This document discusses drugs that modify blood coagulation. It begins by describing two case scenarios involving bleeding during tooth extraction. It then outlines the key learning objectives for medical students regarding drugs that achieve and prevent coagulation. The rest of the document provides details on the mechanisms, pharmacokinetics, uses, and adverse effects of various anticoagulant and coagulant drugs, including heparin, warfarin, vitamin K, fibrinolytics, antiplatelet drugs like aspirin, and dipyridamole.

1. DRUGS MODIFYING
BLOOD COAGULATION
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Assistant Professor, Maharajgunj
MedicalCampus
6 February, 2020 (23 Magh, 2076),Thursday

2. A case scenario
 A 35 years male patient with impacted tooth
 Started tooth extraction
 Bleeding seen…..
 What would you do?
 By your experience, the bleeding was more
than expected
 What could be the reason?

3. Another case scenario

4. By the end of the class, BDS II
Year students will be able to:
☞ List drugs used to achieve coagulation and anti-
coagulation
☞ Describe the pharmacology of heparin and
warfarin
☞ Explain the pharmacological basis of protamine
and vitamin K

5. By the end of the class, BDS II
Year students will be able to:
☞ Describe the pharmacology of anti-platelet
drugs (aspirin, dipyridamole)
☞ Describe the pharmacology of thrombolytic
agents (streptokinase, urokinase)

6. Anti-coagulants: Classification
Used in-vivo Used in-vitro
Parenteral Oral
• Heparin
• Low Molecular Weight
Heparin
• Lepirudin, Bivalirudin
• Warfarin
• Rivaroxaban
• Heparin
• Calcium
complexing
salts

7. Heparin
 Non-uniform mixture of straight chain
mucopolysaccharides
 Effective both in vivo and in vitro
 Heparin binds with and activatesAnti-thrombin
III (AT III)
 Increases interaction betweenAT III and
clotting factors (IIa, Xa, IXa, XIa, XIIa and XIIIa)
 Intrinsic and common pathway affected (aPTT
prolonged)

8. Heparin: Anticoagulant action
•Provides scaffolding
•ActivatesAT III
Simultaneously
bound to thrombin

9. Heparin: Other actions
 Antiplatelet action
 Seen at higher dose
 Prolonged bleeding time
 Lipaemia clearing
 Seen at lower concentration
 Releases Lipoprotein lipase from vessel wall
 Hydrolyses triglycerides of chylomicron and very
low density lipoprotein to free fatty acids
 Passes into tissue  turbid post-prandial
lipaemic plasma becomes clear

10.  Absorption:
 Oral: not absorbed (large, highly
ionised)
 Intravenous: instant action (bolus,
continuous infusion)
 Subcutaneous: inconsistent (every 8-12 hrs)
 Distribution:
 Does not cross blood brain barrier, placenta
 Metabolised in liver (heparinise)
 Excreted in urine
Heparin: Pharmacokinetics

11. Heparin: Adverse effects
 Bleeding due to overdose
 Proper monitoring required (aPTT)
 Thrombocytopenia
 Discontinue heparin
 Osteoporosis on long term use
 Hypersensitivity reactions (rare)

12. Heparin: Contraindications
 Bleeding disorders
 History of heparin induced thrombocytopenia
 Severe hypertension, threatened abortion,
piles, g.i. ulcers
 Subacute bacterial endocarditis, large
malignancies, tuberculosis

13. Heparin: Contraindications
 Ocular and neurosurgery, lumbar puncture
 Chronic alcoholics, cirrhosis
 Renal failure
 Caution:
 Co-administered antiplatelet drugs
 Aspirin, Clopidrogrel

14. Coumarin derivatives
 Warfarin, Nicomalone
 Active in vivo only
 Acts indirectly by:
 Interfering with synthesis of vitamin K
dependent clotting factors
 Lowers plasma level of clotting factors in
dose dependent manner

15. Coumarin derivatives: Mechanism of
action
Clotting factors precursors
(Vitamin K dependent)
Inactive Clotting
factors
Vitamin K
hydroquinone
Vitamin K
epoxide
Vitamin K epoxide
reductase NADHNAD
γ- glutamyl
carboxylase
Warfarin

16. Warfarin: Pharmacokinetics
Parameters Character Remarks
Absorption Rapidly and completely
absorbed from intestine
Given orally
Distribution 99% plasma protein bound Drug interaction
Crosses placenta Contraindicated in
pregnancy
Secreted in breast milk Insignificant
Metabolism R-form: CYP 1A, CYP3A4 Degraded slowly
S-form:CYP2C9 More potent
Both undergo glucuronidation
and enterohepatic circulation
Excretion Urine

17. Coumarin Derivatives
 Adverse effects
 Bleeding
 Ecchymosis
 Epistaxis
 Hematuria
 Intracranial bleeding

18. Coumarin derivatives
 Contraindications
 Pregnancy
 Early: Foetal warfarin syndrome, skeletal
abnormalities
 Late: CNS defects, foetal haemorrhage,
foetal death, neonatal
hypoprothrombinaemia (accentuated)
 Bleeding disorders, patient at risk of bleeding,
patient undergoing ocular surgery, neurosurgery

19. FoetalWarfarin Syndrome

20. Warfarin: Interactions
 Increased effect
 Prolonged
antibiotic therapy,
malnutrition,
malabsorption
 Liver disease,
chronic alcoholism
 Hyperthyroidism
 Decreased effect
 Pregnancy
 Nephrotic Syndrome
 Genetic warfarin
resistance

21. Anticoagulants: Indications
 Deep vein thrombosis, pulmonary embolism
 Myocardial infarction
 Prevent mural thrombi at the site of infarction
and venous thrombi in leg veins
 Unstable angina
 Along with aspirin
 Rheumatic heart disease, atrial fibrillation
 Prevent thromboembolism
 Prior attempting rhythm conversion

22. Anticoagulants: Indications
 Embolic stroke (cerebrovascular disease)
 Vascular surgery, prosthetic heart valves, retinal
vessel thrombosis, extracorporeal circulation,
haemodialysis
 Prevent thromboembolism
 Defribrination syndrome
 Heparin (paradoxical effect)

23. Protamine
 Strongly basic, low molecular weight protein
 Administered intravenously
 1 mg for 100 U of heparin
 More commonly used when heparin action needs
to be terminated rapidly, e.g. after cardiac or
vascular surgery
 Has weak anticoagulant in the absence of heparin
 Adverse effects: Hypersensitivity reaction, flushing
and breathing difficulties on rapid i.v. injection

24. Coagulants: Classification
 Coagulants
 Fresh whole blood/ plasma
 Vitamin K: K1 , K3
 Miscellaneous: Fibrinogen, Antihaemophilic factor
 Local Haemostatics
 Styptics: fibrin, thrombin, vasoconstrictors,
astringents
 Sclerosing agents
 Anti-fibrinolytics
 Epsilon amino-caproic acid (EACA),Tranexamic acid

25. Vitamin K
 K1:
 Phytonadione, Phylloquinone
 Plant source, Fat soluble
 K3:
 Synthetic
 Fat soluble: Menadione, acetomenaphthone
 Water soluble: Menadione sod. bisulphite,
menadione sod. diphosphate

26. Vitamin K
 Co-factor for synthesis of coagulation proteins
by liver
Coagulation protein
precursors
(factor II,VII, IX, X)
Coagulation protein
(factor II,VII, IX, X)
γ glutamyl
carboxylase
Vitamin K
Can bind to Ca2+ and
phospholipid surface

27. Vitamin K
 Absorption
 Fat soluble: lymphatics of intestine, bile salts
required
 Water soluble: portal blood
 Distribution:Temporarily stored in liver
 Metabolism: Liver (side chain cleavage and
glucuronidation)
 Excretion: bile and urine

28. Vitamin K: Uses
 Newborn baby
 Prevent/treat haemorrhagic disease of the
newborn
 Overdose of oral anticoagulants
 Phytonandione
 Prolonged high dose salicylate therapy

29. Vitamin K: Uses
 Dietary deficiency
 Prolonged antimicrobial therapy
 Obstructive jaundice
 Malabsorption syndromes
 Sprue, Regional ileitis, Steatorrhoea
 Liver disease

30. Vitamin K: Adverse effects
 Oral, intra-muscular injection:
 Safe
 Intra-venous injection:
 severe anaphylactoid reaction by emulsified
preparation
 Menadione,Water soluble K3:
 Haemolysis in dose-dependent manner
 Kernicterus in newborn

31. Fibrinolytics (Thrombolytics)
 These are drugs used to lyse thrombi/clot to
recanalize occluded blood vessels (mainly
coronary artery)
 Work by activating the natural fibrinolytic
system
 Includes:
 Streptokinase, Urokinase
 Alteplase,Tenecteplase, Reteplase

32. Thrombolytics: Mechanism of action
Plasmin
tissue Plasminogen
Activator
Fibrin
(insoluble)
Fibrin
(soluble)
Plasminogen
Plasminogen
Plasminogen
Plasmin
Plasmin
Antiplasmin
PAI-1, PAI-2

33. Streptokinase
 Obtained from β haemolytic Streptococci group
C
 Combines with circulating plasminogen
molecules
 Gets activated
 Breaks plasminogen to plasmin (in a limited
manner)
 Non-fibrin specific

34. Streptokinase
 Drawbacks:
 Less effective than newer agents
 Increased risk of bleeding
 Inactivated by antibodies to past streptococcal
infection
 Is antigenic
 Cannot be used second time
 Fever, hypotension, arrhythmia

35. Urokinase
 Commercially prepared from cultured human
kidney cells.
 Activates plasminogen directly and has a
plasma t½ of
10–15 min
 It is nonantigenic
 Side effects: Fever
 Indicated in patients in whom streptokinase has
been given for an earlier episode

36. Thrombolytics: Uses
 Acute myocardial infarction
 Deep vein thrombosis
 Pulmonary embolism
 Stroke
 Peripheral arterial occlusion

37. Thrombolytics: Contraindications
1. H/o Intracranial haemorrhage
2. H/o Ischaemic stroke in past 3 months
3. H/o Head injury in past 3 months
4. Intracranial tumour/vascular abnormality/
aneurysms
5. Active bleeding/bleeding disorders
6. Peptic ulcer, esophageal varices
7. Any wound or recent fracture or tooth extraction
8. H/o major surgery within 3 weeks
9. Uncontrolled hypertension
10. Pregnancy

38. Anti-platelet drugs (anti-thrombotic
drugs)
 These are drugs which interfere with platelet
function and are useful in the prophylaxis of
thromboembolic disorders.
 More useful in arterial thrombosis
 Includes:
 Aspirin, Dipyridamole
 Ticlopidine,Clopidogrel, Prasugrel
 Abicximab, Eptifibatide,Tirofiban

39. Aspirin
 Acetylsalicylic acid gets converted to salicylic
acid
 Antiplatelet action:
 Small doses irreversibly inhibitsTXA2 synthesis
by platelets.
 Interferes with platelet aggregation
 Lasts for 5-7 days

40. Aspirin: Pharmacokinetics
 Absorption:
 Stomach and small intestines
 Microfining the drug particles and inclusion of an
alkali (solubility is more at higher pH) enhances
absorption
 Rapidly deacetylated in the gut wall, liver, plasma
and other tissues to release salicylic acid which is
the major circulating and active form.

41. Aspirin: Pharmacokinetics
 Distribution
 Slowly enters brain but freely crosses placenta
 Metabolism
 Conjugated with glycine (major pathway) and
glucuronic acid
 Excretion
 Glomerular filtration as well as tubular secretion

42. Aspirin: Uses
 As antiplatelet aggregatory
 75-150 mg in post-MI patient
 100-150 mg in new onset angina

43. Dipyridamole
 Initially introduced as vasodilator
 Phosphodiesterase inhibitor:
 Increases platelet cAMP
 Potentiated PGI2  antiaggregatory effect
 Also been used to enhance the antiplatelet
action of aspirin

44. Conclusion
 Heparin effects intrinsic and common pathway of
clot formation
 Inactivates both Xa and Iia
 Warfarin is active only in vivo
 Always check in patients for possible warfarin
(drug) interaction
 Protamine sulfate reverses the action of heparin
 Vitamin K reverses the action of warfarin

45. Conclusion
 Streptokinase and urokinase acts by activating
plasminogen
 Aspirin acts by inhibitingCOX-1 (decreasing
formation of thromboxaneA2 in platelets)
 Dipyridamole shows antiplatelet effect by
inhibiting breakdown of cAMP
 Is a phosphodiesterase enzyme inhibitor

46. Any questions??
 Thank you!