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ANTICOAGULANTS. Jill Gregory Medicinal Chemistry Dr. Buynak 4.23.09. Overview. Review Blood basics composition how blood clots Note Instances where blood clotting is bad Discuss Anticoagulants Heparin Warfarin New Drugs F Xa inhibitors thrombin inhibitors

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anticoagulants

ANTICOAGULANTS

Jill Gregory

Medicinal Chemistry

Dr. Buynak

4.23.09

overview
Overview
  • Review Blood basics
    • composition
    • how blood clots
  • Note Instances where blood clotting is bad
  • Discuss Anticoagulants
    • Heparin
    • Warfarin
    • New Drugs
      • F Xa inhibitors
      • thrombin inhibitors
      • Show example Clinical Trial
blood composition
Blood Composition
  • connective tissue with cells suspended in plasma

Plasma (55%)

Cellular Elements (45%)

water

Ions / electrolytes (K+ Ca++)

plasma proteins (Fibrinogen)

transported substances

erythrocytes (red blood cells)

leukocytes (white blood cells)

platelets

how blood clots
How blood clots
  • Damage to endothelium (vessels)
  • Platelet plug
  • Coagulation Factors from
    • plasma
    • platelets
    • and damaged cells

interact and activate a cascade that leads to…

  • Activated Fibrin: fibers woven into a patch

http://www.advanced-supplements.com/neprinol.html

coagulation cascade

TF

VIIIa

Va

Coagulation Cascade

Intrinsic pathway

Extrinsic pathway

XIIa

XII

VIIa

XIa

XI

IXa

IX

X

Xa

Common pathway

II (prothrombin)

IIa (thrombin)

XIII

XIIIa

  • Each step requires:
  • Zymogen (precursor protein)
  • Activated Protease from step before
  • Cofactors like Ca++

Fibrinogen

Fibrin

Stabilized Fibrin

when would we not want clots to form
When would we not want clots to form??
  • Clotting is good at sites of injury because it minimizes blood loss and prevents infectious agents from getting into our systems.
  • Clotting can be bad when occurs inappropriately in normal vessels [called thrombus] …clot can break free [called embolus] and lodge in heart, causing myocardial infarction, or in brain, causing stroke.
  • Thrombosis is caused by abnormalities in blood composition, vessel wall quality, and/or nature of the blood flow
    • Different types of thrombosis:
      • Venous [i.e. VTE = venous thromboembolism;

DVT = Deep-vein thrombosis]

      • Arterial
when would we not want clots to form1
When would we not want clots to form??
  • Certain people are at a higher risk for thromboembolism:
    • Cardiovascular disease
    • Atrial fibrillation
    • Prosthetic device (i.e. replacement heart valve)
    • Post-surgery (i.e. hip/knee replacements)

Virchow triad for the pathophysiology of thrombus formation.

http://emedicine.medscape.com/article/959501-overview

thromboembolism in the u s
Thromboembolism in the U.S.
  • “Annually, more individuals may die from DVT complications than from the combination of AIDS, breast cancer, and motor vehicle accidents combined”
    • 900,000 to 2,000,000 VTE cases per year in U.S.
    • Estimates of death rates per year vary from 50,000 to 300,000
    • 700,000 Strokes per year
      • 15% of strokes are in people with Atrial Fibrillation
    • 1.2 mil Heart Attacks per year
  • Help prevent thromboembolism withthe anti-thrombotic drugs:

Anticoagulants, Antiplatelets, Thrombolytics

anticoagulants1
Anticoagulants

Inhibit clotting factor activation reactions in the blood

TARGETED FACTOR

Antithrombin (indirectly Xa and IIa)

Antithrombin (indirectly Xa and IIa)

Thrombin (IIa)

Thrombin (IIa)

Thrombin (IIa)

Antithrombin

Va, VIIIa

Prothrombin (II), VII, IX, X

Xa

Xa

Xa

Xa

Xa

Xa

Xa

Xa

Xa

Thrombin (IIa)

Thrombin (IIa)

  • CURRENT DRUGS
    • Unfractionated Heparin______________
    • Low Molecular Weight Heparin________
    • Lepirudin (DTI)____________________
    • Bivalirudin (DTI) ___________________
    • Argatroban(DTI)____________________
    • Danaparoid_______________________
    • Drotrecogin Alfa____________________
    • Vitamin K antagonists (Warfarin)_______
  • NEW/ in DEVELOPMENT DRUGS
    • Fondaparinux_____________________
    • Idraparinux_______________________
    • SSR 126517______________________
    • Rivaroxaban______________________
    • Apixaban_________________________
    • LY517717________________________
    • YM150__________________________
    • DU-176b_________________________
    • Betrixaban________________________
    • Ximelagatran*_____________________
    • Dabigatran etexilate________________

*taken off the market Italics are Oral Drugs

aside other anti thrombotic drug types
Aside: other Anti-thrombotic drug types
  • Anti-platelet agents include:
    • Aspirin (acetylsalicylic acid)
    • clopidogrel
    • dipyridamole
    • ticlopidine
    • glycoprotein IIb/IIIa inhibitors
  • Thrombolytic (/fibrinolytic) drugs include:
    • tissue plasminogen activator - t-PA - alteplase (Activase)
    • reteplase (Retavase)
    • tenecteplase (TNKase)
    • anistreplase (Eminase)
    • streptokinase (Kabikinase, Streptase)
    • urokinase (Abbokinase)
heparin

Heparin

And other current Parenteral Anticoagulants

natural anticoagulation mechanisms
Natural anticoagulation mechanisms
  • Prostacyclin:
    • made by the endothelial cells and prevents platelets from collecting and secreting sticky substances
  • Antithrombin, a plasma protein
    • stimulated by Heparan sulfate proteoglycans from endothelial cells, inhibits coagulation factors of intrinsic and common pathways
  • Activated plasma zymogen Protein C with cofactor protein S
    • degrades certain cofactors and therefore greatly inhibits activation of prothrombin and factor X
  • Tissue Factor Pathway Inhibitor (TFPI)
    • a lipoprotein that can inhibit tissue factor bound factor Va or VIIa

http://en.wikipedia.org/wiki/Coagulation

basics of heparin
Basics of Heparin
  • Derived from mucosal tissues of slaughtered meat animals.

Also exists in your body and is secreted form mast cells at the site of tissue injury

  • Increases Antithrombin activity. (Indirect inhibition method of IIa & Xa)
  • Usually intravenous adminstration
  • Glycosaminoglycan chains attached to a protein core = proteoglycans (750 kiloDaltons to 1000 kiloDaltons)
  • Low molecular weight heparin: different composition; more predictable; subcutaneous injection twice daily; use preferred over unfractionated heparin
action of heparin and similar drugs
Action of Heparin and similar drugs

Dark shaded region is a

high-affinity pentasaccharide sequence

2: Unfractionated Heparin

3: Low-molecular weight Heparin

4: Fondaparinux (discussed later)

Image from Sterling T. Bennett’s chapter on Monitoring Anticoagulant Therapy

slide15

Crystal structure of the antithrombin-pentasaccharide complex

Essentials of Glycobiology

Chapter 35, Figure 2

Second Edition

more about heparin
More about Heparin
  • Fast action intravenously or by injection (not absorbed through the stomach or intestinal wall)
  • peak after injection 2 - 4 hr
  • Complex metabolism (long chains broken up)
  • half life 1 - 5 hr; cleared by the reticuloendothelial system and some excreted in urine.
  • A few Drug-drug interactions
  • Toxicities: Bleeding & Heparin-Induced Thrombocytopenia

A D M E

other parenteral anticoagulants
Other Parenteral Anticoagulants
  • Lepirudin (DTI) derived from hirudin from leech salivary glands
  • Bivalirudin (DTI) approved for use during heparin-induced thrombocytopenia (HIT) & percutaneous coronary interventions
  • Argatroban (DTI) can be used in patients with risk of (HIT)
  • Danaparoid no longer available in the U.S.
  • Drotrecogin Alfa used in patients with sepsis; recombinant form of activated protein C that inhibits f Va and f VIIIa
vitamin k antagonists parent molecules 4 hydroxycoumarin indan 1 3 dione

Dicoumarol

Phenprocoumon

Warfarin Sodium

Vitamin K antagonists:Parent Molecules: 4-Hydroxycoumarin & indan-1,3-dione

Oral Anticoagulants

Acenocoumarol

Anisindione

mechanism of action

Vitamin K antagonists

Mechanism of Action
  • Some clotting factors need a carboxyl group added to their carboxyl-terminal glutamates after synthesis in the liver in order to be able to bind Ca++ during coagulation activation [these are called Vitamin K dependent clotting factors]
  • This γ-carboxylation reaction requires reduced Vitamin K, which leaves the reaction as a Vitamin K epoxide.
  • Vitamin K epoxide is then converted back to its reduced form via the enzyme vitamin K epoxidereductase and NADH
  • The Vitamin K antagonists inhibit the action of the reductase enzyme

http://www.vet.uga.edu/VPP/clerk/Harrell/index.php

http://tollefsen.wustl.edu/projects/coagulation/coagulation.html

effect on coagulation

Vitamin K antagonists

Intrinsic pathway

Extrinsic pathway

XIIa

XII

TF

VIIa

XIa

XI

IXa

IX

VIIIa

Va

X

Xa

Common pathway

II (prothrombin)

IIa (thrombin)

XIII

XIIIa

Fibrinogen

Fibrin

Stabilized Fibrin

Effect on Coagulation
  • Vitamin K dependent clotting factors:Factors II, VII, IX, and X
history of warfarin

Vitamin K antagonists

History of Warfarin
  • 1930s: cows hemorrhaging after eating spoiled sweet clover silage
  • 1939: bishydroxycoumarin (dicoumarol) identified
  • 1948: potent form as rodenticide
    • Called Warfarin (Wisconsin Alumni Research Foundation)

Anticoagulant in humans? No, too toxic!?

  • 1951: Army inductee’s failed attempt at suicide with high dose of warfarin rodenticide
  • Clinical use for over 60 years
warfarin

Vitamin K antagonists

Warfarin
  • Adminstered orally, intravenously, or rectally
  • Bioavailabily nearly complete; absorption dampered by food
  • Peak concentration 2 - 8 hr
  • Binds to albumin 99% of time
  • Can cross placental barrier
  • Racemic mixture: S form by CYP2C9; R by CYP1A2, minor pathway CYP2C19, and minor pathway CYP3A4
  • half-life: 25 - 60 hr; Excreted in urine and stool
  • Food-drug & drug-drug interactions: extensive!!
  • Toxicities: bleeding, fetal bone abnormalities

A D M E

problems with warfarin

Vitamin K antagonists

Problems with Warfarin
  • Food and drug interactions
  • Genetic variation in metabolism
  • narrow therapeutic window
  • slow onset of action

dosage adjustments & freq. monitor with INR

overlap with parenteral drugs

newer anticoagulants

Newer Anticoagulants

Targeting specific factors

factor xa inhibitors

Intrinsic pathway

Extrinsic pathway

XIIa

XII

TF

VIIa

XIa

XI

IXa

IX

VIIIa

Va

X

Xa

Common pathway

II (prothrombin)

IIa (thrombin)

XIII

XIIIa

Fibrinogen

Fibrin

Stabilized Fibrin

Factor Xa Inhibitors
  • Parenteral or Oral
  • Direct or Indirect mech. of inhibition
fondaparinux

Factor Xa Inhibitors

Fondaparinux
  • Parenteral anticoagulant
  • first selective factor Xa inhibitor approved by the FDA (2001)
  • 55% better than enoxaparin (LMWH) at reducing risk of VTE
  • synthetic pentasaccharide: “represents the oligosaccharide consensus sequence of heparin”
  • Indirect inhibition: binds to antithrombin and

increases antithrombin’s affinity for

factor Xa by 300-fold

http://www.fda.gov/cder/foi/nda/2001/21-345_Arixtra_chemr.pdf

indraparinux ssr 126517

Factor Xa Inhibitors

Indraparinux & SSR 126517
  • Hypermethylated form of fondaparinux = tighter binding to antithrombin
  • Status: phase III clinical trials
  • 80 hr half-life = subcutaneous injection once weekly
  • SSR 126517 is a biotinylated form of indraparinux, prepared to have an antidote (avidin)
oral factor xa inhibitors

Factor Xa Inhibitors

Oral factor Xa inhibitors
  • Developed off of success of fondaparinux
  • Can affect free factor Xa OR Xa bound to prothrombinase complex!
  • Many different drugs of this type being developed
    • Rivaroxaban
    • Apixaban
    • LY517717, YM150, DU-176b, and betrixaban
direct thrombin inhibitors

Intrinsic pathway

Extrinsic pathway

XIIa

XII

TF

VIIa

XIa

XI

IXa

IX

VIIIa

Va

X

Xa

Common pathway

II (prothrombin)

IIa (thrombin)

XIII

XIIIa

Fibrinogen

Fibrin

Stabilized Fibrin

Direct Thrombin Inhibitors
ximelagatran

Direct Thrombin Inhibitors

Ximelagatran
  • First target-specific oral anticoagulant in trials
  • Ximelagatran is the oral prodrug of Melagatran
  • Hepatatoxicity
    • Did not receive FDA approval in 2004
    • On the market in Europe but pulled in 2006
  • ‘proof of principle’
    • “efficacious” as warfarin
    • Wider therapeutic index
    • Little dosage adjustment/ no monitoring
dabigatran etexilate

Direct Thrombin Inhibitors

Dabigatran etexilate
  • Prodrug converted to Dabigatran (471 mw) by esterases in

blood after absorbed in stomach in microenvironment from

tartaric acid capsule

  • Peak 2hr; Half life 14 – 17 hr
  • Not metabolized by cytochrome system = no anticipated drug interactions
  • Farthest along in trials
  • History:
    • early 1990s: German scientists at Boehringer-Ingleheim began research
    • 1996 Synthesized novel drug
    • 1999 Phase I trials
    • 2001-3 Phase II trials
    • 2004-present Phase III trials
    • 2008 announced to be entering European market soon as Pradaxa®
    • RE-LY trial results in 2009
  • Promising; improvement in liver safety
dabigatran etexilate clinical trial example

Direct Thrombin Inhibitors

Dabigatran etexilate clinical trial example

“RELY: Randomized Evaluation of Long term anticoagulant therapy (RE-LY) comparing the efficacy and safety of two blinded doses of dabigatran etexilate with open label warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillationStudy Design:Prospective, multi-centre, randomized, open label, controlled parallel group, non-inferiority trial. Study Objective:Demonstrate that the efficacy and safety of two blinded doses of dabigatran etexilate in patients with non-valvular atrial fibrillation are non-inferior to warfarin treatment for the prevention of stroke and systemic embolism.Scope:A total of 15, 000 patients will be randomized from approximately 1,000 clinical sites within 44 countries. Patients will be randomized over a 2-year period with a minimum 1 year follow-up, maximum of 3 years and mean of 1.5 years of follow-up.”

https://www.rely-trial.com/RelyWeb/resources/jsp/emergency/dabigatran_bg.jsp

summary slide

Intrinsic pathway

Extrinsic pathway

XIIa

XII

TF

VIIa

XIa

XI

IXa

IX

VIIIa

Va

X

Xa

Common pathway

II (prothrombin)

IIa (thrombin)

XIII

XIIIa

Fibrinogen

Fibrin

Stabilized Fibrin

Summary Slide

Vitamin K antagonists

Heparin derivatives

Factor Xa inhibitors

Thrombin inhibitors

future of anticoagulants
Future of Anticoagulants
  • Clinical trials of novel anticoagulants will continue
  • New drugs to be on the market soon but cost will determine how wide spread the use will be
  • Parallel development of f Xa inhibitors and direct thrombin inhibitors
  • Drugs with other targets (f VIIa - TF, f Va - VIIIa, f IXa) will go to trials
  • Utilize crystal structures/docking algorithms
references
References
  • http://tollefsen.wustl.edu/projects/coagulation/coagulation.html (Great on blood coagulation)
  • http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ (approved drugs)
  • http://clinicaltrials.gov/ct2/search (searchable database for clinical trials)
  • http://en.wikipedia.org/wiki/Coagulation
  • http://my.clevelandclinic.org/drugs/antiplatelet_drugs/hic_antiplatelet_drugs.aspx
  • http://www.vet.uga.edu/VPP/clerk/Harrell/index.php
  • http://en.wikipedia.org/wiki/Thrombolytic_drug
  • http://www.americanheart.org/presenter.jhtml?identifier=4451
  • http://www.natfonline.org/frequency_te.php
  • http://emedicine.medscape.com/article/959501-overview
  • https://www.rely-trial.com/RelyWeb/resources/jsp/emergency/dabigatran_bg.jsp
  • Brunton, Lazo, Parker. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. Chapter 54: Blood Coagulation and Anticoagulant, Thrombolytic, and Antiplatelet Drugs” by Philip W. Majerus and Douglas M. Tollefsen.1467-1488.
  • Bauer, Kenneth A. “New Anticoagulants.” Current Opinion in Hematology 2008, 15:509-515.
  • Turpie, Alexander. “New oral anticoagulants in atrial fibrillation.” European Society of Cardiology, European Heart Journal 2007, 29:155-165.
  • Esko, Jeffrey D and Robert J. Linhart. “Proteins that bind Sulfated Glycosaminoglycans.” accessed online from Essentials of Glycobiology 2nd edition. CSH Press 2009. <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=glyco2&part=ch35>
  • “Rivaroxaban.” Prous Science. Drugs of the Future 2006, 31 (6): 484-493.