ACE inhibitors, ARBs and direct renin inhibitors

Definitions & Key takeaways

ACE inhibitors, ARBs and direct renin inhibitors are all medications used to treat high blood pressure. ACE or angiotensin-converting enzyme inhibitors work by blocking the enzyme that converts angiotensin I to angiotensin II. This prevents the body from producing too much of the hormone, which can lead to hypertension. ARBs or angiotensin II receptor blockers work by blocking the receptors that angiotensin II binds to constrict blood vessels. This relaxes the blood vessels and lowers blood pressure. Direct renin inhibitors work by inhibiting renin, the enzyme that converts angiotensinogen to angiotensin I, which also reduces blood pressure. All three of these medications can be used alone or in combination with other medications to safely lower blood pressure.

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Introduction0:00–0:18

Antihypertensives are a class of medication used to treat hypertension, or high blood pressure. Certain antihypertensives act upon the renin-angiotensin-aldosterone system to decrease blood pressure by inhibiting vasoconstriction and water reabsorption in the kidneys.

Physiology0:18–2:03

Hypertension affects over a billion people around the world, and it’s a major risk factor for heart disease and stroke. 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.

Direct Renin Inhibitors2:03–2:53

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.
In addition, aliskiren can cause GI side effects like diarrhea and abdominal pain. Other side effects include headache, dizziness, and fatigue.
Okay, so next we have the angiotensin converting enzyme inhibitors, or ACE inhibitors, and their names usually end in “-pril” - like captopril, enalapril, or lisinopril.

ACE Inhibitors2:53–5:00

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.
ACE inhibitors should also be given right after someone suffers an acute myocardial infarction in order to increase the perfusion of the heart to prevent further ischemic damage.
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.
Now, the most common side effect of ACE inhibitors is a dry cough. Normally, ACE also breaks down bradykinin, So when the person takes ACE inhibitors, bradykinins accumulate, and they’re thought to induce the cough reflex.
Another more rare consequence of bradykinin accumulation, is angioedema, a painful swelling in the airways that is life threatening.
Other side effects include hypotension, but it only happens when the person starts taking the medication, then eventually disappears.
Finally, people using ACE inhibitors should avoid a high potassium diet because there’s decreased aldosterone production, which means there’s less potassium excretion in the urine, and this could lead to hyperkalemia.
Finally, we have the angiotensin II receptor blockers, or ARBS. They bind to angiotensin receptor 1 on vascular smooth muscles and the adrenal glands, which prevent angiotensin II from binding.

ARBs5:00–6:03

This results in decreased vasoconstriction and decreased aldosterone synthesis respectively. ARBs ends in “-sartan,” like candesartan, valsartan, and losartan.
They have the same indications as ACE inhibitors and can also be used to treat hypertension, heart failure, and MIs. Unlike ACE inhibitors, they don’t increase bradykinin levels in blood, hence they cause less cough and angioedema.
Other than that, the adverse effects of angiotensin II receptor antagonists, just like ACE inhibitors, are hyperkalemia and hypotension.
Despite having an apparently safer profile than ACE inhibitors, angiotensin II receptor antagonists are the medications of choice only if ACE inhibitors cannot be tolerated.
Candesartan and losartan have relatively long half life, and can be taken once or twice a day whilst valsartan is given once daily.

Contraindications6:03–6:16

Finally, none of these medications we’ve discussed so far should be given during pregnancy because they can cause congenital malformations in the baby.
If an antihypertensive is needed, the pregnant person should be switched to medications like methyldopa or labetalol. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm facts!

Memory Palace6:16–8:12

So let’s go to the RAAS ski lodge that sits halfway up a hill. First, there’s a large blood pressure cuff that sits on the top of the hill to remind you that these are medications for HTN.
For the mechanisms, there are reindeer for renin near the top of the hill. By the lodge, there’s a magician with a giant ace of spades representing ACE, and at the bottom of the hill, there are two angel statues for angiotensin II receptors.
By the reindeer, we have a skiing alien for aliskiren. It’s trying to abduct the reindeer by shooting it with some sort of abduction ray.
This made the reindeer dizzy and also poop, which represents the side effects of aliskiren. By the magician with the Ace of spades, we have the ACE inhibitors that end in “-pril” so we’ll use a jester, or fool, for April fools.
He’s trying to learn a couple of tricks from the magician, but it’s very cold and he developed a cough, which is a side effect of ACE inhibitors.
He’s coughing so hard that he can barely breath, which will help you remember the more serious side effect of angioedema.
At the foot of the hill by the angel statues, we have a man dressed as Santa and he represents the ARBs that ends in “-sartan.” Now, remember that ACE inhibitors and ARBs can be used to treat MIs and heart failure in addition to HTN, so let’s have a big heart drawn in the snow between the magician and the statues.
A mischievous kid is vandalizing it by giving it a big “F” for failure, and he’s hitting it with a stick for heart attack.
ACE inhibitors and ARBs also share some of the same side effects, so let’s have the kid’s bigger brother slipping on a banana, representing hyperkalemia; and he fainted, which represents hypotension.
Finally, skiing all the way down from the top of the slope, we have a pregnant lady who’s out of control! She regrets coming to the ski slopes and this will help you remember that all 3 classes of drugs are contraindicated during pregnancy.
All right, as a quick recap… angiotensin and renin antagonists are a class of medications used to treat hypertension or high blood pressure.

Review8:12–8:44

They work at different levels of the renin-angiotensin-aldosterone system that normally regulates blood pressure. The three main classes of medications include renin inhibitors, ACE inhibitors, and angiotensin receptor blockers.
ACE inhibitors and ARBs can also be used to treat heart failure and MI, but ACE inhibitors can cause coughing and angioedema.
None of these medications should be given during pregnancy. But wait, there's more: Here's a mind map with all of the mnemonics from the video.

Mind Map8:44–8:55

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.