Prasugrel, sold under the brand names Effient and Efient, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y₁₂ ADP receptors and is of the

thienopyridine Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity. They have a significant role in the management of cardiovascular disease. Clinical Uses They are used in the managem ...

drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and marketed in the United States in cooperation with

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

. Prasugrel was approved for use in the European Union in February 2009, and in the US in July 2009, for the reduction of thrombotic cardiovascular events (including

stent In medicine, a stent is a tube usually constructed of a metallic alloy or a polymer. It is inserted into the Lumen (anatomy), lumen (hollow space) of an anatomic vessel or duct to keep the passageway open. Stenting refers to the placement of ...

thrombosis) in people with

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally located pressure-like chest pain, ...

(ACS) who are to be managed with

percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat stenosis, narrowing of the coronary artery, coronary arteries of the heart found in coronary artery disease. The procedure is used to place and ...

(PCI).

Medical uses

Prasugrel is used in combination with low-dose aspirin to prevent thrombosis in patients with acute coronary syndrome, including unstable angina pectoris, non- ST elevation

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

(

NSTEMI A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...

), and ST elevation myocardial infarction (

STEMI A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...

), who are planned for treatment with PCI. Prasugrel is associated with a higher bleeding risk compared to clopidogrel but has demonstrated superiority in reducing the composite endpoint of death, recurrent myocardial infarctions and stroke. Prasugrel does not change the risk of death when given to people who have had a STEMI or NSTEMI. Given the risk of bleeding, prasugrel should not be used in people who are older than 75 years, who have low body weight or a history of transient ischemic attacks or strokes. The initiation of prasugrel before coronary angiography outside the context of primary PCI is not recommended.

Approval status

The drug was introduced to clinical practice in Canada in 2010 but was subsequently withdrawn by the manufacturer in 2020 as a "business decision". This has left a gap in the management of high-risk patients in certain situations in Canada where Effient was the drug of choice.

Contraindications

Prasugrel should not be given to people with active pathological bleeding, such as peptic ulcer or a history of transient ischemic attack or stroke, because of higher risk of stroke (thrombotic stroke and intracranial hemorrhage).

Adverse effects

Adverse effects include: *Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%),

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

(3%), noncardiac chest pain (3%), peripheral edema (3%),

thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in thrombi, blood clots forming in small blood vessels throughout the body. This results in a thrombocytopenia, low platelet count, hemolytic anemia, low red blood cells d ...

(TTP) *Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%) *Dermatologic: Rash (3%) *Endocrine and metabolic: Hypercholesterolemia/hyperlipidemia (7%) *Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%) *Hematologic: Leukopenia (3%), anemia (2%) *Neuromuscular and skeletal: Back pain (5%) *Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%) *Hypersensitivity, including

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

Interactions

Prasugrel has a low potential for interactions. It may, for example, be used with

proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. The body eventually synthesizes ne ...

s to reduce the risk of gastrointestinal bleeding without loss of its antiplatelet effect.

Pharmacology

Mechanism of action

Prasugrel is a member of the

class of

ADP receptor P2Y receptors are a family of purinergic G protein-coupled receptors, stimulated by nucleotides such as adenosine triphosphate, adenosine diphosphate, uridine triphosphate, uridine diphosphate and UDP-glucose.To date, 8 P2Y receptors have been cl ...

inhibitors, like

ticlopidine Ticlopidine, sold under the brand name Ticlid, is a medication used to reduce the risk of thrombotic strokes. It is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially ...

(trade name Ticlid) and

clopidogrel Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet drug, antiplatelet medication used to reduce the risk of Cardiovascular disease, heart disease and stroke in those at high risk. It is also used together with aspi ...

(trade name Plavix). These agents reduce the aggregation ("clumping") of

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

by irreversibly binding to P2Y₁₂ receptors. Prasugrel inhibits platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. The TRITON-TIMI 38 study compared prasugrel with clopidogrel, and showed that prasugrel reduced rates of ischaemic events, but increased bleeding risk. Overall mortality rates were similar for each drug. Clopidogrel, unlike prasugrel, was issued a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

from the FDA on 12 March 2010, as the estimated 2–14% of the US population who have low levels of the

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...

liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not. Unlike clopidogrel, prasugrel is effective in most individual with the exception in patients over the age of 75, weight under 60 kg, and patients with a history of stroke or TIA due to increased risk of bleeding, although several cases have been reported of decreased responsiveness to prasugrel. It has been suggested that the decreased responsiveness observed in prasugrel is likely due to its low but significant frequency of High Platelet Reactivity (HPR).

Pharmacodynamics

Prasugrel produces inhibition of

platelet aggregation Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytop ...

to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of the drug, about 90% of patients had at least 50% inhibition of platelet aggregation by one hour. Maximum platelet inhibition was about 80%. Mean steady-state inhibition of platelet aggregation was about 70% following three to five days of dosing at 10 mg daily after a 60-mg loading dose. Platelet aggregation gradually returns to baseline values over five to 9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. Increasing platelet inhibition could increase bleeding risk. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

Pharmacokinetics

Prasugrel is a

prodrug A prodrug is a pharmacologically inactive 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 ...

and is rapidly metabolized by

carboxylesterase 2 Carboxylesterase 2 is an enzyme that in humans is encoded by the ''CES2'' gene. It is a member of the alpha/beta fold hydrolase family. Carboxylesterase 2 is a member of a large multigene family. The enzymes encoded by these genes are responsi ...

in the intestine and

carboxylesterase 1 Liver carboxylesterase 1 also known as carboxylesterase 1 (CES1, hCE-1 or CES1A1) is an enzyme that in humans is encoded by the ''CES1'' gene. The protein is also historically known as serine esterase 1 (SES1), monocyte esterase and cholesterol es ...

in the liver to a likewise inactive

thiolactone Thiolactones are a class of heterocyclic compounds in organic chemistry. They are analogs of the more common lactones in which an oxygen atom is replaced with a sulfur atom. The sulfur atom is within the ring system and adjacent to a carbonyl gro ...

, which is then converted by CYP3A4 and CYP2B6, and to a minor extent by CYP2C9 and CYP2C19, to a pharmacologically

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

(R-138727). R-138727 has an

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of about 7 hours (range 2 h to 15 h). Healthy subjects, patients with stable

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

, and patients undergoing PCI show similar pharmacokinetics.

Chemistry

Prasugrel has one

chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...

atom. It is used in

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

form as the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

salt, which is a white powder.

References

External links

* claims prasugrel compound; expired on 14 April 2017 * claims hydrochloride salt of prasugrel; will expire on 3 July 2021 {{Authority control Adenosine diphosphate receptor inhibitors Drugs developed by Eli Lilly and Company Daiichi Sankyo 2-Fluorophenyl compounds Ketones Thienopyridines Acetate esters Cyclopropyl compounds