Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor and is used to treat

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

, and after

heart attacks A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...

. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

mellitus. Lisinopril is taken by mouth. Full effect may take up to four weeks to occur. Common side effects include headache, dizziness, feeling tired, cough, nausea, and rash. Serious side effects may include low blood pressure, liver problems, high blood potassium, and angioedema. Use is not recommended during the entire duration of pregnancy as it may harm the baby. Lisinopril works by inhibiting the renin–angiotensin–aldosterone system. Lisinopril was patented in 1978 and approved for medical use in the United States in 1987. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2020, it was the fourth most commonly prescribed medication in the United States, with more than 88million prescriptions. In July 2016, an oral solution formulation of lisinopril was approved for use in the United States.

Structure–activity relationships

Lisinopril has a proline group that is responsible for the availability of the drug in oral formulation. The carboxylate group interacts with zinc ions to inhibit the ACE enzyme found in the kidneys and lungs. The other substituents participate in binding the same enzyme. Unlike Captopril, another ACE Inhibitor, Lisinopril lacks a

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

group.

Medical uses

Lisinopril is typically used for the treatment of

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

, and diabetic nephropathy and after acute myocardial infarction (heart attack). Lisinopril is part of the ACE inhibitors drug class. Compared to other drugs within the same class such as captopril and enalapril, lisinopril has a longer duration of action. FDA-approved Indications: * Lisinopril is approved by the US Food and Drug Administration (FDA) to manage hypertension in adult and pediatric patients six years and older. * as adjunctive therapy in the treatment of heart failure. * It is recommended as a treatment of ST-segment elevation myocardial infarction (STEMI) within 24 hours in hemodynamically stable patients to improve survival. The lisinopril is started at 5 or 10 mg and titrated upwards to 40 mg once daily maximum. The usual effective maintenance dosage is 20mg administered in a single daily dose. A review concluded that lisinopril was effective for treatment of proteinuric kidney disease, including diabetic proteinuria. In people of

sub-Saharan Africa Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...

n descent,

calcium-channel blockers Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

thiazide diuretics Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first ...

may more effectively lower blood pressure than

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...

s such as lisinopril, although convincing evidence is lacking that these drugs differ in their effect on morbidity or mortality in such persons.

Kidney problems

In patients with moderate to severe kidney disease, lisinopril and other

s are superior to angiotensin II receptor blockers and other antihypertensive drugs for prevention of death, fatal cardiac events, and kidney injury. Dose reduction may be required when creatinine clearance is less than or equal to 30mL/min. Since lisinopril is removed by

dialysis Dialysis may refer to: *Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric pote ...

, dosing changes must also be considered for people on dialysis.

Pregnancy and breastfeeding

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. Death and increased toxicity to the fetus and newly born child have been reported 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 current lack of safety data.

Contraindications

Lisinopril is contraindicated in people who have a history of angioedema (

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

or idiopathic) or who have diabetes and are taking

aliskiren Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically reco ...

Adverse effects

The incidence of adverse effects varies according to which disease state the patient is being treated for. People taking lisinopril for the treatment of

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

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. * Difficulty swallowing or breathing (signs of angioedema),

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

(

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

) *

Hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...

(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 A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

may experience the following side effects: *

Hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

(5.3%) *

Kidney dysfunction Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

(1.3%) People taking lisinopril for the treatment of

may experience the following side effects: * Hypotension (3.8%) * Dizziness (12% at low dose – 19% at high dose) * Chest pain (2.1%) *

Fainting Syncope, commonly known as fainting, or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...

(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; a causal relationship has not been established. *Agranulocytosis 003782076lg Lisinopril Lisinopril 40 MG Oral Tablet

003782076lg Lisinopril Lisinopril 40 MG Oral Tablet

Overdose

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

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 Dental surgery is any of a number of medical procedures that involve artificially modifying dentition; in other words, surgery of the teeth, gums and jaw bones. Types Some of the more common are: * Endodontic (surgery involving the pulp or root ...

is more controversial, with some dentists recommending discontinuation the morning of the procedure. 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 and medical referral.

Pharmacology

Lisinopril is the

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

-analog of enalapril. Unlike other ACE inhibitors, it is not a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

, is not metabolized by the liver, and is excreted unchanged in the urine.

Mechanism of action

Lisinopril is an

, meaning it blocks the actions of

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstr ...

(ACE) in the renin–angiotensin–aldosterone system (RAAS), preventing angiotensin I from being converted to

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...

. Angiotensin II is a potent direct vasoconstrictor and a stimulator of aldosterone release. Reduction in the amount of angiotensin II results in relaxation of the arterioles. Reduction in the amount of angiotensin II also reduces the release of

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

from the adrenal cortex, which allows the kidney to excrete sodium along with water into the urine, and increases retention of potassium ions. Specifically, this process occurs in the

peritubular capillaries In the renal system, peritubular capillaries are tiny blood vessels, supplied by the efferent arteriole, that travel alongside nephrons allowing reabsorption and secretion between blood and the inner lumen of the nephron. Peritubular capillaries su ...

of the kidneys in response to a change in Starling forces. The inhibition of the RAAS system causes an overall decrease in blood pressure.

Pharmacokinetics

Absorption

Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about seven hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large interpatient variability (6 to 60%) at all doses tested (5 to 80 mg). Lisinopril absorption is not affected by the presence of food in the gastrointestinal tract. Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Usual bioavailability of ~25% (reduced to 16% in people with

New York Heart Association Functional Classification The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity; the limitati ...

(NYHA) Class II–IV heart failure). Its time to peak concentration is 7 hours. The peak effect of lisinopril is about 4 to 8 hours after administration. Food does not affect its absorption.

Distribution

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

Metabolism

Lisinopril is the only water-soluble member of the ACE inhibitor class, with no metabolism by the liver.

Elimination

Lisinopril leaves the body completely unchanged in the urine. The

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

of lisinopril is 12 hours, and is increased in people with kidney problems. While the plasma half-life of lisinopril has been estimated between 12 and 13 hours, the elimination half-life is much longer, at around 30 hours. The full duration of action is between 24 and 30 hours.

Chemistry

Pure lisinopril powder is white to off white in color. Lisinopril is soluble in water (approximately 13 mg/L at room temperature), less soluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

, and virtually insoluble in

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

History

Captopril Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inh ...

, the first ACE inhibitor, is a

functional Functional may refer to: * Movements in architecture: ** Functionalism (architecture) ** Form follows function * Functional group, combination of atoms within molecules * Medical conditions without currently visible organic basis: ** Functional sy ...

and structural analog of a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

derived from the venom of the jararaca, a Brazilian pit viper (''

Bothrops jararaca ''Bothrops jararaca'' — known as the ''jararaca'' or ''yarara'' — is a highly venomous pit viper species endemic to South America in southern Brazil, Paraguay, and northern Argentina. The specific name, ''jararaca'', is derived from the Tup ...

''). Enalapril is a derivative, designed by scientists at Merck to overcome the rash and bad taste caused by captopril. Enalapril is actually a

; the active metabolite is

enalaprilat Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril. The thiol functional group of captopril was replaced with a carboxylic ...

.> The di-acid metabolite of enalapril,

, and its

analogue lisinopril are potent inhibitors of angiotensin converting enzyme (ACE); they do not contain sulphydryl groups. Both drugs can be assayed by high pressure liquid chromatography and by radioimmunoassay and plasma ACE inhibition remains stable under normal storage conditions. It is therefore possible to study their pharmacokinetics as well as their pharmacodynamic effects in humans.

Enalaprilat Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril. The thiol functional group of captopril was replaced with a carboxylic ...

and lisinopril as well as ACE activity have been measured in blood taken during the course of two studies of the effects of these drugs on blood pressure and autonomic responsiveness. Lisinopril is a synthetic peptide derivative of captopril. Scientists at Merck created lisinopril by systematically altering each structural unit of enalaprilat, substituting various amino acids. Adding

at one end of the drug turned out to have strong activity and had adequate bioavailability when given orally; 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. 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 Zeneca (officially Zeneca Group PLC) was a British multinational pharmaceutical company headquartered in London, United Kingdom. It was formed in June 1993 by the demerger of the pharmaceuticals and agrochemicals businesses of Imperial Che ...

under which Zeneca received the right to co-market lisinopril, and Merck received the exclusive rights to an earlier stage

aldose reductase inhibitor Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Mechanism Their target, aldose reductase, is an enzyme that is normally present in many other parts of the body, and ...

drug candidate, a potential treatment for diabetes. Zeneca's marketing and brand name, "Zestril", turned out to be stronger than Merck's effort. The drug became a blockbuster for AstraZeneca (formed in 1998), with annual sales in 1999 of $1.2B. The US patents expired in 2002.Express Scripts
Patent expirations
/ref> Since then, lisinopril has been available under many brand names worldwide; some formulations include the

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

hydrochlorothiazide.

References

External links

* {{Portal bar , Medicine ACE inhibitors Amino acid derivatives AstraZeneca brands Carboxamides Carboxylic acids Embryotoxicants Enantiopure drugs Merck & Co. brands Pyrrolidines Teratogens Wikipedia medicine articles ready to translate