This document provides an overview of anticoagulants, antiplatelets, and thrombolytics. It discusses the coagulation cascade and platelet activation that leads to thrombus formation. It then summarizes various anticoagulant drugs including indirect inhibitors like heparin and fondaparinux, direct factor Xa inhibitors like rivaroxaban and apixaban, and direct thrombin inhibitors like hirudin, argatroban, and the oral drug dabigatran. It highlights their mechanisms of action, pharmacokinetics, uses, and adverse effects including bleeding risks. Reversal agents like protamine and idarucizumab are also mentioned.

1. Pharmacology of anticoagulants,
antiplatelets and thrombolytics
Mensur.shafie@sphmmc.edu.et
May 2023
1

2. Contents
• Introduction
• Anticoagulants
• Antiplatelets
• Thrombolytics
• Drugs for treatment of bleeding
2

3. Introduction
• Arrest of blood loss from damaged vessels is essential to life
• The main phenomena involved are:
– Platelet adhesion and activation
– blood coagulation (fibrin formation)
• The vascular endothelial cell layer lining blood vessels has an
anticoagulant phenotype
– Circulating platelets and clotting factors do not normally
adhere to it to an appreciable extent
3

4. Introduction…cont
• In absence of injury, resting platelets circulate freely, because the
balance of chemical signals indicates that the vascular system is
not damaged
– Chemicals such as prostacyclin and nitric oxide are
synthesized by intact endothelial cells and act as inhibitors of
platelet aggregation
• Damaged endothelial cells synthesize less prostacyclin than
healthy cells, resulting in lower prostacyclin levels
• The platelet membrane also contains receptors that can bind
thrombin, thromboxane, and exposed collagen
– In normal vessels circulating levels of thrombin and
thromboxane are low, and intact endothelium covers collagen
4

5. Introduction…cont
• When the endothelium is injured, platelets adhere to and
virtually cover the exposed collagen of the subendothelium and
triggers series of chemical reactions, resulting in platelet
activation
• Receptors on the surface of the adhering platelets are activated
by the collagen and von Willebrand factor ((vWF) of the
connective tissue and causes morphologic changes in platelets
and release of platelet granules containing chemical mediators,
such as ADP, thromboxane A2, serotonin, platelet activation
factor, and thrombin
• The released signaling molecules bind to receptors in resting
platelets and as a result the previously dormant platelets
become activated and start to aggregate
• These actions are mediated by several messenger systems that
ultimately result in elevated levels of calcium and a decreased
5

6. Introduction…cont
• The increase in Ca leads to;
– The release of platelet granules containing mediators, such as
ADP and serotonin that activate other platelets
– Activation of thromboxane A2 synthesis
– Activation of glycoprotein (GP) IIb/IIIa receptors that bind
fibrinogen and, ultimately, regulate platelet–platelet interaction
and thrombus formation
• Fibrinogen simultaneously binds to GP IIb/IIIa receptors on two
separate platelets, resulting in platelet cross-linking and platelet
aggregation and leads to an avalanche of platelet aggregation,
because each activated platelet can recruit other platelets 6

7. 7

8. Fig. Thrombus formation at the site of the damaged vascular wall
(EC, endothelial cell) and the role of platelets and clotting
factors
• Platelet membrane receptors include the glycoprotein (GP)Ia
receptor, binding to collagen (C); GPIb receptor,binding vWF; and
GP IIb/IIIa, which binds fibrinogen and other macromolecules
• Antiplatelet prostacyclin (PGI2) is released from the endothelium
• Aggregating substances released from the degranulating platelet
include adenosine diphosphate (ADP), thromboxane A2 (TXA2),
and serotonin (5-HT)
8

9. The Coagulation Cascade
• Blood coagulates by the transformation of soluble fibrinogen into
insoluble fibrin
– Several circulating proteins (clotting factors) interact in a
cascading series to cause this
– At each step, a clotting factor zymogen is activated by
proteases (proteolysis)
• Each protease factor then activates the next clotting factor,
culminating in the formation of thrombin (factor IIa)
9

10. Table: Blood clotting factors and drugs that affect them
10

11. The Coagulation Cascade…cont
11

12. Natural anticoagulants
• Blood coagulation in intact blood vessel is normally prevented by
several regulatory mechanisms that require an intact normal
vascular endothelium
– Prostacyclin (PGI2), synthesized by endothelial cells, inhibits
platelet aggregation and secretion
– Antithrombin is a member of the serine protease inhibitor
(serpin) family that inhibits coagulation factors of the
coagulation pathways
• It inactivates factor IIa, IXa, Xa, XIIa
12

13. Natural anticoagulants…cont
• Heparan sulfate proteoglycans: synthesized by endothelium
and stimulate the activity of antithrombin
• Protein C: in combination with protein S, degrades cofactors
Va and VIIIa and thereby diminishes rates of activation of
prothrombin and factor X
• Tissue factor pathway inhibitor (TFPI): inhibits factor Xa
and the factor VIIa-tissue factor complex
Note: Defects in natural anticoagulants result in an
increased risk of venous thrombosis
13

14. Anticoagulant Drugs
• Could be classified into:
– Indirect clotting factor inhibitors
– Direct factor Xa Inhibitors
– Direct thrombin inhibitors
• Oral
• Parentral
– Oral anticoagulants (Warfarin & Other Coumarin
Anticoagulants) 14

15. Indirect clotting factor inhibitors
• Bind to antithrombin and enhance its inactivation of thrombin
(IIa), IXa, and Xa
• Include;
– Unfractionated heparin (UFH),
– Low-molecular-weight heparins (LMWH)&
– Fondaparinux
15

16. Heparin
• Is a heterogeneous mixture of sulfated mucopolysaccharides found
in the secretory granules of mast cells
• Mechanism of Action
– Active site of heparin that binds antithrombin is composed of
D-glucosamine-L-iduronic acid and D-glucosamine-D-
glucuronic acid
– Thrombin, Xa, and IXa attack a specific Arg-Ser peptide bond
in the reactive site of antithrombin and becomes trapped as a
stable 1:1 complex
16

17. Heparin… MOA cont
• Heparin increases the rate of the thrombin-antithrombin reaction
at least a thousandfold by serving as a catalytic template to
which both the inhibitor and the protease bind
• Heparin binding also induces a conformational change in
antithrombin that makes the reactive site more accessible to
the proteases
• Once thrombin has become bound to antithrombin, the heparin
molecule is released from the complex
17

18. 18

19. Heparin…Pharmacokinetics
• Heparin is generally used as the sodium salt
– Calcium heparin is equally effective
– Lithium heparin is used as in vitro anticoagulant for blood
samples
• Commercial heparin is extracted from porcine intestinal mucosa
and bovine lung
• Not absorbed through the gastrointestinal mucosa ( given IV, SC)
• Acts immediately following IV administration, but onset is
delayed for up to 60 minutes to 2 hrs when given SC
19

20. Heparin…Pharmacokinetics cont
• Cleared and degraded primarily by the reticuloendothelial system
• Close monitoring of the activated partial thromboplastin time
(aPTT) is necessary in patients receiving UFH
• SC administration can be used for the long-term management of
patients in whom warfarin is contraindicated (e.g pregnancy)
• Because of the danger of hematoma formation at the injection site,
heparin must never be administered IM
20

21. Heparin…ADR
• Bleeding (1-5% in IV heparin for venous thromboembolism)
– Decreased by scrupulous pt selection, careful control of dosage,
and close monitoring
– Elderly women and pts with renal failure are more prone to
hemorrhage
– Mild bleeding can be controlled without using antagonist
– Protamine sulfate is used routinely to reverse life threatening
hemorrhage
21

22. Heparin…ADR cont
• Protamine sulfate;
– Strongly basic protein that forms an inactive complex with
heparin
– Minimal amount needed to neutralize heparin should be used
(Otherwise, protamine by itself is anticoagulant)
• 1 mg of protamine for every 100 units of heparin left in the
patient
• Is given IV at slow rate (up to 50 mg over 10 minutes)
22

23. Heparin…ADR cont
• Heparin-induced thrombocytopenia (1-4%)
– Platelet count < 150,000/ml or a 50% decrease from
pretreatment value
– Surgical patients are at risk
– The risk of HIT may be higher in individuals treated with UFH
of bovine origin compared with porcine heparin and is lower in
those treated exclusively with LMWH
– Morbidity and mortality are due to thrombosis
– Patients who develop HIT are treated by discontinuance of
heparin and administration of a direct thrombin inhibitor 23

24. Heparin…ADR cont
• Hypersensitivity reactions (rare)
• Increased loss of hair and reversible alopecia have been reported
• Abnormal hepatic function test
• Osteoporosis
• Long-term use is associated with mineralocorticoid deficiency
(hyperkalemia)
24

25. Heparin…Contraindications
• Hypersensitivity
• Bleeding disorders like hemophilia
• Alcoholics
• HIT, significant thrombocytopenia
• Patients having or have had recent surgery of the brain, eye, or
spinal cord
• Purpura, severe hypertension , intracranial hemorrhage, active
lesions of GIT, threatened abortion, visceral carcinoma, advanced
renal or hepatic disease and others
25

26. Low-Molecular-Weight Heparin Preparations
• Include: enoxaparin, dalteparin, tinzaparin, ardeparin,
nadroparin and reviparin
• Have equal efficacy as UFH and mediate inhibition of factor Xa
• Have more predictable pharmacokinetic properties, permit
administration in a fixed or weight-adjusted dosage regimen once
or twice daily by SC injection, and monitoring is not done
routinely except in setting of renal insufficiency, obesity, and
pregnancy
• LMW heparins—in comparison with UFH—have equal efficacy,
increased bioavailability from the SC site of injection, and less 26

27. Table: Some properties of heparin and LMWHs
27

28. Fondaparinux
• Synthetic pentasaccharide that selectively mediates inhibition of
factor Xa by antithrombin but does not cause thrombin inhibition
• Has a long half-life of 15 hrs, allowing for once-daily dosing by
SC route
• Doesn’t require monitoring
• Effective in prevention and treatment of venous thromboembolism
• Appears to not cross-react with pathologic HIT antibodies in most
individuals
• Major side effect is bleeding episodes and there is no suitable
antidote 28

29. Oral Direct Factor Xa Inhibitors
• A major focus of drug development has been to develop orally
active anticoagulants that do not require monitoring
• Include: rivaroxaban, apixaban, edoxaban
• They have a rapid onset of action and shorter half-lives than
warfarin
29

30. Rivaroxaban
• Is the first oral factor Xa inhibitor approved for prevention of
venous thromboembolism following hip or knee surgery
• Its safety and efficacy appears to be at least equivalent, and
possibly superior, to LMW heparins
• Has high oral bioavailability when taken with food
• Is extensively protein-bound
• One third of the drug is excreted unchanged in the urine and the
remainder is metabolized and excreted in the urine and feces
• The drug half-life is 5–9 hrs in pts age 20–45 years and is
increased in the elderly and in those with impaired renal or hepatic
30

31. Apixaban
• One study indicated better efficacy and similar toxicity of apixaban
with enoxaparin
• Another trial comparing apixaban to aspirin for stroke prevention
in atrial fibrillation was stopped early because of evidence of
increased efficacy in the apixaban arm
• Has an oral bioavailability of 50% and prolonged absorption,
resulting in a half-life of 12 hrs
• Is excreted in the urine and feces
31

32. Edoxaban
• Is a once daily Xa inhibitor
• Has an oral bioavailability of 62%
• Absorption not affected by food
• Has a half-life of 10–14 hrs
• Primarily excreted unchanged in the urine
32

33. Oral Direct Factor Xa Inhibitors…cont
• Use of a hepatically metabolized drug such as warfarin may be
a better alternative in pts having renal failure
• Andexanet alfa is likely to be the first antidote approved for
use in pts treated with anti-Xa agents who require rapid reversal
for surgery or uncontrolled bleeding
– Competes for binding to anti-Xa drugs
33

34. Direct Thrombin Inhibitors
• They exert anticoagulant effect by directly binding to the active
site of thrombin thereby inhibiting thrombin’s downstream effects
• Can be;
– Parentrals (Hirudin, lepirudin, bivalirudin, Argatroban) or
– Oral DTIs (Dabigatran)
34

35. Hirudin
• Is an irreversible thrombin inhibitor from leech saliva
• Now available in recombinant form as lepirudin
• Its action is independent of antithrombin, which means it can reach
and inactivate fibrin-bound thrombin in thrombi
35

36. Lepirudin
• Can reach and inactivate fibrin-bound thrombin in thrombi
• Approved for treatment of pts with heparin-induced
thrombocytopenia
• Administered IV and needs monitoring by the aPTT
• Excreted by the kidneys and has a half-life of about 1.3 hrs
– Should be used cautiously in pts with renal failure
• Up to 40% of patients who receive long-term infusions develop an
antibody directed against the thrombin-lepirudin complex
– These complexes are not cleared by the kidney and may result
in an enhanced anticoagulant effect 36

37. Bivalirudin
• Is administered IV
• Has rapid onset and offset of action
• It has a short half-life with clearance that is 20% renal and the
remainder metabolic
• It also inhibits platelet activation
• FDA-approved for use in percutaneous coronary angioplasty
37

38. Argatroban
• Approved in patients with HIT with or without thrombosis and
coronary angioplasty in patients with HIT
• Given by continuous IV infusion due to short half-life
• Monitored by aPTT
• Not affected by renal disease but dependent on liver function
(dose adjustment needed in liver disease)
• Patients on argatroban will demonstrate elevated INRs, rendering
the transition to warfarin difficult
38

39. Oral DTIs
• Advantages of oral direct thrombin inhibitors include
 Predictable pharmacokinetics and bioavailability
– Allow for fixed dosing and predictable anticoagulant response,
– Make routine coagulation monitoring unnecessary
 These agents do not interact with P450-interacting drugs, and
 Their rapid onset and offset of action allow for immediate
anticoagulation
– Thus avoiding the need for overlap with additional
anticoagulant drug
39

40. Dabigatran etexilate mesylate
• Is the first oral direct thrombin inhibitor approved by the FDA
• Its metabolites are also direct thrombin inhibitors
• Was approved to reduce risk of stroke and systemic embolism
with nonvalvular atrial fibrillation, for prevention of venous
thromboembolism in patients who have undergone hip or knee
replacement surgery
• One study indicated dabigatran was shown to be superior to
warfarin in preventing stroke and systemic embolization
40

41. Dabigatran …cont
• Concomitant use with ketoconazole, amiodarone, quinidine, and
clopidogrel increases the effect of dabigatran
• Renal impairment results in prolonged drug clearance and may
require dose adjustment
– Should be avoided in patients with severe renal impairment
41

42. Dabigatran…ADR
• The primary toxicity is bleeding
– There was an increase in GI adverse reactions and GI bleeding
compared to warfarin
– There was also increased bleeding with dabigatran in patients
older than 75 years
• Idarucizumab is a humanized monoclonal antibody Fab
fragment that binds to dabigatran and reverses its anticoagulant
effect
– Is approved for use in situations requiring emergent surgery
or for life-threatening bleeding 42

43. • Note
– Oral direct thrombin inhibitors and oral direct Xa
inhibitors offer significant advantages over
warfarin, which has a narrow therapeutic window,
is affected by diet and many drugs, and requires
monitoring for dosage adjustment
43

44. Oral Anticoagulants (Warfarin & Other
Coumarin Anticoagulants)
Warfarin
• Discovery: spoiled sweet clover silage caused hemorrhagic disease
in cattle (Campbell and Link, 1939)
• A chemist at the University of Wisconsin identified the toxic agent
as bishydroxycoumarin
• A congener dicumarol was synthesized (warfarin) (Wisconsin
Alumni Research Foundation, with "arin" from coumarin added)
• Initially used as rodenticides but was introduced as an
antithrombotic agent in humans 44

45. Oral Anticoagulants…cont
• The only difference
among different drugs
in this group in
producing and
maintaining
hypoprothrombinemia
is the half-life of each
drug 45

46. Oral Anticoagulants…MOA
• Coumarins block the γ-carboxylation of several
glutamate residues in prothrombin and factors VII, IX,
and X as well as the endogenous anticoagulant proteins
C and S
• The carboxylation reaction is coupled to the oxidation of
vitamin K (the vitamin must then be reduced to
reactivate it)
• Warfarin prevents reductive metabolism of the inactive
vitamin K epoxide back to its active hydroquinone form
46

47. Oral Anticoagulants…MOA
47

48. Warfarin…Pharmacokinetics
• Warfarin is given orally and is absorbed quickly and totally from
the GIT
– Generally administered as Na and has 100% bioavailability
• It is strongly bound to plasma albumin (99%)→ contribute to its
small volume of distribution, its long half-life in plasma (36 hrs),
and lack of urinary excretion of unchanged drug
• The peak Cp occurs within an hr of ingestion but
pharmacological effect occurs about 8-12 hours later (peak at
48h)
• Warfarin crosses the placenta and is not given in the first months
48

49. Warfarin…PKs cont
• It appears in milk during lactation
– Infants are routinely prescribed vitamin K to prevent
hemorrhagic disease
• Metabolism
– S-warfarin is transformed by CYP2C9 and R-warfarin is
transformed by CYP1A2 (major pathway), CYP2C19 and
CYP3A4 (minor pathways)
49

50. Warfarin…Clinical Uses
• Used to prevent the progression or recurrence of
acute DVT or PE in patients undergoing surgery
• In preventing systemic embolization in patients with
acute MI, prosthetic heart valves, or chronic atrial
fibrillation
• The therapeutic range for oral anticoagulant therapy
is defined in terms of an international normalized
ratio (INR)
50

51. Warfarin…Clinical Uses cont
• For most indications the target INR is 2 to 3
– Fasting sample is usually obtained 8 to 14 hrs after the last dose,
and the patient's PT is determined along with that of a sample of
normal pooled plasma
pt = patient
ref= reference
Too low INR means there might be clotting
Too high INR means there might be bleeding
51

52. Warfarin…ADR
• Haemorrhage (especially into the bowel or the brain)
• Teratogenicty: birth defects and abortion
• Hepatotoxicity (rare)
• Skin necrosis with reduced activity of protein C and appearance of
skin lesions 3 to 10 days after treatment is initiated
– Rarely, the same process causes frank infarction of the breast,
fatty tissues, intestine, and extremities
52

53. Warfarin…ADR cont
• Purple toe syndrome, alopecia, urticaria, dermatitis, fever, nausea,
diarrhea, abdominal cramps, and anorexia are the other ADRs
• Excessive anticoagulant effect and bleeding from warfarin can be
reversed;
– By stopping the drug
– By administering oral or parenteral vitamin K1 (phytonadione),
– By using fresh-frozen plasma,
– Using prothrombin complex concentrates such as Bebulin and
Proplex T, and recombinant factor VIIa (rFVIIa)
53

54. Warfarin…Drug Interactions
• The oral anticoagulants often interact with other drugs and with
diseases
• These interactions can be broadly divided into pharmacokinetic
and pharmacodynamic effects
– PK mechanisms for drug interaction with oral anticoagulants
are mainly enzyme induction, enzyme inhibition, and
reduced plasma protein binding
– PD mechanisms for interactions with warfarin are synergism
(impaired hemostasis, reduced clotting factor synthesis, as in
hepatic disease), competitive antagonism (vitamin K), and an
54

55. Table: PK and pharmacodynamic drug and body
interactions with oral anticoagulants
55

56. Other oral anticoagulants
• Phenprocoumon
• Acenocoumarol
• Inandione derivatives (anisinodione, phenindione)
• Ximelagatran (metabolized to melagatran)
• Rodenticides (diphenadione, pindone etc)
56

57. Platelet Aggregation
Inhibitors
57

58. Introduction
• Platelet aggregation inhibitors decrease formation of a platelet-rich
clot or decrease action of chemical signals that promote platelet
aggregation
• The platelet aggregation inhibitors may act;
– By inhibiting cyclooxygenase-1 (COX-1)
– By blocking GP IIb/IIIa receptors
– By blocking ADP receptors
– By inhibiting phosphodiesterase enzyme
• Because these agents have different MOA, synergistic or additive
effects may be achieved when agents from different classes are 58

59. Introduction …cont
• Drugs include
– Aspirin
– ADP receptor antagonists
– GP IIb/IIIa blockers
– Phosphodiesterase inhibitors
59

60. Aspirin
Mechanism of action
• Stimulation of platelets by thrombin, collagen, and ADP results in
activation of platelet membrane phospholipases that liberate
arachidonic acid from membrane phospholipids
• Arachidonic acid is first converted to prostaglandin H2 by COX-1
• Prostaglandin H2 is further metabolized to thromboxane A2, which
is released into plasma and promotes the platelet aggregation
process that is essential for the rapid formation of a hemostatic
plug
60

61. Aspirin MOA…cont
• Aspirin inhibits thromboxane A2 synthesis by acetylation of a
serine residue on active site of COX-1, thereby irreversibly
inactivating the enzyme and shifts balance of chemical mediators
to favor the antiaggregatory effects of prostacyclin and prevents
platelet aggregation
• The inhibitory effect is rapid, and aspirin-induced suppression of
thromboxane A2 and the resulting suppression of platelet
aggregation last for the life of the platelet, which is approximately
7 to 10 days
• Repeated administration has a cumulative effect on the function of
61

62. Aspirin MOA…cont
62
Fig. Aspirin irreversibly inhibits platelet cyclooxygenase-1 and Acetylation of COX-
1 by aspirin.

63. Aspirin…cont
Pharmacokinetics
• When given orally, aspirin is absorbed by passive diffusion and
quickly hydrolyzed to salicylic acid in the liver
• Salicylic acid is further metabolized in the liver, and some is
excreted unchanged in the urine
• The half-life of aspirin ranges from 15 to 20 minutes and for
salicylic acid is 3 to 12 hours
• Complete inactivation of platelets occurs with 75 mg given daily
• The recommended dose of aspirin ranges from 50 to 325 mg daily
63

64. Aspirin…cont
Therapeutic use
• Aspirin is used;
– In the prophylactic treatment of transient cerebral ischemia,
– To reduce the incidence of recurrent MI, and
– To decrease mortality in the setting of primary and secondary
prevention of MI
64

65. Aspirin…cont
Adverse effects
• Higher doses of aspirin increase drug-related toxicities as well as
the probability that aspirin may also inhibit prostacyclin
production
• Bleeding time is prolonged by aspirin treatment, causing
complications that include an increased incidence of hemorrhagic
stroke and GI bleeding, especially at higher doses
65

66. Aspirin…cont
• NSAIDs like ibuprofen, inhibit COX-1 by transiently competing at
catalytic site and if taken within 2 hrs prior to aspirin, can obstruct
access of aspirin to serine residue and antagonize platelet
inhibition by aspirin
– Therefore, immediate release aspirin should be taken at least
1hr before or at least 8 hours after ibuprofen
• Drugs like celecoxib (a selective COX-2 inhibitor) does not
interfere with the antiaggregation activity of aspirin but there is
some evidence indicating celecoxib may contribute to
cardiovascular events by shifting the balance of chemical
66

67. ADP Receptor antagonists
• Drugs include: Ticlopidine, clopidogrel, prasugrel, ticagrelor
Mechanism of action:
• These drugs inhibit binding of ADP to its receptors on platelets
and, thereby, inhibit the activation of the GP IIb/IIIa receptors
required for platelets to bind to fibrinogen and to each other
• Ticagrelor binds to the ADP receptor in a reversible manner but the
other agents bind irreversibly
67

68. ADP Receptor antagonists …MOA
68
Fig. MOA of ticlopidine, clopidogrel prasugrel, and ticagrelor
GP = glycoprotein.

69. ADP Receptor antagonists …cont
Pharmacokinetics
• These agents require loading doses for quicker antiplatelet effect
• Food interferes with absorption of ticlopidine but not with others
• After oral ingestion, the drugs are extensively bound to plasma
proteins
• Hepatic metabolism by CYP 450 system produces active
metabolites
• Elimination of drugs and metabolites occurs by both renal and
fecal routes
• Maximum inhibition of platelet aggregation is achieved in 1-3 hrs
69

70. ADP Receptor antagonists …PKs cont
• Clopidogrel is prodrug and its therapeutic efficacy relies entirely
on its active metabolite produced by CYP 2C19 metabolism
– Genetic polymorphism of CYP 2C19 leads to a reduced clinical
response in patients who are “poor metabolizers”
– Tests are done to identify poor metabolizers but it is
recommended that other antiplatelet agents (prasugrel or
ticagrelor) be prescribed for these patients
• In addition, other drugs that inhibit CYP 2C19, such as
omeprazole should not be administered concurrently with
clopidogrel
70

71. ADP Receptor antagonists …cont
Therapeutic use
• Clopidogrel is approved for prevention of atherosclerotic events in
patients with a recent MI or stroke and in those with established
peripheral arterial disease
• Clopidogrel is also approved for prophylaxis of thrombotic events
in acute coronary syndromes (unstable angina or non–ST-elevation
MI)
• Clopidogrel is used to prevent thrombotic events associated with
percutaneous coronary intervention (PCI) with or without coronary
stenting
71

72. ADP Receptor antagonists …therapeutic uses cont
• Ticlopidine is indicated for prevention of transient ischemic attacks
(TIA) and strokes in patients with a prior cerebral thrombotic event
– Generally reserved for patients who are intolerant to other
therapies due to life-threatening hematologic adverse
reactions
• Prasugrel is approved to decrease thrombotic CV events in patients
with acute coronary syndromes (unstable angina, non–ST-elevation
MI, and ST-elevation MI managed with PCI)
• Ticagrelor is approved for the prevention of arterial thrombo-
embolism in patients with unstable angina and acute MI, including
those undergoing PCI
72

73. ADP Receptor antagonists …cont
Adverse effects
• These agents can cause prolonged bleeding for which there is no
antidote
• Ticlopidine is associated with severe hematologic reactions that
limit its use, such as agranulocytosis, thrombotic thrombocytopenic
purpura (TTP), and aplastic anemia
• Clopidogrel causes fewer ADRs and incidence of neutropenia is
lower
• TTP is reported both for clopidogrel and prasugrel (but not for
ticagrelor)
73

74. GP IIb/IIIa blockers
• Drugs include: Abciximab, eptifibatide, tirofiban
Mechanism of action
• Abciximab is monoclonal antibody that inhibits GP IIb/IIIa
receptor complex
• Abciximab blocks binding of fibrinogen and von Willebrand factor
by binding to GP IIb/IIIa and platelet aggregation does not occur
• Eptifibatide and tirofiban act similarly to abciximab
• Tirofiban is not a peptide, but it blocks the same site as eptifibatide
74

75. 75
Fig. Mechanism of action of glycoprotein (GP) IIb/IIIa receptor blockers

76. GP IIb/IIIa blockers…cont
Pharmacokinetics
• Abciximab is given by IV bolus, followed by IV infusion,
achieving peak platelet inhibition within 30 minutes
• After cessation of abciximab infusion, platelet function gradually
returns to normal, with the antiplatelet effect persisting for 24 to 48
hours
• When IV infusion of eptifibatide or tirofiban is stopped, both
agents are rapidly cleared from the plasma
• Eptifibatide and its metabolites are excreted by the kidney
• Tirofiban is excreted largely unchanged by the kidney and in the
76

77. GP IIb/IIIa blockers…cont
Therapeutic use
• These agents are given IV, along with heparin and aspirin, as an
adjunct to PCI for the prevention of cardiac ischemic
complications
• Abciximab is also approved for patients with unstable angina not
responding to conventional medical therapy when PCI is planned
within 24 hours
Adverse effects
• The major ADR of these agents is bleeding, especially if used with
anticoagulants
77

78. Phosphodiesterase inhibitors
• Drugs include: Dipyridamole, Cilostazol
Dipyridamole
• Is a coronary vasodilator that increases intracellular levels of
cAMP by inhibiting cyclic nucleotide phosphodiesterase, thereby
resulting in decreased thromboxane A2 synthesis
• It may potentiate the effect of prostacyclin to antagonize platelet
stickiness and, therefore, decrease platelet adhesion to
thrombogenic surfaces
• Has variable bioavailability following oral administration
• It is highly protein bound and undergoes hepatic metabolism, as 78

79. Dipyridamole…cont
• Is used for stroke prevention
• Usually given in combination with aspirin
• Commonly causes headache and can lead to orthostatic
hypotension (especially if administered IV)
• Shouldn’t be used in patients with unstable angina because of
its vasodilating properties, which may worsen ischemia
79

80. Cilostazol
• Is an oral antiplatelet agent that also has vasodilating activity
• Cilostazol and its active metabolites inhibit phosphodiesterase,
which prevents the degradation of cAMP, thereby increasing levels
of cAMP in platelets and vascular tissues
• The increase in cAMP levels in platelets and vasculature prevents
platelet aggregation and promotes vasodilation of blood vessels,
respectively
• Is extensively metabolized in the liver by the CYP 3A4, 2C19, and
1A2 isoenzymes and has many drug interactions that require dose
modification
80

81. Cilostazol…cont
• Favorably alters lipid profile, causing a decrease in plasma
triglycerides and an increase in high-density lipoprotein cholesterol
– Is approved to reduce symptoms of intermittent claudication
• Headache and GI side effects (diarrhea, abnormal stools,
dyspepsia, and abdominal pain) are the most common ADRs
observed
• Phosphodiesterase type III inhibitors have been shown to increase
mortality in patients with advanced heart failure and as a result
cilostazol is contraindicated in patients with heart failure
81

82. Table: Summary of antiplatelet drugs
82

83. Table: Summary of antiplatelet drugs
83

84. Fibrinolysis and Thrombolysis
• During clot formation, the fibrinolytic pathway is locally activated
• Fibrinolysis refers to process of fibrin digestion by plasmin (fibrin-
specific protease)
• Plasmin itself circulates in an inactive form as plasminogen
– Plasminogen is converted to plasmin by tissue plasminogen
activator (t-PA) (synthesized in response to injury)
– t-PA is negatively regulated by plasminogen activator inhibitor
(PAI) and fibrinolysis is also inactivated by α2-antiplasmin
84

85. Fibrinolysis and Thrombolysis…cont
85

86. Thrombolytic agents
86

87. Introduction
• Acute thromboembolic disease in selected patients may be treated
by drugs that activate the conversion of plasminogen to plasmin ( a
serine protease that hydrolyzes fibrin and, thus, dissolves clots)
• Drugs include streptokinase, alteplase, urokinase, etc
– Streptokinase is one of the first of such agents to be approved
– Alteplase acts more locally on the thrombotic fibrin to produce
fibrinolysis
– Urokinase is produced naturally in human kidneys and directly
converts plasminogen into active plasmin
• Fibrinolytic drugs may lyse both normal and pathologic thrombi
87

88. Thrombolytic agents…cont
Mechanism of action
• These drugs share some common features
• All act either directly or indirectly to convert plasminogen to
plasmin that cleaves fibrin, thus lysing thrombi
• Clot dissolution and reperfusion occur with a higher frequency
when therapy is initiated early after clot formation because
clots become more resistant to lysis as they age
88

89. 89
Fig. Activation of plasminogen by thrombolytic
drugs.

90. Thrombolytic agents…cont
Therapeutic use
• Originally used for treatment of DVT and serious PE but these uses
are less frequent now a days
• Their tendency to cause bleeding has also blunted their use in
treating acute peripheral arterial thrombosis or MI
• For MI, intracoronary delivery of drugs is most reliable in terms of
achieving recanalization
– However, cardiac catheterization may not be possible in 2- to
6-hr “therapeutic window,” beyond which significant
myocardial salvage becomes less likely
• Thus, thrombolytic agents are usually administered IV
• Thrombolytic agents are helpful in restoring catheter and shunt
function, by lysing clots causing occlusions
• They are also used to dissolve clots that result in strokes
90

91. Thrombolytic agents…cont
Adverse effects
• The thrombolytic agents do not distinguish between the fibrin of an
unwanted thrombus and the fibrin of a beneficial hemostatic plug
– Thus, hemorrhage is a major side effect
– For example, a previously unsuspected lesion, such as a gastric
ulcer, may hemorrhage following injection of a thrombolytic
agent
• These drugs are contraindicated in pregnancy, and in patients with
healing wounds, a history of cerebrovascular accident, brain tumor,
head trauma, intracranial bleeding, and meta-static cancer 91

92. 92
Fig. Degradation of an unwanted thrombus and a beneficial
hemostatic plug by plasminogen activators

93. Alteplase, reteplase, tenecteplase
• Alteplase (formerly known as tissue plasminogen activator or t
PA) is a serine protease originally derived from cultured human
melanoma cells
• It is now obtained as a product of recombinant DNA technology
• Reteplase is genetically engineered, smaller derivative of
recombinant tPA
• Tenecteplase is another recombinant tPA with a longer half-life
and greater binding affinity for fibrin than alteplase
• Alteplase has a low affinity for free plasminogen in plasma, but
rapidly activates plasminogen bound to fibrin in a thrombus or a93

94. Alteplase, reteplase, and tenecteplase
• Alteplase is approved for MI, massive PE, and acute ischemic
stroke
• Reteplase and tenecteplase are approved only for use in acute MI,
although reteplase may be used off-label in DVT and massive PE
• Alteplase has a very short half-life (5 to 30 minutes), and therefore,
10% of the total dose is injected IV as a bolus and the remaining
drug is administered over 60 minutes
• Both reteplase and tenecteplase have longer half-lives and,
therefore, may be administered as an intravenous bolus
• Alteplase may cause orolingual angioedema, and there may be an
94

95. Streptokinase
• Is an extracellular protein purified from culture broths of group C
β-hemolytic streptococci
• It forms an active one-to-one complex with plasminogen
• This enzymatically active complex converts uncomplexed
plasminogen to the active enzyme plasmin
• In addition to the hydrolysis of fibrin plugs, the complex also
catalyzes the degradation of fibrinogen, as well as clotting factors
V and VII
• With the advent of newer agents, streptokinase is rarely used and is
no longer available in many markets 95

96. 96
Fig. MOA of streptokinase

97. Urokinase
• Is produced naturally in the body by the kidneys
• Therapeutic urokinase is isolated from cultures of human kidney
cells and has low antigenicity
• Urokinase directly cleaves the arginine–valine bond of
plasminogen to yield active plasmin
• It is only approved for lysis of pulmonary emboli
• Off-label uses include treatment of acute MI, arterial
thromboembolism, coronary artery thrombosis, and DVT
• Its use has largely been supplanted by other agents with a more
favorable benefit-to-risk ratio 97

98. 98
Fig. A comparison of thrombolytic enzymes

99. Contraindications to thrombolytic therapy
99

100. Drugs Used for Treatment of
Bleeding
100

101. Introduction
• Bleeding problems may have their origin in naturally occurring
pathologic conditions, such as hemophilia, or as a result of
fibrinolytic states that may arise after GI surgery or prostatectomy
• The use of anticoagulants may also give rise to hemorrhage
• Certain natural proteins and vitamin K, as well as synthetic
antagonists, are effective in controlling this bleeding
• Concentrated preparations of coagulation factors are available
from human donors but carry risk of transferring viral infections
• Blood transfusion is also an option for treating severe hemorrhage
• The following are examples of drugs used for treatment of
bleeding
101

102. Aminocaproic acid and tranexamic acid
• Fibrinolytic states can be controlled by the administration of
aminocaproic acid or tranexamic acid
• Both are synthetic and orally active,
• Both are excreted in the urine
• Are inhibitors of plasminogen activation
• Tranexamic acid is 10 times more potent than aminocaproic acid
• A potential side effect is intravascular thrombosis
102

103. Protamine sulfate
• Protamine sulfate antagonizes the anticoagulant effects of heparin
• Is derived from fish sperm or testes
• The positively charged protamine interacts with the negatively
charged heparin, forming a stable complex without anticoagulant
activity
• Adverse effects of drug administration include hypersensitivity as
well as dyspnea, flushing, bradycardia, and hypotension when
rapidly injected
103

104. Vitamin K
• Vitamin K1 (phytonadione) administration can stop bleeding
problems due to warfarin by increasing supply of active vitamin K1
• May be administered via oral, SC, or IV route ( IV should be
administered by slow IV infusion to minimize risk of
anaphylactoid reactions)
• For treatment of bleeding, the SC route is not preferred, as it is not
as effective as oral or IV administration
• The response to vitamin K1 is slow, requiring about 24 hours to
reduce INR
– Thus, if immediate hemostasis is required, fresh frozen plasma
104

105. Table: Summary of drugs used to treat bleeding
105

106. Thank you
106