Lisinopril

Lisinopril

Development:

Lisinopril is a long acting oral angiotensin converting enzyme inhibitor also known as an ACE inhibitor. An ACE inhibitor is used to dilate blood vessels and are commonly treat high blood pressure as well as hypertension or other myocardial infarctions. ACE is the enzyme responsible for converting angiotensin I to angiotensin II. Angiotensin II (AII) is thought to contribute to the development of heart failure because it is a vasoconstrictor and a sympathetic activator. ACE inhibitors blocks the formation of AII relieving the body of its effects. Studies have shown that lisinopril has beneficial effects for those with hypertension and heart failure because of the suppression of the renin-angiotensin-aldosterone system (13).

Lisinopril is a synthetic compound based off of captopril which was the first ACE inhibitor discovered. To be exact, it is the lysine derivative of enalaprilat which is the prodrug of captopril (12). Lisinopril also contains an active metabolite of enalaprilat, so it does not require biotransformation once it has been digested (12). Captopril was discovered when scientists found that peptides from the Brazilian pit viper’s venom inhibited ACE in a dog’s lung. This discovery was then proposed to Bristol Myers Squibb, a US pharmaceutical company, so they could proceed to develop a synthetic ACE inhibitor that would be orally active (9). Captopril is a short acting drug that is given at large doses; doctors needed a longer acting drug that was easier to administered so Lisinopril was developed. The added lysine made the drug more bioavailable and easier to be administered orally making it a safer alternative to captopril.

Most that take lisinopril note dizziness as an adverse effect. Other adverse effects noted were chest pain, abdominal pain, hypotension, diarrhea, headache, upper respiratory infection, and skin rash. Some who have taken lisinopril have had anaphylactoid reactions such as head, neck, and intestinal angioedema. For those that experience tongue or laryngeal edema, airway obstruction that could lead to death can occur. If pregnancy is detected, lisinopril should be stopped immediately due to fetal effects on fetuses. If effects are not fetal, infants who were exposed to lisinopril during the first trimester have a higher rate of congenital malformations (13). Lisinopril can also impair renal function which can lead to higher blood urea nitrogen and serum creatinine (13).

One up and coming drug that is replacing lisinopril is losartan. Losartan is a selective angiotensin type 1 receptor antagonist meaning that it attaches to angiotensin receptors of blood and smooth muscle cells to block the angiotensin from contracting the muscle and blood vessels (11). Losartan is recommended to patients who developed persistent coughing due to lisinopril. One patient example is someone who had developed hypertension and was put on an ACE inhibitor. Shortly after she started taking the ACE inhibitor, she developed a cough. Once taken off the ACE inhibitor and switched to losartan, the cough resolved with in a week (8).

Commercialization:

Lisinopril was developed by Merck & Company, INC and approved for hypertension in 1987 and congestive heart failure in 1993. After doing the clinical trials for lisinopril, Merck didn’t want the sales of this drug to diminish the sales of enalapril, as enalapril was very successful for Merck. Merck instead decided to enter an agreement with Zeneca (now known as AstraZeneca). In this agreement, Zeneca got the marketing rights to sell lisinopril which they did under the brand name Zestril and Merck got an earlier stage aldose reductase inhibitor for the treatment of diabetes. Merck was also allowed to market their own brand of lisinopril but due to poor choice in name, AstraZeneca had much better luck in their sales (5). The contract between Merck and AstraZeneca required AstraZeneca to pay royalties to Merck. When the patent ended in 2002, AstraZeneca started seeking repayment for $38 million of prior royalties since the sales dropped so much. Since sales of third party sellers of lisinopril reached a determined level, a case created under the International Chamber of Commerce to reduce the royalty rate (5). One share of AstraZeneca is currently selling for $39.12. The company’s revenue for 2017 was $22.46 billion (6). After the introduction of generic forms of Zestril sales went from $617 million in 2001 to $467 million in 2002, a drop of 18% (1).

A patent for lisinopril was filed on September 27, 1982 by Merck and was approved on September 18, 1984. The US patent number is 4,472,380. This patent expired in 2002. There are current patents for stable liquid oral forms of lisinopril by Silvergate Pharmaceuticals (7). Since the expiration of the patent, there are now 15 other pharmaceutical companies that are selling a generic form of lisinopril. ZESTRIL ® is a registered trademark of the AstraZeneca group of companies.

A safety study of lisinopril was done on 1,687 hypertensive patients. While some healthy patients volunteered to be a part of the study, the main focus of the study was the patients with hypertension and no adverse effects were reported in the healthy volunteers. Patients were exposed to lisinopril in rates varying from a single dose to taking it daily for 16 months (3). During the duration of the study, only 27 serious adverse experiences occurred with only 8 possibly related to lisinopril. These adverse experiences have now been related to the mechanism of action that ACE inhibitors have. The studied concluded “that lisinopril is generally well tolerated in the treatment of hypertension and congestive heart failure” (3).

According to the U.S. National Library of Medicine, there have been 88 completed clinical trials involving lisinopril. Twenty-four of those studies were phase one, nine were phase two, eighteen were phase three, and eighteen were phase four trials (4). The rest of the trials didn’t fit into a phase. The phase one trials mainly evaluated safety and bioavailability. The phase 2 and 3 trials examined more specific aspects of the drug such as outcomes when paired with another drug

From 2012 to 2017 lisinopril was recalled a total of 29 times.  The recalls were either voluntary by the manufacturer or mandated by the FDA. All recalls occurred with generic brands of lisinopril. There were six major recalls involving more than 5,000 bottles each that impacted Accord Healthcare, Lupin Pharmaceuticals, Wockhardt, Qualitest, Attix, and West-ward Pharmaceutical Corporation (2). There have been no class I recalls; they have all been either class II or class III recalls. The reasons for the recalls varied from the company not investigating consumer complaints to metal pieces being present in the drug.

                                                          Bibliography                                                                             

1.      “AstraZeneca Annual Report 2002.” Securities and Exchange Commission , www.sec.gov/Archives/edgar/data/901832/000095010303000761/mar1303_ex1001.htm.

2.      “Full List of All Lisinopril Recalls, FDA 2012-2017.” MedPro Medical Waste Disposal, 2 Oct. 2018, www.medprodisposal.com/lisinopril-recall.

3.      Rush, Janet E, and Debora D Merrill. “The Safety and Tolerability of Lisinopril in Clinical Trials.” Journal of Cardiovascular Pharmacology, vol. 10, 1987, pp. 99–107., doi:10.1097/00005344-198710100-00006.

4.      “Lisinopril Completed Studies.” ClinicalTrials.gov, clinicaltrials.gov/ct2/results?term=lisinopril&recrs=e&age_v=&gndr=&type=Intr&rslt=&phase=2&Search=Apply.

5.      David R. Glover. Vie D’or: Memoirs of a Pharmaceutical Physician. Troubador Publishing Ltd, 2016. ISBN 9781785894947. Merck Sharp and Dohme: lisinopril section

6.      “AstraZeneca Plc.” Google Finance, Google, 2018, www.google.com/search?safe=active&tbm=fin&ei=dunfW6LCDIOSjwTl1I2YCw&q=astraZeneca&oq=astraZeneca&gs_l=finance-immersive.3..81l3.3944.10112.0.10339.11.11.0.0.0.0.94.929.11.11.0....0...1c.1.64.finance-immersive..0.11.927....0.afRGNkXtBeo#scso=_genfW5_cG-X4jwTmp6KgDQ2:0,_yHzgW_vlJoLIjgTui73IBw2:0&wptab=COMPANY.

7.      “US9463183B1 - Lisinopril Formulations.” Google Patents, Google, patents.google.com/patent/US9463183?oq=patent%2Bfor%2Blisinopril.

8.      Aronson, J.K. “Losartan.” ClincalKey, Elsevier , 2016, www-clinicalkey-com.ezproxy.uky.edu/#!/content/book/3-s2.0-B9780444537171010003.

9.      Bryan, Jenny. “From Snake Venom to ACE Inhibitor - the Discovery and Rise of Captopril.” Pharmaceutical Journal, 17 Apr. 2009, www.pharmaceutical-journal.com/news-and-analysis/news/from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril/10884359.article?firstPass=false.

10.  “NCI Drug Dictionary.” National Cancer Institute, www.cancer.gov/publications/dictionaries/cancer-drug/def/lisinopril.

11.  Ogbru, Omudhome. “Losartan Generic (Cozaar) Side Effects, Dosage, Drug Class.” MedicineNet, www.medicinenet.com/losartan/article.htm#what_is_losartan_and_how_does_it_work_mechanism_of_action.

12.  Simpson, K. & Jarvis, B. Drugs (2000) 59: 1149. https://doi-org.ezproxy.uky.edu/10.2165/00003495-200059050-00012

13.  “ZESTRIL (Lisinopril).” Food and Drug Administration, www.accessdata.fda.gov/drugsatfda_docs/label/2009/019777s054lbl.pdf.