ACE inhibitor (Angiotensin Converting Enzyme Inhibitor) Types, Indications, Effect Angiotensin-converting-enzyme inhibitor (ACE inhibitor) is a pharmaceutical drug used primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure. This group of drugs causes relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart. They inhibit the angiotensin-converting enzyme, an important component of the renin-angiotensin system. Types ACE inhibitors are easily identifiable by their common suffix, ‘-pril’. ACE inhibitors can be divided into three groups based on their molecular structure: Sulfhydryl-containing agents Captopril Zofenopril Dicarboxylate-containing agents This is the largest group, including: Enalapril Ramipril Quinapril Perindopril Lisinopril Benazepril Imidapril Trandolapril Cilazapril Phosphonate-containing agents Fosinopril is the only member of this group Naturally occurring A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides Arfalasin (HOE 409) is an angiotensin antagonist. Dairy products Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain. The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions. In one study, L. helveticus PR4 was isolated from Italian cheeses. Types overall…………………………………………………………………. ACEinhibitors (“-pril”) Sulfhydryl-containing: Captopril Rentiapril Zofenopril Dicarboxylate-containing: Enalapril Benazepril Cilazapril Delapril Imidapril Lisinopril (+HCT) Moexipril Perindopril (+indapamide) Quinapril (+HCT) Ramipril Spirapril Temocapril Trandolapril Phosphonate-containing: Ceronapril Fosinopril (+HCT) Other/ungrouped: Alacepril Mechanism of action Normally, angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. Enalaprilat, the active metabolite of enalapril, inhibits ACE. Inhibition of ACE decreases levels of angiotensin II leading to less vasoconstriction and decreased blood pressure. There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have the much greater affinity for an inhibitory activity against the C-domain. Enalaprilat, the principal active metabolite of enalapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Enalapril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Enalaprilat’s affinity for ACE is approximately 200,000 times greater than that of ATI and 300-1000 times greater than that enalapril. Indications Diabetic Nephropathies High blood pressure (Hypertension) Diabetic kidney disease High blood pressure Left ventricular dysfunction Heart failure Hypertensive emergency Alport syndrome Symptomatic congestive heart failure Asymptomatic left ventricular dysfunction Also for the treatment of essential or renovascular hypertension and symptomatic congestive heart failure. It may be used alone or in combination with thiazide diuretics. Contra-Indications Low amount of sodium in the blood The high amount of potassium in the blood The inherited disorder of continuing episodes of swelling Reduction in the body’s resistance to infection Decreased function of bone marrow Decreased neutrophils a type of white blood cell Narrowing of the aortic heart valve Hypertrophic cardiomyopathy Renal artery stenosis Abnormally low blood pressure Liver problems Pregnancy Brain blood flow problem Hemodialysis with high-flux membrane Side Effects The most common a severe headache, rapid heartbeat, stiffness in your neck, chest pain, fast or slow heart rate; swelling, rapid weight gain; Xerostomia (dry mouth) A headache Fatigue Skin reactions Hypotension Anxiety Constipation Nausea/vomiting Weight gain/loss Erectile dysfunction More common Abdominal or stomach pain, discomfort, or tenderness chills or fever difficulty with moving headache, severe and throbbing joint or back pain muscle aching or cramping muscle pains or stiffness chest pressure or squeezing pain in the chest discomfort in arms, shoulders, neck or upper back excessive sweating feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis sudden tingling or coldness in an arm or leg sudden slow or difficult speech sudden drowsiness or need to sleep fast breathing sharp pain when taking a deep breath fast or slow heartbeat coughing up blood rust colored urine decreased amount of urine Rare Anxiety change in vision chest pain or tightness confusion cough Agitation arm, back, or jaw pain blurred vision chest pain or discomfort convulsions extra heartbeats fainting hallucinations a headache irritability lightheadedness mood or mental changes muscle pain or cramps muscle spasm or jerking of all extremities nervousness Drug Interactions ACEIs may interact with the following drugs, supplements, & may change the efficacy of drugs allopurinol alpha blockers (e.g., alfuzosin, doxazosin, tamsulosin) alpha agonists (e.g., clonidine, methyldopa) amphetamines (e.g., dextroamphetamine, lisdexamphetamine) angiotensin II receptor blockers (ARBs; e.g., candesartan, losartan) antidiabetes medications (e.g., insulin, metformin, glyburide) atypical anti-psychotics (e.g., clozapine, olanzapine, quetiapine, risperidone) azathioprine barbiturates (e.g., butalbital, pentobarbital phenobarbital) beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol) calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil) canagliflozin ciprofloxacin conivaptan diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene) duloxetine “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin) heparin iron dextran complex iron gluconate levodopa medications that increase potassium levels (e.g., potassium supplements, spironolactone, amiloride, and salt substitutes containing potassium) metformin nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen, indomethacin, naproxen) other angiotensin-converting-enzyme inhibitors (ACEIs; e.g., captopril, ramipril) pentoxifylline phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) pregabalin sodium phosphates temsirolimus tizanidine tolvaptan trimethoprim References EPA DSStox https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID8046959 European Chemicals Agency (ECHA) https://echa.europa.eu/information-on-chemicals FDA/SPL Indexing Data https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/ PubMed Health http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009666/ SpectraBase https://spectrabase.com/compound/GZvKMV6f2Uf#CEmB9cil7NY Springer Nature https://pubchem.ncbi.nlm.nih.gov/substance/341241371 WHO ATC https://www.whocc.no/atc/ https://www.whocc.no/atc_ddd_index/ Wikipedia https://www.wikidata.org/wiki/Q27126794 https://en.wikipedia.org/wiki/Clodronic_acid PubChem https://pubchem.ncbi.nlm.nih.gov MeSH https://www.ncbi.nlm.nih.gov/mesh/68004002 http://www.nlm.nih.gov/mesh/meshhome.html https://www.ncbi.nlm.nih.gov/mesh/68050071