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Prasugrel
Prasugrel
(trade name Effient in the US and India, and Efient in the EU) is a drug used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible anatagonist of P2Y12
P2Y12
ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co.
Daiichi Sankyo Co.
and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company. Prasugrel
Prasugrel
was approved for use in Europe in February 2009,[1] and in the US in July 2009, for the reduction of thrombotic cardiovascular events (including stent thrombosis) in people with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI).[2]

Contents

1 Medical uses 2 Contraindications 3 Adverse effects 4 Interactions 5 Pharmacology

5.1 Mechanism of action 5.2 Pharmacodynamics 5.3 Pharmacokinetics

6 Chemistry 7 Patents 8 References

Medical uses[edit] Prasugrel
Prasugrel
is used in combination with low dose aspirin to prevent thrombosis in patients with ACS, including unstable angina pectoris, non- ST elevation
ST elevation
myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI), who are planned for treatment with PCI. In studies, prasugrel was more effective than the related clopidogrel but also caused more bleeding. Overall mortality was the same.[1][3] Prasugrel
Prasugrel
does not change the risk of death when given to people who have had a STEMI[citation needed] or NSTEMI. Prasugrel
Prasugrel
does however increase the risk of bleeding and may decrease the risk of further cardiovascular problems. Thus routine use in NSTEMI
NSTEMI
patients is of questionable value.[4] Contraindications[edit] Prasugrel
Prasugrel
should not be given to patients 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).[5] Adverse effects[edit] Adverse effects include:[6]

Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (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

Interactions[edit] As opposed to clopidogrel, proton pump inhibitors do not reduce the antiplatelet effects of prasugrel and hence it is relatively safe to use these medications together.[7] Pharmacology[edit] Mechanism of action[edit] Prasugrel
Prasugrel
is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12
P2Y12
receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI.[8] Clopidogrel, unlike prasugrel, was issued a black box warning from the FDA
FDA
on March 12, 2010, as the estimated 2–14% of the US population who have low levels of the CYP2C19
CYP2C19
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.[9][10] Unlike clopidogrel, prasugrel is effective in most individuals, although several cases have been reported of decreased responsiveness to prasugrel.[11] Pharmacodynamics[edit] Prasugrel
Prasugrel
produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.[12] 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.[6] Pharmacokinetics[edit]

The reaction of prasugrel (top left) to its active metabolite (R-138727, top right). Unlike the related drug clopidogrel, prasugrel activation does not involve oxidation by the enzyme CYP2C19, as the relevant oxygen (at the thiophene ring) is already present in the prodrug. Instead, both the first and last steps are hydrolyses. The two structures at the bottom represent the inactive thiolactone; they are tautomers of each other.

Prasugrel
Prasugrel
is a prodrug and is rapidly metabolized by esterases in the intestine and blood serum to a likewise inactive thiolactone, which is then converted, via CYP450-mediated (primarily CYP3A4
CYP3A4
and CYP2B6) oxidation,[citation needed] to a pharmacologically active metabolite (R-138727). R-138727 has an elimination half-life of about 7 hours (range 2 h to 15 h). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics. Chemistry[edit] Prasugrel
Prasugrel
has one chiral atom. It is used in racemic form as the hydrochloride salt, which is a white powder. Patents[edit]

US 5288726  claims prasugrel compound; will expire on 14 Apr 2017 US 6693115  claims hydrochloride salt of prasugrel; will expire on 3 Jul 2021

References[edit]

^ a b "European Public Assessment Report for Efient" (PDF). EMA. 2009.  ^ Baker WL, White CM (2009). "Role of prasugrel, a novel P2Y(12) receptor antagonist, in the management of acute coronary syndromes". American Journal of Cardiovascular Drugs. 9 (4): 213–229. doi:10.2165/1131209-000000000-00000. PMID 19655817. CS1 maint: Uses authors parameter (link) ^ "Arzneimittelinformation der Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ): Efient (Prasugrel)" (PDF) (in German). 16 April 2009. pp. 30–44.  ^ Bellemain-Appaix, A; Kerneis, M; O'Connor, SA; Silvain, J; Cucherat, M; Beygui, F; Barthelemy, O; Collet, J-P; Jacq, L; Bernasconi, F; Montalescot, G (2014). "Reappraisal of thienopyridine pretreatment in patients with non- ST elevation
ST elevation
acute coronary syndrome: a systematic review and meta-analysis". BMJ. 349: g6269–g6269. doi:10.1136/bmj.g6269. PMC 4208629 . PMID 25954988.  ^ "Effient (prasugrel hydrochloride) Prescribing Information". FDA. September 2011.  ^ a b Efient: Highlights of prescribing information ^ John, Jinu; Koshy S (2012). "Current Oral Antiplatelets: Focus Update on Prasugrel". Journal of american board of family medicine. 25: 343–349. doi:10.3122/jabfm.2012.03.100270. PMID 22570398.  ^ Wiviott SD, Braunwald E, McCabe CH, et al. (2007). " Prasugrel
Prasugrel
versus clopidogrel in patients with acute coronary syndromes". N Engl J Med. 357 (20): 2001–15. doi:10.1056/NEJMoa0706482.  ^ " FDA
FDA
Announces New Boxed Warning on Plavix: Alerts patients, health care professionals to potential for reduced effectiveness" (Press release). Food and Drug Administration (United States). March 12, 2010. Retrieved March 13, 2010.  ^ " FDA
FDA
Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". Drug Safety and Availability. Food and Drug Administration (United States). March 12, 2010. Retrieved March 13, 2010.  ^ Silvano M, et al. (2011). "A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty". J Thromb Thrombolysis. 31 (2): 233–4. doi:10.1007/s11239-010-0533-x. PMID 21088983.  ^ O'Riordan, Michael. "Switching from clopidogrel to prasugrel further reduces platelet function". TheHeart.org. Retrieved 1 April 2011. 

v t e

Antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs) (B01)

Antiplatelet drugs

Glycoprotein IIb/IIIa inhibitors

Abciximab Eptifibatide Orbofiban Roxifiban Sibrafiban§ Tirofiban

ADP receptor/ P2Y12
P2Y12
inhibitors

Thienopyridines

Clopidogrel Prasugrel Ticlopidine

Nucleotide/nucleoside analogs

Cangrelor Elinogrel Ticagrelor

Prostaglandin analogue (PGI2)

Beraprost Iloprost Prostacyclin Treprostinil

COX inhibitors

Acetylsalicylic acid/Aspirin# Aloxiprin Carbasalate calcium Indobufen Triflusal

Thromboxane inhibitors

Thromboxane synthase inhibitors

Dipyridamole
Dipyridamole
(+ aspirin) Picotamide Terbogrel

Receptor antagonists

Terbogrel Terutroban§

Phosphodiesterase inhibitors

Cilostazol Dipyridamole Triflusal

Other

Cloricromen Ditazole Vorapaxar

Anticoagulants

Vitamin K antagonists (inhibit II, VII, IX, X)

Coumarins: Acenocoumarol Coumatetralyl Dicoumarol Ethyl biscoumacetate Phenprocoumon Warfarin# 1,3-Indandiones: Clorindione Diphenadione Phenindione Other: Tioclomarol

Factor Xa
Factor Xa
inhibitors (with some II inhibition)

Heparin
Heparin
group/ glycosaminoglycans/ (bind antithrombin)

Low molecular weight heparin

Bemiparin Certoparin Dalteparin Enoxaparin Nadroparin Parnaparin Reviparin Tinzaparin

Oligosaccharides

Fondaparinux Idraparinux§

Heparinoids

Danaparoid Dermatan sulfate Sulodexide

Direct Xa inhibitors ("xabans")

Apixaban Betrixaban Darexaban§ Edoxaban Otamixaban§ Rivaroxaban

Direct thrombin (IIa) inhibitors

Bivalent: Hirudin

Bivalirudin Desirudin Lepirudin

Univalent: Argatroban Dabigatran Efegatran Inogatran§ Melagatran‡ Ximelagatran‡

Other

Antithrombin
Antithrombin
III Defibrotide Protein C

Drotrecogin alfa‡

Ramatroban REG1

Thrombolytic drugs/ fibrinolytics

Plasminogen activators: r-tPA

Alteplase Reteplase Tenecteplase Desmoteplase†

UPA

Saruplase Urokinase

Anistreplase Monteplase Streptokinase# Other serine endopeptidases: Ancrod Brinase Fibrinolysin

Non-medicinal

Citrate EDTA Oxalate

#WHO-EM ‡Withdrawn from market Clinical trials:

†Phase III §Never to phase III

v t e

Purine receptor
Purine receptor
modulators

Receptor (ligands)

P0 (adenine)

Agonists: 8-Aminoadenine Adenine

P1 (adenosine)

Agonists: 2-(1-Hexynyl)-N-methyladenosine 2-Cl-IB-MECA 2'-MeCCPA 4'-O-β-D-Glucosyl-9-O-(6''-deoxysaccharosyl)olivil 5'-N-ethylcarboxamidoadenosine Adenosine ADP AMP Apadenoson ATL-146e ATP BAY 60–6583 Binodenoson Capadenoson CCPA CGS-21680 CP-532,903 Evodenoson GR 79236 LUF-5835 LUF-5845 N6-Cyclopentyladenosine Namodenoson Neladenoson dalanate Piclidenoson Regadenoson SDZ WAG 994 Selodenoson Sonedenoson Tecadenoson UK-432,097

Antagonists: 8-Chlorotheophylline 8-Phenyl-1,3-dipropylxanthine 8-Phenyltheophylline Acefylline Aminophylline ATL-444 Bamifylline Cafedrine Caffeine Caffeine
Caffeine
citrate Cartazolate CGH-2466 CGS-15943 Choline theophyllinate CPX CVT-6883 Dimethazan DMPX DPCPX Dyphylline Enprofylline Etazolate Fenethylline IBMX Isovaleric acid Istradefylline KF-26777 MRE3008F20 MRS-1220 MRS-1334 MRS-1706 MRS-1754 MRS-3777 Paraxanthine Pentoxifylline Preladenant Propentofylline Proxyphylline PSB-10 PSB-11 PSB-36 PSB-603 PSB-788 PSB-1115 Reversine Rolofylline SCH-442,416 SCH-58261 Theacrine Theobromine Theodrenaline Theophylline Tozadenant Tracazolate VUF-5574 ZM-241,385

P2 (nucleotide)

P2X (ATP)

Agonists: 2-Me-SATP α,β-Me-ATP Adenosine ADP AMP Ap4A Ap5A ATP ATPγS BzATP Cibacron blue CTP D-β,γ-Me-ATP GTP HT-AMP Ivermectin L-β,γ-Me-ATP MRS-2219 PAPET-ATP UTP Zinc

Antagonists: 5-BDBD A-317491 A-438079 A-740003 A-804598 A-839977 AF-353 AZ-10606120 AZ-11645373 BBG Calcium Calmidazolium Chelerythrine Copper Emodin
Emodin
(Rheum officinale) Evans Blue GW-791343 HMA Ip5I isoPPADS JNJ-47965567 KN-04 KN-62 Magnesium MRS-2159 NF-023 NF-110 NF-157 NF-279 NF-449 Opiranserin (VVZ-149) Oxidized-ATP Phenol Red Phenolphthalein PPADS PPNDS PSB-12062 Puerarin
Puerarin
(Radix puerariae) Purotoxin 1 RB-2 Ro 0437626 Ro 51 RO-3 Sodium ferulate
Sodium ferulate
(Angelica sinensis, Ligusticum wallichii) Suramin TC-P 262 Tetramethylpyrazine
Tetramethylpyrazine
(ligustrazine) (Ligusticum wallichii) TNP-ATP Zinc

P2Y

Agonists: 2-Me-SADP 2-Me-SATP 2-Thio-UTP 5-Br-UDP 5-OMe-UDP α,β-Me-ATP Adenosine ADP ADPβS Ap3A AR-C 67085MX ATP ATPγS CTP dATP Denufosol Diquafosol IDP ITP INS-365 INS-37217 MRS-2365 MRS-2690 MRS-2693 MRS-2768 MRS-2957 MRS-4062 NF-546 PAPET-ATP PSB-0474 PSB-1114 UDP UDPβS UDP-galactose UDP-glucose UDP-N-acetylglucosamine Up3U UTP UTPγS

Antagonists: 2-Me-SAMP A3P5PS AMPαS Ap4A AR-C 66096 AR-C 67085MX AR-C 69931MX AR-C 118925XX ATP BzATP C1330-7 Cangrelor Clopidogrel Elinogrel Ip5I MRS-2179 MRS-2211 MRS-2279 MRS-2395 MRS-2500 MRS-2578 NF-157 NF-340 PIT PPADS Prasugrel PSB-0739 RB-2 Regrelor Suramin Ticagrelor Ticlopidine UDP

Transporter (blockers)

CNTs

6-Hydroxy-7-methoxyflavone Adenosine dMeThPmR Estradiol KGO-2142 KGO-2173 MeThPmR Phloridzin Progesterone

ENTs

Barbiturates Benzodiazepines Cilostazol Dilazep Dipyridamole Estradiol Ethanol Hexobendine NBMPR Pentoxifylline Progesterone Propentofylline

PMAT

Decynium-22

Enzyme (inhibitors)

XO

Allopurinol Amflutizole Benzbromarone Caffeic acid Cinnamaldehyde Cinnamomum osmophloeum Febuxostat Myo-inositol Kaempferol Myricetin Niraxostat Oxipurinol Phytic acid Pistacia integerrima Propolis Quercetin Tisopurine Topiroxostat

Others

Aminopterin Azathioprine Methotrexate Mycophenolic acid Pemetrexed Pralatrexate Many others

Others

Precursors: Adenine Adenosine AMP ADP ATP Cytosine Cytidine CMP CDP CTP Guanine Guanosine GMP GDP GTP Hypoxanthine Inosine IMP IDP ITP Ribose Uracil Uridine UMP UDP UTP

Others: Chrysophanol
Chrysophanol
(rhubarb)

See also: Receptor/signalin

.