Pharmacology of RAAS (Renin-angiotensin-aldosterone system)

Question 1

Learning outcomes

Answer 1

• Contrast the pros and cons of inhibiting the renin-angiotensin-aldosterone axis at the various different levels
• Describe the pharmacodynamic effects of ACE inhibition and how these may benefit patients with hypertension and heart failure
• Analyze the complex relationship ACE inhibition has with renal function
• Identify patient characteristics that may predict potential adverse effects from ACE inhibition
• Outline precautions that should be taken when introducing ACE inhibitor therapy
• Contrast the differences between ACE inhibitor and angiotensin receptor
blockade that may influence choice of use
• Outline the pharmacology of dual angiotensin receptor /neprilysin inhibitors (ARNIs)

Question 2

Overview of RAAS system

Answer 2

• physiological role in maintenance of circulatory volume and BP
• activated when volume/pressure falls and/or glomerular filtration reduced
• angiotensin II promotes vasoconstriction and aldosterone (and vasopressin) secretion, prompting sodium (and water) retention and potassium loss
• Additional actions: angiotensin also mediates vascular and cardiac growth/ structural remodelling and enhances noradrenaline release from sympathetic nerves
Most a1>a2 conversion occurs in vascular beds

Question 3

3 mechanisms of renin secretion

Answer 3

• in response to salt/water loss, fall in blood volume
and blood pressure, reduced glomerular filtration
– detected by volume receptors in central veins and baroreceptors in
carotid arteries and aortic arch leading to disinhibition of renal sympathetic nerves : noradrenaline release is coupled to b1 adrenoceptors which stimulate renin secretion
– pressure-sensitive granular cells also respond directly to localised fall in renal arterial pressure by secreting renin
– reduced GFR and delivery of sodium to the macula densa cells causes them to also stimulate granular cells to secrete renin

Question 4

What effects does angII have on glomerular filtration?

Answer 4

in addition to general systemic vasoconstriction
-AngII contracts renal mesangium reduces filtration area (increases pressure)
-AngII also constricts renal efferent arteriole
> renal artery and afferent arteriole important in pathophysiological conditions
e.g. renal artery stenosis
maintains glomerular filtration but restricts blood flow to
tubule (ischaemia), puts more strain on the kidney

Question 5

Pharmacology of Angiontensin receptors

Answer 5

AT1- Location: blood vessels, heart, kidney, brain, lung, liver, adrenal and pituitary gland
Function: vasoconstriction; cardiac contractility; remodelling of heart and vessels; release of aldosterone and vasopressin; drinking/thirst; noradrenaline release; negative feedback on
renin release

AT2- mainly in brain, reproductive tissues, heart?
foetal tissues?
largely unknown? embryogenesis? anti-proliferative effects? vasodilatation via bradykinin and
nitric oxide release?

Question 6

Pharmacological manipulation of RAAS

Answer 6

Angiotensinogen > angiotensin 1 (renin- renin inhibitors, ‘kirens’)> angiotensin 2 ( ACE- ACE inhibitors, prils)> at 2 receptors ( at 1 antagonists, sartans)

Question 7

ACE inhibitor actions

Answer 7

• peripheral vasodilatation, ↓ BP
– reduces AngII constrictor action in arteries and veins
– more pronounced in hypertensives than normal volunteers
– esp. when renin secretion enhanced due to salt/volume
depletion
• ↓ aldosterone (and vasopressin) secretion
– ↓ Na+ /water retention, blood volume
• ↓ sympathetic activation
– ↓ facilitation of neuronal noradrenaline
release by angiotensin II
• ↑ bradykinin / PG vasodilatation,
– prevent metabolism of bradykinin, helps ↓ BP
– improved endothelial function, ↓risk of cardiovascular
events in atheromatous disease
• ↓ angiotensin mediated generation of ROS
– inhibition of NADPH oxidase, oxidative stress-related injury
• ↓ glomerular filtration rate
– esp. useful in diabetic nephropathy
• ↓ hypertension-related remodelling
– in vasculature, heart and kidney

Question 8

ACE inhibitors ADME (adsorption distribution metabolism excretion) and pharmacokinetics

Answer 8

• most are pro-drugs activated by liver metabolism
– suffix ‘at’ indicates active metabolite e.g. enalaprilat
– captopril and lisinopril active on absorption
• mainly cleared by renal excretion
• differ in potency, action duration, rate of
excretion
– influences frequency and dose of administration

examples-
• Captopril
• Enalapril

• Lisinopril
• Ramipril
• Perindopril
• Trandolapril- these 4 have Slower onset, longer duration allowing once daily dosing Less rash / taste disturbance = More commonly used

Question 9

ACE inhibitors- clinical uses

Answer 9

• Hypertension
• Post-MI especially if associated with ventricular
dysfunction
• In people at high risk of ischaemic heart disease
• Heart Failure
• Diabetic nephropathy (especially Type 1)
• Progressive renal insufficiency

Abnormal RAAS function leads to hypertension due to 
due to:
• sodium retaining effects
• vasoconstrictor effects
• structural remodelling

Question 10

Management of uncomplicated hypertension (without T2DM)

Answer 10

• Step 1 especially younger Caucasian with more active RAAS than elderly or Black who tend to be more volume-expanded with less elevated RAAS activity
• also if other classes contra-indicated or not tolerated
• but also consider hypertensives with other cardiac and renal indications and contra-indications for RAAS
inhibition

Other cardiac indications
• history of myocardial infarction or established
coronary heart disease?
– reduce cardiac work (and oxygen demand) especially when high risk of ischaemia, reduce remodelling and left ventricular dysfunction post-MI, prophylaxis to prevent further cardiovascular events
• recurrent atrial fibrillation
– ↓ atrial fibrosis and remodelling, ↓ stroke

Question 11

Pathophysiology of systolic heart failure

Answer 11

• reduced cardiac output and blood pressure trigger
compensatory activation of RAAS (and SNS) to
maintain tissue perfusion, promote cardiac
remodelling (neurohormonal hypothesis of HF)
• progressively inadequate/deleterious (increased
blood volume, pressure, adverse remodelling)
• frequent hospitalisation, deterioration
• significant morbidity and mortality
– risk of arrhythmia (sudden cardiac death)

Question 12

Benefit of RAAS blockade in asymptomatic left ventricular dysfunction or symptomatic heart failure

Answer 12

• reduce cardiac after-load (↓vasoconstriction)
• reduce cardiac preload (↓ venoconstriction)
• enhance diuresis (↓ Na+ , water, blood volume)
• regress LVH and ↓ risk of arrhythmias (AngII is a
hypertrophic growth factor)
• reduce cardiac work and ischaemia
• improve cardiac output
• preserve potassium (especially in patients taking loop diuretics)
• reduce symptoms (including breathlessness)
• slow progression, reduce frequency and severity
of hospitalisation

Question 13

Renal indications

Answer 13

• diabetic nephropathy
– esp. if proteinuria, microalbuminuria (>30 mg/24 h) present
– ACEI lower glomerular filtration rate and slow progression of renal damage
– greater evidence in T1DM than T2DM?
• possibly beneficial (with caution) in nondiabetic chronic renal parenchyma disease?

Question 14

Adverse effects of ACE1s

Answer 14

accumulation of bradykinin (vasodilator) contributes
to antihypertensive action
• but causes dry cough in 10-15% of patients and
angiooedema in <0.2% of patients

Rapid swelling of lips, tongue, mouth,
throat leading to airway obstruction

acute renal failure
most often seen in those with renovascular disease
or generalised atherosclerosis, caution in elderly
↓ flow and
pressure Need to routinely monitor renal function (serum Urea and Electrolytes)
before and after starting (or increasing dose of) an ACE inhibitor

• first dose hypotension
– often in heart failure or those with high renin levels
(with diuretic intake, sodium / volume depleted,
or renovascular disease)
• hyperkalaemia
– due to reduced aldosterone secretion
• teratogenicity
• skin rash
• taste disturbance

Question 15

ACE inhibitors- drug interactions

Answer 15

In combination with:
• diuretics Na ↓
• potassium –sparing diuretics
• ↑ risk of hyperkalaemia
• other hypotensive agents
• risk of 1st dose hypotension, esp. in volume depleted
• NSAIDS
• reduce renal blood flow
• ↑ risk of renal impairment

Question 16

Precautions for use of ACE1

Answer 16

• use a low dose when starting the drug in patients with heart failure – monitor blood pressure and renal function
• avoid starting the drug in established renovascular disease unless guided by renal physicians
• watch for rising K+ and avoid potassium supplements and potassium sparing diuretics
• probably contraindicated in severe aortic stenosis (all
vasodilators- > risk of hypotension)
• DO NOT GIVE IF PREGNANCY PLANNED

Question 17

AT1 receptor antagonists (ARBs)

Answer 17

• antagonise effects of AngII at AT1 receptors
– including any AngII derived from alternative synthetic pathways as well as ACE (such as heart cell chymase)
• do not prevent metabolism of vasodilator
mediators such as bradykinin
– avoid cough but also ↓ some benefits of ACE inhibitors?
• might also promote AT2 receptor signalling?
• cleared by hepatic metabolism

examples- 
• Losartan
• Irbesartan
• Valsartan
• Candesartan
• (Telmisartan)
• (Olmisartan)

Question 18

Clinical and contraindications/cautions for ARBs

Answer 18

Clinical:
• Hypertension when intolerant of ACE-inhibitor
• Post-MI especially if associated with ventricular
dysfunction
• In people at high risk of ischaemic heart disease
• Heart Failure
• DM nephropathy (more so T2DM than T1DM?)
– more evidence than for ACE inhibitors but ACE inhibitors often still preferred
• Progressive renal insufficiency
i.e. very similar to ACEi (non-inferior?) but ACEi often tried first due to evidence, experience and cost

Contraindications:
• generally similar to ACE inhibitors
• contra-indicated in bilateral renal artery stenosis
• caution in unilateral disease, history of renal
impairment or generalised atherosclerosis, elderly
– monitor renal function / serum K+ (U+E) before and after
• avoid in aortic stenosis
• contra-indicated in pregnancy

Question 19

Adverse effects of AT1 receptor antagonists

Answer 19

• generally mild and better tolerated than ACEI?
• 1st dose hypotension
– esp. in volume-depleted /in combination with diuretics
– less marked than for ACE inhibitors?
• acute renal failure
• hyperkalaemia
– especially with K+ sparing diuretics?
• rarely angio-oedema
Do NOT cause dry cough

Question 20

Dual RAAS blockade with ACEi and ARBs

Answer 20

dual blockade no longer recommended unless
under renal physician guidance
• little ↑ efficacy BUT ↑ side effects (ONTARGET)
• no real benefit seen in meta-analysis in terms of
antihypertensive effect, worsens renal function
generally, limited evidence for benefit in heart failure

Question 21

Dual NEP Enzyme/Angiotensin Receptor Inhibitors (ARNIs)

Answer 21

• EntrestoTM (sacubitril/valsartan, LCZ696)
− inhibition of neprilysin (prevents metabolism of vasodilator
peptides – including ANP, BNP)
− blockade of Angiotensin AT1
receptor (prevents actions of
angiotensin II)
− reduce morbidity and mortality in systolic heart failure
(Paradigm-HF)
− clinical trials ongoing in hypertension (and other current indications for ACEI, ARB use)