Katzung Anticoagulants Hemostasis refers to the finely regulated dynamic process of maintaining the fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs. Either extreme excessive bleeding or thrombosis—represents a breakdown of the hemostatic mechanism. Common causes of dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer. The drugs used to inhibit thrombosis and to limit abnormal bleeding are the subjects of this chapter.

1. Anticoagulants Pharmacology
Reza Heidari
Pharm D & Toxicology PhD

3. What are Anticoagulants?
A substance that prevents
blood from clotting by
suppressing the synthesis
or function of various
clotting factors.
Anticoagulants are given
to prevent thrombosis and
used in drawing and
storing blood.

4. MECHANISMS OF BLOOD
COAGULATION

9. Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen Fribrin monomer
Fibrin polymerXIII
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral
Anticoagulants (e.g Warfarin)

11. Why anticoagulants ?
To reduce the coagulability of blood
Blood clots – Thrombus
Arterial Thrombosis:
Adherence of platelets to arterial walls – “White” in color - Often
associated with MI, stroke and ischemia
 Venous Thrombosis:
Develops in areas of stagnated blood flow (deep vein thrombosis),
“Red” in color- Associated with Congestive Heart Failure, Cancer,
Surgery
Thrombus dislodge from arteries and veins and become an embolus
Venous emboli can block arterioles in the lung and pulmonary
circulation
Thromboembolism

12. Available Anticoagulants
Used in vivo:
1. Parenteral anticoagulants:
– Indirect thrombin inhibitors: Heparin, Low molecular weight heparin,
Fondaparinux, Danaparoid
– Direct thrombin inhibitors: Lepirudin, Bivalirudin
1. Oral anticoagulants:
– Coumarin Derivative: Bishydroxycoumarin (dicumarol), Warfarin sodium,
Acenocoumarol
– Inandione derivatives: Phenindione
– Direct factor Xa inhibitors: Rivaroxaban
Used in vitro:
 Heparin: (150 U in 100 ml of blood)
 Calcium complexing agents: Sodium citrate 1.65 gm for 350
ml of blood – acid citrate dextrose solution – 75 ml in one
unit of blood
 For investigation: Sodium oxalate (10 mg for 1 ml blood and
Sodium edetate – 2 mg for 1 ml of blood)

13. INDIRECT THROMBIN INHIBITORS
• Unfractionated heparin (UFH)
• Low Molecular-Weight Heparin (LMWH)
• Synthetic pentasaccharide: Fondaparinux

14. Heparin as Prototype
Endogenous - strongest organic acid present in
the Body
Present in mast cells (MW – 75,000) – lungs, liver and
intestinal mucosa
Commercially - from Ox lung and Pig mucosa
(slaughter house)
Chemically, non-uniform mixture of straight chain
mucopolysaccharides with MW 10,000 to 20,000
Types - (i) Regular or unfractionated (UFH)
Heparin (MW 5000 to 30,000) – IV or SC and (ii)
LMWH (MW 2000 to 6000) – mostly SC

16. Heparin Actions
• Indirect acting - Activates plasma antithrombin III (AT III)
• Heparin-AT III complex inactivates clotting factors - Xa, IIa, IXa, XIIa
and XIIIa, but not VIIa (extrinsic pathway)
– At low conc. Xa mediated conversion of Prothrombin to thrombin affected
– Overall, Xa and IIa mediated conversion of fibrinogen to fibrin
• AT III (suicide inhibitor) – binds to clotting factors slowly to form
stable complex. Heparin enhances it by
1.Heaprin creates scaffolding to bind each (clotting
factors) other with AT III
2.A specific polysaccharide in heparin binds to AT III and
induce conformational changes

17. Heparin Actions – contd.
• Inhibition of Xa needs only the 2nd
mechanism (LMWH) -
fondaparinuxs
• IIa needs both the mechanism
• Antiplatelet action: High doses prevents platelet aggregation
prolongs Bleeding time
• Pharmacokinetics:
– Highly ionized, not absorbed orally – given IV (instant action) and SC
(slow action)
– Does no cross BBB and placenta
– 100 U/kg dose half life is 1 Hr., but above this dose 1 – 4 Hrs

18. Heparin – Contd.
• Adverse effects:
1. Bleeding due to overdose – hematuria is 1st
sign
2. Thrombocytopenia
3. Hypersensitivity – urticaria, rigor, fever and
anaphylaxis etc.
4. Alopecia and osteoporosis
• Contraindications: Bleeding disorders, Severe
hypertension, GIT ulcer, Ocular & neurosurgery,
Chronic alcoholism, cirrhosis etc.
• Aspirin and antiplatelet drugs - caution

19. Low Molecular eight Heparin (LMWH)
• MW : 2000 to 6000
• MOA: Acts only by interfering with Xa – inducing conformational
change in AT III – smaller effect on a PTT – whole blood clotting time
– Lesser antiplatelet action and lower incidence of hemorrhagic complications
– Better Bioavailability on SC administration (once daily dosing)
– Better half life (4-6 Hrs)
– Laboratory monitoring not needed (a PTT and clotting time affected little)
• Uses: Prophylaxis of DVT and Pulmonary embolism in Surgery, stroke
and immobilized patients, DVT, etc.

20. Dosage of Heparin
• Unitage: Expressed in units as it is standardized by bioassay –
variable molecular size
• 1 mg = 120-140 U activity
• Administered as IV bolus 5000-10,000 u followed by 1000 u
/hr IV drip – adjusted with aPTT value
– Pretreatment aPTT value and followed by 1.5 to 2.5 times during
therapy
• Alternate: 10,000-20,000 deep SC every 8 Hrly (fine needle)
• Or, Low dose SC – 5000 SC 8-12 Hry before and after surgery
to prevent DVT
• Protamine Sulfate: Heparin antagonist – given IV (1mg =
100U) – cardiac and vascular surgery

22. DIRECT THROMBIN INHIBITORS
• Hirudin
• Bivalirudin
• Argatroban
• Melagatran

23. • Leeches have been used for bloodletting since the
age of Hippocrates. More recently, surgeons have
used medicinal leeches (Hirudo medicinalis) to
prevent thrombosis in the fine vessels of
reattached digits.

24. Oral Anticoagulants

26. - Hemorrhagic disease in cattle

28. Warfarin
• In vivo not in vitro
• MOA: Competitive antagonist of
Vit.K – lowers the plasma level of
vit. K dependent clotting factors
– Inhibits VKOR needed to
generate active Vit.K
• Synthesis of clotting factors
diminishes within few hours- at
different times by diff. factors
• But anticoagulant action starts in
1-3 days only
• Commercially, mixture of R and S
enantiomers

31. Warfarin – contd.
• Kinetics: Completely absorbed from intestine and
99% plasma protein bound – only 1% free (many
drugs can displace (sulfonamides, phenytoin –
toxicity) – half life 36 hrs.
• Dosing: Risky – calculate risk-benefit ratio
– Dose is individualized by repeated measurement of PT
– Optimum ratio of PT: 2-2.5 in prophylaxis of DVT, 2-3
in DVT treatment and 3-3.5 in MI etc.
• Uses: DVT, Pulmonary embolism and atrial
fibrillation (drug of choice – 3-4wks before and
after conversion)

32. Warfarin
• ADRs: Bleeding – epistaxis, haematuria,
bleeding GIT Intracranial haemorrhage
– Minor bleeding – Vit K (takes long)
– Fresh blood transfusion or blood factors
– Other ADRs: Alopecia, dermatitis and diarrhea etc.
• Contraindications: Same as heparin
– Fetal warfarin syndrome: skeletal abnormality –
hypoplasia of nose, eye socket, hand bones and
growth retardation

33. Warfarin
• Factors enhancing warfarin effect: (1) Debility, malnutrition
etc. (2) Liver diseases, chronic alcoholism (3) Newborn (4)
prolonged antibiotic therapy
• Factors decreasing warfarin effect: Pregnancy, Nephrotic
syndrome and genetic warfarin resistance
• Drugs enhancing anticoagulant action: Broad spectrum
antibiotics, Aspirin (platelet aggregation inhibition and
hypoprothobinemic action), Newer cephalosporins
(hypoprothobinemic; Chloramphenicol, allopurinol, and
phenytoin (inhibits metabolism)
• Drugs reducing effect: Barbiturates, carbamazepine, OCP and
Rifampicin

36. RIVAROXABAN
Direct factor Xa inhibitor which is taken by mouth. The maximum inhibition
of factor Xa occurs four hours after a dose. The effects last approximately
8–12 hours, but factor Xa activity does not return to normal within 24 hours,
so once-daily dosing is possible.

37. FIBRINOLYTICS

39. Fibrinolytics
• Drugs used to lyse thrombi/clot to recanalize occluded
vessels – coronary artery
• MOA: Produce more plasmin - dissolves fibrin thread
• Drugs: Streptokinase, urokinase, alteplase (rt-PA),
reteplase and tenecteplase
• Streptokinase
– Binds to plasminogen and generate plasmin
– Non-specific – activates circulating + fibrin bound
plasminogen– non-specific fibrinogen depletory – but
less effect than newer ones in fibrinolysis

40. Alteplase and Tenecteplase
• Recombinant tissue plasminogen activator (rt-PA) – human tissue culture
– costlier than Streptokinase
• MOA: tissue specific thrombolytic (acts on fibrin bound plasminogen
within thrombus) – also interferes with circulating plasminogen (50%) –
inactivated by PAI-1
• Plasma half life 5 minutes – given slow IV (heparin needed)
• MI: 1o mg IV bolus – followed by rest 90 mg infusion for 90 minutes
• Pulmonary embolism: 100 mg slow IV for 2 Hrs
• Tenecteplase: genetically engineered, higher
fibrin selectivity, not inactivated by PAI-1, can
be injected over 10 seconds single bolus

41. Uses of Thrombolytics
• AMI
• – aspirin + heparin co-administered to prevent
re-occlusion
• DVT: leg, pelvis and shoulder
• Pulmonary embolism
• Stroke: selected patients

42. Antifibrinolytics
• Epsilon amino-caproic acid (EACA) and
Tranexamic acid
• MOA: Inhibit Plasminogen activation and clot
dissolution
• EACA: Specific antidote for fibrinolytic agents –
also adjunctive value in other conditions
• Tranexamic acid: More potent than EACA
– Uses: fibrinolytic drugs, Bypass surgery, Menorrhagia,
Recurrent epistaxis, tonsillectomy & tooth extraction
(haemophiliacs)

43. Antiplatelet Drugs (Antithrombotic
drugs)

44. Antiplatelet Drugs (Antithrombotic
drugs)
• Drugs which interferes with platelet function and used in
prophylaxis of thromboembolic disorders.
• Drugs: Aspirin, Dipyridamole, Ticlodipine, Clopidogrel and
Prasugrel
• Aspirin as antiplatelet:
– Irreversible Inhibition of COX 1 and TX synthase
– Suppress TXA2 (generated by platelets) in low doses (75-150 mg) – till
fresh platelets are formed – prolonged bleeding time
– Suppress COX-1 and decrease PGI2 synthesis in vessel wall – but
endothelial cells immediately re-synthesize fresh enzyme
– Also inhibits release of ADP from platelets and their sticking to each
other – but not to adhesion to damaged vessel walls

45. • Ticlopidine and clopidogrel reduce platelet
aggregation by inhibiting the ADP pathway of
platelets. These drugs
irreversibly block the ADP receptor on
platelets.

46. Antithrombotic drugs - Ticlodipine
• MOA: Inhibits fibrinogen as well as ADP induced
platelet aggregation
– Gi coupled P2Y12 (P2YAC) purinergic receptors mediate
adeylyl cyclase inhibition due to ADP – blocked irreversibly
– No effect on TXA2
– Irreversible blockade of P2YAC – platelet inhibiton cumulates
– effects appear in 8-10 days
• Uses: Stroke prevention, unstable angina, coronary
bypass, prevention of MI, etc
• Serious ADRs – Bleeding, neutropenia, hamolysis,
thrombocytopenia and jaundice - replaced by
Clopidogrel

47. Antithrombotic drugs - Clopidogrel
• Similar MOA to Ticlodipine – irreversible blockade of platelet
function
– Safer and better tolerated than Ticlodipine
• Advantages over Aspirin in Ischaemia – lower incidence of
ischaemic events
• Synergistic action with aspirin – prevention of Ischaemic episodes
• Kinetics: Prodrug like Ticlodipine, 50% absorbed orally
– Only a fraction slowly activated in liver by CYP2C19 slow acting
– CYP2C19 – genetic polymorphism - interindivdual variability in
antiplatelet action
– Takes 5-7 days for action
• ADRs: Bleeding most common, neutropenia and thrombocytopenia
rarely
• Dose: 75 mg OD

48. Antithrombotics – Other Drugs
• Prasugrel: Faster and potent P2Y12 (P2YAC) purinergic
receptors Blocker
• Newer Drugs: Glycoprotein (GP) IIb/IIIa receptor
antagonists: Abciximab, Ebtifibatide and Tirofiban
– Newer class of drugs
– Blocks the key receptor involved in platelet aggregation
– Collagens, thrombin, TXA2 and ADP etc. – acts through -
GLP IIb/IIIa is an adhesive receptor (integrin) on platelet
surface
– GLP IIb/IIIa antagonists block platelet aggregation

49. Uses of antithrombotics
• Coronary Artery Disease: Aspirin 75-150 mg/day in all
individuals with evidence of coronary artery disease –
clopidogrel is an alternative in ischaemia
• Acute Coronary Syndromes: Aspirin 325 mg orally and
LMW heparin
• Cerebrovascular accidents: Do not alter the course of
cerebral thrombosis
• Prosthetic Heart Valves and arteriovenous shunts: In
conjunction with warfarin
• Venous thrombosis: DVT and PE
• Peripheral vascular disease

50. THANK YOU
Any Questions???