drugs used in coagulation disorders - … of drugs used in coagulation disorders ... the extrinsic...
TRANSCRIPT
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DRUGS USED IN COAGULATION DISORDERS
Course:Integrated Therapeutics 1
Lecturer:Dr. E. Konorev
Date:November 1, 2010
Materials on:Exam #6
Required reading:Katzung, Chapter 34
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DISORDERS OF COAGULATIONTypes of coagulation disorders
– Excessive thrombosis• A thrombus is a blood clot that forms inside a
blood vessel or cavity of the heart• An embolus is a blood clot that moves through
the bloodstream until it lodges in a narrowed vessel and blocks circulation
• Arterial thrombi cause downstream ischemia of extremities or vital organs – may result in amputation or vital organ failure
• Venous thrombi can cause embolism (pulmonary embolism), and pain and severe swelling of the affected tissue
– Excessive bleeding• Increased bleeding due to vascular injury• Bleeding from mucosal sites• Internal bleeding into deep tissues
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TYPES OF BLOOD CLOTS
All clots involve both platelets and fibrin, but the degree of involvement of platelet/fibrin in thrombus formation depends on the vascular location
• White (platelet-rich) thrombus– Forms in high-pressure arteries and is the result
of platelet binding to damaged endothelium and aggregation with little involvement of fibrin
– Pathologic condition associated with white thrombi: local ischemia due to arterial occlusion (in coronary arteries: myocardial infarction / unstable angina)
• Red thrombus (fibrin-rich with trapped RBCs)
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TYPES OF BLOOD CLOTS
All clots involve both platelets and fibrin, but the degree of involvement of platelet/fibrin in thrombus formation depends on the vascular location
• White (platelet-rich) thrombus• Red thrombus (fibrin-rich with trapped RBCs)
– Forms in low-pressure veins and in the heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which red blood cells become enmeshed
– Pathologic condition associated with red thrombi: embolism and distal pathology (deep vein thrombosis resulting in pulmonary emboli; cardiogenic emboli resulting in embolic stroke)
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THROMBUS FORMATION
Scanning electron microphotograph of evolving red thrombus
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CATEGORIES OF DRUGS USED IN COAGULATION DISORDERS
Drugs used in thromboembolic disorders• Anticoagulants – regulate the function and
synthesis of clotting factors– Primarily used to prevent clots from forming in
the venous system and heart (red thrombi)• Antiplatelet drugs – inhibit platelet function
– Primarily used to prevent clots from forming in the arteries (white thrombi)
• Thrombolytics – destroy blood clots after they are formed– Re-establish blood flow through vessels once
clots have formedDrugs used in bleeding disorders
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CATEGORIES OF DRUGS USED IN THROMBOEMBOLIC DISORDERS
Thrombus formation at the site of the damaged vascular wall
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CATEGORIES OF DRUGS USED IN THROMBOEMBOLIC DISORDERS
Anticoagulants
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CATEGORIES OF DRUGS USED IN THROMBOEMBOLIC DISORDERS
AnticoagulantsAntiplatelet drugs
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CATEGORIES OF DRUGS USED IN THROMBOEMBOLIC DISORDERS
AnticoagulantsAntiplatelet drugs Thrombolytics
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ANTICOAGULANTS
• Parenteral anticoagulants– Indirect thrombin inhibitors
• Heparin preparations– Direct thrombin inhibitors (DTIs)
• Hirudin• Lepirudin• Bivalirudin• Argatroban
• Oral anticoagulants– Warfarin
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PARENTERAL ANTICOAGULANTS
Heparin preparations• Heparin sodium – unfractionated heparin (UFH,
combination of low and high molecular weights, purified from animal sources); higher activity
• Enoxaparin, Tinzaparin – low molecular weight heparins (LMW); lower activity
• Fondaparinux – synthetic pentasaccharide
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HEPARINHeparin – mechanism of action• Indirect thrombin inhibitor – binds plasma serine
protease inhibitor antithrombin and increases its activity by 1000-fold
• Direct binding to thrombin, factors IX, X, XI, and XII in the intrinsic system, and inhibition of their activity
ANTITHROMBIN
Heparin
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HEPARINHeparin – mechanism of action (continued)• Antiplatelet action – heparin binding to thrombin
inhibits thrombin-platelet interaction, and prevents platelet activation
• Binding to endothelium and leukocytes prevents leukocyte-leukocyte, leukocyte-platelet, and leukocyte-endothelial adhesion
ANTITHROMBIN
Heparin
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HEPARIN
Heparin – clinical use• Very hydrophilic; must be given IV or SC• Used to treat disorders secondary to red (fibrin-
rich) thrombi and reduce the risk of emboli– Protects against embolic stroke, pulmonary
emboli– Administer to patients with deep vein
thrombosis, atrial arrhythmias and other conditions that predispose towards red thrombi
– Prevention of emboli during surgery or in hospitalized patients (reduces risk of emboli)
– Heparin locks: prevents clots from forming in catheters
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HEPARIN• Adverse effects
– Bleeding– Heparin-induced thrombocytopenia (HIT)
• Mechanism: immunogenicity of the complex of heparin with platelet factor 4 (PF4)
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HEPARIN
• Adverse effects– Heparin-induced thrombocytopenia
(continued)• A systemic hypercoagulable state• Characterized by venous and arterial
thrombosis• Related to the immune response to
heparin• Treatment: to discontinue heparin and
administer DTI or Fondaparinux
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HEPARIN
• Contraindications– Severe hypertension– Active tuberculosis– Ulcers of GI tract– Patients with recent surgeries
• Reversal of heparin action– Protamine sulfate (will not reverse the action
of Fondaparinux)
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ANTITHROMBIN
Indirect thrombin inhibitors
Directthrombininhibitors
DIRECT THROMBIN INHIBITORS
Mechanism of action – direct inhibition of the protease activity of thrombin
• Bivalent direct thrombin inhibitors (bind at both active site and substrate recognition site)– Hirudin– Lepirudin
• Inhibitors binding only at the thrombin active site– Argatroban
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DIRECT THROMBIN INHIBITORS
• Hirudin – purified from medicinal leeches• Lepirudin – recombinant form of this protein
– Should be used with great caution – no antidote exists
– Used in heparin-induced thrombocytopenia– Repeated use may cause anaphylactic reaction
• Argatroban – small molecular weight inhibitor– Used in coronary angioplasty and heparin-
induced angioplasty– Short-acting drug – used intravenously
Adverse effects of direct thrombin inhibitors (DTI)• All DTI’s may cause bleeding
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ORAL ANTICOAGULANTSWarfarin – the most commonly
prescribed anticoagulant in U.S.
• Mechanism of action– Inhibits reactivation of
vitamin K, by inhibiting enzyme vit K epoxide reductase
– Inhibits carboxylation of glutamate residues by GGCX (γ-glutamyl carboxylase) in prothrombin and factors VII, IX, and X, making them inactive
• Two stereoisomers: R and S– S-isomer is 3 to 5-fold
more potent
Vit K epoxide
Vit K epoxidereductase
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ORAL ANTICOAGULANTS• Warfarin – Mechanism of action
VKOC1 – vit K epoxide reductase complex subunit 1GGCX - γ-glutamyl carboxylaseCALU – calumenin Proteins affected by carboxylationFactor II (prothrombin)Factors VII-X (intrinsic hemostatic factors)
Other proteins that function in apoptosis, bone ossification, extracellular matrix formation, etc.
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ORAL ANTICOAGULANTS
• Warfarin – Pharmacokinetics– R-warfarin is metabolized by CYP3A4, and
some other CYP isoforms– S-warfarin is metabolized primarily by
CYP2C9– OH-derivatives are pumped out of
hepatocytes by ABCB1 transporter into bile, excreted with bile
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ORAL ANTICOAGULANTS
• Warfarin – Pharmacokinetics (continued)– Administered orally– Has 100% bioavailability– Delayed onset of action (12 h)– Long half-life (36 hr)– 99% of it is bound to plasma albumin
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ORAL ANTICOAGULANTS
Warfarin• Clinical use
– Used to prevent thrombosis or prevent/treat thromboembolism
– Atrial fibrillation– Prosthetic heart valves– Deep venous thrombosis
• Adverse effects– Teratogenic effect (bleeding disorder in fetus,
abnormal bone formation)– Skin necrosis, infarction of breasts, intestines,
extremities– Osteoporosis – Bleeding
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ORAL ANTICOAGULANTSWarfarin• Narrow therapeutic window• FDA estimates that 2 million patients start taking
warfarin every year in U.S.• Warfarin is second most common drug (after
insulin) implicated in emergency room visits for adverse effects
• Correct warfarin dose varies widely from patient to patient– Significant individual variability based on
disease states and genetic make-up– Multiple drug interactions
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ORAL ANTICOAGULANTS
• Warfarin dose is titrated based on laboratory testing– Prothrombin time (PT) – time to coagulation of
plasma after the addition of a Tissue Factor (TF, or Factor III) – used for the evaluation of the extrinsic pathway
– International normalized ratio (INR)• 0.9-1.3 – normal• 0.5 – high chance of thrombosis • 4.0-5.0 – high chance of bleeding• 2.0-3.0 – range for patients on warfarin
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ORAL ANTICOAGULANTSIndividual variability in the action of warfarin• Pharmacogenomics of warfarin
– VKORC1 (vit K epoxide reductase complex subunit 1) – responsible for 30% variation in dose (low and high dose haplotypes), • High dose haplotype is more common in
African Americans, they are more resistant to warfarin
• Low dose haplotype is more common in Asian American patients, they are less resistant to warfarin
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ORAL ANTICOAGULANTSIndividual variability in the action of warfarin• Pharmacogenomics of warfarin (continued)
– CYP2C9 – responsible for 10% variation in dose, mainly among Caucasian patients
– Calumenin – endogenous endoplasmic reticulum protein inhibitor of GGCX (carboxylase enzyme)
– FDA now encourages health professionals to test patients for their polymorphisms in these specific genes, to determine an effective and safe dose –kits are now available
• Effect of disease states– Hyperthyroidism patients will require lower doses,
while hypothyroid patients are more resistant to warfarin
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ORAL ANTICOAGULANTSWarfarin drug interactions• Pharmacokinetic interactions
– CYP enzyme induction– CYP enzyme inhibition– Reduced plasma protein binding
• Pharmacodynamic interactions– Synergism with other antithrombotic drugs– Reduced clotting factor synthesis (in liver
diseases)– Competitive antagonism (vit K)– Clotting factor concentration (diuretics)
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ORAL ANTICOAGULANTSPharmacokinetic and pharmacodynamic drug and body
interactions with warfarinIncreased Prothrombin Time Decreased Prothrombin Time
Pharmacokinetic Pharmacodynamic Pharmacokinetic PharmacodynamicAmiodarone Drugs Barbiturates DrugsCimetidine Aspirin (high doses) Cholestyramine Diuretics
Disulfiram Cephalosporins, third-generation Rifampin Vitamin K
Metronidazole1 Heparin Other factorsFluconazole1 Other factors HypothyroidismPhenylbutazone1 Hepatic diseaseSulfinpyrazone1 HyperthyroidismTrimethoprim-
sulfamethoxazole1Stereoselectively inhibits the oxidative metabolism of the (S)-warfarin enantiomorph of
racemic warfarin.
Reversal of warfarin action•Vitamin K, fresh-frozen plasma
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• Categories of antiplatelet drugs– Inhibitors of thromboxane A2 synthesis
• Aspirin (acetylsalicylic acid)– ADP Receptor Blockers
• Clopidogrel• Ticlopidine
– Platelet glycoprotein receptor blockers• Abciximab• Eptifibatide• Tirofiban
ANTIPLATELET DRUGS
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ANTIPLATELET DRUGSAspirin• Mechanism of action –
inhibition of cyclooxygenase 1
• Clinical use– Prevent heart
attacks/acute myocardial infarction
– Arterial thrombosis of the limbs resulting in intermittent claudication
– Ischemic stroke• Adverse effects
– Peptic ulcer– GI bleeding
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USE OF ASPIRIN FOR THE PREVENTION OF ACUTE MYOCARDIAL INFARCTION
White thrombus
Aspirin and other anti-platelet drugs
Aspirin: prevents coronary occlusion or re-occlusion due to clot formation:
• Protects against heart attack in individuals with angina pectoris• When taken at the time of or after a heart attack (160 mg),
aspirin increases survival and reduces the risk of another heart attack
• Aspirin reduces the risk of thrombotic stroke• Risk for severe bleeding prevents systematic use of aspirin by
low-risk individuals• When administered prophylactically, should be taken at lowest
dose possible (75 -150 mg/day)
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ANTIPLATELET DRUGSClopidogrelTiclopidine• Mechanism of action –
irreversibly block ADP receptors
• Clinical use– Prevention of arterial
thrombosis in myocardial ischemia and stroke patients
– Prevention of thrombosis in patients undergoing coronary stent surgery
Inhibition of ADP-induced platelet aggregation
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ANTIPLATELET DRUGSPharmacogenomics of Clopidogrel• High variability of Clopidogrel action• Related primarily to metabolism by CYP2C19
isoenzyme• Nonfunctional CYP2C19 allele is present in 50%
Chinese, 34% African Americans, 25% Caucasians, and 19% Mexican Americans
• FDA Boxed warning (March 2010)
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ANTIPLATELET DRUGSClopidogrelTiclopidine• Adverse effects
– Ticlopidine• Thrombotic thombocytopenic purpura• GI: nausea, dispepsia, diarrhea• Bleeding• Leukopenia
– Clopidogrel • Less side effects that ticlopidine – is a
preferred drug over ticlopidine
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ANTIPLATELET DRUGSPlatelet glycoprotein (GP) receptor antagonists• Abciximab – Anti-GPIIb/IIIa antibody• Tirofibane, Eptifibatide – GPIIb/IIIa Antagonists• Mechanism of action
– Antagonize receptors on platelet cell membranes to prevent physical interaction of platelets with fibinogen; inhibit platelet aggregation
Platelet GP (glycoprotein) IIb/IIIa receptorfor fibrinogen, vitronectin, fibronectin, von Willebrand factor
Fibrinogen
Platelet Platelet
GP IIb/IIIa Antagonist
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ANTIPLATELET DRUGSPlatelet glycoprotein (GP) receptor antagonists• Abciximab – Anti-GPIIb/IIIa antibody• Tirofibane, Eptifibatide – GPIIb/IIIa Antagonists• Clinical use
– Prevention of thrombosis in unstable angina, other acute coronary syndromes and percutaneous coronary angioplasty
Platelet GP (glycoprotein) IIb/IIIa receptorfor fibrinogen, vitronectin, fibronectin, von Willebrand factor
Fibrinogen
Platelet Platelet
GP IIb/IIIa Antagonist
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THROMBOLYTIC (FIBRINOLYTIC) DRUGS
• Induce fibrinolysis (lyse fibrin in thrombi after they have formed)
• General mechanism: activate endogenous fibrinolytic system by different mechanisms
Fibrinolytic drugs
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THROMBOLYTIC (FIBRINOLYTIC) DRUGSPlasminogen – plasma zymogen that forms active enzyme upon cleavage of the peptide bond between Arg-560 and Val-561 by tPA or uPA
Plasmin – active serine protease that cleaves and degrades fibrin and other proteins (fibronectin, laminin, thrombospondin, vWf)
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Streptokinase
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THROMBOLYTIC (FIBRINOLYTIC) DRUGS
Types of fibrinolytic drugs (they all activate plasmin)• Tissue-type plasminogen activator (tPA) –
endogenous protein that cleaves plasminogen, released by endothelium, needs fibrin as coactivator
• Urokinase-type plasminogen activator (urokinase, uPA) – endogenous protein, produced in kidneys; a human enzyme directly converting plasminogen to plasmin
• Streptokinase – protein released by β-hemolytic Streptococci, forms the complex with plasminogen, converts it into plasmin by non-proteolytic mechanism
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FIBRINOLYTIC DRUGS
•tPA: Tissue-type Plasminogen Activator drugs•Alteplase (Activase): recombinant human protein•Reteplase: recombinant modified human protein •Tenecteplase: recombinant mutated human protein
•uPA: urokinase-type Plasminogen Activator•Urokinase
•Streptokinase preparations•Streptokinase (Streptase): purified from bacteria•Anistreplase, a complex of purified human plasminogen and bacterial streptokinase
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FIBRINOLYTIC DRUGS• Clinical uses
• Embolic/thrombotic stroke• Acute myocardial infarction• Pulmonary embolism• Deep venous thrombosis• Ascending thrombophlebitis
44Clot in cerebral artery – stroke
Before t-PA After t-PA • Treat with t-PA to break down the clot and open up artery
• Most effective within 3 hrs after embolic and thrombotic stroke
• Can exacerbate the damage produced by hemorrhagic stroke
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FIBRINOLYTIC DRUGSAdverse effects• Bleeding from the systemic fibrinogenolysis
(streptokinase, urokinase)• Allergic reactions (streptokinase)
Systemic fibrinogenolysis with Streptokinase
Streptokinase,Urokinase
tPA
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CATEGORIES OF DRUGS USED IN COAGULATION DISORDERS
Drugs used in thromboembolic disorders• Anticoagulants• Antiplatelet drugs• ThrombolyticsDrugs used in bleeding disorders• Inhibitors of fibrinolysis
– Aminocaproic acid– Aprotinin
• Vitamin K• Protamine – reverses effects of heparin
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INHIBITORS OF FIBRINOLYSISAminocaproic acid• Mechanism of action
– Structurally similar to amino acid lysine– Plasminogen binds to arginine and lysine
residues on fibrinogen– Aminocaproic acid inhibits binding and
activation of plasminogen into plasmin• Clinical indications
– Hemophilia– Bleeding from thrombolytic therapy– Prevention of bleeding from intracranial
aneurysms– Post-surgery bleeding
• Adverse effects– Intravascular thrombosis
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INHIBITORS OF FIBRINOLYSIS
Aprotinin• Serine protease inhibitor – inhibits fibrinolysis by
plasmin• Used to reduce bleeding from surgery,
especially involving extracorporeal circulation (open heart surgery, liver transplant)
• Adverse effects– Intravascular thrombosis – myocardial
infarction, stroke– Renal damage– Anaphylactic reaction
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OTHER PROCOAGULANT DRUGS
Vitamin K• Induces activity of prothrombin and factors VII, IX, X
(postranslational modification – carboxylation)• Synthesized by bacterial flora in human intestine• Antagonist of an oral anticoagulant warfarin• Clinical uses
– Overdose of warfarin– In newborns (especially prematurely born
infants), and other cases of vitamin K deficiency
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OTHER PROCOAGULANT DRUGS
Protamine• Antagonist of parenteral anticoagulant heparin• Highly basic peptide that reacts with negatively
charged heparin forming a stable complex with no anticoagulant activity
• Will not reverse the activity of fondaparinux• Inactivation of LMW heparin preparations is
incomplete
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