Drugs affecting coagulation

1. Drugs affecting coagulation Applied Clinical Sciences Lecture Programme Dr Cathy Armstrong Anaesthetic SpR & Clinical Fellow in Undergraduate Medical Education May 2010

2. Aims and objectives • To understand the principles of haemostasis & clotting • To classify anticoagulants & antiplatelets into groups • Describe mechanisms of action • Describe relevant pharmacokinetic aspects • Discuss common clinical uses

3. Why do we need to know about them?

4. Haemostasis Vasoconstriction secondary to endothelial mediators Platelet activation & aggregation Formation of fibrin mesh (enhanced by clotting factors) Opposing effects of fibrinolysis

5. Main drug categories Drugs that inhibit the clotting cascade Drugs that inhibit platelet activity Drugs that augment fibrinolysis

6. The coagulation cascade

7. The intrinsic pathway Activated when blood comes into contact with subendothelial tissues Quantitatively most important of 2 pathways slower

8. The Extrinsic pathway Rapid response to tissue injury Main function to augment intrinsic pathway Factor VII & factor III (Tissue factor) unique to extrinsic pathway Factor VIIa/TF/Ca complex rapidly activates factor x

9. The Final Common pathway Results in production of thrombin which converts fibrinogen to fibrin

10. Tests of Coagulation • Activated partial thromboplastin time (APTT) • Normal range 25-45s • Prothrombin time (PT) • Normal range 11-15s • International normalised ratio (INR)

11. The APTT tests the: • Intrinsic & final common pathway • The extrinsic and final common pathway • The final common pathway only

12. The PT tests the: • Intrinsic & final common pathway • The extrinsic and final common pathway • The final common pathway only

13. Cell-based Theory of coagulation • Focuses on the central role of specific cell surfaces in controlling and directing the haemostatic process • 3 phases • Initiation • Amplification • propagation http://www.frca.co.uk/article.aspx?articleid=100097

14. Drugs that inhibit the clotting cascade Vitamin K Antagonists Warfarin Indirect thrombin inhibitors Heparin LMWH Factor Xa inhibitors Fondaparinux Danaparoid Direct thrombin inhibitors E.g Levirudin, Bivalirudin, Argatroban, Dabigatran

15. Warfarin Vitamin K antagonist Inhibits Vit k reductase which catalyses the reduction of vit k Racemic mixture of 2 optically active isomers S more potent than R Inhibits synthesis of vit k dependent clotting factors II, VII, IX & X + protein C & S Inactive precursor Active Clotting Factor Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase S-Warfarin R-Warfarin CYP2C9 CYP1A2 CYP3A4 WARFARIN

16. Warfarin primarily affects the: • Intrinsic & final common pathway • Extrinsic & final common pathway • Final common pathway only

18. Warfarin Uses Treatment of VTE Prevention of systemic embolism in patients with prosthetic heart valves & AF Therapeutic effects take 48-72hrs to develop Highly water soluble High bioavailability – rapid GI absorption Half life 36-48 hrs Circulates bound to plasma proteins Accumulates in liver Potent S enantiomer metabolised by CYP2C9

19. Warfarin challenges Narrow therapeutic window Exhibits variability in dose response among patients Subject to interactions with drugs & diet Laboratory tests difficult to standardise

20. Warfarin drug interactions

21. Warfarin adverse effects Haemhorrhage Hypersensitivity Skin rashes Alopecia Pupura Congenital malformations / IUD

22. Treatment of high INR – no significant bleeding (ACCP guidelines) INR <5 ↓ / omit dose + regular INR monitoring INR >5 & < 9 Omit 1 – 2 doses + regular INR monitoring OR Omit 1 dose + administer Vit k 1-2mg PO

23. Treatment of high INR- reduction for urgent surgery No significant bleeding + 24 hrs Omit warfarin + Vitamin K 5mg PO Further 1-2mg Vit K if required Serious bleeding or emergency surgery Omit warfarin Vit K 10mg slow IV + FFP or prothrombin complex concentrate (octaplex) or recombinant factor VIIa

24. Prothrombin Complex Concentrate (PCC) Octaplex Combination of clotting factors II, VII, IX & X + protein C & S Reverses warfarin Expensive, only given at advice of senior haematologist Contraindicated in patients with known HIT Caution in IHD Max dose 3,000IU (120ml) – slow iv infusion INR recheck 20 min post administration Can cause hypersensitivity reactions Ideally given via separate, fresh, cannula

25. Indirect thrombin inhibitors

26. Heparin Anionic, highly sulphated mucopolysaccharide MW 3,000 → 30,000 Da Enhances activity of endogenous antithrombin Arginine reactive centre on AT binds covalently to serine active centre of thrombin & other coagulation factors & irreversibly inhibits their procoagulant activity Heparin binds to AT via specific pentasaccharide sequence (present in ⅓ molecules) AT AT Clotting Factor Clotting Factor Heparin

27. Heparin Thrombin inhibition requires heparin to bind to AT via pentasaccharide sequence but also relies on non-specific charge related effects – dependent on mw Factor Xa inhibition only requires heparin to bind via pentasaccharide sequence (explains effects of LMWH) Heparin AT complex inactivates Thrombin, factors Xa, IXa, XIa, XIIa Inhibition of thrombin by heparin – prevents fibrin formation but also thrombin induced activation of platelets & factors V, VIII & XI Other effects Attenuates proliferation of vascular smooth muscle cells Inhibits osteoblast formation & activates osteoclasts → promotes bone loss

29. Heparin Uses Anticoagulation during vascular & cardiac surgery Anticoagulation priming for RRT and CPB circuits ‘Bridging’ anticoagulation Not absorbed orally – requires parenteral administration Binds to various plasma proteins – accounts for variability of response Monitoring APTT & ACT

30. Heparin adverse effects Haemorrhage Hypotension (rapid iv administration) Osteoporosis Alopecia Hyperkalaemia (due to aldosterone inhibtion) Thrombocytopenia Non- immune Immune mediated (HIT)

31. Reversal of Heparin Protamine Basic protein derived from fish sperm Positive charge Binds to heparin to form stable salt 1mg iv neutralises approx 100 IU of heparin Adverse reactions Hypotension (due to histamine release) Bradycardia Pulmonary hypertension Flushing Allergic reactions

32. LMWH Derived from UFH by chemical / enzymatic depolymerisation Reduced activity against thrombin relative to factor Xa Mw approx 5,000 Da Longer plasma half life - due to ↓ binding to endothelial cells & macrophages Lower incidence of HIT (less binding to platelets) Less bone loss

33. LMWH More predictable anticoagulant response than UFH Elimination half life 3-6 hours Anti-Xa levels peak at 3-5 hrs after dosing Cleared by kidneys – prolonged action in renal failure Monitoring Not regularly monitored Some advice that anti-Xa levels should be measured in obese patients, renal failure & pregnancy No antidote Complications 3 fold lower incidence of HIT Less risk osteoporosis

34. Fondaparinux Synthetic analogue of AT binding pentasaccharide Specific anti-Xa activity > LMWH Longer half life than LMWH (17 vs 4 hrs) Predictable anticoag response – linear pharmacokinetics in sc doses 2-8mg Lab monitoring not required (anti Xa levels can be used) Excreted unchanged in urine Contraindicated in renal failure Fixed dose Thromboprophylaxis 2.5mg Treatment dose (50-100kg) 7.5mg Complications Not known to cause HIT No effect on bone Contraindicated in pregnancy (due to lack of safety data)

35. Direct Thrombin Inhibitors Have their own intrinsic activity – bind to thrombin and blocks its enzymatic activity Hirudins Lepirudin licensed for thrombosis complicating HIT Bivalirudin Hirudin analogue Licensed as alternative to heparin in patients undergoing PCI (e.g previous HIT) Dabigatran (Pradaxa) Licensed for DVT prophylaxis following hip & knee replacement surgery British Heart Foundation campaigning for drug to be used in place of warfarin Oral preparation No monitoring required Predictable anticoagulant effect – little variation between individuals

36. Antiplatelet therapy

37. Platelet adhesion & Activation Damage to vascular endothelium & collagen exposure Platelet Adhesion (via GPIa & GPIb) Platelet Activation Platelet Aggregation Platelets become more spherical GPIIa/IIIb bind with fibrinogen (with aid of vwf) to build bridge between platelets Platelet release reaction (degranulation) Release of 5-HT → vasoconstriction Release of ADP Release of arachidonic acid → thromboxane A2 ↑ cycloxygenase 1 Release of ADP & thromboxane A2 stimulate further platelet activation, aggregation and release → formation of platelet plug

38. What is the average lifespan of a platelet? • 1 - 2 days • 7 - 10 days • 20 - 40 days • 100 - 120 days

39. Drugs affecting platelets Cyclooxygenase Inhibitors Inhibitors of ADP-mediated platelet activation Phosphodiesterase Inhibitors Glycoprotein IIb/IIIa Inhibitors

40. Cyclooxygenase Inhibitors Aspirin Irreversibly blocks the activity of COX-1 Platelet function impaired for 7 -10 days until new platelets are formed COX-1 is responsible for the production of thromboxane A2, a potent vasoconstrictor and stimulator of platelet aggregation Rapidly orally absorbed Aspirin has been found to reduce vascular death by 15% & non-fatal vascular events by 30 % in high risk patients

41. Damage to vascular endothelium & collagen exposure Platelet Adhesion (via GPIa & GPIb) Platelet Activation Platelet Aggregation Platelets become more spherical GPIIa/IIIb bind with fibrinogen (with aid of vwf) to build bridge between platelets Platelet release reaction (degranulation) Release of 5-HT → vasoconstriction Release of ADP Release of arachidonic acid → thromboxane A2 ↑ cycloxygenase 1 Release of ADP & thromboxane A2 stimulate further platelet activation, aggregation and release → formation of platelet plug

42. Inhibitors of ADP-mediated platelet activation Thienopyridines – ticlopidine & clopidogrel Reduce platelet aggregation by the selective irreversible inhibition of the P2Y12ADP receptor on the platelet surface Both pro-drugs requiring metabolism by liver Side effects Thrombocytopenia Aplastic anaemia & severe neutropenia (ticlopidine only) Clopidogrel Rapid oral absorption Irreversible blockade for life of platelet

43. Damage to vascular endothelium & collagen exposure Platelet Adhesion (via GPIa & GPIb) Platelet Activation Platelet Aggregation Platelets become more spherical GPIIa/IIIb bind with fibrinogen (with aid of vwf) to build bridge between platelets Platelet release reaction (degranulation) Release of 5-HT → vasoconstriction Release of ADP Release of arachidonic acid → thromboxane A2 ↑ cycloxygenase 1 Release of ADP & thromboxane A2 stimulate further platelet activation, aggregation and release → formation of platelet plug

44. Phosphodiesterase Inhibitors Dipyridamole Predominantly inhibits platelet adhesion to damaged vessel walls Usually used in combination with aspirin in management of cerebrovascular disease Biliary excretion

45. Glycoprotein IIb/IIIa Inhibitors Block the final common pathway of platelet activation Used in management of acute coronary syndrome and PCI Examples Abciximab Eptifibatide Tirofibran

46. Damage to vascular endothelium & collagen exposure Platelet Adhesion (via GPIa & GPIb) Platelet Activation Platelet Aggregation Platelets become more spherical GPIIa/IIIb bind with fibrinogen (with aid of vwf) to build bridge between platelets Platelet release reaction (degranulation) Release of 5-HT → vasoconstriction Release of ADP Release of arachidonic acid → thromboxane A2 ↑ cycloxygenase 1 Release of ADP & thromboxane A2 stimulate further platelet activation, aggregation and release → formation of platelet plug

47. Summary • Discussed the principles of haemostasis & clotting • Briefly discussed tests of coagulation • Categorised anticoagulants & antiplatelets • Described mechanisms of action • Described relevant pharmacokinetic aspects • Discuss common clinical uses

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