24. Drugs used for the treatment of hypertension III: Drugs acting on the renin-angiotensin-aldosterone system

Question 1

List the ACE inhibitors.

Answer 1

First group: All are prodrugs.

1. Enalapril: may also be available IV for hypertensive crisis, but not the main method (usually oral)
2. Perindopril
3. Ramipril
4. Others that are less important: Cilazapril, Benazepril, Fosinopril, Spirapril, Quinapril, Trandolapril, Zofenopril, Moexipril.

Second group: not prodrugs, but active as they are.

1. Lisinopril: most important of the two
2. Captopril: the first ACE-inhibitor invented, but not given as much anymore, needs 3x/day administration while the others are 1x/day.

Question 2

List the renin antagonists.

Answer 2

1. Aliskiren

Question 3

Name the Aldosterone Antagonists.

Answer 3

1. Spironolactone
2. Canrenone
3. Eplerenone

Question 4

List the drugs acting on RAAS.

Answer 4

1. Renin antagonists.
2. ACE inhibitors (most popular of the RAAS antagonist drugs).
3. Angiotensin 2 R blockers.
4. Aldosterone antagonists.

Question 5

List the Angiotensin II receptor blockers (ARBs).

Answer 5

1. Losartan
2. Valsartan
3. Irbesartan
4. Candesartan
5. Telmisartan
6. Olmesartan
7. Eprosartan

Question 6

What is the MOA of Renin Antagonists/Inhibitors?

Answer 6

Renin is responsible for cleaving angiotensinogen to angiotensin. By blocking this pathways you decrease AT-II and Aldosterone secretion.

Question 7

What is the MOA of Angiotensin 2 receptor blockers (aka AT-I blockers, ARBs)?

Answer 7

Most functions are the same as ACE-inhibitors, except don’t affect bradykinin system. They also don’t cause dry cough or edema. However other side effects are the same.

Question 8

What is the route of administration of Enalapril?

Answer 8

May also be available IV for hypertensive crisis, but not the main method (usually oral).

Question 9

What is the MOA of Perindopril?*

Answer 9

Perindopril is a nonsulfhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class. It is rapidly metabolized in the liver to perindoprilat, its active metabolite, following oral administration. Perindoprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII).

Question 10

What is the MOA of Ramipril?**

Answer 10

Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class. It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys. Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII).

Question 11

What are the side effects of taking Aldosterone Antagonists?

Answer 11

1. Hyperkalemia: these are the MOST hyperkalemia-causing drugs.
2. Hyponatremia
3. Metabolic acidosis: from hyperkalemia
4. Spironolactone may cause gynecomastia because it antagonizes androgen receptors.

Question 12

What are the indications for starting ACE inhibitor therapy?

Answer 12

1. Hypertension: First choice drugs, even in young patients. In first 6 weeks, BP may fluctuate. Diastolic P may be affected more. Often combined with thiazide diuretics (usually hydrochlorothiazide). The anti-hypertensive dose of this is much less than the diuretic dose. The combo of these drugs is ONLY indicated for hypertension, nothing else. Both drugs are anti-hypertensive, marked decrease in BP. But may cause hypotension, in which case one should reduce the dose. It Balances hyperkalemia/hypokalemia. It’s primarily indicated in new patient that have never been diagnosed before with HTN (Can be ace-inhib + thiazide). It’s secondarily indicated in patient already on a drug, but the action isn’t sufficient, so you may add a thiazide. Then the combo can only be used if monotherapy is insufficient. Substitution: patient was on 2 medications at once separately, and pharma company combines the 2 drugs into 1 pill so the pt compliance is increased.
2. Congestive heart failure: even from grade I, first-line drugs.
3. Post-myocardial infarction: can inhibit the fast remodeling. Can also be used after stroke for same reason. Titration very important: MI may make person prone to hypotension! careful.
4. Diabetic Nephropathy: dilates efferent arteriole. Initially GFR ↓ when started, later improves. from bradykinin point of view, doesn’t seem logical for edema reasons. but AT-II seems to be involved in remodeling, so it seems to help. proteinuria drops quickly when you take it.

Question 13

What are the indications for giving Aldosterone Antagonists?

Answer 13

1. Needed when aldosterone level is high, e.g. Conn syndrome or secondary hyperaldosteronism problems.

Question 14

What is the MOA of ACE inhibitors?

Answer 14

1. Less angiotensin II leads to vasodilation.
2. Less aldosterone leads to slight diuretic action, causing decreased volume, increased potassium, less cardiac remodeling (AT-II seems to be responsible for this) - may increase survival.
3. ACE also cleaves Bradykinin. Bradykinin has many action, it’s a vasodilator, it increases capillary permeability, it’s also an inflammation mediator and important pain transmission molecule, etc. When Bradykinin is not cleaved its levels increase, which might contribute to the vasodilator effect.

Question 15

What are the SE of renin inhibitors?

Answer 15

1. Some diabetics got ARF from it and died after combining with other drugs.
2. Hyperkalemia: but typical this occurs from all RAAS antagonists.

Question 16

What are the indications for Angiotension 2 receptor blockers?

Answer 16

Basically the same as ACE-inhibitors. They are less used than ACE inhibitors. These drugs are newer than ACE-inhibitors and therefore usually more expensive, and possibly the remodeling inhibition is a little bit less.

Question 17

What are some side effects of taking ACE inhibitors?

Answer 17

1. Hyperkalemia: (aldosterone causes K+ excretion). Don’t combine with other hyperkalemic drugs.
2. Dry cough: May cause unpleasant dry cough. Some afferent nerves may be affected by bradykinin increase, causing this increased cough reflex. It’s a very common complaint and patients don’t tolerate this very well either.
3. Hypotension
4. Acute renal failure: (usually reversible) aortic stenosis or bilateral renal artery stenosis clearly will cause ARF. pt will have high rate of renin production, and AT-II is keeping kidney perfused.
5. Teratogenic: RAAS antagonists in general are forbidden in pregnancy. In 2nd or 3rd trimester there is absolute proof of teratogenicity. If a hypertensive woman plans to have a baby, it is mandatory that she stops ACE-inhibitor treatment. Skull and kidney development of the fetus are impaired. Babies born w/ practically no kidney and heart tube may also be damaged.
6. Bradykinin increases the capillary permeability which could lead to edema. Some sensitive patients can get angioedema, Quincke edema. May have swollen tongue, subQ edema, mesenteric edema, and it won’t be clear in advance if they’ll have this reaction or not, or it can occur suddenly after being on ACE-inhibitor for a long time.

Question 18

What are the contraindications of taking ACE inhibitors?

Answer 18

1. ARF: Acute renal failure
2. Pregnancy
3. Black people do not respond as well to RAAS antagonists, general feature of African-origin people to have low renin level. No activity of RAAS inhibitors.
4. 4. Contraindicated after this reaction edema rxn or in hereditary angioedema.

Question 19

Are renin antagonists frequently used for hypertension therapy?

Answer 19

Renin antagonists are not popular drugs because its not better than ACE-inhibitors or ARBs. Also its bioavailability is Low.

Question 20

What is the MOA of Aliskiren?

Answer 20

Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non‐ACE pathways, is not known. All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACEIs and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.

Question 21

What are the biological effects of Losartan?

Answer 21

It also ↓ uric acid, ↓ cholesterol.

Question 22

What are the indications for Perindopril?

Answer 22

Perindopril may be used to treat:

1. Mild to moderate essential hypertension
2. Mild to moderate congestive heart failure
3. To reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.

Question 23

Which ARB has the longest duration?

Answer 23

Telmisartan

Question 24

Which ARB improves cognitive function in the elderly?

Answer 24

Candesartan

Question 25

What are the indications of Ramipril?

Answer 25

Ramipril may be used in the treatment of hypertension, congestive heart failure, nephropathy, and to reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.

Question 26

Physiology: What are the effects of Renin?

Answer 26

Mechanism of action

Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by ACE and non‐ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin‐angiotensin‐aldosterone system (RAAS).