Mechanism of Action
ACE is involved in the renin-angiotensin-aldosterone system (RAAS; media item 1) and stimulates the conversion of angiotensin I to angiotensin II. ACE inhibitors are competitive inhibitors of ACE, which prevents the conversion of angiotensin I to angiotensin II. Angiotensin II acts as a potent vasoconstrictor that, when inhibited, can reduce blood pressure by dilating vessels and decreasing aldosterone secretion.
It is essential to understand the role of the RAS hormonal system in depth to appreciate the therapeutic effects of ACE inhibitors and understand why this is a target for hypertensive therapy. Initially, afferent arteriole juxtaglomerular cells synthesize prorenin, which is actively cleaved to renin. Angiotensinogen produced from the liver is then cleaved by renin to form angiotensin I. The angiotensin I molecule is converted to angiotensin II by ACE. Angiotensin II is the molecule that has significant actions on various systems. Initially, Angiotensin II induces vasoconstriction, which ultimately increases systemic blood pressure. Even further, Angiotensin II stimulates the adrenal cortex and the pituitary to produce Aldosterone and Anti-diuretic hormone (ADH), respectively. Aldosterone induces sodium reabsorption and, in turn, water reabsorption through internal mineralocorticoid receptor activity ; ADH increases the synthesis of aquaporin-2 channels in the collecting duct inducing selective reabsorption of water.
Most Common Adverse Reactions
- Dry Cough (10% to 20%)
- Dizziness (12% to 19%)
- Hypotension (7% to 11%)
- Increased BUN and Cr (2% to 11%)
- Syncope (5% to 7%)
- Hyperkalemia (2% to 6%)
Commonly, patients on ACE inhibitors have reported dry cough between the one week of initiation up to six months, with some sources citing up to one year after initiation. Discontinuing therapy usually resolves the cough 1 to 4 days after but can be prolonged up to a month. The concern for dry cough with therapy initiation is a decrease in medication adherence. Additionally, there is an increased propensity to develop bronchospasm in these patients. ACE metabolizes bradykinin and other local molecules. Inhibiting ACE in the lung increases the concentration of kinins, causing bronchial irritation. After discontinuation of ACE inhibitor therapy, an angiotensin receptor blocker (ARB) can initiate as an alternate therapy. ARB’s have a lower incidence of cough recurrence compared to reinitiating ACE inhibitor therapy. If cough recurs on ARB therapy, switch to a different drug class entirely.
One percent to 10%: flushing, orthostatic effect, chest pain, altered sense of smell, fatigue, headache, alopecia, diaphoresis, erythema, pruritus, skin photosensitivity, Steven-Johnson Syndrome, toxic epidermal necrolysis, urticaria, diabetes mellitus, gout, SIADH, constipation, diarrhea, dysgeusia, flatulence, pancreatitis, xerostomia, impotence, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia, thrombocytopenia, common cold, weakness, blurred vision, diplopia, photophobia, vision loss, tinnitus, cough.
Hypotension can cause intolerance to therapy leading to discontinuation in a small population of patients, which is more common in patients with increased renin baseline concentrations. Allowing repletion of fluids and discontinuing diuretic medication before therapy can minimize hypotensive episodes.
A slight reduction of glomerular filtration rate (GFR) is common when initiating therapy. GFR reduction can become severe in certain settings and co-morbidities. Patients with diseases affecting renal perfusion can cause further reduction of GFR to a severe level warranting discontinuation. Some co-morbidities can include heart failure, chronic kidney disease, and bilateral renal artery stenosis.
Hyperkalemia from ACE inhibitors is a direct result of the mechanism of action. The blockade of angiotensin II prevents the downstream secretion of aldosterone. Aldosterone causes reabsorption of sodium and, subsequently, water. Consequently, protons and potassium get secreted into the urine. Without the secretion of potassium through aldosterone, potassium can easily increase in patients on ACE inhibitors. Co-morbidities that decrease kidney function or medications that cause potassium retention increases the risk of hyperkalemia.
Angioedema is a rare but potentially life-threatening side effect of ACE inhibitor use. The side effect is a swelling of the face, lips, and upper airway in an episodic nature. The inflammation creates difficulty in the patient’s ability to maintain an airway; therefore, endotracheal intubation is necessary to secure the airway. The mechanism of angioedema is thought to be through an extensive accumulation of bradykinins in select individuals. Bradykinin induces prominent vasodilation and plasma extravasation into the local tissue. The primary treatment of ACE inhibitor-induced angioedema is the discontinuation of ACE inhibitor therapy. It is also suggested to avoid ACE inhibitor therapy in individuals with hereditary angioedema or a history of angioedema episodes.
Less than 1%: Acute renal failure, anaphylactoid reactions, angioedema, anuria, arthralgia, arthritis, asthma, ataxia, azotemia, bronchitis, bronchospasm, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, chills, confusion, cutaneous pseudolymphoma, dehydration, drowsiness, dyspepsia, dyspnea, dysuria, eosinophilia, eosinophilic pneumonitis, epistaxis, facial edema, fever, gastritis, hallucination, heartburn, hemoptysis, hepatic necrosis, hepatitis, herpes zoster, hypersomnia, hypervolemia, hypoglycemia, hyponatremia, increased erythrocyte sedimentation rate, insomnia, intestinal angioedema, irritability, laryngitis, leukocytosis, malaise, malignant neoplasm of lung, mastalgia, memory impairment, mood changes, muscle spasm, musculoskeletal pain, myalgia, myocardial infarction, oliguria, orthopnea, orthostatic hypotension, palpitations, paresthesia, paroxysmal nocturnal dyspnea, pemphigus, peripheral edema, peripheral neuropathy, pharyngitis, pleural effusion, pneumonia, positive ANA titer, psoriasis, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, pyelonephritis, rhinitis, rhinorrhea, sinusitis, skin infection, skin lesion, skin rash, sore throat, systemic lupus erythematosus, transient ischemic attacks, tremor, uremia, urinary tract infection, vasculitis, vertigo, viral infection, visual hallucination, weight gain, weight loss, wheezing.
The use of drugs that inhibit the renin-angiotensin system correlates with teratogenic effects such as oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia, and death.
The proposed mechanism behind oligohydramnios is evident at the level of the fetal kidney. The low-pressure hemodynamics of the fetus becomes easily disrupted with a decreased amount of angiotensin II. Fetal renal pressure becomes lower, reducing the ability to maintain GFR, leading to oligohydramnios and anuria.
ACE inhibitors are contraindicated in a patient with a history of hypersensitivity to any ACE inhibitor or component of the formulation, angioedema related to previous treatment with ACE inhibitor, idiopathic or hereditary angioedema, or current use of aliskiren in a patient with diabetes mellitus. Also, consider drugs with cross-reactivity with ACE inhibitors.
ACE inhibitors are not recommended in pregnant patients and require discontinuation as soon as pregnancy is detected.
Use with great caution in the following situations:
- Patients with abnormal renal function. ACE inhibitors can cause elevation of potassium and worsen renal function in patients already on ACE inhibitors. If the patient has an abnormal but stable renal function, close monitoring is required while he or she is on an ACE inhibitor. If the renal function starts to decline, the clinician should discontinue the ACE inhibitor immediately.
- Patients with aortic valve stenosis should not be administered afterload reducers like ACE inhibitors because it can lead to severe hypotension.
- Similarly, patients who are dehydrated or have hypovolemia should not receive treatment with ACE inhibitors.
When used at therapeutic doses, the risk of toxicity is rare. Toxicity is more likely when the drug is used in combination or at supratherapeutic doses.
When combining ACE inhibitors with other antihypertensive drugs, they have the potential to increase side effects like hyperkalemia, hypotension, and renal failure. One should pay more attention when the patient is given an ACE inhibitor and is already on a potassium-sparing diuretic, NSAIDs, cyclosporine, and anticoagulants.
All the presently available ACE inhibitors have similar antihypertensive effects at equivalent doses. The only ACE inhibitor that is different is captopril. This agent has a short duration of action and is more likely to induce side effects. It is the only ACE inhibitor to penetrate the blood-brain barrier and potentially cause confusion and lethargy.
Enhancing Healthcare Team Outcomes
Clinicians widely use ACE inhibitors in medicine for the treatment of hypertension, heart failure, and patients with chronic kidney disease. While effective, healthcare workers (nurse practitioners, physicians, and pharmacists) who prescribe these agents should be aware of their side effects and limitations. Patients also need to be monitored for their renal function and electrolyte concentrations regularly. Finally, the healthcare worker should be aware that these agents can produce a chronic dry cough, and the clinician should try another class of antihypertensive medication.
Even though ACE inhibitors are among the oldest drug classes available, there is a threat that familiarity can lead to carelessness. That is why, like any other drug, these agents require the oversight and coordination of an interprofessional team. Pharmacists need to verify that dosing is appropriate, and check for drug interactions. Nursing will monitor and for female patients, emphasize that if they think they are pregnant or trying to get pregnant, that therapy will need to change to accommodate that. Nursing will also be taking blood pressure at every visit, and charting so the prescriber can determine if dosing or other changes may be for hypertensive control. The clinician must remain informed by these findings from the other members of the interprofessional healthcare team, so he can take corrective action if necessary. Communication and collaboration among healthcare team members will make ACE inhibitor therapy more effective, leading to better patient outcomes. [Level V]