AssessmentsACE inhibitors, ARBs and direct renin inhibitors
ACE inhibitors, ARBs and direct renin inhibitors
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 58-year-old man with controlled hypertension presents to the emergency department with a 2 week history of dry, hacking cough. The patient states that the cough is persistent and disruptive, and he finds himself lying down to improve the symptoms, although they usually do not. The patient states that 3 months ago he was switched to a different drug to treat his hypertension, and he is also currently taking a multivitamin for his health. Physical examination is unremarkable, and a plain chest radiograph is obtained which is also unremarkable. The attending physician switches the patient to a different antihypertensive drug in order to improve his symptoms. Which of the following is the most likely mechanism of action for the alternative drug?
Content Reviewers:Yifan Xiao, MD
Blood pressure is the force that blood exerts on the walls of blood vessels.
Now, there’s a number of factors that determine blood pressure. For example, imagine a hose connected to a pump where the hose is the blood vessel and the pump is the heart. If more water is pumped out, the pressure in the hose increases.
Now if we squeeze the hose, narrowing the diameter, the pressure inside would be greater and the water will shoot out more strongly. This is similar to how the diameter of the blood vessels can affect blood pressure, which can change in response to different stimuli.
One important mechanism that regulates blood pressure is the Renin-Angiotensin-Aldosterone System - or RAAS for short - which is a cascade of events that ends up increasing blood pressure.
When blood pressure is low, blood flow to the kidneys decreases. The kidneys respond by secreting renin into the bloodstream.
Renin is a proteolytic enzyme that breaks down a protein made in the liver called angiotensinogen, and this gives rise to angiotensin I.
When it reaches the lungs, angiotensin I is converted into angiotensin II by an enzyme called Angiotensin-converting enzyme, or ACE for short.
Now, angio- refers to the blood vessels; and -tens, well it means “to tense.”
So angiotensin II binds to receptors in vascular smooth muscle and causes them to constrict, which increases the blood pressure.
Finally, angiotensin II also stimulates the release of aldosterone by the adrenal glands.
Aldosterone increases reabsorption of sodium in the kidneys which also increases water reabsorption. This results in increased blood volume, which also increases blood pressure.
Now, there are three main classes of medications that work against - or antagonize - the RAAS.
First, there’s direct renin inhibitors such as aliskiren, which are relatively new compared to other antihypertensives.
Aliskiren binds really tightly to the active site of renin enzymes. This blocks angiotensinogen from binding, so angiotensin I levels fall.
Aliskiren has a long half life, so one tablet taken peroral daily is enough.
But, since it’s “younger” in the medical field, it hasn’t been as extensively tested. So it’s commonly used for patients who don’t respond to other antihypertensives, or it can be given in combination with other antihypertensives.
So, by inhibiting the action of ACE, they prevent the formation of angiotensin II, and therefore decreases its level in the blood.
With less angiotensin II in the bloodstream, there’s less vasoconstriction and therefore these medications effectively lower the blood pressure.
In addition, they lower aldosterone release, which causes natriuresis, or excretion of sodium by the kidneys.
Captopril should be taken two to three times daily because it has a short half life.
Both enalapril and lisinopril are highly potent, and have a longer half life than captopril.
Because ACE inhibitors are effective in lowering blood pressure, they can be used not only to treat hypertension, but also to treat heart failure, where the heart isn’t strong enough to pump out an adequate amount of blood.
In this situation, the decreased vasoconstriction leads to decreased peripheral vascular resistance and afterload, so the heart doesn’t have to pump as hard against that resistance.
Most ACE inhibitors are taken by mouth, and they are eliminated by the kidneys.
So care must be taken with people that suffer from renal impairment, who must receive lower doses.
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