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