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Ticagrelor

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Ticagrelor
Clinical data
Trade namesBrilinta, Brilique, others
Other namesAZD-6140
AHFS/Drugs.comMonograph
MedlinePlusa611050
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability36%
Protein binding>99.7%
MetabolismLiver(CYP3A4)
Eliminationhalf-life7 hrs (ticagrelor), 8.5 hrs (active metaboliteAR-C124910XX)
ExcretionBile duct
Identifiers
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.114.746Edit this at Wikidata
Chemical and physical data
FormulaC23H28F2N6O4S
Molar mass522.57g·mol−1
3D model (JSmol)
  • CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
  • InChI=1S/C23H28F2N6O4S/c1-2-7-36-23-27-21(26-15-9-12(15)11-3-4-13(24)14(25)8-11)18-22(28-23)31(30-29-18)16-10-17(35-6-5-32)20(34)19(16)33/h3-4,8,12,15-17,19-20,32-34H,2,5-7,9-10H2,1H3,(H,26,27,28)/t12-,15+,16+,17-,19-,20+/m0/s1☒N
  • Key:OEKWJQXRCDYSHL-FNOIDJSQSA-N☒N
☒NcheckY(what is this?)(verify)

Ticagrelor,sold under the brand nameBrilintaamong others, is amedicationused for the prevention ofstroke,heart attackand other events in people withacute coronary syndrome,meaning problems with blood supply in thecoronary arteries.It acts as aplatelet aggregation inhibitorby antagonising theP2Y12receptor.[7]The drug is produced byAstraZeneca.

90 mg tablet of Brilinta

The most common side effects includedyspnea(difficulty breathing), bleeding and raised uric acid level in the blood.[6]

It was approved for medical use in the European Union in December 2010,[6][8][9]and in the United States in July 2011.[5][10][11]In 2020, it was the 247th most commonly prescribed medication in the United States, with more than 1million prescriptions.[12][13]

Medical uses

[edit]

In the US, ticagrelor isindicatedto reduce the risk ofstrokein people with acute ischemic stroke or high-risk transient ischemic attack.[5]

In the EU, ticagrelor, co-administered with acetylsalicylic acid (aspirin), is indicated for the prevention of atherothrombotic events in adults withacute coronary syndromesor a history ofmyocardial infarctionand a high risk of developing an atherothrombotic event; and for the prevention of atherothrombotic events in adults with a history of myocardial infarction and a high risk of developing an atherothrombotic event.[6]

Contraindications

[edit]

Contraindications to ticagrelor are active bleeding, increased risk of bradycardia, concomitant therapy of ticagrelor and strong cytochrome P-450 3A (CYP3A4) inhibitors and moderate or severe hepatic impairment due to the risk of increased exposure to ticagrelor.[14][15]

Adverse effects

[edit]

The common adverse effects are increased risk of bleeding (which may be severe)[16]andshortness of breath(dyspnoea).[17]Dyspnoea is usually transient and mild-to-moderate in severity, with a higher risk at<1 month, 1–6 months and >6 months of follow up compared to clopidogrel.[17][18][19][20]Discontinuation of therapy is rare, although some people do not persist or switch therapies.[17][18][19]People who develop tolerable dyspnoea as a side effect of ticagrelor should be reassured to continue therapy, as it does not impact on the drug's cardiovascular benefit and bleeding risk inacute coronary syndrome(ACS).[17]Furthermore, two small subgroup analyses found no associations between ticagrelor and adverse changes in heart and lung function that may induce dyspnoea in stable coronary artery disease (CAD) and people with ACS without heart failure or significant lung disease.[18][21]

Ventricular pauses ≥3 seconds may occur in people with ACS the first week of treatment, but are likely to be mostly asymptomatic and transient, without causing increased clinical bradycardic adverse events.[22]Caution is recommended when using ticagrelor in people with advancedsinoatrial nodedisease.[23]Allergic skin reactions such asrashanditchinghave been observed in less than 1% of people taking ticagrelor.[24]

Interactions

[edit]

Inhibitors of the liver enzyme CYP3A4, such asketoconazoleand possiblygrapefruit juice,increaseblood plasmalevels of ticagrelor and consequently can lead to bleeding and other adverse effects. Ticagrelor is a weak CYP3A4 inhibitor and can increase the plasma concentration of CYP3A4 substrates[25]Current evidence suggests that use of ticagrelor with statins can increase the risk of adverse effects like myopathy and rhabdomyolysis. However, this evidence is weak, and more research is needed.[25][26]While it appears that the risk is low for most people, caution should be used when the medications are combined.[25][26]This is especially important in elderly patients, and some evidence suggests that extra caution should be used with renally impaired patients as well.[26][25]CYP3A4 inducers, for examplerifampicinand possiblySt. John's wort,can reduce the effectiveness of ticagrelor. There is no evidence for interactions viaCYP2C9.

The drug also inhibitsP-glycoprotein(P-gp), leading to increased plasma levels ofdigoxin,ciclosporinand other P-gp substrates. Levels of ticagrelor and AR-C124910XX (the active metabolite of ticagrelor formed by O-deethylation[27]) are not significantly influenced by P-gp inhibitors.[24]

It is generally recommended to use low-dose aspirin (75-100 mg per day) with ticagrelor when dual antiplatelet therapy (DAPT) is indicated. It has been observed that the use of 325 mg daily aspirin in DAPT increases the risk of bleeding events, without lowering the rate of a major adverse cardiovascular event (MACE) such as cardiovascular death, heart attack, stroke or unplanned revascularisation (restoration of blood flow).[28]

Pharmacology

[edit]

Mechanism of action

[edit]

Like thethienopyridinesprasugrel,clopidogrelandticlopidine,ticagrelor blocksadenosine diphosphate (ADP) receptorsof subtypeP2Y12.In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it anallostericantagonist, and the blockage is reversible.[29]Moreover, the drug does not needhepaticactivation, which might work better for people with genetic variants regarding the enzymeCYP2C19(although it is not certain whether clopidogrel is significantly influenced by such variants).[30][31][32]Ticagrelor was found to result in a lower risk of stroke at 90 days than clopidogrel, which requires metabolic conversion, among Han Chinese CYP2C19 loss-of-function carriers with minor ischemic stroke or TIA.[33]

Pharmacokinetics

[edit]

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[27]

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly people, women, people ofAsian ethnicity,and people with mild hepatic impairment. They are decreased in people that self-identified as 'black' and those with severe renal impairment. These differences are not considered clinically relevant. InJapanese people,concentrations are 40% higher than inCaucasians,or 20% after body weight correction. The drug has not been tested in people with severe hepatic impairment.[24][34]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[35]This means it has to be taken twice instead of once a day which is a disadvantage in respect ofcompliance,but its effects are more quickly reversible which can be useful beforesurgeryor if side effects occur.[24][36]

Chemistry

[edit]

Ticagrelor is anucleosideanalogue: the cyclopentane ring is similar to thesugarribose,and the nitrogen richaromatic ringsystem resembles thenucleobasepurine,giving the molecule an overall similarity toadenosine.The substance has low solubility and low permeability under theBiopharmaceutics Classification System.[8]

Ticagrelor as anucleosideanalogue
The nucleosideadenosinefor comparison

Research

[edit]
[edit]

With clopidogrel

[edit]

The PLATO trial concluded superiority of ticagrelor compared to clopidogrel in reducing the rate of death from vascular causes, MI, and stroke in people presenting with acute coronary syndromes.[14]Apost-hocsubgroup analysis of the PLATO trial suggested a reduction in total mortality with ticagrelor compared to clopidogrel in people with non-ST elevation acute coronary syndrome.[37]However, this finding should only be considered exploratory as it was not a primary endpoint of the PLATO trial.[14]Ticagrelor, as monotherapy, dual antiplatelet therapy (DAPT), and in comparison to clopidogrel, is associated with decreased all-cause mortality. When in comparison to clopidogrel, there is evidence for increased risk of bleeding.[38]

The PLATO trial[39]found that ticagrelor use, in conjunction with low-dose aspirin (where tolerated), had better all-cause mortality rates than the same treatment plan with clopidogrel (4.5% vs. 5.9%) in treating people with acute coronary syndrome. People given ticagrelor were less likely to die from vascular causes, heart attack, or stroke, regardless of whether the treatment plan was invasive.

There is some conjecture in the safety and efficacy of ticagrelor within the Asian population, despite significant thrombotic benefits.[37]A meta-analysis of observational studies in several Asian countries proposed that ticagrelor did not increase the risk of considerable bleeding events in Asian individuals.[40]There is evidence to suggest that East Asian individuals are at a higher risk of bleeding events when using ticagrelor.[41][42][43]The guidelines recommend that people of East Asian origin exercise caution and that treatment continuation after six months be based on net-clinical benefit.[44]

With prasugrel

[edit]

In 2019, the ISAR-REACT 5 trial comparing ticagrelor andprasugrelin participants with acute coronary syndrome showed that people with acute coronary disease receiving prasugrel had lower incidence of death, myocardial infarction, or stroke compared to those who received ticagrelor.[45]

A 2019 study showed antibacterial activity againstantibiotic-resistantGram-positivebacteria includingmethicillin-resistantStaphylococcus aureusandvancomycin-resistantenterococcus.[46]This study used concentrations of ticagrelor for bactericidal activity that far exceeded those achieved by standard post acute coronary syndrome doses.[46]Research indicates that ticagrelor may help reduce the risk of infections, such as pneumonia and sepsis.[47][48]

References

[edit]
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