ACE Inhibitors and ARBs Flashcards
What suffix do ACE inhibitors have?
‘pril
e.g. Cilazapril
What suffix to ARBs have?
‘sartan
e.g. Losartan
Describe what RAAS system works with to form AT II, and why it does this
The renin-angiotensin-aldosterone system works synergistically with the ANS to form angiotensin II, and to stimulate the release of aldosterone from the adrenal cortex.
This is done to control Na+ excretion, fluid volume (aldosterone) and vascular tone (AT II)
Describe the steps of angiotensin II production
- Sympathetic stimulation of renal β1 receptors, low renal blood pressure and low Na+ conc. in distal tubule (detected by macula densa cells) causes renin release from the juxtaglomerular cells.
- Renin converts angiotensinogen (in liver) to angiotensin I
- AT I is converted to AT II by ACE (extrinsic form mainly)
How is aldosterone produced?
When AT II acts on the adrenal cortex to stimulate release of aldosterone
Aldosterone increases Na+ retention to increase blood volume, and this restores blood pressure to maintain MAP
Which receptors do AT II act as an agonist for?
AT II acts as an agonist for AT1 and AT2 subtype receptors.
AT1 = pathological
AT2 = Beneficial
What happens when AT II binds to AT1 subtype receptor?
Mediates pathological hypertensive effects of AT II (hypertension, fibrosis, hypertrophy, vasoconstriction)
What happens when AT II binds to AT2 subtype receptor?
- This is considered beneficial.
- It increases cell proliferation
- increases nitric oxide production
- anti-fibrotic, antihypertensive
- vasodilation
What physiological effects does AT II have when it binds to AT1 receptor
- Powerful vasoconstrictor
- Promotes Na+ and fluid retention by nephron
- Stimulates release of aldosterone from adrenal cortex to increase blood volume by retaining more Na+ and fluid
- Enhances sympathetic activity
- acts winin the CNS and sympathetic nerve endings
- stimulates synaptic NA release and inhibits NA reuptake
- stimulates cardiac hypertrophy and vascular hypertrophy
- stimulates collagen deposition promoting fibrosis (stiffening and scarring) - can cause scarring of organs
- stimulates the release of vasopressin (Antidiuretic hormone, ADH from posterior pituitary)
What is the action of AT II of pre-synaptic AT1 receptors?
NA is kept within the vesicles of the nerve endings
And this NA is then released into the synaptic cleft
The increase in NA negatively feeds back on alpha 2 receptors and decreases NA output (like clonidine)
BUT, we AT II is added to this situation, this binds to the AT subtype 1 receptors and has the opposite effect.
- AT II causes an increase in tyrosine hydroxylase activity (TH), this causes more NA formation, causing more NA output.
- and AT II also inhibits the re-uptake of NA into the pre-synaptic cell back across the synaptic cleft (so it exaggerates the effects of the sympathic nervous system)
Decrease the action of cilazapril (ACE inhibitor)
- It decreases the levels of AT II formed from AT I
- Therfore reducing arterial vasoconstriction, reducing systemic vascular resistance (reduced ventricular afterlaod)
- produces vasodilation of veins (reduced ventricular preload)
- Inihibition of ACE also increases levels of bradykinin (vasodilator)
- Also downregulates ATII provoked sympathetic activity (helps promote vasodilation)
Cilzapril reduces both ATII synthesis and bradykinin degradation
What is preload?
It’s all of the factors that contribute to passive ventricular wall stress (or tension) at the end of diastole
Whats afterload?
It’s all of the factors that contribute to total myocardial wall stress (or tension) during systolic ejection
Afterload is essentially the amount of work the heart has to do to eject blood during systolic ejection.
What effect do ace inhibitors have on the kidney and vascular remodelling and fibrosis?
ACE inhibitors promote both Na+ (naturesis) and water excretion (Diuresis) reducing plasma volume, and this plasma volume reduces blood pressure, and reduces aldosterone production leading to K+ retention in plasma.
ACE inhibitors also inhibit cardiac and vascular remodelling and fibrosis, which is typically associated with chronic hypertension, MI and HF
Describe the pharmkinetics of Cilazapril (ACE inhibitor)
Cilazapril is taken orally, it has good oral absorption with a ~60% bioavailability.
Cilazapril is metabolised to active drug cilazaprilat by 1st pass
- heptic impairment affects cilzaprilat formation but not clearance
- renal impairment reduces clearance resulting in raised plasma concentrations of cilazaprilat.
typically has peak plasma levels 2 hours after taking, and it has a half life of 8-9h
How can ACE inhibitors interact with NSAIDs in the kidney?
ACE inhibitors reduce vasocontriction of the efferent arteriole, dropping GFR. And NSAIDs reduces release of prostaglandins (PGI2, PGE2) which are needed to keep the afferent arteriole dilated.
Therefore if we using both drugs together, we get narrowing on the afferent arteriole due to there not being enough prostaglandins to keep it dilated, and we get dilation of the efferent arteriole - reducing GFR alot. This is cause a build up of drugs and metabolites in the body, causing a toxic effect
Decrease where ARBs have their effect
They inhibit binding of ATII to the AT1 subtype receptor
AT II is produced not just by the RAAS system, but also by many other systems - therefore by blocking AT1 we can inhibit all pathways
What are the benefits of ARBs over ACEI’s
What are the side effects of ARBs
What are the pharmokinetics of ARBs?
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