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1. CV Pharmacology
Drugs that Influence Coagulation
Review Hemostasis
Audiovisual Tutorial McGraw Hill
Recommended Reading:
Management of
Coagulation Disorders
Prepared and Presenter:
Marc Imhotep Cray, M.D. Formative Assessment
Professor Pharmacology Practice question set #1
Clinical:
E-Medicine Article
Disseminated
Intravascular Coagulation

2. Lecture Outline
 Review of Hemostasis /Coagulation/
Thrombogenesis / Fibrinolysis
 Anticoagulant Drugs Pharmacology
 Fibrolytic Drugs Pharmacology
 Antithrombotic / Antiplatelet Drugs
Pharmacology
2

3. Coagulation Physiology
 Coagulation is a complex process by which blood forms
clots
 It is an important part of hemostasis (the cessation of
blood loss from a damaged vessel) whereby a damaged
blood vessel wall is covered by a platelet and fibrin
containing clot to stop bleeding and begin repair of the
damaged vessel
 Disorders of coagulation can lead to an increased risk of
bleeding (hemorrhage) and/or clotting (thrombosis)
3

4. Coagulation Physiology(2)
Platelet activation
1. Damage to blood vessel walls exposes
subendothelium proteins, most notably
collagen, present under the endothelium
2. Circulating platelets bind collagen with
surface collagen-specific glycoprotein Ia/IIa
receptors
4

5. Coagulation Physiology(2)
3. Adhesion is strengthened further by
the large, multimeric circulating
proteins von Willebrand factor (vWF),
which forms links between the
platelets glycoprotein Ib/IX/V and the
collagen fibrils.
4. This adhesion activates the
platelets
5

6. Review Hemostasis
Audiovisual Tutorial McGraw Hill
Pathway of Thrombogenesis
Click to read source:
http://www.heartzine.com/170.pdf
6

7. Thrombogenesis: Sequence
and Characteristics
 Normal:
 Normal vascular endothelial cells:
 not thrombogenic (platelet/clotting factors do not
adhere)
 Injury thrombogenesis
 Immediate response: vasospasm
 Platelet adherence to damaged epithelium (binds
to collagen) referred to as platelet adhesion.
(collagen-platelet membrane glycoprotein Ia
receptor interaction)
7

8. Thrombogenesis: Sequence
and Characteristics
 Platelets binding to each other: platelet
aggregation
 Platelets form a gelatinous mass (losing
individual membranes): viscous
metamorphosis platelet plug (temporary
cessation of bleeding)
 Platelet plug -- reinforcement by fibrin
8

9. Thrombogenesis: Sequence
and Characteristics
 Fibrin reinforcement:
 damaged vessel exposed collagen + platelet content
released
 Platelet degranulation releases aggregating substances:
 ADP
 TXA2
 5-HT
 local thrombin production:
 platelet ADP release (ADP inducer of platelet aggregation)
 prostaglandin synthesis (derived from platelet membrane
arachidonic acid)
 Thrombogenesis/vasoconstriction: thromboxane A2 , TXA2)
 Thrombogenesis inhibitor: prostacyclin
9

10. See Notes for Explanation
From:http://en.wikipedia.org/wiki/Coagulation
10

11. Inactivation of coagulation
proteins
 Plasma Protease Inhibitors:
 a1-antiprotease
 a2-macroglobulin
 a2-antiplasmin
 antithrombin III
 -----Failure of plasma protease inhibitor system: -----
Disseminated Intravascular Coagulation (DIC)-- may
occur following:
 obstetrical emergencies (abruptio placentae; bacterial
sepsisreprint
 major tissue injury
 cell lysis: neoplastic disease
11

12. Clotting Factors: Drug Target
Sites
Factor/Component also called Target
I Fibrinogen
II Prothrombin Heparin (IIa); Warfarin (synthesis)
III Tissue Thromboplastin
IV Calcium
V Proaccelerin
VII Proconvertin Heparin (VIIa); Warfarin (synthesis)
VIII Antihemophilic globulin (AHG)
Christmas factor, plasma thromboplastin
IX Heparin (IXa); Warfarin (synthesis)
component (PTC)
X Stuart-Prower factor Heparin (IXa); Warfarin (synthesis)
XI Plasma thromboplastin antecedent (PTA)
XII Hageman factor
XIII Fibrin-stabilizing factor
Proteins C and S ------- Warfarin (synthesis)
Plasminogen ------- Thrombolytic enzymes, aminocaproic acid
12

13. Anticoagulant Drugs:
Pharmacology
Heparin Mechanism of Action:
 Binds to endothelial cell surface membrane
 Heparin activity dependent on: plasma
protease inhibitor antithrombin III
 Antithrombin III -- inhibitor of clotting factors
proteases (forming 1:1 stable complexes)
 Complex forming reactions normally slow --
accelerated by three orders of magnitude (1000
times) by heparin
13

14. Anticoagulant Drugs:
Pharmacology
Heparin Toxicity:
Long-term
 major adverse/toxic effect: bleeding
heparin use--
 Risk managed by attention to:
increased
 patient selection
incidence of:
 dosage control
 monitoring of partial
thromboplastin time (PTT)  osteoporosis
 Factors predisposing to hemorrhage:  spontaneous
 elderly fractures
 renal failure patients
14

15. Anticoagulant Drugs:
Pharmacology
Heparin Contraindications:
 Heparin hypersensitivity
 Hematologic disease:
 hemophilia, thrombocytopenia, purpura
 Cardiovascular:
 severe hypertension, intracranial
hemorrhage, infective endocarditis
 Active tuberculosis
15

16. Anticoagulant Drugs:
Pharmacology
Heparin Contraindications:
 Gastrointestinal tract
 ulcerative lesions
 visceral carcinoma
 Advanced hepatic/renal dysfunction
 Threatened abortion
 Related to medical procedures:
 after brain, spinal cord, or eye surgery
 lumbar puncture/regional anesthesia blocks
16

17. Anticoagulant Drugs:
Pharmacology
Reversal of Heparin Effects:
 drug discontinuation
 Use specific antagonist, e.g.
protamine sulfate (note!- excess
protamine also has an anticoagulant
effect)
17

18. Anticoagulant Drugs:
Pharmacology
Warfarin & Coumarin
 Chemistry/Pharmacokinetics: Warfarin &
Coumarin
 Coumarin: produces plasma prothrombin
deficiency
 active agent --: bishydroxycoumarin (synthesis -
- dicumarol)
 Uses:
 rodenticide
 humans: antithrombotic agent
18

19. Anticoagulant Drugs:
Pharmacology
 Oral anticoagulants:
 Warfarin -- agent in use
 high bioavailability; most bound to
plasma albumin (99%)
 racemate-- equal amounts of two
enantiomorphs
 levorotatory-S-warfarin: four times
more potent than dextrorotatory- R-
warfarin
19

20. Anticoagulant Drugs:
Pharmacology
Mechanism of Action: Coumarin
anticoagulants
 Blockade of g-carboxylation of glutamate
residues in:
 prothrombin
 factors: VII, IX, X
 endogenous anticoagulant protein C
 g-carboxylation results in biologically inactive
molecules
 Carboxylation reaction is coupled with
oxidative deactivation of vitamin K
20

21. Anticoagulant Drugs:
Pharmacology
Mechanism of Action: Coumarin
anticoagulants
 Anticoagulant effect dependent on two
considerations
1. Partially inhibited synthesis of the four vitamin
K-dependent clotting factors and
2. Altered degradation rates of these factors
Higher initial doses (loading doses) speed
onset by maximally inhibiting synthesis
21

22. Anticoagulant Drugs:
Pharmacology
Toxicity: coumarin anticoagulants
 Warfarin: crosses the placenta
hemorrhagic fetal disorder
 Fetal abnormal bone formation
(Warfarin effects on fetal proteins with
g-carboxylglutamate residues)
 Never administer Warfarin during
pregnancy
22

23. Anticoagulant Drugs:
Pharmacology
Other Adverse Effects: coumarin
anticoagulants
 Cutaneous necrosis related to reduced
protein C activity
 Rare: reduced protein C activity breast,
fatty tissues, intestine, extremity infarction
23

24. Anticoagulant Drugs:
Pharmacology
Drug-Drug Interactions: oral anticoagulants
 Pharmacokinetic effects include:
 enzyme induction
 reduced plasma protein binding
 Pharmacodynamic effects include:
 synergistic interactions with Warfarin
 impaired hemostasis, diminish clotting factor
synthesis (e.g. hepatic disease)
 competitive antagonism (vitamin K)
 abnormal physiologic vitamin K control loop
(hereditary oral anticoagulant resistance)
24

25. Drug-Drug Interactions
 See:American Family Physician Vol. 61/No. 6 (March 15,
2000)
 Clinical Pharmacology
Clinically Significant Drug Interactions
PAUL W. AMENT, PHARM.D., JOHN G. BERTOLINO, M.D., M.S.P.H., and JAMES
L. LISZEWSKI, M.D.
Family physicians should be alert for drug interactions and
should have appropriate resources to help them avoid or
manage these interactions. Drug interactions may be
encountered with such commonly used medications as
antibiotics, warfarin, antidepressants and oral
contraceptives…
25

26. Anticoagulant Drugs:
Pharmacology
Drug-Drug Interactions: oral anticoagulants
Most serious interaction:-- interactions that
increase anti-coagulation (promote bleeding risk)
 most dangerous: pharmacokinetic interactions
with:
 pyrazolones phenylbutazone & sulfinpyrazone-- effects: a
 added hypoprothrombinemia
 platelet function inhibition
 promotion: peptic ulcer disease
 Amiodarone, disulfram, cimetadine:
 inhibit metabolism of Warfarin (both enantiomorphs)
26

27. Anticoagulant Drugs:
Pharmacology
Drug-Drug Interactions: oral anticoagulants
 Aspirin, hepatic disease, hypothyroidism --
enhance Warfarin effects
pharmacodynamic:
 Aspirin:effects on platelets
 hepatic disease /hypothyroidism: increasing
clotting factors turnover rates
 Third-generation cephalosporins -
 kill intestinal bacteria that produce vitamin K
 directly inhibit vitamin K epoxide reductase
27

28. Anticoagulant Drugs:
Pharmacology
Drug-Drug Interactions: oral
anticoagulants
Decrease of anticoagulant action:
 Barbiturates & rifampin: anticoagulant
reduction by increasing liver enzymes
that transform racemic Warfarin.
 Cholestyramine: promotes intestinal
Warfarin binding
28

29. Anticoagulant Drugs:
Pharmacology
Pharmacodynamic -mediated reduction of
anticoagulant effects:
1. vitamin K -- {increased clotting factors synthesis}
2. diuretics -- chlorthalidone, spironolactone {affect
clotting factor concentration}
3. genetics -- {molecular mutations of vitamin K
reactivation cycle components}
4. hypothyroidism -- {reduced clotting factors
turnover rate}
29

30. Anticoagulant Drugs:
Pharmacology
Reversal of Warfarin anticoagulant effects:
 discontinue drug administration
 administer vitamin K1 (phytonadione) &
fresh-frozen plasma or factor IX concentrates
 Objective of intervention: establishing normal
clotting factor activity
 serious bleeding: large amounts of vitamin K1
(intravenous administration), factor IX concentrates,
and possibly whole blood transfusion
30

31. Fibrolytic Drugs
Pharmacology
Overview: fibrolytic drugs
 Lyse thrombi by catalyzing plasmin
(serine protease) formation from
plasminogen (the zymogen precursor)
 Lytic state induced following IV
administration
 Note: both target thromboemboli and
hemostatic thrombi are dissolved
31

32. Fibrinolysis
 Major process: conversion plasminogen (inactive)
plasmin (proteolytic enzyme, active)
 plasminogen activators: released from damaged cells
 Plasmin:
 limits thrombosis extension (by proteolytic fibrin digestion)
 Drug interventions: fibrinolytic system:
 Activators of fibrinolysis:
 tissue plasminogen activator (t-PA)
 urokinase (Abbokinase)
 streptokinase (Streptase, Kabikinase)
 Inhibitors of fibrinolysis:
 aminocaproic acid (Amicar)
32

33. Fibrinolysis
See: Graphical
representation of the
fibrinolytic pathway
Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.
From: http://en.wikipedia.org/wiki/Fibrinolysis
33

34. Fibrolytic Drugs
Pharmacology
 streptokinase,
 alteplase,
 tissue plasminogen activator,
 reteplase,
 urokinase
34

35. Fibrolytic Drugs
Pharmacology
Streptokinase (Streptase,
Kabikinase):(protein {not an enzyme}
derived from streptococci)
 combines with plasminogen (proactivator)
 Enzymic complex catalyzes: plasminogen
active plasmin
35

36. Fibrolytic Drugs
Pharmacology
Urokinase (Abbokinase):(human enzyme; renal)
 Catalyzes: plasminogen active plasmin
 Note: Plasmin cannot be directly used
because of endogenous inhibitors;
 endogenous antiplasmins do not affect urokinase or
streptokinase-proactivator complex
 Urokinase (and streptokinase-proactivator complex)
promote plasmin formation inside the thrombus
lyse thrombus from within
36

37. Fibrolytic Drugs
Pharmacology
Anistreplase (APSAC, Eminase) (anisoylated
plasminogen streptokinase activator complex; APSAC)
 purified human plasminogen - bacterial acylated
streptokinase complex {upon administration
deacylation activates streptokinase-proactivator
complex}
 rapid IV injection
 enhanced clot selectivity -- more plasminogen activity
clot-associated than associated with free blood
plasminogen
 more thrombolytic activity
37

38. Fibrolytic Drugs
Pharmacology
Tissue Plasminogen Activators (t-PA)
 Plasminogen activator
 preferential activation of fibrin-bound
plasminogen
 Human t-PA: recombinant DNA
technology
 Alteplase: unmodified human t-PA
 Reteplase: modified human t-PA
38

39. Fibrolytic Drugs
Pharmacology
Clinical Uses: Fibrolytic Drugs---
1. Multiple pulmonary emboli (not
requiring surgery)
2. Central deep venous thrombosis
 superior vena caval syndrome
 ascending thrombophlebitis (iliofemoral vein)
3. Intra-arterial use -- peripheral vascular
disease
4. Acute Myocardial Infarction:
 careful patient selection (early intervention)
39

40. Antithrombotic / Antiplatelet
Drugs Pharmacology
Antithrombotic -- Antiplatelet Drugs
 Overview: antithrombotic agents
 Regulation of platelet function –
 Three types of substances:…
40

41. Antithrombotic / Antiplatelet
Drugs Pharmacology
1. Substances developed outside the
platelet but interacts with platelet
membrane receptors:
 catecholamines
 collagen
 thrombin
 prostacyclin
41

42. Antithrombotic / Antiplatelet
Drugs Pharmacology
2. Agents generated internal to the
platelet and interact with membrane
receptors:
 ADP
 prostaglandin D2
 prostaglandin E2
 serotonin
42

43. Antithrombotic / Antiplatelet
Drugs Pharmacology
3. Agents generated internal to the
platelet and interact within the
platelet:
 prostaglandin endoperoxidases
 thromboxane A2
 cAMP
 cGMP
 Ca2+
43

44. Antithrombotic / Antiplatelet
Drugs Pharmacology
Pharmacological Targets: antithrombotic
agents
 Inhibition of prostaglandin metabolism:
aspirin
 inhibition of ADP-induced platelet
aggregation: ticlopidine
 blockade of GP IIb/IIIa platelet membrane
glycoprotein receptors: abciximab(ReoPro)&
integrelin
44

45. Antithrombotic / Antiplatelet
Drugs Pharmacology
Aspirin:
 Mechanism of Action: aspirin
 Prostaglandin thromboxane A2 (arachidonate
product) causes:
 platelet aggregation
 platelet shape changing
 platelet degranulation
 inhibition of this process inhibits platelet
aggregation, prolonging in vivo bleeding time
45

46. Antithrombotic / Antiplatelet
Drugs Pharmacology
Mechanism of Action: aspirin
 Aspirin inhibits thromboxane A2 synthesis
by:
 irreversible acetylation of cyclooxygenase
 new cyclooxygenase cannot be synthesize
during the 10-day lifespan of the platelet
 Other cyclooxygenase inhibitors are reversible
and therefore have shorter duration of action,
e.g. other salicylates & other nonsteroidal anti-
inflammatory drugs
46

47. Antithrombotic / Antiplatelet
Drugs Pharmacology
aspirin
Clinical Use --antithrombotic effects
 Possible primary prophylaxis of myocardial
infarction
 FDA approval for this indication
Adverse Effects: aspirin
 increased gastrointestinal bleeding
 increased frequency of peptic ulcer disease
47

48. Antithrombotic / Antiplatelet
Drugs Pharmacology
Ticlopidine:
 Inhibits ADP platelet pathway: reduces platelet
aggregation
 no effect on prostaglandin metabolism
Clinical Use-Ticlopidine:
 Efficacy in prevention:
 completed strokes
 unstable angina
 transient ischemic attacks
48

49. Antithrombotic / Antiplatelet
Drugs Pharmacology
Adverse Effect: ticlopidine
 gastrointestinal disturbance: frequency
= 20%
 hemorrhage: frequency = 5%
 leukopenia (serious): frequency: =
1%
 requires blood testing during first three
months of ticlopidine treatment
49

50. Blood Animations and Tutorials
 Red Blood Cells Wisconsin  Atlas of Hematology by
Online Nivaldo Medeiros M. D.
 White Blood Cells Wisconsin  Blood Typing Game
Online Nobel e-Museum
 Rh Factor and ABO Compatibility  Hemophilia Your Genes
Baltimore Community College Your Health
 Genetic Immune Deficiency
called SCID-X1 Sumanas Inc.  Hemostasis McGraw Hill
 Hemostasis and Platelet Info  Blood Type Wayne's
platelet-research.org Word
 Interpreting Hematology Lab  Blood Tutorials
Results Wisconsin Online GetBodySmart
 Clotting of Blood Cold Spring  Blood Groups Wisconsin
Harbor Laboratory Online
50