Anti Coagulant

8/8/2019 Anti Coagulant

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Anticoagulant, Antithromboticand Anti-Platelet Drugs

Department of Pharmacology

Robert Taylor, MD, Ph.D .


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Clinical Thrombosis

>2.5 million cases of deep venousthrombosis (DVT) per year >600,000 cases of pulmonary embolism(PE) per year >50,000 deaths per year from PE

PE contributes to another 150,000 deaths per year > 11,000 postsurgical PE deaths per year


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I ndications For Antithrombotic Therapy

Venous thromboembolic disease Deep venous thrombosis (DVT) Pulmonary embolism (PE) Primary prophylaxis of DVT or PEArterial thromboembolic disease

Prosthetic heart valves

Mitral valve disease, especially with atrial fibrillationC ongestive cardiomyopathies, especially with atrial fibrillatioAtrial fibrillationMural cardiac thrombiTransient ischemic attacksStroke in evolution

Disseminated intravascular coagulationMaintenance of patency of vascular grafts, shunts, bypasses


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Recombinant Human ActivatedProtein C

Drotrecogin alfa (activated)- XigrisIndicated for Severe Sepsis in Adultswith Acute Organ Dysfunction with HighRisk of DeathReduction in Death as Primary End Point

Antithrombotic, Antiinfammatory,Profibrinolytic PropertiesSerious Bleeding is Major Side Effect


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Antithrombin III Inhibits theFollowing Serine Proteases

C oagulation

Factor X II aFactor X I aFactor I Xa

Factor XaThrombin

Fibrinolysis

Plasmin

Inhibitory activity against all these enzymes is substantially accelerated by heparin


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HeparinHeterogeneous; 3,000-30,000 dAverage=15,000 d (~45monosaccharidechains)

About 1/3 of dose binds to AT IIITo form the AT III: Heparin :C lotting Factor

C omplex- requires at least 18 saccarides

except Unique high affinity pentasaccaride heparinsequences catalyze inhibition of Xa by AT


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Anticoagulant Properties of Heparin1. I nhibits the thrombin-mediated conversion

of fibrinogen to fibrin

2. I nhibits the aggregation of platelets bythrombin

3. I nhibits activation of fibrin stabilizing

enzyme4. I nhibits activated factors X II , X I , I X, Xand II


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HeparinBiologic SourcesBioavailability

MetabolismEliminationSide EffectsOverdoseContraindicationsPregnancy- YES


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Unfractionated HeparinHigh Dose Treatment of venous/arterial thrombi Requires monitoring I V- 5,000 Units bolus, then 30,000-35,000

units/24 hrs

80 Units/kg bolus, then 18 Units/kg/hr tomaintain aPTT in therapeutic range


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Monitoring of Anticoagulant

TherapyHeparin

s.q. no monitoring requiredi.v. - partial thromboplastin time (P.T.T.)

*daily or more frequent if PTT varies

mechanism measures intrinsic pathwaytherapeutic goal 2-2.5 times normalcontrol value (-30 sec)


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Low Dose Unfractionated Heparin

Surgical Prophylaxis 5,000 Units SQ 2 hr preop 5,000 Units SQ every 12 hours

Medical Prophylaxis 5,000 Units SQ every 12 hours

No monitoring required


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I ndications for and C ontraindications toParenteral Anticoagulant Agents

Anticoagulant Agent Class Approved & AppropriateIndications

Contraindication

Unfractionated heparin

Enoxaparin( Lov eno x)

Dalteparin( Fragmin )

Tinzaparin( Inn oh ep)

Antithrombin III inhibitor

L ow-molecular-weight heparin

L ow-molecular-

weight heparin

L ow-molecular-weight heparin

Treatment of venousthromboembolism or unstableangina; used when rapid reversal isimportant

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 anesthesiaPregnancyProsthetic Heart Valves

Regional anesthesia

Regional anesthesia


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I ndications for and C ontraindications toParenteral Anticoagulant Agents (contd)

Ardeparin

L epirudin

Argatroban

Danaparoid

Bivalirudin

Fondaparinux A rixtra

L ow-molecular-weight

heparin

Hirudin derivative

Direct thrombin inhibitor

Heparinoid

Hirudin derivative

Synthetic factor Xainhibitor

Approved; not being

marketed

Heparin-inducedthrombocytopenia withthrombosis

Heparin-inducedthrombocytopenia withthrombosis

Prophylaxis againstthrombosis in heparin-inducedthrombocytopenia

Unstable angina or angioplasty

Prophylaxis in high-risk patients?

Regional anesthesia

Thrombocytopenia other than heparin-inducedthrombocytopenia

Thrombocytopenia other than heparin-inducedthrombocytopenia

Thrombocytopenia other than heparin-induced

thrombocytopenia

Unknown

Unknown


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Heparin-AntibioticInteractions

The second-generation cephalosporins- cefamandole,cefotetan, and cefoperazone, contain an N-

methylthiotetrazole (NMTT) side chain. This NMTT group can:- Dissociate from the parent antibiotic in solution or in vivoand competitively inhibit vitamin K action, leading toprolongation of the prothrombin time and bleeding.

- This side chain is also associated with a disulfiram-likereaction to alcohol.

- Clinical bleeding has been less frequently reported withCefotetan than with cefoperazone or cefamandole.


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Mechanisms of HIT

Type 1: In most of these cases, the fall in platelet count occurs withinthe first two days after heparin initiation, often returns to normal withcontinued heparin administration, and is of no clinical consequence.The mechanism of the thrombocytopenia is non-immune and appears

to be due to a direct effect of heparin on platelet activation.

Type 2: Approximately 0.3 to 3 percent of patients receivingheparin develop an immune thrombocytopenia, mediated byantibodies to a heparin-platelet factor 4 complex. One study, forexample, randomly assigned 665 patients to therapy withunfractionated heparin or LMW heparin. Type 2 HIT developed in 2.7percent of patients treated with unfractionated heparin but in none of those receiving LMW heparin.


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Therapy of HIT

There are two recommended approaches: Use of the heparinoid danaparoid The direct thrombin inhibitor lepirudin (recombinant

hirudin) Based upon the data published to date, either

danaparoid or lepirudin should be used to treat HITthat is complicated by thrombosis; these agentsshould also be considered for prophylactic therapy in

patients with HIT without thrombosis until theplatelet count has recovered


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W arfarinBioavailabilityMetabolismSerum Protein Binding

Vitamin K StatusProtein C EffectsEliminationSide EffectsOverdoseContraindicationsPregnancy- NO


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C ontraindications to AntithromboticTherapy

General risk factors-Pre-existing coagulation or platelet defect, thrombocytopenia, or

other bleeding abnormality-Inaccessible ulcerative lesion (e.g., gastrointestinal tract lesion)

-C entral nervous system lesion (e.g., caused by stroke, surgery,trauma)-Spinal anesthesia or lumbar puncture-Malignant hypertension-Bacterial endocarditis-Advanced retinopathy

-Old age (relative)-Aspirin or other antiplatelet drugs-Neoplastic disease


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C ontraindications to Antithrombotic

TherapySpecific to warfarin (ambulatory patients)

-Early and late pregnancy-Poor patient cooperation,

understanding, reliability-Unsatisfactory laboratory or patient

follow-up-Occupational risk to trauma


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C ontraindications to Antithrombotic

TherapySpecific to thrombolytic agents

-Recent thoracic, abdominal, or centralnervous system surgery

-Recent cerebrovascular accident, trauma, or neoplasm

-Bleeding ulcer -Hypertension-Anticipated invasive procedures (arterial

punctures, biopsies, central lines)-C oncurrent hemostatic dysfunction


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Platelet Receptor MediatedPathways : Drugs

Arachidonic Acid ASA NSA I Ds

ADP TiclopidineC lopidogrel

Thrombin-Final C ommon Pathway

-Promotes PlateletAdhesion (Fibrinogen,vWF)

GP II B/ III A I nhibitorsAbciximab (ReoPro)

Eptifibatide ( I ntegrilin)Tirofiban


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Anti Platelet DrugsDrug Mechanism Uses

Aspirin Permanentlyinhibits C OX-1and C OX-2

C ADStroke-T I As

NSA I Ds Reversiblyinhibits C OX-1

L imited

Dipyridamole I nhibits PDE;

increases cAMP

TI As

TiclopidineC lopidrgrel

I nhibits ADPPlatAg;activemetabolite

TI As;StrokeC AD;PVD

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