1. Medical uses
     Kidney problems    Pregnancy and breastfeeding  

2. Contraindications

3. Adverse effects

4. Overdose

5. Interactions
     Dental care  

6. Pharmacology
     Mechanism of action    Pharmacokinetics   Absorption  Distribution  Metabolism  Elimination   Chemistry  

7. History

8. References

9. Further reading

10. External links

Common side effects include headache, dizziness, feeling tired, cough, nausea, and rash.^[2] Serious side effects may include low blood pressure, liver problems, high blood potassium, and angioedema.^[2] Use during pregnancy is not recommended as it may harm the baby.^[2] Lisinopril works by inhibiting the renin-angiotensin-aldosterone system.^[2]

Lisinopril was patented in 1978 and approved for medical use in the United States in 1987.^[1][2] It is available as a generic medication.^[1] In the United States the wholesale cost per month was less than 0.70 USD as of 2018.^[3] In the United Kingdom it cost the NHS about 10 pounds per month as of 2018.^[4] In 2016, it was the 2nd most prescribed medication in the United States, with more than 110 million prescriptions.^[5]

Medical uses

Lisinopril is typically used for the treatment of high blood pressure, congestive heart failure, acute myocardial infarction (heart attack), and diabetic nephropathy.^[6]

A review concluded that lisinopril was effective for treatment of proteinuric kidney disease, including diabetic proteinuria.^[7]

Kidney problems

The dose must be adjusted in those with poor kidney function. Dose adjustments may be required when creatinine clearance is less than or equal to 30mL/min. Since lisinopril is removed by dialysis, dosing changes must also be considered for people on dialysis.^[20]

Pregnancy and breastfeeding

Lisinopril has been assigned to pregnancy category D by the FDA. Animal and human data have revealed evidence of lethal harm to the embryo and teratogenicity associated with ACE inhibitors. No controlled data in human pregnancy are available. Birth defects have been associated with use of lisinopril in any trimester. However, there have been reports of death and increased toxicities to the fetus and newly born child with the use of lisinopril in the second and third trimesters. The label states, "When pregnancy is detected, discontinue Zestril as soon as possible." The manufacturer recommends mothers should not breastfeed while taking this medication because of the lack of safety data that currently exists.^[20]

Contraindications

Treatment with lisinopril should be avoided for people who have a history of angioedema (hereditary or idiopathic) or who have diabetes and are taking aliskiren.^[8]

Adverse effects

The incidence of adverse effects varies according to which disease state the patient is being treated for.^[8]

People taking lisinopril for the treatment of hypertension may experience the following side effects:

• Headache (3.8%)
• Dizziness (3.5%)
• Cough (2.5%) Persons with the ACE I/D genetic polymorphism may be at higher risk for ACE inhibitor-associated cough.^[9]
• Difficulty swallowing or breathing (signs of angioedema), allergic reaction (anaphylaxis)
• Hyperkalemia (2.2% in adult clinical trials)
• Fatigue (1% or more)
• Diarrhea (1% or more)
• Some severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson syndrome; causal relationship has not been established.

People taking lisinopril for the treatment of myocardial infarction may experience the following side effects:

• Hypotension (5.3%)
• Kidney dysfunction (1.3%)

People taking lisinopril for the treatment of heart failure may experience the following side effects:

• Hypotension (3.8%)
• Dizziness (12% at low dose – 19% at high dose)
• Chest pain (2.1%)
• Fainting (5-7%)
• Hyperkalemia (3.5% at low dose – 6.4% at high dose)
• Difficulty swallowing or breathing (signs of angioedema), allergic reaction (anaphylaxis)
• Fatigue (1% or more)
• Diarrhea (1% or more)
• Some severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson syndrome; causal relationship has not been established.

Overdose

In one reported overdose, the half-life of lisinopril was prolonged to 14.9 hours.^[10] The case report of the event estimates that the individual consumed between 420 and 500 mg of lisinopril and survived.^[11] In cases of overdosage, it can be removed from circulation by dialysis.^[8]

Interactions

Dental care

ACE-inhibitors like lisinopril are considered to be generally safe for people undergoing routine dental care, though the use of lisinopril prior to dental surgery is more controversial, with some dentists recommending discontinuation the morning of the procedure.^[12] People may present to dental care suspicious of an infected tooth, but the swelling around the mouth may be due to lisinopril-induced angioedema, prompting emergency, medical referral.^[12]

Pharmacology

Lisinopril is the lysine-analog of enalapril. Unlike other ACE inhibitors, it is not a prodrug and is excreted unchanged in the urine.^[8]

Mechanism of action

Lisinopril is an ACE inhibitor, meaning it blocks the actions of angiotensin-converting enzyme (ACE) in the renin-angiotensin-aldosterone system (RAAS), keeping angiotensin I from being converted to angiotensin II. This prevents the release of aldosterone from the adrenal cortex, which allows the kidney to excrete sodium along with water into the urine, and retention of potassium ions.^[31] Specifically, this process occurs in the peritubular capillaries of the kidneys in response to a change in Starling forces.^[13] The inhibition of the RAAS system causes an overall decrease in blood pressure.^[31]

Pharmacokinetics

Absorption

Lisinopril has a poor bioavailability of 25% (reduced to 16% in people with NYHA Class II-IV heart failure).^[8][14] Its time to peak concentration is 7 hours.^[8][14] The peak effect of lisinopril is about 4 to 8 hours after administration.^[38] Food does not affect its absorption.^[38]

Distribution

Lisinopril does not bind to proteins in the blood.^[8][14] It does not distribute as well in people with NYHA Class II–IV heart failure.^[8][14]

Metabolism

Lisinopril is the only water-soluble member of the ACE inhibitor class, with no hepatic metabolism.^[38]

Elimination

Lisinopril leaves the body completely unchanged in the urine.^[8][14] The half-life of lisinopril is 12 hours, and is increased in people with kidney problems.^[8][14] While the plasma half-life of lisinopril has been estimated between 12–13 hours, the elimination half-life is much longer, at around 30 hours.^[15] The full duration of action is between 24 and 30 hours.^[15]

Chemistry

Pure lisinopril powder is white to off-white in color.^[8] Lisinopril is soluble in water (approximately 13 mg/L at room temperature),^[16] less soluble in methanol, and virtually insoluble in ethanol.^[8]

History

Captopril, the first ACE inhibitor, is a functional and structural analog of a peptide derived from the venom of the jararaca, a Brazilian pit viper (Bothrops jararaca).^[17] Enalapril is a derivative, designed by scientists at Merck to overcome the rash and bad taste caused by captopril.^[18][19]{{rp|12–13}}

Enalapril is actually a prodrug; the active metabolite is enalaprilat.^[20]

Lisinopril is a synthetic peptide derivative of captopril.^[21] Scientists at Merck created lisinopril by systematically altering each structural unit of enalaprilat, substituting various amino acids. Adding lysine at one end of the drug turned out to have strong activity and was orally available; analogs of that compound resulted in lisinopril, which takes its name from the discovery with lysine. Merck conducted clinical trials, and the drug was approved for hypertension in 1987 and congestive heart failure in 1993.^[20]

The discovery posed a problem, since sales of enalapril were strong for Merck, and the company did not want to diminish those sales. Merck ended up entering into an agreement with Zeneca under which Zeneca received the right to co-market lisinopril, and Merck received the exclusive rights to an earlier stage aldose reductase inhibitor drug candidate, a potential treatment for diabetes. Zeneca's marketing and brand name, "Zestril", turned out to be stronger than Merck's effort.^[22] The drug became a blockbuster for Astrazeneca (formed in 1998), with annual sales in 1999 of $1.2B.^[61]

The US patents expired in 2002.^[23] Since then, lisinopril has been available under many brand names worldwide; some formulations include the diuretic hydrochlorothiazide.^[24]

References

Further reading

• {{cite journal | vauthors = Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P | title = Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients | journal = Br J Clin Pharmacol | volume = 46 | issue = 5 | pages = 467–71 |date=November 1998 | pmid = 9833600 | pmc = 1873694 | doi = 10.1046/j.1365-2125.1998.00811.x }}
• {{cite journal | vauthors = Bussien JP, Waeber B, Nussberger J, Gomez HJ, Brunner HR | title = Once-daily lisinopril in hypertensive patients: Effect on blood pressure and the renin-angiotensin system | journal = Curr Therap Res | volume = 37 | pages = 342–51 | year = 1985 | pmid = | pmc = }}

External links

• U.S. National Library of Medicine: Drug Information Portal – Lisinopril

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