Pharmacology of anticoagulants, antiplatelets , fibrinolytics , steptics

1. ANTICOAGULANTS
04/11/19 PATKI 1

2. • Def:
The drugs used to prevent the
coagulation
04/11/19 PATKI 2

3. •
COAGULATION
04/11/19 PATKI 3

4. • Mechanism of blood coagulation
• Hemostasis: Spontaneous arrest of
bleeding from damaged blood vessels.
first thing to happen is precapillary
constriction.
04/11/19 PATKI 4

5. • Injured blood vessel
• subendothelial collagen exposure
• platelets adhere to exposed collagen
fibrils at glycoprotein receptor release of
granules from platelets including ADP
• Activation of intrinsic pathway
04/11/19 PATKI 5

6. •
04/11/19 PATKI 6

7. •
04/11/19 PATKI 7

8. •
04/11/19 PATKI 8

9. BLOOD COAGULATIONBLOOD COAGULATION
ThrombinThrombin
FibrinogenFibrinogen Fibrin MonomersFibrin Monomers
Fibrin threadsFibrin threads
CaCa+2+2, factor XIII, factor XIII
04/11/19 PATKI 9

10. • Anticoagulants:
In vitro:
Sodium oxalate 10mg
Sodium Edetate
Sodium citrate,
EDTA
Heparin
150U ----- 100 ml blood
Used in blood taken
For investigations
04/11/19 PATKI 10

11. • Anticoagulants:
In vivo anticoagulants:
Parenteral :
In direct thrombin inhibitors:
Heparin, Foundaparinux
Direct thrombin inhibitors
hirudin, lepirudin,
Bivalirudin, Argatroban
Danaparoid
04/11/19 PATKI 11

12. • Anticoagulants:
In vivo anticoagulants:
Oral
coumarin derivatives
e.g. Warfarin,
Bishydroxycoumarin
Indandione derivatives
e.g. Phenindione
Anisindione04/11/19 PATKI 12

13. HEPARIN
• Heparin was discovered by McLean.
• Naturally occurring substance.
• It is found in the metachromatically
staining granules of mast cells.
Mainly in lung, liver, intestinal mucosa
• Commercial Heparin obtained from
bovine lung and porcine intestinal
mucosa.
04/11/19 PATKI 13

14. • It is a mucopolysaccharide.
• It is composed of D- glucosamine and
D-glucuronicacid .
• It is a strongest organic acid in the body.
• Strongly electronegative compound.
• Two types:
Unfractioned Heparin
( 10,000- 30,000)
Low molecular weight Heparin
(4000-6500)04/11/19 PATKI 14

15. • Action of unfractioned Heparin:
AT III IIa AT III II a
+ + + + +
- - - - - - - - - - -
heparin
AT III X a
04/11/19 PATKI 15

16. Mechanism of action:
It increases the activity of antithrombin III
Heparin combines with Antithrombin III
Heparin induces conformational changes in
antithrombin III to expose its interactive sites.
Factor IIa combines with Antithrmbin III and
Heparin.
Inactivation of Factor IIa.
But factor Xa combines with only
antithrombin III.
Inactivation of factor Xa.
04/11/19 PATKI 16

17. •
HEPARIN mechanism of action04/11/19 PATKI 17

18. • Monitoring of Heparin therapy:
Whole blood clotting time:
which should be kept at 2-3 times the normal
Activated partial thromboplastin time: (APTT)
which should be kept at 11/2 - 2 times normal
04/11/19 PATKI 18

19. Pharmacological actions:
1. Blood Coagulation:
2. Activation of Lipoprotein lipase
3. Antiplatelet action
Pharmacokinetics:
Orally not effective
should not be injected IM
subcutaneous route ( action after 60min
IV ( immediate action )
Does not cross BBB, Placenta
Metabolized by Heparinase04/11/19 PATKI 19

20. • PREPARATIONS:
1) Low fixed dose SC regimen:
5000 u every 12 hrs
2) Dose adjusted SC regimen:
15,000- 20,000 every 12 hrs
3) IV intermittent regimen:
5000-10,000 every 4-6 hrs
4) IV infusion: 0.5u/kg /min
04/11/19 PATKI 20

21. ADVERSE REACTIONS:
• Allergic and Anaphylactoid reactions:
• Bleeding
• Thrombocytopenia:
mild reaction:
heparin induced platelet aggregation
severe reaction
heparin induced antiplatelet antibodies
• Alopecia
• Osteoporosis04/11/19 PATKI 21

22. • Low molecular weight Heparins:
Molecular weight 4000-6500
Enoxaparin
Dalteparin
Tinzaparin
Nardoparin
Reviparin
04/11/19 PATKI 22

23. • ADVANTAGES:
1) Better subcutaneous bioavailability 70-90%
2) Longer duration of action
once daily administration
3) PTT, clotting time are not prolonged
Laboratory monitoring is not needed
Predictable anticoagulant effect
4) Dose is given in mg and calculated on body
weight basis
5) Less thrombocytopenia
6) Less antigenic04/11/19 PATKI 23

24. • Mechanism of action of L.M.W Heparin:
AT III Xa AT III X a
LMW Heparin
04/11/19 PATKI 24

25. •
L.M.W HEPARIN mechanism of action04/11/19 PATKI 25

26. • Enoxaparin:
2000 units SC 2hrs before surgery
then 2000 units every 24 hrs for 7-10 days
• Dalteparin :
2000 units SC 2hrs before surgery
then 2000 units every 24 hrs for 7-10 days
• Tinzaparin:
3500 units SC 2hrs before surgery
then 3500 units every 24 hrs for 7-10 days
04/11/19 PATKI 26

27. INDICATIONS:
• Prevention and treatment of deep venous
thrombosis and pulmonary embolism
• Myocardial Infarction
• Rheumatic heart disease
• Cerebrovascular disease
04/11/19 PATKI 27

28. • Contraindications:
Haemorrhagic tendency
blood dyscrasias
bleeding ulcers
subacute bacterial endocarditis
Threatened abortion
Regional and lumbar anesthesia
uncontrolled hypertension
Pregnancy
Recent operation upon CNS, eye04/11/19 PATKI 28

29. • Heparin antagonists:
Protamine sulphate
1mg for 100 units of heparin
obtained from salmon sperm
> 50-100 mg ----
itself produces some anticoagulant activity
Histamine liberator:
hypotension ,bradycardia, flushing, bronchosasm
trongly basic compound, which neutralizes
trongly acidic Heparin weight by weight.
04/11/19 PATKI 29

30. Fondaparinux:
Synthetic pentasaccharide
Inactivation of factor X
Long half-life 15days
SC, once daily dosing
Prevention & treatment of venous
thromboembolism
Alternative anticoagulant in heparin
induced thrombocytopenia.04/11/19 PATKI 30

31. Direct thrombin inhibitors:
Hirudin
Hirudo medicinalis
Lepuridin
by Recombinant DNA technology
Bivalirudin
Argatroban
Ximelagatron: orally active
04/11/19 PATKI 31

32. Oral anticoagulants
Warfarin:
In vivo anticoagulant
Oral anticoagulant
Coumarin derivative
Synthetic
Delayed onset of action ( 1-3 days )
Duration of action 3-6 days
04/11/19 PATKI 32

33. WARFARIN: MECHANISM OF ACTIONWARFARIN: MECHANISM OF ACTION
Inactive factors II,
VII, IX, and X
Proteins S and C
Active factors II,
VII, IX, and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WARFARIN
Prevents the reduction of vitamin K, which is essential forPrevents the reduction of vitamin K, which is essential for
activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Epoxide reductase
Inactive
II, VII, IX, X
Active
II, VII, IX, X
Warfarin
Warfarin mechanism of action
04/11/19 PATKI 33

34. Mechanism of action:
It inhibits the synthesis of vit K
dependent clotting factors in the liver by
inhibiting Epoxide reductase enzyme.
This enzyme is essential for formation of
reduced vitK.
This reduced VitK activates clotting
factors II,VII, IX, X.
Monitoring of Warfarin therapy:
Prothrombin Time
04/11/19 PATKI 34

35. The commercial preparation is mixture
of R( Dextro, less potent ) &
S ( Levo, more potent)
99% protein bound
It crosses Placenta
Undergoes enterohepatic Circulation
Excreted in urine
Dose: 5-10mg/day
04/11/19 PATKI 35

36. Adverse Reactions:
Bleeding
Cutaneous necrosis
Alopacia
Dermatitis
Diarrhoea
Foetal Warfarin syndrome:
04/11/19 PATKI 36

37. Treatment of Warfarin toxicity:
Withhold the anticoagulant
fresh blood transfusion
Antidote vit K1
04/11/19 PATKI 37

38. Drug Interactions:
Increases the Warfarin effect:
Malnutrition, malabsorption
Enzyme inhibitors: Cimetidine
Drugs which displace the Warfarin
from protein binding site: Phenytoin
drugs inhibits the gut flora: antibiotics
Liquid paraffin
Drugs causing Hypoprothrombinaemia
Cephalosporins
04/11/19 PATKI 38

39. Drug Interactions:
Decreases the Warfarin effect:
Enzyme inducers: Barbiturates
Drugs that inhibits absorption
Cholestyramine
Drugs that increases the synthesis of
clotting factors: Oral contraceptives
04/11/19 PATKI 39

40. Mucopolysaccharide
Bovine lung
Binds with antithrombin III &
Inactivates factor IX a & xA
Immediate action
Duration 6 hrs
PT
Indicated in pregnancy
No drug interactions
Protamine antidote
Monitored by APTT
HEPARIN
Parenteral
In vitro & in vivo
5-7 days
Vit K antidote
Drug interactions
Not indicated
WARFARIN
After 1-3 days
Inhibits the epoxide reductase
Inactvates II, VII,IX, X
Synthetic
Coumarin derivative
Oral
In vivo
04/11/19 PATKI 40

41. FIBRINOLYTIC AGENTS
These are the drugs used to lyse
Thrombi / clot recanalize the
occluded blood vessels
04/11/19 PATKI 41

42. Fibrinolytic agents:
Streptokinase
Urokinase
Anistreplase (Acylated plasminogen
streptokinase activator
complex)
Recombinant tissue type
plasminogen activators:
04/11/19 PATKI 42

43. Mechanism of action:
They activate the natural
fibrinolytic system
04/11/19 PATKI 43

44. Plasminogen
Plasminogen activator
Plasmin
Fibrin Degradation products
Clot dissolution
Natural fibrinolytic system04/11/19 PATKI 44

45. THROMBOLYTIC AGENTS
04/11/19 PATKI 45

46. Lytic activity:
Streptokinase > Urokinase > rt- PA
Disadvantage:
Mainly for treatment not for prophylaxis
Venous thrombi better than arterial thrombi
Do not distinguish between fibrin of
a thrombus and fibrin of a
haemostatic plug04/11/19 PATKI 46

47. Streptokinase:
beta hemolytic streptococci group C
Half-life: 15-20min
Dose: 1.5 million units IV over one hour
Bind with the free plasminogen in circulation
more bleeding
Allergic reactions & hypotension are common
Indirect plasminogen activator
No fibrin specificity
04/11/19 PATKI 47

48. Urokinase:
• Cultured human renal cells
• Half-life: 15-20min
• Dose: 1.5million units IV bolus then
1.5 m.units IV over one hour
Direct plasminogen activator
It lacks fibrin specificity
Non antigenic: no allergic reactions
No hypotension
04/11/19 PATKI 48

49. • Alteplase:
recombinant tissue plasminogen activator
Always combine with heparin
10mg IV 1-2min f.by 50mg IV 1 hour
40 mg IV next 2 hours
It activates only fibrin bound plasminogen
( avoids activation of systemic plasminogen)
no bleeding
It is a short half-life 4-8min
rethrombosis
04/11/19 PATKI 49

50. STREPTOKIN
ASE
Urokinase Anistreplase Alteplase
Plasma half
life-min
15-25 15-25 50-90 4-8
Fibrin
specificity
minimal moderate minimal maximum
Plasminogen
binding
indirect direct indirect direct
allergy yes no yes no04/11/19 PATKI 50

51. • Uses:
1) MI:
indications:
with in 6 hours of onset
minimum duration of pain 30min
ST elevation in two leads
< 75 years age
Streptokinase 1.5 million units over one hour
2) Stroke
3) pulmonary embolism
4) DVT
5) peripheral arterial occlusion04/11/19 PATKI 51

52. Adverse reactions:
Bleeding
Micro emboli
Allergic reactions
Hypotension
Rethrobosis
04/11/19 PATKI 52

53. Contraindications:
active bleeding
recent trauma
surgical procedure in past 10 days
neurosurgical procedure in past 2 months
stroke in past 12 months
active peptic ulcer disease
HTN
DM
Pregnancy04/11/19 PATKI 53

54. • ARVIN: It is a enzyme
venom of malayan pit viper( agkistroden
rhodostoma)
Mechanism of action:
Converts the fibrinogen to imperfect fibrin
Dose: 2units /kg every 12 hours IV
Resistance to IM administration ( antibody formation)
Mainly for venous thrombosis
adv: no bleeding
Adverse reactions:
urticaria, unilateral vision impairment
04/11/19 PATKI 54

55. • Mechanism of action of HEPARIN
• Name LMW Heparins
• Advantages of LMW Heparins
• Antidote for Heparin
• Warfarin mechanism of action
• Name direct thrombin inhibitors
• Antidote for warfarin
• Name fibrinolytic agents
• Streptokinase dose in MI
04/11/19 PATKI 55

56. ANTI PLATELET DRUGSANTI PLATELET DRUGS
04/11/19 PATKI 56

57. MRK
What happens when the vessel is damaged?
Vasospasm (immediate response)
Platelet adhesion
Platelet aggregation
Viscous metamorphosis (gelatinous mass)
PLATELET PLUG
Fibrin reinforcement (activation of coagulation)

58. Antiplatelet drugs:
These drugs interfere with platelet function
Useful in prophylaxis of thromboembolic
disorders.
Cyclooxygenase inhibitors: Aspirin
Phosphodiesterase inhibitors: Dipyridamole
ADP antagonists : Clopidogrel, Ticlopidine
Gp II b | III a antagonists: Abciximab
Eptifibatide, Tirofiban
04/11/19 PATKI 58

59. GP IIb, IIIa
DP Clopidogrel
Ticlopidine
PGI2
ATP
cAMP
ADP
Dipyridamole
Arachidonic acid
TXA2
COXAspirin
ADP, 5HT
TXA2TXA2
04/11/19 PATKI 59

60. 04/11/19 PATKI 60

61. Aspirin: Aspirin is NSAID
Antiplatelet dose of Aspirin: 75-150mg
Mechanism of antiplatelet action:
It acetylates & inhibits the cyclo-oxygenase I
Irreversibly in portal circulation
So it inhibits the production of
thromboxane A2 till fresh platelets are formed.
> 325mg it inhibits the production of
prostacycline and thromboxane A2.
other NSAIDs reversible inhibition04/11/19 PATKI 61

62. MRK
AspirinAspirin
Platelets – major COX product is TXA2
– platelet aggregation & vasoconstriction.
Aspirin – Ecosprin75, 150mg tab
 Irreversibly inhibits COX
 160 mg/day complete inactivation of platelet COX
 Antithrombotic effect dose  160-320 mg/day
 At low doses TXA2 formation selectively suppressed
 Higher doses > 900mg/d may ↓ both TXA2 & PGI2 production
 Other NSAID’s –short lasting inhibition of P function

63. Dipyridamole:
It is a vasodilator
It inhibits the phosphodiesterase
blocks the uptake of adenosine
Finally it increases the cyclic AMP which
potentiates the PG I2& interferes with
platelet aggregation.
DOSE: 150-300mg | day
04/11/19 PATKI 63

64. Ticlopidine
Theinopyridine
Mechanism of action:
alters the surface receptors on platelets and
inhibits the ADP induced platelet aggregation.
It binds with the Gi coupled purinergic
receptors, so it blocks the ADP action.
Finally it increases the cyclic AMP levels and
interferes with the platelet function.
04/11/19 PATKI 64

65. Synergistic effect with aspirin.
Kinetics:
Oral
Half-life: 8hours- 8days
Dose : 250mg BD with meals
ADR:
Diarrhea, vomiting, abdominal pain
Thrombocytopenia, neutropenia , jaundice
04/11/19 PATKI 65

66. CLOPIDOGREL
Newer congener of Ticlopidine
Mechanism of action, efficacy similar
to Ticlopidine but better tolerated
Lower frequency of neutropenia and
thrombocytopenia
Dose: 75 mg OD
04/11/19 PATKI 66

67. Glycoprotein IIb| IIIa receptor
antagonists:
• Glycoprotein IIb| IIIa receptor
antagonists blocks the platelet
aggregation induced by all platelet
agonists through Glycoprotein IIb/IIIa
receptor.
Abciximab
Eptifibatide
Tirofiban04/11/19 PATKI 67

68. ABCIXIMAB:
It is a monoclonal antibody against
Glycoprotein IIb| IIIa receptor.
It is given along with Aspirin & heparin in
PCI.
It reduces the incidence of restenosis
Dose: 25mg|kg
Adverse reactions:
hemorrhage, thrombocytopenia,
arrhythmias
04/11/19 PATKI 68

69. • Eptifibatide,Tirofiban:
Inhibits the ligands binding to the
Glycoprotein IIb| IIIa receptor by their
occupancy of the receptors.
04/11/19 PATKI 69

70. Uses of antiplatelet drugs:
Coronary artery disease
Unstable angina
Cerebrovascular disease
Prosthetic heart valves
Arterio venous shunts
Venous thromboembolism
Peripheral vascular diseases
04/11/19 PATKI 70

71. HEMOSTATIC AGENTS:
These are the substances used to control the bleeding
from local & approachable site
Natural: contraction of blood vessels
platelet aggregation
fibrin deposition
Physical methods:
manual pressure, tourniquet, cold, cautery
04/11/19 PATKI 71

72. Locally acting agents:
Thrombin ( bovine plasma , dry powder )
Thromboplastin ( rabbit brain)
Fibrin ( human plasma )
Gel foam
Oxidized cellulose
Microfibrillar collagen
left in situ these materials are absorbed in 1-4 weeks
Transfusional agents:
fibrinogen
Antihaemophilic globulin
plasma or blood04/11/19 PATKI 72

73. Non- transfusional agents:
VIt K
antifibrinolytics:
Epsilon amino- caproic acid
Tranexaemic acid
Aprotinin
Vit C
Ethamsylate
Desmopressin
Conjugated estrogens04/11/19 PATKI 73

74. • Vit K:
Fat soluble vitamin
Essential for synthesis of clotting factors
( II, VII, IX. X activation )
Vit K1( phytonadione): from foods
Vit K2 : colonic bacteria
Vit K3 : ( Menadione ) synthetic ( water soluble)
Deficiency:
liver disease
jaundice, malabsorption
long term antimicrobial therapy04/11/19 PATKI 74

75. Uses:
1) Over dose of oral anticoagulants
phytonadione 10mg IM
2)Treatment of bleeding in Vit K deficiency states
3) Premature infants:
Phytonadione 1 mg IM after birth
5mg IM 4-6 hours before delivery
Menadione not indicated in newborn, pregnancy
& warfarin induced bleeding:
it induces hemolysis( increases bilirubin load)
competitive inhibition of glucuronidation of
bilirubin
04/11/19 PATKI 75

76. Epsilon amino - caproic acid:
Plasminogen
Plasmin
Uses:
prmary menorrhagia
after prostatic surgery
upper GI bleeding
dental extraction
50mg/kg 6th
hourly04/11/19 PATKI 76

77. Tranexamic acid:
Aprotinin:
• It inhibits the plasmin
• It inhibits the coagulation & fibrinolysis
Ethamsylate:
500mg four times a day
It corrects the abnormal platelet adhesion
04/11/19 PATKI 77

78. Sclerosing agents:
these are irritants
they cause inflammation, coagulation & fibrosis
They are useful only for local injection
into the hemorrhoids and varicose veins
Phenol in almond oil
Ethanolamine oleate
Sodium tetradecyl sulphate
Sodium linoleate
Sodium morrhuate04/11/19 PATKI 78

79. • Name four antiplatelet drugs
• Antiplatelet dose of Aspirin
• Why other NSAIDs are not antiplatelet drugs
• Mechanism of action of HEPARIN
• Name LMW Heparins
• Advantages of LMW Heparins
• Antidote for Heparin
• Warfarin mechanism of action
• Name direct thrombin inhibitors
• Antidote for warfarin
• Name fibrinolytic agents
• Streptokinase dose in MI
• Name antifibrinolytic drugs04/11/19 PATKI 79

80. ANTIFIBRINOLYTICS
04/11/19 PATKI 80

81. ANTIFIBRINOLYTICS:
• Epsilon amino caproic acid :
• combines with lysine binding sites of
plasminogen and plasmin so latter is not
able to bind fibrin and lyses it
• Specific antidote for fibrinolytic agents
used in hyper plasminemic states
associated with excessive
intra vascular fibrinolysis.
04/11/19 PATKI 81

82. USES:
• To prevent recurrence of subarachnoid and GI
haemorrhage .
• Abruptio placentae
• PPH
• menorrhagia
• Traumatic surgical bleeding
• haemophilics
• Dose-
• 5g oral / IV followed by 1g hourly
04/11/19 PATKI 82

83. • Trenexaemic acid
• It binds to lysine binding site on plasminogen
prevents combination with fibrin. Seven times
more potent
• USE:
• Over dose of fibrinolytics
• After cardiopulmonary by pass surgery
• Tooth extraction in hemophiliacs
• Menorrhagia due to IUCD
• Recurrent epistaxis
• ocular trauma
• bleeding peptic ulcer
• Dose 10 to 15 mg / kg Day
04/11/19 PATKI 83

84. APROTININ:
• Polypeptide isolated from bovine tissue.
polyvalent protease inhibitory activity
• It inhibits Trypsin, chymotrypsin, kallikrein.
• USES:
• Beginning of cardio pulmonary by pass
surgery – reduces blood loss
• Acute pancreatitis
• Fibrinolytic states
• prostatic surgery
• carcinoid afford symptomatic relief04/11/19 PATKI 84

85. • Adverse effects :
Renal toxicity
MI
Stroke
• Dose
5 lac KIU followed by 2 lac KIU every
4hr slow IV infusion
04/11/19 PATKI 85

86. THE END
04/11/19 PATKI 86
•drdrpatki@gmail.com