What Are ACE Inhibitors And How Do They Work?
ACE inhibitors (Angiotensin-Converting Enzyme inhibitors) are drugs used to relax the veins and arteries in order to lower blood pressure. They also help reduce blood volume and the heart’s demand for oxygenated blood.
ACE inhibitors bring down the activity of the angiotensin-converting enzyme. This enzyme controls fluid volumes in the body. It converts a hormone called angiotensin I into a more active form called vasoconstrictor angiotensin II.
This conversion causes constriction of blood vessels and increased blood flow. These lead to an increase in blood pressure.
ACE inhibitors reduce the conversion of angiotensin I into vasoconstrictor angiotensin II and hence relax blood vessels.
Image: Action of ACE Inhibitors
Studies have reported that ACE Inhibitors can reduce the chances of developing heart failure that occurs due to high blood pressure.
Beta-blockers and diuretics are similar drugs used to treat high blood pressure and related health conditions.
Beta-blockers work by reducing the effects of the adrenaline hormone. This causes the heart to beat slowly and relaxes veins and arteries.
Diuretics reduce the amount of water in the blood, thereby reducing blood volume and blood pressure.
Angiotensin II Receptor Blockers (ARBs) also work very similarly to ACE inhibitors. These drugs can offer better inhibition of angiotensin II and are becoming popular types of antihypertensive medications.
Digoxin is another drug commonly prescribed for reducing heart rate. Digoxin is usually used along with other kinds of heart medicines to treat symptoms of heart failure. It is preferred when ACE inhibitors or beta-blockers cannot be used.
Side Effects Of ACE Inhibitors
The common side effects of ACE inhibitors are:
- Fatigue
- Dizziness
- Nausea
- Headaches
- Hyperkalemia (high potassium levels)
- Dry cough
Other extreme side effects of ACE inhibitors are:
- Kidney impairment
- Increased bradykinin levels (leads to increased inflammation)
- Angioedema (swelling of the deeper skin layers)
- Hepatotoxicity (liver damage due to drug overdose)
- Kidney failure and liver damage in fetuses when consumed during pregnancy
Interactions With Other Drugs
ACE inhibitors can interact with many drugs and can lead to extreme side effects. Inform your doctor if you are on the following medications.
ng medications.
- Angiotensin II Receptor Blockers (ARBs) and Aliskiren (direct renin inhibitors) - used to treat hypertension
- Chronic Kidney Disease (CKD) medications
- Diuretics - used to increase the production of urine
- NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) - used to treat pain, inflammation, and clots
- Calcineurin inhibitors (immunosuppressive drugs)
- Dipeptidyl peptidase-IV (DPP-IV) inhibitors - used to treat type II diabetes mellitus
ACE Inhibitors: Gene-Drug Interactions
ACE Inhibitors-Related Angioedema - XPNPEP2 Gene
Angioedema is a condition that causes rapid swelling beneath the skin. Studies report that up to one-third of all emergency visits for angioedema are by those who use ACE inhibitor drugs.
The XPNPEP2 gene contains instructions for the production of X-Prolyl Aminopeptidase 2 protein. The gene plays a role in the functioning of bradykinin, a molecule that helps relax the blood vessels.
rs3788853 is a Single Nucleotide Polymorphism (SNP) in the XPNPEP2 gene.
According to a study, the A allele of this SNP is associated with low aminopeptidase P (APP) activity.
Low APP activity leads to increased bradykinin production, which increases the risk of developing angioedema in black men.
However, this relationship was not found in women or white men.
| Allele | Implications |
| A | Increased risk of developing angioedema in black men |
| C | Normal risk of developing angioedema |
ACE Inhibitors And ADRB2 Gene
The ADRB2 gene (Adrenoceptor beta 2 gene) helps produce the beta-2 adrenergic receptor. This receptor is activated by adrenaline and is associated with mental health conditions like anxiety and phobias.
A study analyzed the association between ACE inhibitors and changes in the ADRB2 gene. 336 participants were treated with ACE inhibitor drugs. The time taken to reach a Mean Arterial Pressure (MAP) of 107 mmHg was noted.
rs2053044 is an SNP in the ADRB2 gene. People with the GG genotype of this SNP reached the MAP about 12 days later than those with the AA or AG genotype.
| Genotype | Implications |
| GG | Lowered response to ACE inhibitors in reducing blood pressure |
| AG | Normal response to ACE inhibitors in reducing blood pressure |
| AA | Normal response to ACE inhibitors in reducing blood pressure |
ACE Inhibitors And NOS3 Gene
The NOS3 gene (Nitric Oxide Synthase 3 gene) helps produce the endothelial NOS (eNOS) or nitric oxide synthase 3 enzyme. This enzyme plays a role in Nitric Oxide (NO) synthesis.
rs3918226 is an SNP in the NOS3 gene. According to a study, people with the T allele of this SNP responded better to enalapril, a type of ACE inhibitor. An opposite effect was observed in those with the A allele.
| Allele | Implications |
| T | Better response to ACE inhibitors |
| A | Lowered response to ACE inhibitors |
Recommendations To Safely Use ACE Inhibitors
ACE Inhibitors Efficacy Lowers With Age
ACE inhibitors are more effective for people younger than 55. This is because young individuals have higher levels of renin in the blood.
Renin is a type of enzyme released by the kidney - higher levels of this enzyme are associated with higher blood pressure in younger adults.
ACE inhibitors effectively bring down renin levels.
People older than 55 are less responsive to renin, and hence, ACE inhibitors don’t make an impressive difference to blood pressure levels.
Cautious Use In People With Existing Health Conditions
ACE inhibitors lead to lowered blood flow, which can be problematic in those with existing circulatory problems.
Low blood volume and hypotension can lead to ischemia (inadequate blood supply to organs), myocardial infarction, stroke, and even kidney failure.
ACE inhibitors also cause kidney failure in those with existing renal artery stenosis (narrowed/blocked arteries that lead to the kidneys) or chronic kidney disease.
People with diabetes (both type 1 and type 2) are at increased risk of developing hyperkalemia with ACE inhibitor intake.
Opt For Genetic Testing
Genetic testing can help understand how a person is likely to respond to ACE inhibitor treatment. It gives insights into how a person’s body reacts to the drug and identifies if dosage alterations are needed to improve the efficiency of the medicine and reduce its toxicity risk.
Analyze Your Genetic Response to ACE Inhibitors
Summary
- ACE inhibitors are drugs used to treat high blood pressure.
- Beta-blockers, diuretics, and Angiotensin II Receptor Blockers are drugs similar to ACE-Inhibitors, used to manage hypertension and cardiovascular issues.
- Some of the side effects of ACE inhibitors are fatigue, nausea, headaches, high potassium levels, kidney impairment, angioedema, and liver damage and kidney failure in fetuses.
- ACE inhibitors interact with other hypertensive medications, chronic kidney disease medications, NSAIDs, calcineurin inhibitors, and DPP-IV inhibitors.
- Changes in the XPNPEP2, ADRB2, and NOS3 genes can alter the body’s response to ACE inhibitors.
- People younger than 55 respond better to ACE inhibitors. People with certain existing diseases can develop extreme health conditions when they consume ACE inhibitors.
- Genetic testing can help understand how a person will respond to ACE inhibitor treatment.
References
- https://www.ncbi.nlm.nih.gov/books/NBK431051/
- https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480
- https://www.medscape.com/viewarticle/443226
- https://www.healthline.com/health/heart-disease/ACE-inhibitors
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369859/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369859/
- https://www.genecards.org/cgi-bin/carddisp.pl?gene=NOS3
