Thrombolytic drugs
by
Mohie Aldien Elsayed (MD)
Antithrombotic drugs
1st generation: streptokinase 2nd generation: tissue plasminogen activator(t-PA) 3rd generation: *recombinant plasminogen activator(r-PA) *A TANK mutant
Indirect Thrombin Is
• Heparins (↓thrombin
production ,
↑antithrombin (AT)
• Vitamin K antagonists
(Non-selectively inhibit
thrombin production)
• Inhibitors of thrombin
production (Block
specific “upstream”
factor in thrombin
production)
II)Direct Thrombin
(DTIs): Hirudin –
Lepirudin ,Bivalirudin
,Argatroban,Melagatrn
Ximelagatran (oral) ,Dabigatran (oral)
Fibrinolytics ( arterial/venous thrombosis)
THROMBOLYTIC DRUGS Pathophysiologic Rationale
Re-establishing coronary flow during a period of occlusion will limit myocardial infarct (MI) size was first demonstrated in a dog model of MI by Reimer et al. in 1977
These experiments demonstrated that after coronary occlusion there was a wavefront of ischemic cell death, which progressed over time from the subendocardium toward the epicardium
The time frame for this process was quite short, in the range of 3 to 4 hours
Thus these studies provided the basis for the rationale that re-canalization and reperfusion early in the course of MI would limit myocardial necrosis, improve left ventricular function, & improve patient outcome
Wave-front Phenomenon of Ischemic Cell
Death
THROMBOLYTIC DRUGS Pathophysiologic Rationale
• Angiographic studies in the early 1980s showed that early in the course of MI with ST-segment elevation, most patients had complete coronary occlusion
• Pathologic studies established the importance of plaque rupture in the pathogenesis of acute coronary syndromes
THROMBOLYTIC DRUGS Pathophysiologic Rationale
• Acute coronary syndromes varies with the degree of thrombus-induced obstruction, ranging from a persistent complete occlusion corresponding to ST-segment elevation MI to a subocclusive thrombus corresponding to unstable angina
Thrombolytic Therapy Benefit
• The ability of streptokinase to lyse clots was first recognized in the 1930s
• Thrombolytic therapy was not applied to acute MI until the early 1980s after the establishment of the central role of acute thrombotic coronary occlusion in the pathogenesis of acute MI
• Clinical trials have firmly established the benefit of thrombolytic therapy for patients with acute MI with ST-segment elevation within 12 hours of symptom onset
• Patients with unstable angina or MI without ST elevation do not benefit from thrombolytic therapy
• Rapid initiation of thrombolytic therapy is essential to optimize patient outcome because each additional hour of delay from symptom onset to treatment corresponds to a 0.5% to 1% increase in mortality
Gibson CM. Ann Intern Med. 1999;130:841-847.
Characteristics of the Ideal Fibrinolytic Agent
• Longer half-life/single-bolus administration
• Increased fibrin specificity/decreased bleeding and ICH
• More rapid and consistent achievement of TIMI grade 3 flow
• No effect on blood pressure
• No antigenicity
• Lower re-occlusion rates
• Greater resistance to PAI-1
• Compatible with other intravenous agents
• Low cost
Plasminogen As Plasminogena Is Plasmin Is
•Secretion: Urine(UK,u-PA)Bile,bilokinase,Latex,saliva、tear PAI-3 α2-plasmin inhibitor (α2-PI)
α2- macroglobin (α2 –MG)
•Vascular endothelium: t-PA, u-PA PAI-1
•Tissue: lung、prostate、uterus, RBC, Platelet PAI-2
•Exogenous pathway :IIa , XIIa , Ixa, KK
Exogenous (thrombolytic) :Streptokinase (SK),Urokinase(UK),
rt-PA include alteplase, reteplase & tenecteplase (TNKase
Aprotinin
↑colagenase
Fibrinolysis
Coagulation and Fibrinolysis
Fibrinolysis
Fibrin
Coagulation Factors
Fibrinogen
Plasmin
Plasminogen
Tissue Plasminogen Activator
Fibrinolysis
•Injured endothelial cells
•Plasminogen activators
•Plasmin cleaved from plasminogen
•Fibrin degrades
Fibrinolytic agents First-generation Streptokinase Streptase, Kabinase,Urokinase Abbokinas Second-generation Alteplase (tissue plasminogen activator, t-PA) Activase Anistreplase (APSAC) Eminase Prourokinase (scu-PA)* Third-generation Reteplase (r-PA) Retavase Tenecteplase (TNK-t-PA) TNKase Lanoteplase* (n-PA) Staphylokinase* (SAK 42D) Antibody-targeted PAs* Vampire bat-PA* Alfimeprase* *Not approved for clinical use
Mechanism of Thrombolytic Drugs • The plasmin(ogen) molecule has lysine binding sites, which bind to and
degrade fibrin
• Fibrin-specific agents are much more active upon binding to fibrin, thereby increasing the affinity for plasminogen at the clot surface
Fibrin Specificity TNK-tPA t-PA r-PA / n-PA SK
t-PA (alteplase) n-PA (lanoteplase)
Mechanism of Thrombolytic Drugs
Summary of Selective Thrombolytic Agents
FDA = Food and Drug Administration; IV = intravenous; mins = minutes; sec = seconds
Characteristics of alteplase compared with the third-generation fibrinolytic drugs
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 1 JANUARY 2004
*15 mg bolus over 1–2 minutes, then 0.75-mg/kg infusion (50-mg maximum) over 30 minutes, followed by 0.5-mg/kg infusion (35-mg maximum) over 60 minutes †15 mg over 1–2 minutes, then 50 mg over 30 minutes and 35 mg over 60 minutes
Fibrinolytics in Development: Comparative Overview
Tenecteplase (TNK-tPA)
Lanoteplase (n-PA) Staphylokinase Saruplase
Half-life (minutes) 20 37 6 9
Dosing Single bolus Single bolus 2 boluses
30 min apart Bolus + 60-
min infusion
Provides patient- specific weight- based dosing
Yes Yes ?? ??
Fibrin specificity +++ + +++ +
PAI-1 resistance Increased ?? ?? ??
Antigenic No No Yes Yes
Plasminogen activation
Direct Direct Indirect Direct
Thrombolytic drugs – major drawbacks
• Treatment is limited to acute in-hospital treatment. There is a high risk of bleeding inherent in this treatment
• Patients using anticoagulants are contraindicated for treatment with thrombolytics
Risks Plasmin breaks down fibrin = fibrin degradation products (FDPs). FDPs compete with thrombin = slow down the conversion of fibrinogen to fibrin (and thus slows down clot formation). Secondary impact tPA – binds circulating plasminogen
Lysis of normal haemostatic plugs - bleeding Intracranial haemorrhage, absolute risk is increased 6% in patients of first 10 days, maximal during the first 36 hours after treatment. (c.f. 3 month overall risk reduction of 11% )
Potential interactions with anticoagulants, ACE inhibitors, platelet function altering drugs etc. Cholesterol embolisms Immune problems – plasmin also cleaves C3 component of complement system
Uses of Thrombolytics:
1) Coronary Thrombolytics
2) Pulmonary embolism
3) DVT
4) Arterial occlusion e.g. Popliteal artery
5) Ischaemic stroke
6) Occluded AV shunts
7) Blocked central vacuum catheters
Contraindications to Thrombolytic Therapy Absolute contraindications include:
Recent head trauma (3monthes)or caranial tumor
Previous hemorrhagic shock
Stroke or cerebro-vascular events, Intracranial hemorrhage 1 year old
Major surgery within two weeks
Ischemic Stroke within 3 month
Known structural cerebrovascular lesion (AVMs, aneurysms, tumor)
Aortic dissection
Severe uncontrolled hypertension SBP > 180 DBP > 110
Active bleeding or bleeding diathesis
Acute pericarditis
Relative contraindications include:
Active peptic ulcer, diabetic retinopathy, pregnancy, uncontrolled HTN
Haemostatic agents 1) Ε – aminocaproic acid, Tranexamic acid – Urinary tract bleeding, prostatic surgery tonsillectomy, Clinical menorrhagia , vWD, hemophilia patients with tooth extraction 2) Aprotinin – Cardiac surgery
Topical absorbable haemostatic 1) Thrombin 2) Microfibrillar collagen hemostat 3) Absorbable gelatin–Sponge film and powder, oral–G.I,
bleeding 4) Oxidized cellulose -physical effect - requires phagocytosis
Contraindications to Antithrombotic Therapy
• Specific to warfarin (ambulatory patients)
-Early and late pregnancy
-Poor patient cooperation, understanding, reliability
-Unsatisfactory laboratory or patient follow-up
-Occupational risk to trauma
Contraindications to Antithrombotic Therapy
• Specific to thrombolytic agents -Recent thoracic, abdominal, or central
nervous system surgery -Recent cerebrovascular accident, trauma, or
neoplasm -Bleeding ulcer -Hypertension -Anticipated invasive procedures (arterial
punctures, biopsies, central lines) -Concurrent hemostatic dysfunction
Fibrinolytic Inhibitors
Aminocaproic Acid & tranexamic cid
They have lysine-like structure
They inhibit fibrinolysis by competitive inhibition of plasminogen activation
Adjuvant therapy in hemophilia, fibrinolytic therapy-induced bleeding & postsurgical bleeding
Aprotinin is a serine protease inhibitor
It inhibits fibrinolysis by free plasmin
Used to stop bleeding in some surgical procedures
Anticoagulant
The global anticoagulants market.
Ideal Anticoagulant
• Oral administration
• Rapid and predictable anticoagulant effect
• Broad therapeutic window
• Efficacious with a low bleeding risk
• No food-drug and drug-drug interactions
• No need for laboratory monitoring
• Easily reversible
• Affordable (acceptable cost-benefit ratio)
Historical Perspective
1916
Heparin
1950s 1990s 2002
Warfarin LMWHs Indirect
Factor Xa Inhibitors
DTIs
Lepirudin
Argatroban
Bivalirudin
Desirudin
Fondaparinux
Enoxaparin
Dalteparin
Tinzaparin
2010
Dabigatran
Rivaroxaban
Apixaban
2012
Endoxaban
Betrixaban
Vitamin K Antagonists
Half-life of Vitamin K-dependent clotting factors Factor VII - 4 to 6 hours Factor IX - 24 hours Factor X - 48 to 72 hours Factor II - 60 hours Protein C - 8 hours Protein S - 30 hours
•Vitamin K is required for binding to phospholipid membranes • Vitamin K antagonism results in the inability of clotting factors to attach to phospholipid membranes • No effect upon existing factors • Onset of action determined by half-life
Oral Anticoagulants - WARFARIN
• Dicoumarol first isolated from sweet clover silage
- caused haemorrhagic disease in cattle.
• Subsequent synthesis of chemically related coumarin, WARFARIN
- patent holder = Wisconsin Alumni Research Foundation
coumARIN.
The site of action of WARFARIN
Vitamin-K oxidation is coupled to -
carboxylation of Glu residues on clotting
factor proteins, which is necessary for
full biological activity (as Ca++
chelators). Warfarin blocks the vit K
epoxide reductase step in this cycle. The
delayed onset of Warfarins effect
actually reflects the half-lives of these
modified clotting factors (shortest,
Factor VII 6h; longest, Factor II 40-60h).
Interactions with WARFARIN that matter
Reduced absorption – cholestyramine or similar resins.
Reduced protein binding – hypoproteinaemic states e.g.
nephrotic syndrome
Altered clearance – P450 induction by rifampicin, barbiturate or
phenytoin; P450 inhibition by amiodarone, metronidazole and
cimetidine.
Altered vit K intake – vitamin K rich foods/supplements or
antibiotic induced reduction in gut-derived vitamin K.
Altered levels of clotting factors – reduced in
hypermetabolic states e.g. hyperthyroidism; increased in pregnancy.
Augmented bleeding tendency – in combination with
antiplatelet agents e.g. NSAIDs. Substitute non-NSAID analgesics
with care: dextropropoxyphene and high dose paracetamol (1.5-2g/d)
can block W metabolism.
Important points about WARFARIN’s
Pharmacokinetics
• Rapidly and completely absorbed after oral
administration
• Highly protein bound (>99% to serum albumin)
• Crosses the placenta (teratogenic)
• Breast feeding OK (active W not detected in breast milk)
• Variable but usually slow systemic clearance – t1/2 ~24-
60hrs
• Clearance dependent on hepatic P450s (especially 2C9*)
* Slow metabolism through some alleles explains why ~10% of
patients have therapeutic INRs on low doses of Warfarin <1mg/d.
Reversal of WARFARIN-induced bleeding
Is pharmacological reversal required?
• INR a poor guide unless very high (>10)
• Bleeding into ‘closed’ compartments most problematic especially
intracerebral, joints and retroperitoneal
Dose of vitamin K1 (phytomenadione)?
• Slow onset ~hrs
• Full dose (10mg) may prevent rewarfarinisation e.g. prosthetic
valves
- Low-dose (1mg) +/- FFP most flexible regime in this case
Contraindications
1) Pre-existing hemostatic defects
2) GI bleeding
3) CNS hemorrhage
4) Pregnancy, esp. 1st trimester
Side Effects
1) Hemorrhage
2) Unmasking of underlying anatomic lesion
3) Localized skin necrosis (protein C deficiency)
4) Fetal abnormalities
Limitation Clinical Implications
Slow onset and offset of action Need for bridging with a rapidly acting anticoagulant
Interindividual variability in anticoagulant effect Variability in dosing requirements
Narrow therapeutic index Need for routine coagulation monitoring
Food and drug interactions Dietary precautions; need for routine coagulation monitoring
Reduce synthesis of all vitamin K–dependent proteins
Risk of skin necrosis in patients with protein C or S deficiency; potential for osteoporosis
Genatic polymorphysm
Table 1. Limitations of Oral VKAs
Anticoagulant action of
HEPARIN
LMWH
UFH
Unfractionated Heparin LMWH pentasaccarides
(↓Th = ↓x,) Multiple sites of action,reversible/less efficacy
(3+) (↓Th > ↓xa)/less reversible
more effectively (4+) ↓xa
Nonspecific binding to P. P & heparinase, PF4, Endothelial
cells → variable anticoagulation level (aPTT 1.5-2.5 x
normal) → reduced effect in ACS
Less binding consistent efficacy More consistant efficacy
safe in pregnancy No data No data
Short T1/2 → Iv/SC moderate T1/2 →easy SC Long T1/2→SC once/W
Cleared by heparinase, Renal clearance /Long half-life
Monitoring necessary unnecessary No
Antidot Protamin, 1mg :100UNITS UFH given in last 4h
(*risk of anaphylaxis, 30% mortality; reserve only for
major bleeding complications*)
Antidot; Protamine(↓60 %/)
;heparinase No
HIT 3.5% HIT 6% No (used in HIT)
Bleeding risk 3+ Bleeding risk 2+ less
IIa
SC
Direct antithrombin
LMWH
ATXa AT
Xa
Pentasaccharide
ATIIaIIa
UFHlow molecular weight heparin (LMWH)
(Bemiparin ·Certoparin · Dalteparin ·
Enoxaparin· Nadroparin· Parnaparin·
Reviparin · Tinzaparin
oligosaccharides
Fondaparinux · Idraparinux
heparinoid,Danaparoid ·
Dermatan sulfate ·
Sulodexide
Heparins *Impair thrombin production *Inhibit thrombin through antithrombin (AT)
*does not inhibit clot-bound thrombin)
INDICATIONS FOR THE USE OF HEPARIN
* FULL DOSE: 5000 U IV bolus followed by 1200-1600 U/hr adjusted to therapeutic
range OR 80 U/kg then 18 U/kg/hr
1) Acute deep venous thrombosis
2) Pulmonary emboli
3) Unstable angina and myocardial infarction
*LOW DOSE: 5000 U SC q12h
1) Postoperative prophylaxis for any major abdominal, thoracic,
gynecologic, or orthopedic procedure
2) Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease
3) Prophylaxis for underlying hypercoagulable state.
* OTHER DOSE 1) Extracorporeal bypass 2) Hemodialysis 3) After
thrombolytic therapy
Indications for and Contraindications to Parenteral Anticoagulant Agents
Anticoagulant
Agent
Class Approved & Appropriate
Indications
Contraindication
Unfractionated
heparin
Enoxaparin
(Lovenox)
Dalteparin
(Fragmin)
Tinzaparin
(Innohep)
Antithrombin
III inhibitor
Low-molecular-
weight heparin
Low-molecular-
weight heparin
Low-molecular-
weight heparin
Treatment of venous
thromboembolism or unstable
angina; used when rapid reversal
is important
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism
? Prophylactic
treatment
Regional anesthesia
Pregnancy
Prosthetic Heart
Valves
Regional anesthesia
Regional anesthesia
Indications for and Contraindications to Parenteral Anticoagulant Agents (cont’d)
Ardeparin
Lepirudin
Argatroban
Danaparoid
Bivalirudin
Fondaparinux
(Arixtra)
Low-molecular-weight heparin
Hirudin derivative
Direct thrombin inhibitor
Heparinoid
Hirudin derivative
Synthetic factor Xa inhibitor
Approved; not being
marketed
Heparin-induced
thrombocytopenia with
thrombosis
Heparin-induced
thrombocytopenia with
thrombosis
Prophylaxis against
thrombosis in heparin-
induced
thrombocytopenia
Unstable angina or
angioplasty
Prophylaxis in high-
risk patients?
Regional anesthesia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Unknown
Unknown
New oral and parenteral anticoagulants in the pipeline
Target sites of novel anticoagulants (in blue) in the coagulation cascade (in orange) along with their routes of administration (in brackets). po - Oral; iv - Intravenous; sc - Subcutaneous; rNAPc2 - Recombinant nematode anticoagulant protein; ASO - Antisense oligonucleotides
Advantage Clinical Implications
Rapid onset of action No need for bridging
Predictable anticoagulant effect
No need for routine coagulation monitoring
Specific coagulation enzyme target
Low risk of off-target adverse effects
Low potential for food interactions
No dietary precautions
Low potential for drug interactions
Few drug restrictions
Advantages of New Oral Anticoagulants
A. Parenteral DTIs – Currently, all approved DTIs are
parenteral and limited for use in hospitalized patients
B. Oral DTIs
– Predictable and consistent antithrombotic effect
– Highly specific for thrombin
– Inhibit free and clot-bound thrombin
– Unlike parenteral DTIs, can be used both in the hospital and out-patient setting
Dabigatran Etexilate
IV) Direct thrombin inhibitors : (DTIs) ;Specifically and directly block
thrombin activity
Advantages *Predictable anticoagulant response
*Inhibits soluble and fibrin-bound thrombin
*Inhibits thrombin-induced platelet aggregation
*Minimal drug interaction/bleeding
*No HIT
Disadvantages *No antidote *Cost
univalent
Reversible
Bivalent
Irreversible Reversible
Dabigatran♣ xemalgatran♠ Argatroban Lepirudin+ Desirudin Bivalirudin
Route/
dose
Oral Od/BID Oral BID *2 mg kg-1 h IVI
*Mild Hep. failure:
0.5 mg kg-1 min-1
*Severe Hep.F :≠
Iv/SC…..m
g/Kg
15mg BOD
SC
*IV Bolus of 0.75 mg kg →
1.75 mg kg-1 h -1 4 h. *CLCR
15–60 ml min-1 : 15–50%
*CLCR /<15 ml min-1 : ≠
onset 1.5-2h 30-60m 2-4h 2-3h 0.5-1.5h T1/2 14–18 h ? ~ 45’ 1.3 h 120 min ~25’ offset 1–2( 3–5 d in
RI ) rapid
2–4 h ?
Excretion R(80%),
R(20%) R(80%) H R R R(20%) H (proteolytic cleavage
Monitori
ng aPTT (1.5–3.0) aPTT
(1.5–2.5)
aPTT
(1.5–2.5) ACT after 5 min Of IV
Indicatio
n
↓stroke em-
boli in AF VTI(Europe) ↓ thromb-osis in
HIT
↓ thromb-
osis in HIT VTE ↓AIC in UA/ HIT need PTCA
or PCI
Bleeding + + + + ♣ lack of interaction with CYP450, food or drugs, broad TI, fixed dose administration and good safety profile, not associated with hepatotoxicity for long-term use ♠=Long term therapy (›35 days) is associated to hepatotoxicity – taken off market in Europ +=antihirudid antibodies are formed in 40% of patients
V) Direct inhibitors of Xa:
Apixaban Rivaroxaban Edoxaban Betrixaban Desirudin
Route/dose Oral/ BID Oral/2.5- 5 mg b.i.d. od Oral OD 15mgBOD SC
onset 3h 2.5-4 h 1-2h 2-4h T1/2 14-17 h 5-9 h(9-13 elderly) 9-11 19h 120 min offset 1 day Drug
interaction CYP3A4 Is
(↓Abs.) ↓CYP3A4 or P-gp Pgp Is less lesser
Excretion Fecal(75%)
R(25%) Fecal,(66%),R (33%) R(25%) H,R(5%) R
Indication Non ↓stroke & embolic events in
non-valvular AF; treatment of
DVT& PE
VTE VTE VTE
Bleeding + + Antidot No No No yes No monitoring NO No No
Characteristic AVE5026 Idrabiotaparinux Otamixaban RB006
Target fXa* fXa fXa Factor IXa
Antithrombin dependent
Yes Yes No No
Dosing Subcutaneous, fixed, once daily
Subcutaneous, fixed, once weekly
Intravenous infusion Intravenous infusion
Half-life 16–20 h 130 h 25 min Not reported
Renal clearance, % 100 100 < 25 No
Routine coagulation monitoring
No No No No
Antidote No Yes, avidin No Yes, RB007
Drug interactions Nil known Nil known Nil known Nil known
Comparison of Pharmacological Characteristics of AVE5026, Idrabiotaparinux,
Otamixaban, and RB006
*AVE5026 primarily inhibits fXa and has minimal thrombin-inhibitory activity.
TSOAs
J Thromb Thrombolysis 2013;36:133-140.
Specific inhibition of upstream coagulation factors:
– Factor VIIa/tissue factor complex
– Factor IXa
– Factor Xa
Inhibitors of Thrombin Production
Antiplatlets
Antiplatelet therapy: in search of the 'magic bullet' Shaun P. Jackson & Simone M. Schoenwaelder
Nature Reviews D rug D iscovery 2, 775-789 (October 2003)
doi:10.1038/nrd1198
Antiplatelet therapy: in search of the 'magic bullet' Shaun P. Jackson & Simone M. Schoenwaelder Nature Reviews D rug D iscovery 2, 775-789 (October 2003)
doi:10.1038/nrd1198
Mohie al-dien Elsayed
•Platelets Functions:
FIRM, BUT REVERSIBLE ADHESION
IRREVERSIBLE ADHESION
Scanning electron micrograph of discoid, dormant platelets
Activated, aggregating platelets illustrating fibrin strands
Adapted from: Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34.
Platelet Aggregation
Flowing disc-shaped platelet
Rolling ball-shaped platelet
Hemisphere-shaped platelet
Spreading platelet
Endothelial functions related to procoagulation and anticoagulation
Schematic of platelet adhesion, activation, and aggregation.
Coller B S Circulation 1995;92:2373-2380 Copyright © American Heart Association
Receptor Ligand
AdhesionI/ntegrins
GPIa/IIa (VLA-2) Collagen
GPIc/IIa (VLA-6) Laminin
GPIc*/IIa (VLA-5) Fibronectin
αv/IIIa (αvβ3) Vitronectin, fibrinogen,
von Willebrand factor,
thrombospondin
GPIIb/IIIa (αIIbβ3) Fibrinogen, fibronectin,
von Willebrand factor,
vitronectin
(thrombospondin?)
Others
GPIb/IX von Willebrand factor
GPIV Thrombospondin, collagen
Aggregation
GPIIb/IIIa (αIIbβ3) Fibrinogen, fibronectin,
von Willebrand factor,
vitronectin
(thrombospondin?)
Platelet Granule Content
-Granules Dense-
Granules Lysosomal-Granules
Adhesion proteins Coagulation/fibrinolysis
components Cytokine-like proteins
P-selectin (CD62P) Fibrinogen -thromboglobulin ADP Cathepsin D
IIb3 FVa GRO- (CXCL1) ATP Cathepsin E
vWF FVIII Platelet factor 4 (CXCL4) GDP Carboxypeptidase A
Thrombospondin FXI ENA-78 (CXCL5) GTP Carboxypeptidase B
Vitronectin High molecular weight kininogen NAP-2 (CXCL7) Serotonin Collagenase
Fibronectin TFPI Interleukin-8 (CXCL8) Calcium Proline carboxypeptidase
CD40 ligand (CD154) Protein S MIP-1 (CCL3) Magnesium -N-acetyl-D-hexosaminidase
CD36 Plasminogen RANTES (CCL5) Phosphate -D-glucuronidase
proCPU MCP-3 (CCL7) -D-galactosidase
PAI -1 TARC (CCL17) -D-mannosidase
Enzyme
inhibitors Growth factors Other -L-arabinofuraniosidase
antiplasmin PDGF Gas6 -D-galactosidase
1-antitrypsin Transforming growth factor Albumin -L-fucosidase
2-macroglobulin Epidermal growth factor Immunoglobulins -D-fucosidase
C1-inhibitor Endothelial growth factor -D-glucosidase
Vascular endothelial growth factor -D-glucosidase
Basic fibroblast growth factor Acid phosphatase
Epidermal growth factor Arylsulphatase
Hepatocyte growth factor Elastase
Heparinase
Hydrolase
Antiplatelet therapy: in search of the 'magic bullet' Shaun P. Jackson & Simone M. Schoenwaelder Nature Reviews Drug Discovery 2, 775-789 (October 2003)
doi:10.1038/nrd1198
major adhesion and agonist receptors on the surface of platelets
Factor Xa
Targets for Antithrombotics
Fibrinogen
Platelet aggregation
Conformational activation of GPIIb/IIIa
Collagen
AT
ADP
Fibrin
Thrombus
Thromboxane A2
AT
Aspirin
clopidogrel prasugrel cangrelor ticagrelor elinogrel
GPIIb/IIIa inhibitors
bivalirudin hirudin
dabigatran
fondaparinux LMWH heparin
Direct Xa inhib: rivaroxaban apixaban otamixaban
TRA
Tissue factor
Coagulation cascade
Prothrombin
Thrombin
Platelet activation mechanisms (modified after Storey R.F. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des 2006;12:1255–1259 with permission).
Inhibition of platelet activation by ADP-receptor antagonists
Paikin, J. S. et al. (2010) New antithrombotic agents—insights from clinical trials Nat. Rev. Cardiol. doi:10.1038/nrcardio.2010.101
inhibitor of P2Y 12 component of ADP receptor
Irreversible (thienopyridines, ADP binding site) Reversible (nucleotide/nucleoside,other binding
site)
clopidegril Prasugrel Ticagrelor cangrelor route oral oral oral IV Pro-drug Yes, 2 step Yes, 1-step++ No, active drug+ No Potency Medium High High High T.M.C 30-60m 30 m 1-2h onset 2-4 h 30m 30m ~ 5 min duration 3–10 days 5–10 days 3–4 days
Pre-surgery stop 5 days 7 days 5 days <1 h
Loading dose 300mg 6omg 180mg 4 -30 μg/kg/m
for 2 h Maintenance 75 mg OD 10mg OD 90 mg BID NO T1/2 6 hours 7 hours 7–8.5 hours ~ 5 min Excretion Urine, faeces Urine, faeces Urine, faeces Indication for patients who
cannot receive
ticagrelor or prasugrel
naïve pts (e.g.D) + known
coronary anatomy proceeding
to PCI except high risk of life-
thretening bleeding / other
contraindications♣
All moderate-to-high risk pt. at
ischemic events (e.g.↑
troponin) , including pretreated
with clopidogrel (which should
be discountinued if ticagrelor is
commenced)♣
NA
Bleeding + ++ ++ + Contraindication
s
Hypersensitivity,
active bleeding,
significant liver
impairment, and
cholestatic jaundice
Hypersensitivity, active
bleeding, history of intracra-
nial hemorrhage, hepatic
impairment, strong CYP3A4
inhibitors (ketocon-azole,
clarithromy-cin, ritonavir,
ataza-navir,nefazodone
Hypersensitivity, active
bleeding,history of TIA, or
stroke
Ticagrelor Contra-indications
•Active pathological bleeding
• History of intracranial haemorrhage
* Moderate to severe hepatic impairment
* Co-administration of with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nefazodone, ritonavir,
andatazanavir)
* Hypersensitivity to the active substance or to any of the excipients
Ticagrelor Cautions
•↑ bleeding risk, e.g. clinically important thrombocytopenia or anaemia, gastrointestinal bleed within the past 6
months or major surgery within the past 30 days. These groups were excluded from PLATO and so ticagrelor
should be used with consideration of the balance of the risks and the expected benefit to the patient.
Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-
steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, or fibrinolytics) within 24 hours of ticagrelor
dosing.
•Patients at risk of bradycardia
•Asthma/COPD: If a patient, particularly those with pre-existing asthma/COPD reports new, prolonged or
worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be
stopped and replaced with clopidogrel or prasugrel.
•Renal impairment: Creatinine levels may increase during treatment with ticagrelor. Renal function should be
checked at baseline and after one month and six months, paying special attention to patients 75 years, patients
with moderate/severe renal impairment and those receiving concomitant treatment with an ARB.
Commonly Used Interacting Drugs : Clarithromycin - contraindicated. Consider using
erythromycin as an alternative.
- contraindicated.( Ketoconazole, Nefazodone, Ritonavir and atazinavir, Dexamethasone,
phenytoin, carbamazepine and phenobarbital can reduce the efficacy of ticagrelor. Consider
clopidogrel or prasugrel as an alternative.
Verapamil, quinidine, and cyclosporine may increase ticagrelor exposure. Consider clopidogrel or
prasugrel as an alternative.
Schematic of platelet adhesion, activation, and aggregation.
Coller B S Circulation 1995;92:2373-2380
Receptor Ligand
AdhesionI/ntegrins
GPIa/IIa (VLA-2) Collagen
GPIc/IIa (VLA-6) Laminin
GPIc*/IIa (VLA-5) Fibronectin
αv/IIIa (αvβ3) Vitronectin, fibrinogen, von Willebrand
factor, thrombospondin
GPIIb/IIIa (αIIbβ3) Fibrinogen, fibronectin, von Willebrand
factor, vitronectin (thrombospondin?)
Others
GPIb/IX von Willebrand factor
GPIV Thrombospondin, collagen
Aggregation
GPIIb/IIIa (αIIbβ3) Fibrinogen, fibronectin, von Willebrand
factor, vitronectin (thrombospondin?)
Abciximab Eptifibatide Tirofiban
Molecule Monoclonal AB Peptide Nonpeptide
Mechanism of IIb/IIIa
Receptor Blockade
Agent binding causes steric hindrance
and conformational changes
Mimics native protein sequence
in receptor
Mimics native protein
sequence in receptor
Specificity +++ +++ +++
offset (h) 72 3–4 4
Reversibility Platelets Time Time
Clearance Platelet binding, protease degradation Renal (98%), partially
metabolized
Renal (60–70%), Biliary
(20–30%)
Dose 0.25 mg/kg bolus followed by 0.125
μg/kg/min infusion for 12 h
180 μg/kg bolus followed by
2.0 μg/kg/m infusion and
additional 180 μg/kg bolus 10
m after first bolus for 18–24 h
0.10 μg/kg bolus
followed by 0.10
μg/kg/min infusion for
18–24 h
Dose Adjustment in
Renal Insufficiency
No Yes Yes
Provoke Antibody
Response
Yes Yes or no??? Yes or no???
Currently Available Glycoprotein IIb/IIIa
Antagonists
Table 1 Phase III randomized controlled trials of new ADP-receptor antagonists
Paikin, J. S. et al. (2010) New antithrombotic agents—insights from clinical trials Nat. Rev. Cardiol. doi:10.1038/nrcardio.2010.101
Applicable to All Three Agents Specific to Abciximab
Specific to Eptifibatide
Specific to Tirofiban
Hypersensitivity to agent component
Active internal bleeding or recent significant GI or GU bleed within past 6 months
History of bleeding diathesis within 30 days
Severe uncontrolled hypertension
Major surgery or trauma Within previous 6 weeks
Within previous 6 weeks
Within previous 4 weeks
Thrombocytopenia (platelets <100,000)
Thrombocytopenia (platelets <100,000)
Stroke within previous 2 years Stroke with neurologic deficit at any time
Intracranial neoplasm, AVM, aneurysm or tumor
Vasculitis
Aortic dissection
Acute pericarditis
Contraindications and Precautions for the Glycoprotein IIb/IIIa Antagonists
Agent Trial Indication Dosage Regimen
Bolus (μg/kg) Infusion (dose/min)
Infusion Duration (h)
Death MI Urgent Intervention
Major Bleeding*
Abciximab EPIC High risk for abrupt closure during PTA
250 10 μg 12 1.7 5.2 3.2
EPILOG Elective or urgent PTA
250 0.125 μg/kg to a maximum dose of 10 μg
12 0.4 3.8 2.3
CAPTURE PTA for UA 250 10 μg 18–24 1.0 4.8 7.8
EPISTENT Elective or urgent PTA or stent placement for UA, post-MI, stable angina
250 0.125 μg/kg to a maximum dose of 10 μg
12 Post-stent
0.3 (30 d), 1.0 (1 year),
4.5 (30 d), 5.9 (1 year)
1.3 (30 d)
Post-PCI
0.8 (30 d), 2.1 (1 year)
5.3 (30 d), 7.7 (1 year)
1.9 (30 d)
Eptifibatide IMPACT-II PTA for UA, post MI, stable angina
135 0.5 μg/kg 20–24 0.5 6.6 4.7
135 0.75 μg/kg 20–24 0.8 6.9 5.4
ESPIRIT Elective or urgent stent placement
180×2, every10 minutes
2 μg/kg 18–24 0.1 (48 h), 0.4 (30 d), 0.8 (6 m)
5.4 (48 h), 6.2 (30 d), 7.0 (6 m)
0.6 (48 h), 1.9 (30 d), 8.6 (6 m)
Tirofiban RESTORE PTA within 72 h of UA or MI
10 0.15 μg/kg 36 0.8 4.2 7.6
Review of the Clinical Trials of the Glycoprotein IIb/IIIa Antagonists in the Coronary Circulation
Figure 1. Roles of PARs in thrombosis and atherosclerosis.
Leger A J et al. Circulation 2006;114:1070-1077
Copyright © American Heart Association
Antiplatelet therapy: thrombin receptor antagonists
Antiplatelet therapy: thrombin receptor antagonists
British Journal of Clinical Pharmacology Volume 72, Issue 4, pages 658-671, 9 SEP 2011 DOI: 10.1111/j.1365-2125.2010.03884.x
Vorapaxar Atopaxar
Formulation Oral Oral
Mechanism of action Competitive and reversible Competitive and reversible
Onset ∼2 h ∼3.5 h
Half-life 311 h 23 h
IC50 to inhibit thrombin-induced platelet aggregation
47 nm 64 nm
Main metabolic activation CYP3A4 CYP3A4
Major route of elimination Faeces Faeces
Development status Phase III Phase II
Characteristics of vorapaxar (SCH530348) and atopaxar (E5555)
Mode of Action In Vivo Studies
PAR1 inhibitors
BMS-200661 PAR1 competitive antagonist …
RWJ-58259 PAR1 competitive antagonist Cynomolgus monkey, rat
SCH205831 Orally active PAR1 inhibitor Cynomolgus monkey
P1pal-7 pepducin Inhibitor of PAR1-dependent activation of G proteins
Guinea pig, mouse
P1pal-12 pepducin Inhibitor of PAR1-dependent activation of G proteins
Mouse
PAR4 inhibitors
P4pal-10 pepducin Inhibitor of PAR4-dependent activation of G proteins
Mouse
P4pal-i1 pepducin Inhibitor of PAR4-dependent activation of G proteins
Guinea pig
PAR Inhibitors
Thanks