Pharmacology of RAAS (Renin-angiotensin-aldosterone system) Flashcards
Learning outcomes
• 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)
Overview of RAAS system
• 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
3 mechanisms of renin secretion
• 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
What effects does angII have on glomerular filtration?
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
Pharmacology of Angiontensin receptors
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?
Pharmacological manipulation of RAAS
Angiotensinogen > angiotensin 1 (renin- renin inhibitors, ‘kirens’)> angiotensin 2 ( ACE- ACE inhibitors, prils)> at 2 receptors ( at 1 antagonists, sartans)
ACE inhibitor actions
• 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
ACE inhibitors ADME (adsorption distribution metabolism excretion) and pharmacokinetics
• 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
ACE inhibitors- clinical uses
• 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
Management of uncomplicated hypertension (without T2DM)
• 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
Pathophysiology of systolic heart failure
• 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)
Benefit of RAAS blockade in asymptomatic left ventricular dysfunction or symptomatic heart failure
• 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
Renal indications
• 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?
Adverse effects of ACE1s
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
ACE inhibitors- drug interactions
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
