Dawes: Angiotensin Converting Enzyme Inhibitors Flashcards
What is the function of the Renin-Angiotensin-Aldosterone-System?
Acts to regulate blood pressure, intravascular volume/Na+/K+ and fetal development.
Where is renin produced?
Renin is produced in the juxtaglomerular cells of the kidney.
Draw the RAAS pathway…
What does activation of AT-1 receptors lead to?
- Vasoconstriction
- Na+ Retention and therefore increased sympathetic tone
- Oxidant Stress
- Vascular smooth muscle hypertrophy
- Vascular Fibrosis due to raised endothelin and aldosterone
What AT receptors does Angiotensin II antagonists work to inhibit?
Performs a Sartan Block which only blocks AT-1 Receptors
What is raised in the blood when an ACE inhibitor is used?
ACE inhibitors act to inhibit the function of the Angiotensin Converting Enzyme. As a result the negative feedback from aldosterone is lost so you get a build-up (increase) in the concentration of renin and angiotensin I.
Also get increased concentrations of bradykinin.
How does Angiotensin II lead to vasoconstriction?
- Angiotensin II binds to AT I receptor.
- Activates G Protein that converts GTP to GDP and activates phospholipase C.
- Phospholipase C cleaves PIP2 to IP3 and DAG.
- IP3 causes increased release of calcium leading to raised intracellular calcium concentrations. This spike causes vasoconstriction.
- DAG activates protein kinase C which starts a downstream phosphorylation cascade.
What are the pathophysiological effects of Angiotensin II on the cardiac myocyte?
- Hypertrophy
- Apoptosis
- Cell Sliding
- Increased Wall Stress
- Increased O2 consumption
- Impaired Relaxation
What are the pathophysiological effects of Angiotensin II on the fibroblasts?
- Hyperplasia
- Collagen Synthesis
- Fibrosis
What are the pathophysiological effects of Angiotensin II on the peripheral arteries?
- Vasoconstriction
- Endothelial Dysfunction
- Hypertrophy
- Decreased Compliance
What are the pathophysiological effects of Angiotensin II on the coronary arteries?
- Vasoconstriction
- Endothelial Dysfunction
- Atherosclerosis
- Restenosis
- Thrombosis
What does the binding of Angiotensin II to AT-2 receptors cause?
- Antiproliferation
- Tissue Repair
- Apoptosis ‘
- Vasodilation
- Kidney Development
Where are AT-1 receptors found?
- Heart
- Kidney
- VSM
- Brain
- Adrenal Glands
- Adipocytes
- Placenta
Where are AT-2 receptors found?
- Heart
- Adrenal Gland
- CNS
- Kidney
What are the effects of aldosterone on the cardiac myocytes?
- Hypertrophy
- Norepinephrine Release
What are the effects of aldosterone on the fibroblasts?
- Hyperplasia
- Collagen Synthesis
- Fibrosis
What are the effects of aldosterone on the peripheral arteries?
- Vasoconstriction
- Endothelial Dysfunction
- Hypertrophy
- Decreased Compliance
What are the effects of aldosterone on the kidney?
- Potassium Loss
- Sodium Retention
What are the benefits of using an ACE inhibitor?
In first few weeks you get a decreased concentration of Angiotensin II and Aldosterone. However, these return to normal due to chymase activity. Despite this bradykinin levels remain high.
This raised bradykinin leads to vasorelaxation and increased endothelial function.
What are the different type of ACE inhibitors and Angiotensin II antagonists?
What are the pharmacokinetics of ACE inhibitors?
They are prodrugs such as cilazapril and enalapril that are activated via liver hydrolysis. They have variable half-lives and are excreted by the kidneys and therefore accumulate in renal failure.
What are the pharmacokinetics of the Angiotensin II Antagonists?
Some such as losartan and candesartan are active metabolites. They have variable half-lives and have variable routes of excretion. It is important that renally impaired patients treatment is approached with care and that electrolyte checks are performed.
Losartan and Candesartan are excreted 60% via the renal systemand 40% via the bile.
What are the pharmacodynamics of Angiotensin II Antagonists?
They block AT-1 receptors in a non-competitive way.
When is an ACE inhibitor used?
- In hypertensive patients an ACEi and Diuretic are often used as a combination therapy.
- In congestive heart failure it is often used as part of a multidrug therapy in combination with beta-blockers, diuretics, aldosterone antagonists and possibly angiotensin-II antagonists.
