Drugs Used in Disorders of Coagulation
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Transcript of Drugs Used in Disorders of Coagulation
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LEARNING OBJECTIVES:1.Understand the coagulation mechanism2.Define the terms antithrombotics and thrombolytics3.Classify the drugs used in coagulation disorder4.Describe the mechanism of action of each drug5.Give the clinical significance of each agent6.Discuss the adverse effects of each class or drug
Chapter 34
Drugs Used in Disorders of Coagulation
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EVENTS IN HEMOSTASISPLATELET MIGRATION AND AGGREGATION
Product: PLATELET PLUG (white thrombus/primary hemostasis)ACTIVATION OF COAGULATION CASCADE
Product: PERMANENT CLOT (red thrombus/secondary hemostasis)
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PLATELET MIGRATION AND ACTIVATION
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PLATELET ADHESIONPlatelet membrane
receptors include;The glycoprotein (GP) Ia
receptor binding to collagen (C); GP Ib receptor binding von
Willebrand factor (vWF)
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PLATELET ACTIVATIONPlatelet membrane receptors include;
GP IIb/IIIa, which binds fibrinogen and other macromolecules
Aggregating Substances:Adenosine Diphosphate (ADP)Thromboxane A2 (TXA2)Serotonin (5-HT)
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Aggregating SubstancesThromboxane A2 (TXA2) is synthesized
from arachidonic acid within platelets and is a platelet activator and potent vasoconstrictor.
Products secreted from platelet granules;Adenosine Diphosphate (ADP), a powerful
inducer of platelet aggregation, and Serotonin (5-HT), which stimulates
aggregation and vasoconstriction.
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PLATELET AGGREGRATION
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ACTIVATION OF BLOOD COAGULATION CASCADEOccurs within 6-12 hours from time of injuryGOAL: To activate thrombin (Clotting Factor
IIa), which is required in converting fibrinogen (Clotting Factor I) to its activated form (Fibrin)Fibrin – polymerized form of fibrinogen that
stabilizes the platelet plugDeposit onto platelet plug and glues platelets togetherAttracts other cells esp. RBC to deposit onto the platelet
plug (red thrombus)2 Pathways:
Extrinsic - dominantIntrinsic
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Blood Coagulation Cascade (Extrinsic Pathway)
Initiation of clotting
soluble insoluble
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REGULATION OF THROMBOSISPlasminAntithrombin IIIProtein C and Protein S
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PLASMINA protease; responsible for facilitating
FIBRINOLYSISFIBRINOLYSIS – process of fibrin digestion
t-PA
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ANTITHROMBIN III; PROTEIN C and SAntithrombin III (ATIII)
ROLE: Directly inactivates activated clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa)
Protein C and SAttenuate the blood clotting cascade by
proteolysis of two co-factors Va and VIIIa.
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ANTITHROMBOTICSa. Anticoagulants
- slow down clotting/prevent formation of clottingb. Antiplatelets
- prevent platelet aggregationTHROMBOLYTICS
- degrade clots that have already formed
ANTITHROMBOTICS and THROMBOLYTICS
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Drugs Used in Coagulation Disorders
ANTICOAGULANTS (ANTITHROMBOTICS)Endogenous anticoagulant – Protein C Mucopolysaccharide Antithrombin III – Heparin
Vitamin K analogue – WarfarinDirect thrombin inhibitors
Hirudin (leech protein) LepirudinBivalirudin ArgatrobanDabigatran
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Drugs Used in Coagulation Disorders
ANTIPLATELETS (ANTITHROMBOTICS)GP IIb/IIIa receptor antagonist
Abciximab (monoclonal antibody)EptifibatideTirofiban
ADP receptor antagonistTiclopidineClopidogrel
TXA2 (COX) inhibitorAspirin
PDE/adenosine uptake inhibitorDipyridamoleCilostazol
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Drugs Used in Coagulation Disorders
THROMBOLYTICS (FIBRINOLYTICS)StreptokinaseAnistreplaseUrokinaseAlteplaseReteplase
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HEPARIN• A heterogeneous mixture of sulfated mucopolysaccharides• An indirect thrombin inhibitor (parenteral)
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HEPARINFORMS:
Regular Heparin/ HMW Heparin/ Unfractionated Heparin
LMW HeparinsEnoxaparinDalteparinFondaparinuxFraxiparinDanaproid
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MECHANISM OF ACTIONREGULAR HEPARIN:
Binds and forms an active complex to antithrombin III (inhibits clotting factors IIa, IXa, Xa, XIa, XIIa, XIIIa) The binding accelerates ATIII’s action by 1000-fold
LMWHs:More selective binding at Xa.
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CLINICAL USESGiven when initiating anti-coagulation
therapyMx of acute coronary syndromeTx (IV) and prevention (IV or SQ) of
pulmonary embolismMx of Deep Vein Thrombosis (DVT)When anticoagulation is necessary
during pregnancy
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Toxicity and Miscellaneous effects of Heparin
BLEEDING Close monitoring is recommended
Should be used with caution in hypersensitive patients
Increased hairloss and reversible alopeciaOsteoporosis - long-term therapyHeparin accelerates the clearing of postprandial
lipemia by causing the release of lipoprotein lipase from tissues
Heparin-induced thrombocytopenia (HIT)Long-term use is associated with
mineralocorticoid deficiency
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CONTRAINDICATIONSHITHypersensitivity to the
drugActive bleedingHemophiliaSignificant
thrombocytopeniaPurpuraSevere hypertensionIntracranial hemorrhageInfective endocarditis
Active tuberculosisUlcerative lesions of
the gastrointestinal tract
Threatened abortionVisceral carcinomaAdvanced hepatic or
renal disease
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CONTRAINDICATIONSShould be avoided
in patients who have recently had surgery of the brain, spinal cord, or eye, and in patients who are undergoing lumbar puncture or regional anesthetic block
Should be used in pregnant women only when clearly indicated
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REVERSAL OF EFFECTS OF HEPARINPROTAMINE SULFATE
Highly basic100 units of Heparin = 1 mg Protamine
Sulfate (IV)
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WARFARIN & THE COUMARIN
ANTICOAGULANTS
Historical Drugs:Dicumarol: Now used as rodenticide
SE: inc. risk of GI bleeding, ulceration,
Indanediones: Phenindione SE: thrombocytopenia, fatal hypersensitivity rxn
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WARFARINThe only oral anticoagulant used in clinicsS-isomer is the active isomerMechanism of Action:
Inhibits hepatic synthesis of Vitamin K-dependent clotting factors
Blockade of gamma-carboxylation of several glutamate residues in clotting factors X, IX, VII, II
8- to 12-hour delay in the action
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Mechanism of ActionProtein carboxylation reaction is coupled to the oxidation of Vit.K
Vitamin K epoxide (inactive)
Hydroquinone form (active)
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INDICATIONSDeep venous thrombosisIsch.heart diseaseRHDPulmonary Embolism
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WARFARINThe therapeutic range for oral
anticoagulant therapy is defined in terms of an Prothrombin Time-International Normalized Ratio (PT-INR) Category PT-INRMost Patients 2-3
Px has prosthetic heart valves
2.5-3.5
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DRUG INTERACTIONSINCREASED PT-INR: INCREASED RISK OF
HEMORRHAGE/BLEEDINGPharmacokinetic:
Reduced plasma protein binding: Pyrazolone derivatives
Enzyme Inhibitors: Amiodarone, Cotrimoxazole, Cimetidine, Azole Antifungals, Macrolides, Metronidazole
Pharmacodynamic: ASA (high doses), 3rd Generation Cephalosporins,
Heparin, Chronic liver disease, Hyperthyroidism
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DRUG INTERACTIONSDECREASED PT-INR: INCREASED RISK OF
THROMBOSISPharmacokinetic:
Enzyme Inducers: Barbiturates, RifampinSome drugs that prevent absorption
Pharmacodynamic: Vitamin K, Diuretics, Hypothyroidism
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UNDERSIRABLE EFFECTSCutaneous necrosis within the 1st week of
treatment“Purple Toe" syndrome - seen after at least 3 weeks
of warfarin use due to cholesterol embolizationBleeding / hemorrhageGI upsetComplications in pregnancy (CI):
Within 1st trimester - abnormal bone development - teratogenic effect
Within 3rd trimester - hemorrhagic disorder in the newborn - present with necrotizing enterocolitis (fatal in newborn)
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DIRECT THROMBIN INHIBITORS
PARENTERAL• Hirudin – from leech saliva• Lepirudin - recombinant form of Hirudin• Bivalirudin• Argatroban ORAL• Ximelagatran – withdrawn from the market• Dabigatran
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DIRECT THROMBIN INHIBITORS
Exert their anticoagulant effects by directly binding to the active site of thrombin
Intrinsic
Prothrombin
Fibrin
Xa
Extrinsic
Thrombin
Fibrinogen
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Therapeutic usesLepirudin - use in patients with thrombosis
related to heparin-induced thrombocytopeniaBivalirudin - FDA-approved for use in
percutaneous coronary angioplastyArgatroban - FDA-approved for use in
patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT
Dabigatran - approved for use in Europe for prevention of venous thromboembolism in patients who have undergone hip or knee replacement surgery
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Summary of anticoagulants
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ANTITHROMBOTICS (ANTIPLATELET DRUGS)
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MECHANISM OF ACTION OF ANTITHROMBOTIC AGENTS
DRUG MECHANISM OF ACTIONASPIRIN Inhibits COX, thus prevents TXA2 and
PGsCLOPIDOGREL & TICLOPIDINE
Inhibit ADP pathway of platelet formation
DIPYRIDAMOLE PDE inhibitor, thus increasing cAMP levels to potentiate PGI2 (platelet aggregation inhibitor)
ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN
Inhibit glycoprotein IIb/IIIa, necessary molecule for platelet aggregation
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ASPIRIN
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ASPIRINFor primary prophylaxis of myocardial
infarction 325 mg/day
For secondary prevention of vascular events among patients with a history of vascular disease
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CLOPIDOGREL AND
TICLOPIDINE
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General MOA of Antithrombotic Drugs
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USES AND UNDESIRABLE EFFECTS OF ANTITHROMBOTIC AGENTS
DRUG INDICATION UNDESIRABLE EFFECTSASPIRIN Reduces the risk of MI in
patients with unstable angina
GI ulcer, bleeding, hemorrhage
CLOPIDOGREL & TICLOPIDINE
Reduction of atherosclerotic events, prevent thrombosis
Ticlopidine: Nausea, dyspepsia, hemorrhage, leukopenia
Clopidogrel: fewer adverse effects than ticlopidine
DIPYRIDAMOLE Prevents emboli May worsen angina, dizziness, headache, syncope, GI disturbances, rash
ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN
Acute coronary syndrome
Bleeding
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THROMBOLYTIC AGENTSStreptokinaseUrokinaseAnistreplaseTissue Plasminogen Activator (TPA)AlteplaseReteplase
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USES OF FIBRINOLYTICSIn the management of acute myocardial
infarction Indicated in cases of ;
pulmonary embolism with hemodynamic instability,
severe deep venous thrombosis such as the superior vena caval syndrome, and
ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema
Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset
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Drugs Used in Bleeding Disorders
• VITAMIN K• PLASMA FRACTIONS• DESMOPRESSIN ACETATE • FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID• SERINE PROTEASE INHIBITORS: APROTININ (removed from the market)
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VITAMIN KTwo natural forms exist:
Vitamin K1 (phytonadione) is found in food Vitamin K2 (menaquinone) is found in human
tissues and is synthesized by intestinal bacteriaUsed in treating Warfarin overdosage
Vit.K3 (menadione) – water soluble; ineffective in warfarin overdosage
Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency
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PLASMA FRACTIONSUsed for the treatment of blood clotting
factors deficiencies such as;Factor VIII deficiency (classic hemophilia,
or hemophilia A) Factor IX deficiency (Christmas disease, or
hemophilia B) Humate-P
is a factor VIII concentrate approved by the FDA for the treatment of bleeding associated with von Willebrand disease
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DESMOPRESSIN ACETATE Increases the factor VIII activity of patients
with mild hemophilia A or von Willebrand disease
Can be used in preparation for minor surgery such as tooth extraction
Available in high-dose intranasal desmopressin
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CRYOPRECIPITATEPlasma protein fraction obtainable from
whole bloodContains 300 mg of fibrinogenUsed to treat deficiencies or qualitative
abnormalities of fibrinogenMay also be used for patients with factor
VIII deficiency and von Willebrand disease if desmopressin is not indicated and a pathogen-inactivated, recombinant, or plasma-derived product is not available
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AMINOCAPROIC ACIDA synthetic inhibitor of fibrinolysisAn adjunctive therapy in hemophiliaAs therapy for bleeding from fibrinolytic
therapy,Prophylaxis for rebleeding from intracranial
aneurysmsHas been used in patients with postsurgical
gastrointestinal bleeding and postprostatectomy bleeding and bladder hemorrhage secondary to radiation- and drug-induced cystitis
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AMINOCAPROIC ACIDAdverse effects of the drug include;
Intravascular thrombosis from inhibition of plasminogen activator
HypotensionMyopathyabdominal discomfortdiarrhea, andnasal stuffiness
Should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract because of the potential for excessive clotting
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TRANEXAMIC ACID Is an analog of aminocaproic acidSame properties as Aminocaproic acid