Anticoagulants, Thrombolytics and Antiplatelet.pptx

8/10/2019 Anticoagulants, Thrombolytics and Antiplatelet.pptx

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Intrinsic System

the direct contact of the first clotting factor (factorXII) with the damaged vessel wall activates theclotting factor and initiates the cascade

Extrinsic System tissue factor (known also as thromboplastin) is

released from the damaged vascular cell

Tissue factor directly activates clotting factor VII,which then activates subsequent factors in theclotting mechanism


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Both the intrinsic and extrinsicsystems ultimately lead to theconversion of prothrombin to

thrombin

Thrombin is an enzyme that quickly

converts the inactive fibrinogenmolecule to fibrin


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Clot Breakdown Tissue plasminogen activator (t-PA)

converts plasminogen to plasmin

Plasmin, also known as fibrinolysin, is anenzyme that directly breaks down thefibrin mesh, thus destroying the clot

(Fibrinolysis) Endogenous anticoagulant proteins:

protein C, protein S, and antithrombin III


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Anticoagulants


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Heparin (Unfractionated, LMW)

Oral Anticoagulants- Anisindione (Miradon)

- Dicumarol (generic)- Warfarin (Coumadin)


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DVT 1indication for anticoagulant therapyOther indications:

after surgical procedures (joint replacement,

mechanical heart valve replacement)

following certain cardiovascular incidents(myocardial infarction, ischemic stroke)

when patients will be relatively inactive forextended periods of time


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Heparin

1drug used in the initialtreatment of venous thrombosis

Heparin works by potentiating theactivity of a circulating proteinknown as antithrombin III


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UFH

High-molecular-weight (HMW), also knownas UFH, fractions of heparin with highaffinity for antithrombin markedly inhibit

blood coagulation by inhibiting all threefactors, especially thrombin and factor Xa

Unfractionated heparin

- Calciparin

- Liquaemin


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LMWH

Low-molecular-weight (LMW) fractions ofheparin inhibit activated factor X but haveless effect on thrombin

Low molecular weight heparins:

- Ardeparin (Normiflo)

- Dalteparin (Fragmin)- Enoxaparin (Lovenox)

- Tinzaparin (Innohep)


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Advantages

LMWHs can be administered by subcutaneousinjection into fat tissuesdecreasing theneed for repeated intravenous administration

Dosing schedules of LMWHs are typicallyeasier (once per day), compared to 2 or moredaily injections of unfractioned heparin

less risk of adverse effects such as hemorrhageand death


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primary method of treating acute venousthrombosis

LMWHs are now used routinely to prevent

or treat deep vein thrombosis (DVT)following various types of surgery ormedical conditions (ischemic stroke, CA)

More predictable pharmacokinetic profilewhich allows weighted-adjusted subQadministration s lab monitoring


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Administration and Dosage

Continuous IV infusion (infusion pump)-initial: 80100 units/kg, continuousinfusion: 1522 units/kg/hto maintain

the anti-Xa activity in the range of 0.30.7units/mL

Therapy routinely is monitored by theaPTT or PTT (activated partialthromboplastin time)


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Low-dose prophylaxis: subcutaneousadministration of heparin

5000 units every 8

12 hours. Because of the danger of hematoma

formation at the injection site, heparinmust never be administeredintramuscularly.


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Subcutaneous administration forlong term management of pts

(warfarin is CI) ex: pregnancy

35 000 U every 8-12 hours


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Prophylactic enoxaparin Subcutaneously; 30 mg twice daily or 40 mg

once daily.

Full-dose enoxaparin 1 mg/kg; subcutaneously every 12 hours ;

anti-factor Xa level of 0.51 unit/mL

Selected patients may be treated withenoxaparin 1.5 mg/kg once a day, with a targetanti-Xa level of 1.5 units/mL.


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Dalteparin 5000 units subcutaneously od

200 units/kg odforvenous disease

120 units/kg every 12 hoursacutecoronary syndrome

LMWH should be used with caution inpatients with renal insufficiency or bodyweight >150 kg.


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Monitoring of Heparin Effect

activated partial thromboplastin time (aPTT orPTT ) is necessary in patients receiving UFH

protamine titration (0.20.4 unit/mL) or anti-Xa

units (0.3

0.7 unit/mL) Weight-based dosing of the LMWH levels are not

generally measured except in the setting of renalinsufficiency, obesity, and pregnancy.

anti-Xa units (0.51 unit/mL for twice-daily 4hours after administration and ~1.5 units/mL foronce-daily)


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Adverse Effects of Heparin

Hemorrhage - 1

Increased loss of hair and reversiblealopecia

Osteoporosis, fractures andmineralocorticoid deficiencylong termtherapy

Heparin Induced Thrombocytopenia (HIT)a systemic hypercoagulable state

Caution: Allergic reaction


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Contraindications HIT Hypersensitivity to the drug

Active bleeding

Hemophilia

Significant thrombocytopenia

Purpura

Severe htn

Recent surgery of the brain, SC oreye

Pts undergoing lumbar punctureor regional anesthetic block

Intracranial hemorrhage

Infective endocarditis

Active tuberculosis

Ulcerative lesions of GItract

Threatened abortion

Visceral carcinoma

Advanced hepatic orrenal disease


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Oral Anticoagulants


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block the conversion of vitamin K epoxide tovitamin K

impairs the hepatic synthesis of several clottingfactors

dec. level of circulating clotting factors (II,VII,IX, X)

dec. blood coagulation and thrombogenesis


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Warfarin (Coumadin)

one of the most commonlyprescribed drugs

8- to 12-hour delay in the action

100% bioavailability Half life: 36 hrs


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Prevention of stroke in atrialfibrillation, clotting on new

prosthetic heart valves, and clotsin dilated cardiomyopathy


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Administration and Dosage

Initial: 510 mg

Initial adjustment of theprothrombin time takes about 1week, which usually results in amaintenance dose of 57 mg/d


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Adverse Effects and CI

Warfarin

Pregnancy

Hemorrhagic disorder in the fetus Birth defect abN bone formation

Cutaneous necrosis

Frank infarction of the breast, fatty tissues,intestine, and extremities Rare

Dicumarol

gastrointestinal distress (nausea, stomach cramps,

diarrhea)


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Other Anticoagulants


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Lepirudin (Refludan)

- a drug that directly inhibits thrombin; itcan be administered intravenously to preventexcessive clotting in conditions such as

heparin-induced thrombocytopenia


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Fondaparinux (Arixtra)

newer agent that can be administered by

subcutaneous injection to prevent DVTfollowing orthopedic procedures (hip, kneereplacement) and other surgeries

inhibits clotting factor Xa


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Ximelagatran

is new drug that is currently beingdeveloped to prevent or treat DVT. Itdirectly inhibits thrombin, but has theadvantage of oral administration


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Antithrombotic Drugs


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Standard therapy during the acutephase of myocardial infarction

Prolonged use of Aspirin one of theprimary pharmacological methodsused to prevent reinfarction and

maintain coronary artery patency


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Helps prevent the type of stroke causedby cerebral ischemia and infarction

Reduces the risk of ischemic stroke inpeople with atrial fibrillation

Prevents thrombus formation in

peripheral veins and thromboembolismfollowing surgical procedures


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Suggested daily dosage = 75 to 325mg/day

Adult Aspirin tablet = 325 mg/dayPediatric Aspirin tablet = 160 mg/day

Antithrombotic effects can be achievedat very low Aspirin doses


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Glycoprotein IIb-IIIa Inhibitors Most powerful inhibitors of platelet

activity Block (antagonize) the GP receptor on

the platelet membrane that is

stimulated by fibrinogen and otherchemical mediators


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Primarily used during balloonangioplasty and other percutaneouscoronary interventions that help re-establish coronary artery blood flow

Not typically administered orally

Abciximab (ReoPro), Eptifibatide(Integrilin), Tirofiban (Aggrastat)


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ADP Receptor Inhibitors Produce moderate inhibiton of platelet

activity

Aspirin < ADP Receptor inhibitors produce beneficial effects

Contraindication:

Hx of hemorrhagic stroke

Intracranial neoplasm

Active internal bleedingPossible aortic dissection

S ki


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Streptokinase

Most commonly used type ofthrombolytic

Indirectly activates plasmin to theprecursor molecule plasminogen

Dosage: 100,000units/hr for 24-72hrs.

U ki


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Urokinase

Directly converts plasminogen toplasmin

Dosage: 300,000units/hr for 12 hrs

Streptokinase and Urokinase

Both bring the activation ofplasmin

Ti l i i ( PA)


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Tissue plasminogen activator (t-PA)

Generic name:ALTEPLASE

Rapidly and effectively initiates clotbreakdown

Joins streptokinase as one of the primarythrombolytic agents

Used preferentially during ischemic stroke Dosage: 20mg/hr

A i t l (E i )


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Anistreplase (Eminase)

AKA: Anisoylated plasminogen-streptokinase activator complex (APSAC)

Formed by combining plasminogen with

streptokinase

More selective for clots that have alreadyformed

Less effect on systemic fibrinolysis

Dosage: 30units over 3-5mins

R l d T l


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Reteplase and Tenecteplase

Actions similar to t-PA (alteplase)

Administration through IV bolus injection

ADVERSE EFFECTS OF THROMBOLYTICDRUGS

Hemorrhage -> major adverse effect

FeverAllergic reaction (itching,nausea,headache

and other symptoms)


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Treatment of Clotting

Deficiencies


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Hemophilia

Replacing the missing clotting factor

Can be administered on a regular basis

or during acute hemorrhagic episode


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Deficiency of Vitamin K-dependentclotting factors

Treated by administering exogenousVitamin K

Available for oral or parenteraladministration


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Antifibrinolytics Prevent the activation of plasmin thus

preserving clot formation

Aminocaproic Acid (Amicar) andTranexamic Acid (cyklokapron)

For patient with hemophilia to prevent clotbreakdown when undergoing surgery

Oral or IV administration


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Adverse Effects:

Nausea Diarrhea

Dizziness

Headache


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THANK YOU and

GOD BLESS!

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Anticoagulants, Thrombolytics and Antiplatelet.pptx