1. ANTIPLATELETS AND ANTICOAGULANTS
Dr.Hardik Patel

2. Arterial thrombus
Rich in platelets
Venous thrombus
Rich in fibrin and RBC

3. Classification

4. Coordinated role of platelets and the coagulation system in thrombogenesis

5. Site of action of antiplatelet drugs.

6. Aspirin
Aspirin produces its antithrombotic effect by irreversibly acetylating and inhibiting platelet COX -1, a critical enzyme in the biosynthesis of thromboxane A2
Aspirin is widely used for secondary prevention of cardiovascular events in patients with coronary artery, cerebrovascular,or peripheral vascular disease.

7. Dosage:
mg/day
Higher dose not more effective than lower dose
Side effects:
Gastritis, peptic ulcer
Bleeding
Aspirin resistance
Poor absorption, drug interaction, overexpression of cox-2

8. ADP receptor antagonists
Theinopyridine (Clopidogrel & Prasugrel)
They selectively inhibit ADP-induced platelet
aggregation by irreversibly blocking P2Y12
Clopidogrel and prasugrel are prodrugs that require metabolic activation by the hepatic cytochrome P450 (CYP) enzyme system

9. Clopidogrel is more effective than aspirin in patients with recent ischemic stroke, recent MI, or a history of peripheral arterial disease
Clopidogrel and aspirin are combined to capitalize on their capacity to block complementary pathways of platelet activation in certain situations
The combination of clopidogrel and aspirin should only be used when there is a clear benefit

10. Prasugrel has better role in treatment of MI and prevention of stent rethrombosis , but at the cost of high bleeding tendency
The drug is generally avoided in patients with age > 75 years and contraindicated in those patient with history of CVD

11. Dosing Side effects Clopidogrel Loading 300mg f/b 75mg OD Prasugrel
Loading dose of 60 mg f/b 10mg OD
Side effects
Bleeding , more common with prasugrel than clopidogrel

12. Thienopyridine Resistance
The ability of Clopidogrel to inhibit ADP activity varies among individuals
This is mainly due to genetic polymorphism of CYP (mainly CYP2C19) enzyme involved the metabolic activation of Clopidogrel.
PPI are inhibitors of CYP2C19 enzymes
This CYP polymorphism is less significant with Prasugrel activation

13. Ticagrelor Orally active inhibitor of P2Y12
Not a prodrug and its produces reversible inhibition of ADP receptor
Rapid onset and offset of action
Studies have found Ticagrelor superior to clopidogrel for MI
Dosage : Loading 180 mg, f/b 90mg BD

14. Dipyridamole
Dipyridamole is a relatively weak antiplatelet agent on its own
An extended-release formulation of dipyridamole combined with low dose aspirin (Aggrenox), is used for prevention
of stroke in patients with TIA

15. GPIIB/IIIA Receptor Antagonists
Abciximab, Eptifibatide and Tirofiban
All target GpIIb/IIIa receptor
Mainly used in patients undergoing percutaneous coronary interventions and in high-risk patients with unstable angina.

17. Dosing All drugs given as IV bolus f/b infusion Side effects
Bleeding, thrombocytopenia (immune mediated)
Drug
Bolus
(ugm/kg)
Infusion (Ugm/kg/min)
Abciximab
0.25
0.125
Eptifibatide 2
Tirofiban
0.4 for 30 min
0.1

18. Newer agents
New agents in advanced stages of development include Cangrelor, a parenteral, rapidly acting, reversible inhibitor of P2Y12
Vorapaxar, an orally active inhibitor of protease-activated receptor 1 (PAR-1), the major thrombin receptor on platelets

19. Anticoagulants
Parenteral anticoagulants Heparin, LMWH Fondaparinux Lepirudin, Desirudin, Bivalirudin, Argatroban. Oral anticoagulants Warfarin Oral thrombin inhibitor - Dabigatran etexilate) Oral factor Xa inhibitors- Rivaroxaban, Apixaban, Edoxaban

20. Parentral Anticoagulants
Heparin
A sulphated polysachharide, isolated from mast cells
Heparin acts by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa.

21. Mechanism of action

22. Pharmacology
Heparin has equal capacity to promote the inhibition of thrombin and factor Xa
anti-factor Xa to anti-factor IIa ratio of 1:1
In the circulation, heparin binds to the endothelium and to plasma proteins other than antithrombin
Heparin binding to endothelial cells explains its dose-dependent clearance

23. Clearance is mainly extrarenal; heparin binds to macrophages,which internalize and depolymerize the long heparin chains and secrete shorter chains
back into the circulation.
Because of its dose-dependent clearance mechanism, the plasma half-life of heparin ranges from 30 to 60 min with bolus IV doses of 25 and 100
units/kg, respectively

24. Activated platelets also release PF4, a highly cationic protein that binds heparin with high affinity. The large amounts of PF4 found in the vicinity of platelet-rich arterial thrombi can neutralize
the anticoagulant activity of heparin.
This phenomenon may attenuate heparin’s
capacity to suppress thrombus growth.

26. Monitoring Monitored using the aPTT or anti-factor Xa level
Therapeutic heparin levels are achieved with a two- to three fold prolongation of the aPTT

27. Dosage For prophylaxis : 5000 units SC two or three times daily
Coagulation monitoring is not necessary
Therapeutic dose
Coronary disease : IV heparin bolus of 5000 units or 70 units/kg, a heparin infusion rate of 12–15 U/kg per/hr
PTE: Initial bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/kg per h.

28. Complications Bleeding Thrombocytopenia Osteoprosis
Elevated transaminases

29. HIT 5T’s

30. Management

31. Low-Molecular-Weight Heparin
Small fragments of heparin, mean molecular weight 1/3 of UH
Acts by activating antithrombin, but more affinity towards Xa than thrombin
Longer and predictable half life, doesn't need coagulation monitoring

32. Mechanism of action

34. Dosing Monitoring For prophylaxis: OD SC doses of 4000–5000U
Venous thromboembolism:100U/kg BD
Unstable angina: U/kg BD
Monitoring
Anti factor Xa monitoring required in certain situations

35. Fondapurinox
Aa synthetic analogue of the antithrombin-binding pentasaccharide sequence
Acts by inhibiting factor Xa , no activity against thrombin
Dosage :
2.5 mg OD for prophylaxis and ACS
7.5 mg OD for VTE

37. Parenteral Direct Thrombin Inhibitors
Approved parenteral direct thrombin inhibitors include recombinant hirudins (lepirudin and desirudin), argatroban, and bivalirudin
Mainly used in patients with HIT. Usually given as IV infusion
Monitoring done using aPTT

39. ORAL ANTICOAGULANTS Vit K Antagonists Warfarin Thrombin inhibitors
Dabigatran
Factor Xa inhibitors
Rivoroximab, Apixaban, Edoxaban

40. Warfarin
Warfarin interferes with the synthesis of the vitamin K–dependent clotting proteins, which include prothrombin (factor II) and factors VII, IX, and X.
The synthesis of the vitamin K–dependent anticoagulant proteins, proteins C and S are also reduced

41. Pharmacology Warfarin is a racemic mixture of R and S isomers
CYP polymorphism alters metabolism of warfarin
Because of the variability in the anticoagulant response to warfarin,coagulation monitoring is essential to ensure that a therapeutic response is obtained

42. Dosing
For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0
Warfarin is usually started at a dose of 5-10mg
A minimum 5-day course of parenteral anticoagulation is recommended to ensure that the levels of factor Xa and prothrombin have been reduced into the therapeutic range with warfarin

43. Side effects Bleeding : Narrow therapeutic range Skin necrosis :
Occurs 2-5 days after start of treatment
Contraindicated during pregnancy
To be stopped 5 days before elective surgery

44. Newer oral anticoagulants

45. USES
Dabigatran, rivaroxaban, and apixaban are licensed as alternatives to warfarin for stroke prevention in nonvalvular atrial fibrillation
Rivaroxaban, and apixaban have been approved for use in elective hip or knee arthroplasty.
Rivaroxaban and dabigatran are also licensed for treatment of DVT or PE
In Europe Rivaroxaban along with dual antiplatelets for ACS

46. Dosing For stoke prevention Rivaroxaban ; 20mg OD
Dabigatran : 150mg BD
Apixaban : 5mg BD
For treatment of DVT or PTE
Rivaroxaban 15mg BD for 3 weeks f/b 20mg OD
Post surgical prophylaxis
Rivaroxaban 10mg OD
Apixaban mg BD

47. Monitoring Not routinely required For Xa inhibitors: aPTT
Dabigatran : PT

48. Side effects Bleeding Reduced incidence compared to Warfarin
GI bledding common
Contraindicated during pregnancy

49. Thank you