ACE inhibitors work by manipulating the renin-angiotensin system. This system is a self-regulating feedback loop that begins in the kidney with the production of renin in response to a drop in blood pressure. Renin is converted into angiotensin. In turn, angiotensin is converted into angiotensin II through the action of angiotensin converting enzymes. Angiotensin II is a potent vasoconstrictor that causes constriction of the arteries in the body, as well as retention of water and sodium. Thus, lower levels of angiotensin II are desirable because arteries are more relaxed and open.
As their name implies, ACE inhibitors work by inhibiting the action of the angiotensin converting enzymes, thus preventing the conversion of angiotensin to angiotensin II. ACE inhibitors are not the only blood pressure medication that works on the renin-angiotensin system. The closely related angiotensin II receptor blockers, or ARBs, work by preventing angiotensin II from connecting with its receptor, thus negating its effect. Additional drugs are under development that would prevent the production of renin.
ACE inhibitors are widely used in the treatment of high blood pressure (hypertension), as well as other conditions such as heart failure and after heart attack. They are generally taken in the following forms:
- Intravenous (IV) injection
The medication generally begins to affect the body within one to two hours after each oral dose (i.e., tablet, capsule or liquid) and almost instantly after IV injection.
In addition to standard ACE inhibitor medications, a number of combination therapies may be used. For instance, medications may combine an ACE inhibitor and a low-dose diuretic in one pill. This combination has proven especially effective among black Americans. Others might contain low doses of several antihypertensive medications (e.g., calcium channel blockers) in addition to an ACE inhibitor.
ACE inhibitors are prescribed for a variety of conditions, including:
A condition in which blood is pumped with excessive force against the artery walls. ACE inhibitors cause blood vessels to relax, or widen, reducing blood pressure. They may be used alone or in combination with other antihypertensives (e.g., beta blockers, A-II blockers, calcium channel blockers) or diuretics. Research has found that low doses of two or three blood pressure-lowering medications can be effective in treating high blood pressure.
A condition in which one or more of the heart’s chambers is not pumping well enough to meet the body’s demands, leading to fluid in the lungs and shortness of breath. ACE inhibitors are often given in combination with beta blockers to reduce the workload on the heart and slow the progression of the heart failure. ACE inhibitors may also improve survival rates in patients with weak hearts, whether or not they have heart failure.
An event that results in permanent heart damage or death. A heart attack occurs when one of the coronary arteries becomes severely or totally blocked, usually by a blood clot. When the heart muscle does not obtain the oxygen-rich blood that it needs, it will begin to die. When given shortly after a heart attack, certain ACE inhibitors may prevent some of the damage to the heart and improve the survival rate of heart attack patients.
Also, recent research has shown that, when used in combination with other proven therapies (e.g., anticoagulants, beta blockers and statins), ACE inhibitors may increase survival rates for patients after a heart attack or other acute coronary event.
A condition in which one or more of the blood vessels supplying the heart muscle (coronary arteries) becomes narrowed due to a buildup of plaque (atherosclerosis). There is increasing evidence to suggest that patients with coronary artery disease may benefit from the use of ACE inhibitors even before a coronary event, such as a heart attack, occurs. In addition, ACE inhibitor use in patients undergoing bypass surgery may help decrease the risk of developing atrial fibrillation following surgery.
A metabolic condition in which the body cannot properly absorb blood sugar (glucose) because of a lack of, or inability to use, insulin. As a result, glucose levels can rise to dangerously high levels in the bloodstream, which can lead to complications such as kidney damage and increased risk of heart disease. Large studies have shown that ACE inhibitors were able to reduce the risk of developing diabetes. This is a relatively major finding because other blood pressure medications, such as diuretics, are known to cause diabetes at higher doses.
Certain ACE inhibitors (e.g., captopril) have been found to slow the process that leads to kidney damage, or renal insufficiency, in many patients with type 2 diabetes, as well as increase insulin sensitivity. Research has indicated that ACE inhibitors may even improve survival rates in diabetes patients without heart disease. While ACE inhibitor use following a heart attack has been found to be beneficial in general, people with diabetes may benefit even more from these medications than patients without blood sugar problems. Unfortunately, recent research indicates that a significant percentage of people with diabetes (up to 57 percent) are not taking ACE inhibitors.
ACE inhibitors are beneficial for certain types of kidney disease (e.g., proteinuria). Research has shown particular benefit of ACE inhibitors in reducing the progression of kidney disease in black Americans, which is most often caused by high blood pressure. Although a few newer studies have called into question the efficacy of ACE inhibitors in preventing Heart attack when compared to diuretics, these drugs are still effective and widely prescribed.
A type of peripheral arterial disease (PAD) in which one or more of the blood vessels supplying the legs become narrowed due to atherosclerosis. Research has indicated that patients taking ACE inhibitors prior to a peripheral bypass operation have increased survival rates after the operation.
Research has supported the use of ACE inhibitors as a treatment for patients at risk for cardiovascular conditions. The Heart Outcome Prevention Evaluation (HOPE) trial looked at the effect of ramipril on patients at risk for heart attack and stroke but who had normal left ventricular function. Patients with Coronary artery disease, vascular disease or diabetes were given ramipril. None of the patients had a prior history of heart failure. Results showed a significant reduction in rates of death, heart attack, stroke and diabetes, as well as complications from diabetes.
Patients should not take ACE inhibitors if they have been diagnosed with any of the following conditions:
- Hyperkalemia. Because ACE inhibitors often cause an increase in potassium levels in the body, they should not be prescribed for patients who already have abnormally high levels of potassium in their blood (hyperkalemia).
- Low blood pressure (hypotension). ACE inhibitors may lower blood pressure to dangerous levels in hypotensive patients, especially after the initial dose. However, physicians will often prescribe ACE inhibitors for certain patients with heart failure despite relatively low blood pressure.
- Kidney disease. In certain types of kidney disease (e.g., bilateral renal artery stenosis), ACE inhibitors can interfere with blood flow to the kidneys and worsen the condition. Also, some forms of kidney disease may cause this medication to be removed from the body at a slower rate, increasing the risk of overdose and/or side effects.
- Liver disease. Some diseases of the liver can slow the removal of ACE inhibitors from the body. This can lead to an increased risk of side effects and/or overdose.
- Lupus (systemic lupus erythematosus). Patients with this chronic disorder have an increased risk of blood-related side effects from ACE inhibitors.
- Previous allergic reaction to an ACE inhibitor.
- Pregnancy. ACE inhibitors may be harmful to the fetus.
By far, the most common side effect associated with ACE inhibitors is a dry, persistent cough, which occurs in up to 20 percent of patients. It tends to affect women more often than men and usually begins within one to two weeks of starting the medication, although it can be delayed for up to six months. This side effect is usually not serious, but it often leads the physician to change the patient to a different class of medications, such as the closely related angiotensin II receptor blockers (ARBs). Rarely, stridor (swelling within the airway) may occur, requiring prompt hospital treatment.
A potentially serious side effect is hyperkalemia – an abnormally high level of potassium in the blood. Therefore, patients usually have regular blood tests to check potassium levels and avoid any serious consequences. This test is essential because most people will not be aware of a rise in potassium.
Patients may also experience acute renal (kidney) failure or a decline in kidney function. This typically occurs in patients who have existing kidney disease.
Also, people should seek medical attention immediately if they experience any side effects that could indicate an allergic or other severe reaction to ACE inhibitors.
- Fainting (syncope)
- Difficulty swallowing or breathing
- Swelling of the head or face
- Abdominal pain or swelling (with or without nausea or vomiting)
- Skin rash, with or without itching
- Allergic reaction (sneezing, respiratory congestion, itching or skin rashes)
- Tachycardia (abnormally fast heartbeat)
- Edema (swelling) in the face, mouth, hands or feet
- Drowsiness, weakness or fatigue
- Loss of taste (especially with captopril)
- Nausea or upset stomach
- Abdominal cramps, pain or distention
- Joint pain
- Chest pain
- Jaundice (rare, but serious)
When first taking ACE inhibitors, or after any increase in dosage, there is a possibility of a “first dose effect.” During the first dose effect, the patient’s blood pressure drops rapidly, which causes dizziness, nausea and possibly fainting. To avoid experiencing the first dose effect, it may be recommended that the first dose of this medication be taken at bedtime, or the physician may recommend that the patient forgo other medications (e.g., diuretics) for a few days after starting therapy.
In addition, ACE inhibitors rarely cause a decrease in white blood cells in some patients, making them more prone to infection. Patients should report any signs of infection to their physician immediately, which include fever, sore throat, nausea or vomiting.
A patient’s physician should be called immediately if the patient shows any of the following:
- Low pressure blood (hypotension)
- Edema (swelling) in the face, mouth, throat, hands or feet
- Fainting (syncope)
- Fever or chills
- Sore throat
- Convulsions or seizures
- Coma (prolonged unconsciousness)
Swelling within the throat may lead to stridor (swelling within the airway, making it difficult to breathe). This condition, while rare, requires prompt hospital treatment.
Patients should consult their physician before taking any other medication (either prescription or over-the-counter), herbal remedies or nutritional supplements. Of particular danger to individuals taking ACE inhibitors are the following:
- Potassium supplements. Use increases the risk of hyperkalemia (too much potassium in the body).
- Diuretics (some types). Medications that stimulate the kidneys to produce more urine, flushing excess fluids and minerals (e.g., sodium) from the body. Most diuretics cause the body to lose potassium, as well as sodium and fluids. One type – potassium-sparing diuretics – actually preserves potassium while flushing other minerals from the body. Because of this, using potassium-sparing diuretics in conjunction with ACE inhibitors may increase the risk of hyperkalemia. In patients taking both types of medications, risk of hyperkalemia increases with age and the dosage of diuretic prescribed (greater that 25 milligrams). People with kidney disease or diabetes are also more likely to develop hyperkalemia when taking these medications in combination.
- Salt substitutes. Many of them contain potassium chloride, which increases the risk of hyperkalemia.
- Low-salt milk. Use increases the risk of hyperkalemia.
- Alcohol. Drinking alcoholic beverages can produce a drop in blood pressure. Patients taking ACE inhibitors should consult their physician before drinking alcohol.
- Nonsteroidal anti-inflammatory drugs (NSAIDs). These can decrease the effectiveness of the ACE inhibitors, worsen high blood pressure or increase the risk of kidney problems. Patients should consult with their physician before using them. A possible exception to this is aspirin. While aspirin is technically a type of NSAID, research has suggested that aspirin use – especially the low doses associated with daily aspirin therapy – may be safe for heart patients. Patients should discuss the potential benefits and risks with their physicians.
- COX-2 inhibitors. These medications decrease the blood pressure-lowering effects of ACE inhibitors. However, they may pose less of a risk for future kidney problems than some NSAIDs. Patients taking ACE inhibitors should consult with their physicians before using these medications.
- Grapefruit juice.
- Over-the-counter (OTC) medications that increase blood pressure. Patients taking ACE inhibitors for high blood pressure should avoid OTC products that may increase blood pressure, such as those used for appetite control, asthma, flu, colds, cough, sinus problems or hay fever.
- Other substances that may adversely react with ACE inhibitors include narcotics (prescription painkillers), tobacco, and marijuana or other illegal drugs.
When first taking ACE inhibitors, patients should avoid operating heavy machinery (e.g., driving) until they know how the medication will affect them. Many patients taking ACE inhibitors for high blood pressure (hypertension) will be on the medication for the rest of their lives, provided no serious side effects occur. Patients should remember that ACE inhibitors control high blood pressure but do not cure it. Even though they may not have any symptoms (which is very common among those with high blood pressure), patients should continue to take their medication exactly as directed and to keep all scheduled follow-up appointments with their physician. Patients should take and record their blood pressure readings regularly if ordered to do so, reporting anything unusual to their physician.
Patients on ACE inhibitors should inform their physician if they become ill, especially with severe vomiting or diarrhea. These conditions can cause the body to lose too much water and potassium, leading to low blood pressure (hypotension).
Patients are more likely to have side effects from ACE inhibitors if they spend too much time in the heat. Therefore, patients should be certain to drink enough liquids during exercise or in hot weather and to follow their physician’s orders about exercise, activity levels and diet.
Women are advised against taking ACE inhibitors during pregnancy, especially during the second and third trimesters but also in the first trimester. The medication can cause low blood pressure, severe kidney failure, hyperkalemia (too much potassium in the blood), or death or deformity of the newborn. Patients taking ACE inhibitors should inform their physician immediately if they become pregnant, or are planning to become pregnant, so they can start alternative therapy to ACE inhibitors.
When breastfeeding, some ACE inhibitors will pass into breast milk. Although this has not been found to cause problems in nursing infants, an alternative feeding method is recommended when ACE inhibitors are being used.
Because children are more sensitive to the effects of ACE inhibitors on blood pressure, they are at higher risk of having side effects and of having more severe side effects.
Parents are encouraged to discuss the potential risks and benefits with a pediatric cardiologist before their children begin taking ACE inhibitors.
In addition, use of certain ACE inhibitors may not be recommended in children under 6 years old.
Certain types of ACE inhibitors may not be recommended for use in older adults. In general, older adults may be more sensitive to the effects of ACE inhibitors and therefore at higher risk of side effects. Dosages, therefore, tend to begin on the lower end of acceptable ranges for this population.
In addition, elderly patients are more likely to have impaired renal (kidney) function, which can increase the risk of hyperkalemia (too much potassium in the blood). Therefore, elderly patients may undergo blood or other testing to determine kidney function before being prescribed ACE inhibitors.
Patients may wish to ask their doctor the following questions related to ACE inhibitors:
- When should I take my medication? Should I take it at the same time every day? With food? Can I take it with other liquids besides water?
- What happens if I run out or miss a dose?
- When I'm first taking ACE inhibitors, are there any normal side effects that I can expect but that shouldn't be alarming?
- How long will it take for my body to adjust to the medication?
- What are the side effects that should cause me to call you?
- Are there any dietary supplements that might affect the ACE inhibitors?
- Which over-the-counter medications should I avoid?
- How long will I be taking ACE inhibitors?
- Do ACE inhibitors cure my disease or only prevent it from worsening?
- What lifestyle modifications can I make to help the medication work?
- Is this the lowest possible dose?
- If I react poorly to ACE inhibitors, are there other medications I can switch to?