Overview
Definition
Renin-angiotensin-aldosterone system inhibitors constitute an important class of medications for the treatment of cardiovascular diseases, and are 1st-line agents for the treatment of hypertension.
Review of the RAAS
- Renin (from the kidneys) converts angiotensinogen (from the liver) to angiotensin I.
- ACE (from the lungs) converts angiotensin I to angiotensin II.
- Angiotensin II:
- Binding to angiotensin-1 receptors stimulates:
- Vasoconstriction and ↑ sympathetic activity
- Release of aldosterone (from the adrenal cortex), which stimulates Na+ and water reabsorption as well as K+ and H+ secretion
- Release of antidiuretic hormone (ADH) from the posterior pituitary, which stimulates water reabsorption
- Direct stimulation of Na+ and water
- Thirst
- Binding to angiotensin-2 receptors stimulates:
- Vasodilation
- Antiproliferative and cardiovascular-protective effects
- Chronically ↑ levels of angiotensin II cause:
- Vascular smooth muscle proliferation
- Endothelial dysfunction
- Platelet aggregation
- Enhanced inflammatory responses
- Binding to angiotensin-1 receptors stimulates:
- The overall effect of RAAS stimulation is to increase BP via:
- ↑ Effective circulating blood volume
- ↑ Peripheral vascular resistance
Overview of the RAAS
Image by Lecturio. License: CC BY-NC-SA 4.0Drugs in the RAAS inhibitor class
Drugs in the RAAS inhibitor class include:
- ACEis:
- Captopril (prototypical ACEi)
- Enalapril (Vasotec®)
- Lisinopril (Prinivil®, Zestril®)
- Benazepril (Lotensin®)
- Multiple others (names ending in “-pril”)
- ARBs:
- Losartan (Cozaar®, prototypical ARB)
- Telmisartan (Micardis®)
- Valsartan (Diovan®)
- Multiple others (names ending in “-tan”)
- Direct renin inhibitors (DRIs): aliskiren
- Aldosterone antagonists: spironolactone
- Angiotensin receptor-neprilysin inhibitor (ARNi): sacubitril/valsartan (Entresto®)
Overview of antihypertensive agents
| Location of action | Class | Subclass |
|---|---|---|
| Renal | Drugs affecting the RAAS |
|
| Diuretics |
| |
| Extrarenal | Direct vasodilators |
|
| Agents acting via the sympathetic nervous system |
|
Chemistry and Pharmacodynamics
Chemical structure
All drugs within a class have the same basic structure but different functional groups attached, which explains their different pharmacokinetic and safety profiles.
- ACEis: functional groups include carboxyl, sulfhydryl, and phosphinyl groups, which confer different pharmacokinetic properties:
- Captopril is the prototypical drug (1st in class) containing a sulfhydryl group, which confers antioxidant properties.
- The prodrug, enalapril, is hydrolyzed to enalaprilat, which has effects similar to those of enalapril.
- Lisinopril is a lysine derivative of enalaprilat.
- Other long-acting prodrugs in the class include benazepril, fosinopril, and quinapril.
- ARBs: include a tetrazole group (ring with 4 nitrogens and a carbon) along with 1 or 2 imidazole groups
Chemical structure of captopril (brand name Capoten), a widely used ACEi
Image: “Captopril structure” by Vaccinationist. License: Public Domain
Chemical structure of losartan, a widely used ARB
Image: “Losartan structure” by Techelf. License: Public Domain
Mechanisms of action
| Drug class | Mechanism of Action | Physiologic effects |
|---|---|---|
| ACEis | Inhibit ACE, preventing:
| Decreased peripheral vascular resistance via:
|
| ARBs | Inhibit angiotensin-1 receptors, preventing them from exerting their effects |
|
| DRis | Directly inhibits renin activity, blocking the conversion of angiotensinogen to angiotensin I | ↓ Angiotensin I, angiotensin II, and aldosterone → ↓ peripheral vascular resistance |
| ARNIs | Combination of ARB and a neprilysin inhibitor:
|
|
DRi: direct renin inhibitor
BNP: brain natriuretic peptide
ARNi: angiotensin receptor-neprilysin inhibitor
Overview of RAAS inhibitors and their location of action:
ACE inhibitors block both the degradation of bradykinin and the generation of angiotensin II.
ARBs block the angiotensin II type 1 receptors. Direct renin inhibitors block the generation of angiotensin I.
Spironolactone blocks mineralocorticoid receptors at the principal cells in the distal renal tubules and cortical collecting duct.
Pharmacokinetics
| Drug | Absorption | Distribution | Metabolism | Excretion |
|---|---|---|---|---|
| ACEis |
| Most drugs have minimal protein binding and relatively modest volumes of distribution | Prodrugs are activated via hydrolysis in the liver; active drugs are unchanged. |
|
| ARBs |
|
| Hepatic metabolism |
|
| DRI: aliskiren |
| Protein binding: 50% | Extent of hepatic metabolism unknown |
|
DRI: direct renin inhibitor
Indications
Angiotensin-converting enzyme inhibitors and ARBs
- Choosing a medication:
- Indications for ACEis and ARBs are similar.
- An ARB may be chosen over an ACEi in patients with (or at high risk for) ACEi-induced side effects, such as cough or angioedema.
- Some of these drugs are formulated as combinations with drugs from other antihypertensive classes (e.g., hydrochlorothiazides) → taking a single pill may improve compliance in patients requiring multiple medications
- FDA-approved indications for the use of ACEis/ARBs:
- Hypertension (1st-line agent), especially in patients who also have:
- Type II diabetes mellitus
- CKD
- Coronary artery disease (CAD)
- Diabetic nephropathy
- Heart failure with reduced ejection fraction
- STEMI: Treatment within 24 hours improves survival of hemodynamically stable patients.
- Hypertension (1st-line agent), especially in patients who also have:
- Off-label uses include:
- Non-ST-elevation acute coronary syndrome (ACS)
- Stable CAD
- Proteinuric CKD
- Posttransplant erythrocytosis in renal transplant recipients
- Mortality benefits are seen in patients with:
- Hypertension
- Heart failure
- Acute MI
- Stroke
- Diabetes mellitus
- Principles of therapy:
- ACEis and ARBs are generally not used together except in rare circumstances, generally by nephrologists.
- ACEis and ARBs are frequently combined with:
- Diuretics (most commonly, hydrochlorothiazide)
- Calcium channel blockers
- ARBs are better tolerated (and more likely to actually be taken by patients) than ACEis.
Direct renin inhibitors and ARNIs
- DRIs: aliskiren
- Indicated for hypertension
- Typically used as “add on” therapy for patients already taking antihypertensives (note: not recommended as initial treatment)
- ARNIs: sacubitril/valsartan (newer medications and the only drugs in this class)
- Indicated in patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF)
- Shown to reduce cardiovascular death and hospitalizations in patients with HFrEF
Adverse Effects and Contraindications
Adverse effects
The most common adverse effects of ACEis and ARBs are shown in the table.
| Symptom | ACEis | ARBs (and ARNIs) |
|---|---|---|
| Hyperkalemia | 1% | 0.3% |
| Cough | 10%‒20% | 1 per 1,000 |
| Pancreatitis | 1 per 5,000 |
|
| Angioedema | 1 per 2,000 | 1 per 20,000 |
Additional side effects may include:
- Hypotension
- Dizziness/syncope
- Headache
- Increase in BUN/creatinine (rarely, ACEis and ARBs can lead to acute renal failure)
- Diarrhea (with aliskiren)
Contraindications
- Absolute contraindications:
- History of angioedema
- Pregnancy
- Patients with diabetes should not use both a DRI (aliskiren) and an ACEi/ARB.
- Relative contraindications:
- Patients with abnormal renal function
- Aortic stenosis (ACEis/ARBs are afterload reducers and can lead to severe hypotension)
- Dehydration/hypovolemia
- Patients taking other medications that may lead to hyperkalemia (e.g., K+-sparing diuretics)
Comparison of Medications
| Medications | Mechanisms | Physiologic effects | Indications |
|---|---|---|---|
| ACEis | Inhibit ACE, which:
|
|
|
| ARBs | Inhibit angiotensin-1 receptors, preventing them from exerting their effects |
|
|
| Calcium channel blockers | Bind to and inhibit L-type calcium channels in cardiac myocytes and vascular smooth muscle |
|
|
| Beta blockers | Inhibit β catecholamine receptors with varying affinity for the β1 vs β2 receptors |
|
|
| Thiazide diuretics | ↓ Reabsorption of NaCl in the distal convoluted tubule through inhibition of the Na+/chloride cotransporter |
|
|
| Loop diuretics | Inhibit the luminal Na+/K+/chloride cotransporter in the thick ascending limb of the loop of Henle |
|
|
| K+-sparing diuretics |
|
|
|
ACS: acute coronary syndrome
CD: collecting duct
ENaC: epithelial sodium channel
References
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