Pharmacy pharmacology

1. Anti-Coagulant & Antiplatelet
Therapy: 1
Anti-platelet Agents & Anticoagulants
Prof. Leong Ng
Pharmacology Group

2. Introduction
◼ Scene Setting
◼ Disorders of haemostasis are common
◼ Some Basic Pharmacology
◼ Concentrate on Clinical Aspects of Anti
Coagulant Agents (ACAs):
◼ Warfarin
◼ Heparins
◼ Refer to objectives
◼ Briefly Antiplatelets Agents (APA)

3. Disorders of haemostasis are
common
◼ Normal=Haemostasis,
◼ Abnormal=Thrombosis, Embolism
◼ Arterial: White clot: CVA, MI:
Antiplatelets and Thrombolysis
◼ Venous: Red clot: DVT, PE: Anti-
Coagulation
◼ Other uses: Pro thrombotic state, &
primary prevention

4. Arterial
Arterial
Venous
Virchow’s Triad

5. Formation of Arterial Thrombus

6. Clotting Cascades

7. Basic Pharmacology: ACAs
◼ Warfarin Inhibits production of Vitamin K
dependent clotting factors
◼ Stops conversion of Vit K to active reduced form
◼ II (Prothrombin), VII, IX, X: Extrinsic Pathway
◼ Onset: Days due to turnover of clotting factors (t1/2)

8. Basic Pharmacology: ACAs
◼ Heparins
◼ Glycosaminoglycan – glucose backbone
◼ One of 5 different groups on each glucose,
some with sulphate. Produced by mast cells
◼ Unfractionated Vs Low Molecular Weight
◼ Both Activate Anti-Thrombin III (ATIII)
◼ Via Unique Pentasaccharide Sequence
◼ Deactivates Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)

9. Clotting Cascade & ACAs

10. Anticoagulants: Warfarin
Wisconsin Alumni Research Foundation, with
“arin” added to end to indicate it’s a coumarin

11. Warfarin: Action

12. Summary of Action
Warfarin
Synthesis of Non
Functional
Coagulation
Factors: Long
onset of action
Antagonism
of
Vitamin K
Vitamin K
VII
IX
X
II

13. Pharmacokinetics

14. PKs and Clinical Consequences
◼ Good GI Absorption: Give PO
◼ Preferred choice for long term AC
◼ Slow onset of action:
◼ Heparin cover
◼ Slow offset: t1/2 48 hrs but variable!
◼ Need to stop 3 days before surgery
◼ Time to synthesize new clotting factors
◼ Heavily Protein Bound
◼ Caution with drugs that displace it

15. PKs and Clinical Consequences
◼ Hepatic Metabolism: MFO p450 System
◼ Caution with Liver Disease
◼ Caution if used with drugs that affect p450
system
◼ Crosses Placenta:
◼ Do not give in 1st Trimester: Teratogenic
◼ Do not give in 3rd Trimester: Brain Haem
◼ If Female patient on warfarin advise re pregnancy

16. Monitoring Warfarin
◼ Extrinsic Pathway Factors
◼ Prothrombin Time
◼ Citrated plasma Clotting Time after adding
Calcium and Thromboplastins
◼ I.N.R=International Normalised Ratio
◼ Allows a standard value between labs
◼ Corrected for different lab thromboplastins
reagents

17. Drug Interactions
◼ Effects on Anticoagulation
◼ Majority increase anticoagulant effect
◼ But some decrease effect
See the BNF!
N.B: Perhaps more than with any
other drug:
INTERACTIONS WITH WARFARIN
ARE HIGHLY SIGNIFICANT !!!!

18. Drugs potentiating Warfarin
3 Ways are Clinically Significant
1. Inhibit Hepatic Metabolism
• Amiodarone, Quinolone, Metronidazole, Cimetidine,
ingesting alcohol
2. Inhibit Platelet function
• Aspirin
3. Reduce Vitamin K from gut bacteria
• Cephalosporin Antibiotics
Albumin Displacement (NSAIDS) & drugs that
decrease GI absorption of Vit K have lesser effect
INR will if you start one de novo

19. Drugs inhibiting Warfarin
Antiepileptics (except Na valproate)
Rifampicin
St Johns Wort
Most work by inducing hepatic enzymes thereby
increasing metabolism of warfarin
INR

20. Uses

21. Main Uses of Warfarin
Indication (Duration) INR Range
DVT (3-6 months) 2.0–3.0
PE (6 Months)
Atrial fibrillation (Until Risk > Benefit)
Mechanical prosthetic valves (high risk) 2.5–4.5
Patients with recurrent thromboses on Warfarin
Thrombosis associated with inherited thrombophilia conditions
Other Uses: Cardiac Thrombus, CVA esp with AF, cardiomyopathy

22. Adverse Effects

23. Safety Issues: High INR
Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They
determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above
2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

24. Practical Information
◼ Initiation
1. Indication
2. PMH e.g PUD, SAH, Bleeding Disorder
3. Medications (interactions)
4. Age, Mobility (blood tests and clinics),
Falls risk score
5. Review blood tests (LFTs, Plt, INR),
6. Consider Loading Dose and Heparin cover
7. Prescribe (when to start)

26. Discuss with Patient
◼ Side effects
◼ Bleeding and when to consult a doctor
◼ Young and female ?
◼ Interactions
◼ Other Medication (starting or stopping!)
◼ Over the Counter drugs
◼ Alcohol and Cranberry/Grapefruit Juice
◼ INR Monitoring (1-4 weeks)
◼ Give patient Anticoagulant Card

27. Warfarin Reversal
◼ Common Sense: Stop Warfarin!
◼ Consider
◼ Bleeding, INR, Indication
◼ Mechanical Valve call cardiologist
◼ Agents
◼ IV Vit K
◼ pro-coagulant affects re-warfarinisation for 6 weeks
◼ Prothrombin Complex Concentrate
◼ Fresh Frozen Plasma
◼ Source of Bleeding (OGD, surgery)
◼ Elective Surgery

28. Management of  INR(no mechanical valve)

29. Anticoagulants: Heparin

30. Heparin Molecules
◼ Glycosaminoglycan Molecules (disaccharides+)
◼ Unfractionated Heparin (intravenous, continuous,
occasionally, subcutaneous for prophylaxis) 20 kDa
◼ Low Molecular Weight Heparins (subcutaneous)
3-4 kDa

31. Unfractionated Heparin
◼ Mix of variable long length heparin chains
◼ Variable lengths (12-15 kDaltons)
◼ Unique pentasaccharide sequence which
binds to ANTI-THROMBIN III
◼ This causes conformational change and
increased AT III activity
◼ AT III inactivates thrombin (IIa) and factor
Xa: but also V,VII,IX,XI

32. Heparins and AT III
◼ To catalyse inhibition of IIa by AT III, heparin
needs to bind simultaneously to IIa and AT
III. Unfractionated heparin is large enough
for this, but not Low MW Heparin.
◼ Xa inhibition by AT III needs only heparin to
bind to AT III, so both Low and
unfractionated heparin can act here.

33. IIa and Xa inhibitors

34. IIa and Xa inhibitors
Bivalirudin,
desirudin,
lepirudin,
argatroban,
dabigatran
Fondaparinux,
idaparinux,
rivaroxaban,
apixaban,
edoxaban

35. Low Molecular Weight
Heparins (LMWH)
◼ Smaller chains (usually 4-5 kDaltons)
◼ < 18 saccharide units, usually about 15 units
◼ Absorbed more uniformly, high bioavailability >90%
◼ Long biological half life
◼ More predictable dose response (does not bind to macrophages,
endothelial cells, plasma proteins)
◼ Like UH, have unique sequence to bind to ANTI-THROMBIN III
◼ Unlike UH, they do not inactivate thrombin (IIa)
◼ Affects Factor Xa specifically. No monitoring required usually.
◼ Cleared by Kidneys, care in Renal Failure
◼ Less likely to cause thrombocytopenia

36. Clotting Cascade & ACAs

37. 2. Pharmacokinetics

38. Pharmacokinetics
UFH LMWH
Dose-response Non-linearity Predictable
Bio-availability Variable
(unpredictable binding to
cells and proteins)
Predictable (less
binding to macrophages
and endothelium)
Action Variable
Monitor with APTT test
No monitoring
Little affect on APTT
Administration IV SC (Not IM!)
Initiation Bolus then IVI OD/BD
•Must be given parenterally as poor GI absorption
•Rapid onset and offset of action

39. 3. Uses

40. Prevention of Thrombo-embolism
◼ Peri-operative: LMWH low dose
◼ Immobility: CCF, frail or unwell patient
◼ Used to cover for risk of thrombosis around times of
operation in those normally on warfarin but who have
stopped it for the surgery, as quick offset time allows
its cessation if bleeding

41. Treatment
◼ DVT/PE and AF
◼ Administered prior to warfarin-quick onset to cover patient
whilst warfarin loading is achieved
◼ LMWH often used unless fine control required
◼ Acute Coronary Syndromes
◼ Reduces recurrence/extension of coronary artery thrombosis
◼ MI, unstable angina
◼ Pregnancy
◼ Can be used cautiously in pregnancy in place of warfarin

42. 4. Adverse Effects

43. Adverse Effects
◼ Bruising/bleeding Sites
◼ Intracranial
◼ Injection sites
◼ Gastrointestinal loss
◼ Epistaxis
◼ Thrombocytopenia (HIT)
◼ Autoimmune phenomenon (usually 1-2 weeks of Rx)
◼ May bleed or get serious thromboses
◼ Heparin and PF4 on platelet surface are immunogenic – immune
complexes activate more platelets, release more PF4, forms more
IgG and complexes, leads to depletion of platelets, thrombosis
◼ Platelets <100 (or a 50% reduction)
◼ Lab assay for these antibodies
◼ Stop heparin, add hirudin
◼ Osteoporosis

44. Reversal of Therapy
◼ Protamine sulphate
◼ Dissociates heparin from anti-thrombin III
◼ Irreversible binding to heparin
◼ Allergy/Anaphylaxis
◼ Stop Heparin
◼ If actively bleeding, give Protamine
◼ Monitor APTT if unfractionated

45. 5. Practical Info

46. Heparin
◼ UNFRACTIONATED
◼ Loading dose, then IV infusion
◼ Monitor APTT
◼ LMWH
◼ No monitoring. Occasionally, may need
Xa assay

47. Anti-platelet Drugs
◼ Aspirin
◼ COX-1 inhibition
◼ Dipyridamole
◼ Phosphodiesterase Inhibitors
◼ Clopidogrel
◼ ADP antagonists
◼ Glycoprotein IIb / IIIa Inhibitors

48. The Platelet
ANTI-PLATELET DRUGS
Aspirin, dipyridamole
Glycoprotein IIb/IIIa Inhibitors

49. Platelet Activation
Aspirin
NSAIDS
G IIb / IIIa Inhibitors
Abciximab, tirofiban,
eptifibatide
Decreases platelet
crosslinking by fibrinogen
Aspirin inhibits
COX1 irreversibly-
Covalent acetylation
of serine:
“hit and run” drug

50. Platelet Activation
Clopidogrel,
prasugrel,
ticagrelor
blocks P2Y12
Dipyridamole
inhibits PDE
PGI2 increases
cAMP –
reduces
aggregation
P2Y12
receptor
decreases
cAMP via Gi

51. Clopidogrel, Prasugrel, {Ticagrelor}
◼ Ticlodipine now out dated due to S/Es
◼ Inhibit ADP Dependent Aggregation
◼ Cardiac Indications:
◼ ACS, PCI (do NOT stop)
◼ Used with Aspirin
◼ More serious bleeds but same rate of life
threatening
◼ Not for long term use if possible,
◼ Eg use for 1 year after NSTEMI

52. Dipyridamole
◼ Probably Phosphodiesterase Inhibitor
◼ Positive Ionotrope and vasodilatory
(flushes & headaches)
◼ Secondary Prevention of Stroke

53. Glycoprotein IIb/IIIa Receptor
Antagonists
◼ Fibrinogen binds these receptors which
causes platelet aggregation
◼ Antagonists block this final pathway
◼ 3 Classes – Mab Abciximab
Peptides – eptifibatide, tirofiban
◼ Uses
◼ High risk ACS
◼ Post PCI (Increases bleeding complications
but decreases acute thrombosis and re-
stenosis)

54. Further Reading
◼ Oxford Textbook of Clinical
Pharmacology and Drug Therapy –
Grahame-Smith / Aronson
◼ www.americanheart.org
◼ BNF
◼ Local Guidelines (ward based)