Clopidogrel

• IUPAC: (S) -methyl-( 2-chlorophenyl) -2 - ( 6,7- dihydro -4H -thieno [ 3,2-c ] pyridin- 5-yl ) acetate
• ( )- Methyl (2-chlorophenyl ) -2 - ( 6,7- dihydro -4H -thieno [ 3,2-c ] pyridin- 5-yl ) acetate
• Latin: Clopidogrelum

• C16H16ClNO2S

Salts:

• C16H16ClNO2S · H2SO4
• C16H16ClNO2S · C6H5SO3H
• C16H16ClNO2S · HCl
• 2 ( C16H16ClNO2S ) · C10H6 ( SO3H ) 2

• 90055-48-4 ( (± ) - ( RS) -Base)
• 113665-84-2 [( ) - (S ) base ]
• 120202-66-6 ( hydrogen sulfate )
• 744256-69-7 ( besilate )
• 120202-65-5 (hydrochloride)
• 945775-34-8 ( Napadisilat )

B01AC04

• Colorless oil [( ) - (S ) base ]
• Colorless crystals ( hydrogen sulfate )

Antiplatelet

• 321.83 g.mol -1 [( ) - (S ) base ]
• 419.91 g · mol -1 ( hydrogen sulfate )
• 479.06 g · mol -1 ( besilate )
• 358.28 g.mol -1 (hydrochloride)
• 931.94 g · mol -1 ( Napadisilat )

184 ° C

• Very poor in water: 50.78 mg · l-1
• Soluble in water and methanol; practically insoluble in water at neutral pH, soluble in water at pH 1 ( hydrogen sulfate )
• Practically insoluble in water ( besilate )
• Practically insoluble in water at neutral pH, soluble in water at pH 1 and in methanol (hydrochloride)

Template: Infobox chemical / molecular formula search available

Clopidogrel is an inhibitor of adenosine diphosphate (ADP ) receptor subtype P2Y12 from the family of the Gi- protein coupled inhibitory purine receptors (GPCR). This receptor mediates on the surface of thrombocytes ( platelets) ADP-induced platelet aggregation. Clopidogrel therefore acts as a platelet aggregation inhibitor.

Clopidogrel belongs to the group of drugs that affect hemostasis ( blood clotting). It is used for therapy and prevention of the formation of blood clots. The platelet hemostasis caused especially in the arterial part of the vascular system of shutters which lead to a heart attack or stroke, or even to infarcts in other organs (eg mesenteric infarction ). One of the clopidogrel similar but considerably weaker activity has acetylsalicylic acid ( ASA), which acts via a different mechanism on platelets.

Mechanism of action

Clopidogrel is a prodrug. After absorption is formed by oxidation by cytochrome P-450 3A4, followed by hydrolysis of the pharmacologically active metabolite. Potent inhibitors of CYP3A4 (such as itraconazole, gemfibrozil, fluvoxamine, tricyclic antidepressants), are therefore able to restrict the bioactivation of clopidogrel and therefore its efficacy. The pharmacologically active metabolite is then responsible for the blockade of the binding of adenosine diphosphate (ADP) to its platelet receptor ( the P2Y12 receptor ) such that ADP -dependent platelet activation by the Glykoprotein-IIb/IIIa-Rezeptorkomplex omitted. Clopidogrel herein differs from the mechanism of action of acetylsalicylic acid, the platelet aggregation by blocking the cyclooxygenases COX- 1 (and COX-2) inhibiting.

Since blocking the P2Y12 receptor is irreversible, the platelets remain affected during their lifetime. The clotting ability comes only with the formation of platelets during 5-7 days again.

A possibility to estimate the effect of clopidogrel provides ADP-induced aggregometry.

Clopidogrel is chiral; in the literature multistep synthetic pathways of clopidogrel have been described. The two enantiomers of the (S) - ( ) - form of pharmaceutically used, clopidogrel in the form of a salt, such as hydrogen sulfate, besylate ( benzenesulfonate ) or hydrochloride, is used.

Areas of application

Clopidogrel is indicated for the prevention of atherothrombotic events

• As monotherapy after a short previously encountered heart attack or with the presence of peripheral arterial disease (PAD). For the prevention of recurrence of stroke occurs due to its side effect profile only in the presence of an increased risk of recurrence into consideration at the same time or if there are other reasons for its regulation.

• In combination with acetylsalicylic acid in

• An acute coronary syndrome without ST- segment elevation ( " unstable angina " or " non-Q- wave myocardial infarction ", cf ECG nomenclature), even if a stent (stent ) was inserted into a blocked or narrowed coronary artery, to increase blood flow to restore
• After a myocardial infarction with ST- segment elevation (STEMI, "ST - segment elevation myocardial infarction " ) accompanying the thrombolysis

Studies

A significantly better efficacy compared with ASA monotherapy was in trials in the indication " symptomatic peripheral arterial disease " are seen ( CAPRIE ).

In the course of coronary vascular stenting both substances concomitantly. While aspirin 100 mg permanently, so should be given a lifetime according to current knowledge after stent implantation, the duration of treatment with clopidogrel directed 75 mg one hand, according to the type of implanted stents ( four weeks after bare metal stents, usually six to twelve months after drug- eluting stents ), on the other hand, according to acuteness of coronary syndrome (nine months in acute coronary syndrome ). The exact duration of this dual antiplatelet therapy is controversial and the subject of scientific debate.

In the context of stroke double antiplatelet therapy does not improve the outcome of treatment and leads to more severe bleeding (MATCH Study). For this reason, monotherapy is recommended with aspirin for stroke patients in general. Only in so-called high-risk patients, clopidogrel monotherapy is considered.

Side effects and limitations of use

Because Clopidogrel inhibits platelet aggregation, the most common adverse effects are the occurrence of bleeding, such as nosebleeds, stomach or intestinal bleeding, hematoma ( bruising ), blood in the urine, in a few cases, bleeding in the eye, inside the head, in the lungs or in the joints. In addition, gastrointestinal discomfort and occasionally headache, drowsiness, dizziness and rash may occur. A very rare side effect probably represents the Thrombotic thrombocytopenic purpura (TTP Moschcowitz syndrome) dar. Compared to aspirin side effects in the gastrointestinal tract with clopidogrel rare.

Treatment with clopidogrel should be started after neuraxial anesthesia procedures such as spinal anesthesia or epidural anesthesia only after the removal of the catheter. Before neuraxial anesthesia should be passed since the last dose of clopidogrel at least seven days. Likewise, clopidogrel should be discontinued seven days prior to elective surgery, when a platelet aggregation- inhibiting effect is temporarily not desirable.

If clopidogrel is overdosed, or, for example, because of an emergency operation, the clopidogrel effect should be lifted immediately, the problem is that located in the body platelets are irreversibly inhibited. An antidote to reverse the effects of clopidogrel does not exist. Since platelets have a life time of 7 to 10 days, and new platelets are produced only slowly and continuously, it will take several days to return sufficient functional new platelets are formed. If the platelet function such as must immediately be restored because of an emergency operation, foreign blood platelet concentrates must be given. It should be noted that even 6 hours after taking Clopidogrel 50 % of clopidogrel are in the blood ( half-life) and therefore the administered new platelets are also inhibited.

Pharmacokinetics

• Bioavailability: 50 %
• Metabolism: liver
• Half-life: 7-8 hours
• Excretion: 50 % kidney, 46% of liver

Interaction between clopidogrel and proton pump inhibitors

Clopidogrel is a prodrug, which is converted, inter alia, on the enzyme cytochrome P450 2C19 ( one isoenzyme of cytochrome P450 ) in its active form. Some proton pump inhibitors such as omeprazole and lansoprazole are also metabolized by this enzyme. Concomitant treatment with these drugs decreased plasma levels of the active clopidogrel metabolites were found. There is evidence from studies that this interaction is not clinically relevant.

The cytochrome P-450 2C19 also undergoes extensive genetic polymorphism. It can be made either less or enhanced. In "Poor Metabolizern " ( poor metabolizers ) the competition between the proton pump inhibitor and clopidogrel to the CYP P -450 - 2C19, the situation that too little Clopidogrel is converted to the active form, in addition worsen.

Clopidogrel resistance

Several studies showed 5 to 44% of patients an insufficient effect of clopidogrel. One reason for this Clopidogrel resistance is in the frequent loss of function of the gene CYP2C19, whose gene, CYP P- 450 - 2C19, is involved in the formation of the active drug from the prodrug ineffective.

Around 25 % of the white American population and around 30% of the African- American population carry a CYP2C19 allele with lost or reduced function of the enzyme in the processing of clopidogrel. Whether a partial resistance by higher doses, an enhanced activity could be achieved is unclear. Since the beginning of 2013 there is a test by which the individual activity of the CYP 2C19 can be determined in order to determine the possible invalidity of clopidogrel.

Development and marketing

Clopidogrel was developed by ticlopidine ( entry 1993) as its structural variant jointly by Sanofi -Aventis and Bristol- Myers Squibb, it differs by a methyl side chain of this. As clopidogrel - containing medicines were first introduced in 1998, Plavix or Iscover on the market, which are among the first to be authorized EU wide via the centralized procedure, introduced in 1995.

After the first approval for clopidogrel - containing generics were issued in Germany in May 2008, the first mover Sanofi -Aventis had tried in vain by legal means to prevent the launch because he new providers and the licensing authority in violation of the drug legally allotted 10 - years of data exclusivity protection ( which ended in July 2008) imputed to the dossier of the original product. However, the new preparations had not received the drug legal marketing permit a relative participating to the clinical data of the initial supplier registration, but through the process of re-registration, although only one created in India comparative study with 46 subjects of Clopidogrelbesilat was presented with clopidogrel. The early market access was explosive against the background that Plavix is the medicine with the world's second largest revenue. The newly approved drugs were initially around a fifth cheaper than the Originalpäparate.

While Sanofi -Aventis and Bristol- Myers Squibb clopidogrel use in the form of its bisulfate salt in Iscover or Plavix, the generics contain other salts. Patent rights of first mover are not violated. Evidence of varying degrees of effectiveness does not exist.

Sanofi Pharma Bristol -Myers Squibb also developed a means consisting of the fixed combination of 75 mg of clopidogrel and 75 or 100 mg acetylsalicylic acid, the (see application areas) with a single tablet, the combined maintenance therapy.

Cost-benefit comparison

Clopidogrel 75 mg is approximately 247, - € per 100 tablets than original product about 80 times as expensive and as a generic with about 180, - € about 60 times as expensive as ASA 100 mg ( Generic approximately 3, - € per 100 tablets) (09 /2009).

On behalf of the Federal Joint Committee ( G -BA ) examined the Institute for Quality and Efficiency in Health Care ( IQWiG), whether this 60 to 80 times higher price compared to acetylsalicylic acid (ASA ) is justified or whether this preparation no superior benefit over treatment with ASA has. In published on June 30, 2006 final report, the Institute concludes: Long-term therapy with clopidogrel ( monotherapy) in comparison to treatment with ASA in patients with symptomatic peripheral arterial occlusive disease an additional benefit in terms of reducing the risk for vascular / thromboembolic events. However, the report continues, had been no evidence of a reduction in total mortality.