P2Y12- /ADP-hämmare: Clopidogrel, Prasugrel, Ticagrelor, Cangrelor

P2Y12-hämmare är läkemedel som påverkar trombocytfunktionen genom att blockera en receptor på trombocyten. Denna receptor har namnet P2Y12 och är trombocyternas ADP (adenosine 5’-diphosphate)-receptor. Därför kallas läkemedel som blockerar denna receptor för P2Y12-hämmare eller ADP-antagonister.1 2 3 P2Y12-hämmare används inom kardiologi vid akut koronart syndrom och PCI.

Denna sidan ger en koncis överblick över fyra ADP-hämmare. För mer utförlig information om indikationer läs sidorna om dubbel trombocythämning och antitrombotisk trippelterapi.

P2Y12-hämmare= ADP-hämmare:

Clopidogrel och Prasugrel tillhör samma kemiska grupp (Thienopyridiner), Ticagrelor är en Cyclopentyl-triazolopyrimidine och Cangrelor en adenosin- trifosfat analog. Clopidogrel och Prasugrel är prodrugs som behöver konverteras till en aktiv metabolit 4.

P2Y12-hämmare är läkemedel som påverkar trombocytfunktionen genom att blockera en receptor på trombocyten. Denna receptor har namnet P2Y12 och är trombocyternas ADP (adenosine 5’-diphosphate)-receptor. Därför kallas läkemedel som blockerar denna receptor för P2Y12-hämmare eller ADP-antagonister.1 2 3 P2Y12-hämmare används inom kardiologi vid akut koronart syndrom och PCI.

Adenosine diphosphate (ADP) är en nukleotid som förvaras i trombocyternas dense granules. Vid aktivering släpps ADP ut från trombocyterna och aktiverar andra trombocyter genom att binda till deras P2y12-receptorer. Aktiverade trombocyter ändrar sedan formen av sina glycoprotein IIb/IIIa (GpIIbIIIa)-receptorer på cellmembranen, GpIIbIIIa-receptorerna blir lätt bindande fibrinogen binding sites. Fibrinogen (som delvis cirkulerar fritt, och delvis blir utsläppt från aktiverade trombocyter) binder till (GpIIbIIIa)-receptorerna på flera trombocyter och håller på så sätt samman flera trombocyter: Trombocytaggregation, som blir en tromb. 5

Läs alltid även på FASS.se. Källor 6 7

Clopidogrel (patentfri, förut Plavix)

  • Indikation:8
    • Tillsammans med ASA som DAPT vid AKS:
      Vid AKS är DAPT med ASA + Ticagrelor eller Prasugrel förstahandsval. Clopidogrel används vid AKS (istället för Ticagrelor eller Prasugrel) om Ticagrelor eller Prasugrel är kontraindicerade, om patienten planeras för oral antikoagulation, eller vid hög blödningsrisk (=1 major eller 2 minor ARC-HBR kriterier). ESC ger en IIbB rekommendation att välja Clopidogrel över Ticagrelor eller Prasugrel för patienter>70-80 år. 8
    • Tillsammans med ASA som DAPT vid CCS (stabil angina): Efter PCI för stabil angina/CCS är Clopidogrel den enda P2Y12 antagonist som används.
  • Kontraindikation:
    • Hög blödningsrisk
    • Clopidogrel rekommenderas inte för cancerpatienter med <30 000 trombocyter (ESC 2023 Class IIIC) 9
  • Dosering: 10
    • Laddningsdos 600 mg (8 tabletter à 75 mg) om effekt önskas så snabbt som möjligt (laddning på PCI-lab, eller om laddning ska ges ett fåtal timmar innan planerad PCI). Annars 300 mg laddningsdos (t.ex laddning dagen innan planerad PCI)
    • Underhållsdos 75 mg 1×1
  • Behandlingstid: Vid DAPT: Se DAPT
  • Kommentar:
    • Enda P2Y12-antagonist som används vid PCI för stabil angina och vid PCI på patienter med indikation för oral antikoagulation.
    • Ingen dosjustering vid kronisk njursvikt, dock ingen data för GFR<15 eller dialys.
    • Läkemedelseffekt 2-6 timmar efter laddningsdos.

Ticagrelor (Brilique)

Prasugrel (patentfri, förut Efient)

  • Indikation:
    Tillsammans med ASA som DAPT 8
    ESC ger år 2023 en IIaB-rekommendation 8 att föredra Prasugrel över Ticagrelor vid ACS som behandlas med PCI (=Prasugrel är förstahandsval vid ACS+PCI) Detta pga ISAR-REACT 5 studien 13
  • Kontraindikation:
    • Hög blödningrisk, pågående blödning. Använd ARC-HBR score (är en major eller 2 minor kriterier uppfyllda, använd Clopidogrel istället)
    • Kontraindicerat vid tidigare stroke/TIA/intrakraniell blödning (använd Clopidogrel istället)
    • Ges ej samtidigt som oral antikoagulation (använd Clopidogrel istället, se sidan om antitrombotisk trippelbehandling)).
    • Prasugrel rekommenderas inte för cancerpatienter med <50 000 trombocyter (ESC 2023 Class IIIC) 9
  • Laddningdos 60 mg p.o.
    • Underhållsdos 10 mg 1×1 (vikt <60 kg eller ålder ≥75 år ges 5 mg 1×1) 10 6 14
  • Behandlingstid: Vid DAPT: Se DAPT
  • Kommentar:
    • Ingen dosjustering vid kronisk njursvikt, dock ingen data för GFR<15 eller dialys.
    • Läkemedelseffekt 0,5-4 timmar efter laddningsdos.
    • Prasugrel testades mot Clopidogrel i TRITON-TIMI 38.
    • Prasugrel testades som förbehandling (mot icke-förbehandling) på NSTE-ACS-patienter i ACCOAST-studien, studien avslutades i förtid pga skadlig effekt av förbehandling. 15
    • Prasugrel är en prodrug som behöver konverteras till en aktiv metabolit 4.

Ticlopidine (Tiklid)

  • Ticlopidine (Tiklid)
    • den första P2Y12-hämmaren, ej längre i bruk.
    • samma effekt och samma blödningsrisk som efterträdaren Clopidogrel, men andra allvarliga biverkningar dessutom.

Cangrelor (Kengrexal)

  • Indikation: Intravenös P2Y12-hämmare. Ges när P2Y12-blockad behövs direkt eller orala P2Y12 antagonister inte kan ges (t.ex intuberad patient utan V-sond)16 eller om snabb offset-effekt önskas (t.ex. nyligen stentad patient som har en akut operationsindikation). 1718
    Se assessment report, European Medicines Agency och EMA-produktresumé Cangrelor (svenska)
  • Dosering:
    • En flaska Cangrelor innehåller 50 mg pulver, som ska spädas.
    • PCI-dosering (patienter som inte är förbehandlade med en oral P2Y12-hämmare): Bolus 30 μg/kg i.v. (bolus ges innan PCI börjas, kan ges under <1 minut) följt av 4 μg/kg/min infusion under minst 2 timmar, upp till 4 timmar (oral P2Y12-hämmare behöver ges innan/kort efter avslutad infusion, se nedan).
    • Bridging-dosering (patienter som står på oral P2Y12-hämmare som behöver sättas ut inför operation): 0.75 μg/kg/min startas utan bolusdos när den orala P2Y12 hämmaren pausas. Infusionen avslutas senast 1 timme innan operationen. Denna dosen är testad i upp till 7 dygn.1920
    • Se även FASS.se/Cangrelor
  • Byta till oral P2Y12-hämmare:
    • Byte till Ticagrelor eller Prasugrel: Ge ladningsdos Ticagrelor 180 mg eller Prasugrel 60 mg 30 minuter innan Cangrelorinfusionen avslutas.
    • Byte till Clopidogrel: På grund av en interaktion har Clopidogrel laddningdosen inte full effekt om den ges under pågående Cangrelorinfusion. Bolusdos Clopidogrel ska därför ges direkt (ett par minut) efter avslutad Cangrelorinfusion.
  • Kommentar:

Antidoter

Än så länge finns det ingen antidot mot trombocythämmare (men det är under utveckling för Ticagrelor, detaljer se Ticagrelor).

PPI vid DAPT

se avsnitt PPI på DAPT-sidan här

Switching mellan olika P2Y12-antagonister:

Se avnitt om switching på DAPT-sidan här

Preoperativ utsättning av P2Y12-antagonister:

Se avnitt om DAPT vid (icke-hjärt) kirurgi här

Historisk utveckling av P2Y12-receptorantagonister

(originalpublikationen- en disputation från 2019 – är på engelska):

The first P2Y12 –receptor antagonist was coincidentally developed in the 1970s, and although the prothrombotic effect of ADP has by this time already been known for some years, it took 30 more years until the P2Y12 receptor was isolated as the target of this drug.  

In 1960, A.J. Hellem observed at Rikshospitalet in Oslo that a small molecule originating from red blood cells caused platelets to adhere to glass.1 The next year, researchers in Oslo identified this small molecule as the purine adenosine diphosphate (ADP), proved that it converts non-adhesive platelets into adhesive platelets and thus causes platelet aggregation, and assumed that ADP release based on cellular damage might play an important role in thrombosis.21 ADP does not normally circulate in the bloodstream, but is stored in large quantities in platelets’ dense granules, which can release ADP when they are stimulated by other substances, like collagen or thrombin. 22 23 24 25 ADP causes platelets to change shape from disc-shaped to a spherical structure with pseudopods with a substantial increase in surface area 1 to increase cytosolic free calcium, to express a fibrinogen binding site (GP IIb/IIIa receptor), 26 and finally to aggregate to a white thrombus by adhering to each other with the help of fibrin links. 27 In 1964, it was determined that other purines, adenosine and adenosine triphosphate, 28 are inhibitors of ADP-induced platelet aggregation.  1 27 29

Ticlopidine and clopidogrel were developed when the exact site of action of these thienopyridines was still unknown and the first antagonist of the P2Y12 receptor was created by chance 1 26: In 1972, French scientists were searching for new anti-inflammatory drugs related to Tinoridine, a drug from the chemical class thienopyridine with anti-inflammatory properties that was published in 1970, and started synthesizing derivates and testing them on rats. 30 They did not succeed in finding anti-inflammatory agents, but some of the compounds showed unanticipated antiplatelet activity and the most active was selected for further development and named ticlopidine.30 In 1978, the thienopyridine ticlopidine hit the market in France under the name Ticlid, was tested in clinical trials (initially in stroke patients), 31 and reached the U.S. market in 1991. Soon after marketing, the drug showed severe side effects in some patients: agranulocytosis and pancytopenia. So, in France, the search for ticlopidine analogs with an improved benefit/risk ratio continued, and after testing thousands of analogs, clopidogrel was found. The preclinical development started in 1987 and led to the worldwidelaunch of clopidogrel in 1998, which became the second-bestselling drug in the first decade of the 21stcentury. 32

Today, we know that there are different types of purinergic receptors (P-receptors) on platelets (as on other cell surfaces). 33 In 1995, a French-Italian team was able to show that there are at least two different P2-receptors for ADP on platelets, one inducing shape change and another coupled to the inhibition of adenylyl cyclase and causing platelet aggregation, with the latter being receptive to thienopyridines. 23 This receptor then had several names (P2T for thrombocyte, P2YAC for adenylyl cyclase, P2YADP) and was finally called the P2Y12 receptor when it was cloned and analyzed in San Francisco in 2001 23 34 and identified as the clopidogrel-receptor. 35

The scientists who developed the new antiplatelet drugs knew that clopidogrel, like ticlopidine, was a prodrug that had to be ingested orally to be processed in the liver by cytochrome P450 pathways to an active metabolite, but it was not until 2001, 30 years after the discovery of ticlopidine, that some of them succeeded in isolating the active metabolite.30 Interestingly, the detection of ticlopidine as an active antiplatelet drug would not have been possible if  the initial tests had not been performed on rats but instead on, e.g., guinea pigs, which lack the enzyme to produce the active metabolite. 30

It has been argued that clopidogrel’s main drawbacks are based on its status as a prodrug: Because of the mandatory cytochrome P450-dependent metabolism in the liver, the pharmacodynamic effect is delayed and varies substantially between individuals (15–40% of patients are poor responders). 3637 In addition, clopidogrel binds (like all thienopyridines45) irreversibly to the P2Y12 receptor so that the effect lasts until new thrombocytes are ready to replace them. Because of these downsides of clopidogrel, the search for an ideal antiplatelet drug continued and led to the last-generation P2Y12antagonists prasugrel and ticagrelor. 

Prasugrel, a third-generation thienopyridine, is a prodrug like the second-generation thienopyridineclopidogrel, but is less dependent on hepatic cytochrome P450 activity and therefore faster acting (maximal effect after approximately 30 minutes instead of 3–5 hours for clopidogrel) and shows less variation in the effect size. 3 38 39 The differences are in the pharmacokinetics; The active metabolites of clopidogrel and prasugrel are chemically similar and have the same potency.40 37 Prasugrel was tested in the TRITON TIMI-38 trial(2007) 41 against clopidogrel in invasively treated ACS patients following coronary angiography and the trial found higher efficiency but lower safety for prasugrel. The FDA later criticized the trial for shortcomings in design and disadvantages for patients treated with clopidogrel. 42

Ticagrelor is the first oral non-thienopyridine P2Y12 antagonist, an ATP analog that belongs to the new chemical class of cyclopentyl-triazolopyrimidines. 38 43 It is a direct-acting drug (i.e., not a prodrug that requires conversion to an active metabolite) and a reversible P2Y12 antagonist 37 that binds to a P2Y12 binding site that differs from the adenosine binding site. 29 The PLATO trial, published in 2009, 44 compared the use of ticagrelor and clopidogrel in ACS patients and reported better prevention of the composite endpoint death, MI, or stroke without differences in overall bleeding (but an increase in non-CABG bleeding).

Litteratur

2023 ESC Guidelines for the management of acute coronary syndromes 10

ESC 2017 update DAPT

ESC Guideline NSTE-ACS 2020

Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use. (Capodanno 2019) 17

Current status of data on cangrelor (2016) 18

EMA-produktresumé Cangrelor (svenska)

Platelets in atherothrombosis 5

Antiplatelet agents for the treatment and prevention of atherothrombosis 45

Relaterade sidor

ASA/Trombyl
Dubbel trombocythämning (DAPT) vid PCI och AKS
Antitrombotisk trippelbehandling efter PCI (DAPT+OAK)
GPIIb/IIIa antagonister: Integrilin, Aggrastat
DAPT-History

Last Updated on January 5, 2024 by Christian Dworeck

Christian Dworeck
Latest posts by Christian Dworeck (see all)
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