Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent formation of blood clots. It is a

platelet inhibitor An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effectiv ...

and an irreversible antagonist of P2Y₁₂ ADP receptors and is of the

thienopyridine Thienopyridines are a class of selective, reversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity. Examples Drugs in this class include: clopidogrel (Plavix), prasugrel (Effient), and ticlopidine (Ticlid). Tinoridine ...

drug class. It was developed by Daiichi Sankyo Co. and produced by

Ube UBE or Ube may refer to: * Ubiquitin-activating enzyme * Ube, Yamaguchi, a city in Japan * Uniform Bar Examination * Unilateral Biportal Endoscopy * Ube Industries, chemical company * Union bound estimate, a probability theory bound * Union of Bo ...

and marketed in the United States in cooperation with

Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...

. 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 metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...

thrombosis) in people with

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome (a set of signs and symptoms) 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 l ...

(ACS) who are to be managed with

percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the ...

(PCI).

Medical uses

Prasugrel is used in combination with

low dose aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to trea ...

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 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 ma ...

( NSTEMI), and ST elevation myocardial infarction ( STEMI), 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 sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, ...

(3%), noncardiac chest pain (3%), peripheral edema (3%), thrombotic thrombocytopenic purpura (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. They are the most potent inhibitor ...

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 inhibitors, like ticlopidine (trade name Ticlid) and

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

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

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ...

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 on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

from the FDA on March 12, 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 p ...

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 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.Efient: Highlights of prescribing information
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Pharmacokinetics

Prasugrel is 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 dru ...

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 respon ...

in the intestine and carboxylesterase 1 in the liver to a likewise inactive thiolactone, 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 is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

(R-138727). R-138727 has an

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic 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 b ...

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

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

, 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 (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

atom. It is used in

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts 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 racemates. ...

form as the hydrochloride 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 {{Portal bar , Medicine Adenosine diphosphate receptor inhibitors Eli Lilly and Company brands Daiichi Sankyo Fluoroarenes Ketones Thienopyridines Acetate esters Cyclopropanes