Where is angiotensinogen produced? What organs play a role in its conversion to angiotensin II?
Angiotensinogen is produced in the liver. Renin is made in the kidney. ACE is made in the lungs.
What enzymes allow for conversion of angiotensin I? Once converted to angiotensin II, how is aldosterone release triggered?
ACE (in the lung) and human heart chymase form angiotensin II from angiotensin I. Angiotensin II then goes on to bind to AT1 receptors that stimulate aldosterone release. AT2 receptors are actually antagonize AT1.
How do ACE inhibitors not only decrease aldosterone secretion, but also stimulate vasodilation?
Accumulation of angiotensin I is a result of an ACE inhibitor. Aside from decreased binding of angiotensin II to AT2 receptors and decreased aldosterone secretion, angiotensin I increasingly binds to AT receptors 1-7, causing vasodilation.
A patient comes to see you for high blood pressure with a history of heart failure. You prescribe him an ARB (angiotensin II receptor blocker). What effects are you protecting his body from?
1) Rapid pressor response (vasoconstriction) 2) Slow pressor response (fluid retention) 3) Hypertrophy and Remodeling (growth factors turned)
You are performing an experiment on a cat and after administering a drug that agonizes the AT1 receptor, causes hypertension. How is blood pressure increased?
Vasoconstriction, cell growth and catecholamine release increases peripheral resistance. Increased contractility and volume overload increases cardiac output.
A patient with uncontrolled hypertension comes to see you looking for help. After getting lab tests done you note that her blood renin levels are very low. How else might her blood pressure be increased in the absence of renin?
There are other ways to activate the AT1 receptor and induce volume overload, cell growth, increased peripheral resistance, increased cardiac output and ultimately hypertension. These include receptor dimer formation, mechanical stretch, autoantibodies (pre-eclampsia), and EGFR (epidermal growth factor).
What are the four classes of drugs that target the renin, angiotensin, aldosterone pathways?
Renin inhibitors, ACE inhibitors, ARB (AT1 receptor inhibitor), and aldosterone antagonists.
What are the ACE inhibitors?
Catopril, enalapril, and other "prils".
What effects does ACE have when it is not inhibited?
Conversion of angiotensin I to angiotensin II. Degradation of bradykinin to inactive bradykinin.
A 44 year old patient comes to see you for his check up. Since you last saw him his blood pressure has gone down after taking catopril regularly. He does, however, notice a new cough. What is the cause of this side effect?
In addition to blocking angiotensin II production, ACE inhibitors also block degradation of bradykinin. Bradykinin vasodilates which lowers BP, but it also causes bronchiole smooth muscle contraction and cough.
Why are ACE inhibitors good drugs for patients suffering from hypertension? CHF, cardiomyopathy and MI? Diabetes? Renal failure?
Decreased TPR, decreased venous return, decreased renal actions and decreased cardiovascular smooth muscle cell growth.
What are some of the ACE inhibitors' advantages over other vasodilators in patients with congestive heart failure?
They inhibit remodeling, they do not produce neurohormonal activation or reflex tachycardia and tolerance does not develop.
What adverse effects and contraindications come with ACE inhibitors?
Why aren't ACE inhibitors effective when you are taking NSAIDs?
ACE inhibitors inhibit vasoconstriction of renal arteries that lowers glomerular filtration pressure. NSAIDs reduce prostaglandin production which induces vasoconstriction. The two cancel each other out.
Why can't you use ACE inhibitors when you have renal stenosis?
Angiotensin II vasoconstricts the efferent arterioles to increase glomerular filtration rate (GFR) via increased perfusion pressure. With stenosis, afferent flow cannot be increased, and taking angiotensin II out of the picture with ACE inhibitors takes out GFR regulation and increases kidney failure.
What are drug interactions you need to be award of when using ACE inhibitors?
What are the drugs that are AT1 receptor antagonists (ARBs)?
How do contraindications and adverse reactions of ARBs compare with ACE inhibitors?
They are the same minus the cough.
Why would you prescribe a patient valsartan for acute myocardial infarction?
To inhibit extensive remodeling of the myocardium by antagonizing AT1 receptors.
What drug are aldosterone receptor antagonists? How are these drugs therapeutic?
Spironolactone and eplerenone. They decrease volume uptake, reduce myocardial NE uptake, reduce baroreceptor sensitivity and reduce fibrosis.
When is it a good time to start usage of aldosterone antagonists with ARBs or ACE inhibitors?
After 17 weeks. Before that the ARBs and ACE inhibitors can prevent aldosterone production on their own, then they wear out.
Why is epierenone preferred to spironolactone?
Epierenone binds to the mineral corticoid receptor where spironolactone binds to both the mineral corticoid receptor and glucocorticoid receptor, giving increased side effects.
How does a chronically high level of aldosterone cause edema, arrhythmias and fibrosis?
Edema = Na+ and H2O retention. Arrhythmias = K+ and Mg2+ excretion. Fibrosis = collagen deposition
Why are you at a higher risk for developing arrhythmias when you are taking spironolactone?
It antagonizes aldosterone receptors which decreases K+ excretion and can cause hyperkalemia.
Though diuretics are great for CHF and hypertension, what contraindications exist for these patients?