedema
- teratogen
- increased creatinine
- hyperkalemia
- hypotension
Angiotensin II receptor blockers prototype
Losartan
Angiotensin II receptor antagonist mechanism
Angiotensin II receptor antagonist in heart failure
Losartan uses
- heart failure
- hypertension
- chronic kidney disease
- diabetic nephropathy
Losartan side effects
- Angioedema (less common)
- teratogen
- increased creatinine
- hyperkalemia
- hypotension
Losartan interactions
- K+ sparing diuretics, K+ supplements and K+ iodide = risk of hyperkalemia
- Increase effects of other anti-hypertensive meds (e.g. hypovolemic patients taking diuretics, also be careful with patients on NaCL restricted diets or with GI disorders)
Aldosterone antagonists mechanism of action
Aldosterone antagonists prototypes
- Spironolactone
- Eplerenone
Aldosterone antagonists clinical uses
Aldosterone antagonists toxicity
Spironolactone and gynecomastia
Overview
