Drugs that Influence Coagulation

Review Hemostasis Audiovisual Tutorial McGraw Hill Recommended Reading: Management of Coagulation Disorders Formative Assessment Practice question set #1 Clinical: E-Medicine Article Disseminated Intravascular Coagulation

CV Pharmacology

Prepared and Presenter: Marc Imhotep Cray, M.D. Professor Pharmacology

Lecture Outline

Review of Hemostasis /Coagulation/ Thrombogenesis / Fibrinolysis Anticoagulant Drugs Pharmacology Fibrolytic Drugs Pharmacology Antithrombotic / Antiplatelet Drugs Pharmacology

Coagulation Physiology

Coagulation is a complex process by which blood forms clots It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet and fibrin containing clot to stop bleeding and begin repair of the damaged vessel Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) and/or clotting (thrombosis)
3

Coagulation Physiology(2)
Platelet activation 1. Damage to blood vessel walls exposes subendothelium proteins, most notably collagen, present under the endothelium 2. Circulating platelets bind collagen with surface collagen-specific glycoprotein Ia/IIa receptors
4

Coagulation Physiology(2)
3.

4.

Adhesion is strengthened further by the large, multimeric circulating proteins von Willebrand factor (vWF), which forms links between the platelets glycoprotein Ib/IX/V and the collagen fibrils. This adhesion activates the platelets
5

Review Hemostasis
Audiovisual Tutorial McGraw Hill
Pathway of Thrombogenesis Click to read source: http://www.heartzine.com/170.pdf

Thrombogenesis: Sequence and Characteristics

Normal:

Normal vascular endothelial cells:

not thrombogenic (platelet/clotting factors do not adhere)

Injury

thrombogenesis

Immediate response: vasospasm Platelet adherence to damaged epithelium (binds to collagen) referred to as platelet adhesion. (collagen-platelet membrane glycoprotein Ia receptor interaction)
7

Thrombogenesis: Sequence and Characteristics

Platelets binding to each other: platelet aggregation Platelets form a gelatinous mass (losing individual membranes): viscous metamorphosis platelet plug (temporary cessation of bleeding) Platelet plug -- reinforcement by fibrin

Thrombogenesis: Sequence and Characteristics

Fibrin reinforcement:

damaged vessel released

exposed collagen + platelet content

Platelet degranulation releases aggregating substances: ADP TXA2 5-HT platelet ADP release (ADP inducer of platelet aggregation) prostaglandin synthesis (derived from platelet membrane arachidonic acid) Thrombogenesis/vasoconstriction: thromboxane A2 , TXA2) Thrombogenesis inhibitor: prostacyclin
9

local thrombin production:

See Notes for Explanation

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

10

Inactivation of coagulation proteins

Plasma Protease Inhibitors:

a1-antiprotease a2-macroglobulin a2-antiplasmin antithrombin III

-----Failure of plasma protease inhibitor system: ----Disseminated Intravascular Coagulation (DIC)-- may occur following:

obstetrical emergencies (abruptio placentae; bacterial sepsisreprint major tissue injury

cell lysis: neoplastic disease
11

Clotting Factors: Drug Target Sites

Factor/Component I II III IV V VII VIII IX X XI XII XIII Proteins C and S Plasminogen Fibrinogen Prothrombin Tissue Thromboplastin Calcium Proaccelerin Proconvertin Antihemophilic globulin (AHG) Christmas factor, plasma thromboplastin component (PTC) Stuart-Prower factor Plasma thromboplastin antecedent (PTA) Hageman factor Fibrin-stabilizing factor ------------Warfarin (synthesis) Thrombolytic enzymes, aminocaproic acid Heparin (IXa); Warfarin (synthesis) Heparin (IXa); Warfarin (synthesis) Heparin (VIIa); Warfarin (synthesis) Heparin (IIa); Warfarin (synthesis) also called Target

12

Anticoagulant Drugs: Pharmacology

Heparin Mechanism of Action: Binds to endothelial cell surface membrane Heparin activity dependent on: plasma protease inhibitor antithrombin III

Antithrombin III -- inhibitor of clotting factors proteases (forming 1:1 stable complexes) Complex forming reactions normally slow -accelerated by three orders of magnitude (1000 times) by heparin
13

Anticoagulant Drugs: Pharmacology

Heparin Toxicity: Long-term major adverse/toxic effect: bleeding heparin use- Risk managed by attention to: increased patient selection incidence of: dosage control monitoring of partial osteoporosis thromboplastin time (PTT) Factors predisposing to hemorrhage: spontaneous elderly fractures renal failure patients
14

Anticoagulant Drugs: Pharmacology

Heparin Contraindications: Heparin hypersensitivity Hematologic disease:

hemophilia, thrombocytopenia, purpura

Cardiovascular:

severe hypertension, intracranial hemorrhage, infective endocarditis

Active tuberculosis
15

Anticoagulant Drugs: Pharmacology

Heparin Contraindications: Gastrointestinal tract

ulcerative lesions visceral carcinoma

Advanced hepatic/renal dysfunction Threatened abortion Related to medical procedures:

after brain, spinal cord, or eye surgery lumbar puncture/regional anesthesia blocks
16

Anticoagulant Drugs: Pharmacology

Reversal of Heparin Effects: drug discontinuation Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)

17

Anticoagulant Drugs: Pharmacology

Warfarin & Coumarin Chemistry/Pharmacokinetics: Warfarin & Coumarin Coumarin: produces plasma prothrombin deficiency active agent --: bishydroxycoumarin (synthesis - dicumarol) Uses: rodenticide humans: antithrombotic agent
18

Anticoagulant Drugs: Pharmacology

Oral anticoagulants:
Warfarin -- agent in use high bioavailability; most bound to plasma albumin (99%) racemate-- equal amounts of two enantiomorphs

levorotatory-S-warfarin: four times more potent than dextrorotatory- Rwarfarin

19

Anticoagulant Drugs: Pharmacology

Mechanism of Action: Coumarin anticoagulants Blockade of g-carboxylation of glutamate residues in:

g-carboxylation results in biologically inactive molecules Carboxylation reaction is coupled with oxidative deactivation of vitamin K
20

prothrombin factors: VII, IX, X endogenous anticoagulant protein C

Anticoagulant Drugs: Pharmacology

Mechanism of Action: Coumarin anticoagulants Anticoagulant effect dependent on two considerations 1. Partially inhibited synthesis of the four vitamin K-dependent clotting factors and 2. Altered degradation rates of these factors Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis
21

Anticoagulant Drugs: Pharmacology

Toxicity: coumarin anticoagulants Warfarin: crosses the placenta hemorrhagic fetal disorder
Fetal abnormal bone formation (Warfarin effects on fetal proteins with g-carboxylglutamate residues) Never administer Warfarin during pregnancy

22

Anticoagulant Drugs: Pharmacology

Other Adverse Effects: coumarin anticoagulants Cutaneous necrosis related to reduced protein C activity Rare: reduced protein C activity breast, fatty tissues, intestine, extremity infarction

23

Anticoagulant Drugs: Pharmacology

Drug-Drug Interactions: oral anticoagulants Pharmacokinetic effects include: enzyme induction reduced plasma protein binding Pharmacodynamic effects include: synergistic interactions with Warfarin impaired hemostasis, diminish clotting factor synthesis (e.g. hepatic disease) competitive antagonism (vitamin K) abnormal physiologic vitamin K control loop (hereditary oral anticoagulant resistance)
24

Drug-Drug Interactions

See:American Family Physician Vol. 61/No. 6 (March 15, 2000) Clinical Pharmacology Clinically Significant Drug Interactions

PAUL W. AMENT, PHARM.D., JOHN G. BERTOLINO, M.D., M.S.P.H., and JAMES L. LISZEWSKI, M.D.

Family physicians should be alert for drug interactions and should have appropriate resources to help them avoid or manage these interactions. Drug interactions may be encountered with such commonly used medications as antibiotics, warfarin, antidepressants and oral contraceptives

25

Anticoagulant Drugs: Pharmacology

Drug-Drug Interactions: oral anticoagulants Most serious interaction:-- interactions that increase anti-coagulation (promote bleeding risk) most dangerous: pharmacokinetic interactions with:

pyrazolones phenylbutazone & sulfinpyrazone-- effects: a

added hypoprothrombinemia platelet function inhibition promotion: peptic ulcer disease

Amiodarone, disulfram, cimetadine:

inhibit metabolism of Warfarin (both enantiomorphs)

26

Anticoagulant Drugs: Pharmacology

Drug-Drug Interactions: oral anticoagulants

pharmacodynamic: Aspirin:effects on platelets hepatic disease /hypothyroidism: increasing clotting factors turnover rates Third-generation cephalosporins kill intestinal bacteria that produce vitamin K directly inhibit vitamin K epoxide reductase

Aspirin, hepatic disease, hypothyroidism -enhance Warfarin effects

27

Anticoagulant Drugs: Pharmacology

Drug-Drug Interactions: oral anticoagulants Decrease of anticoagulant action: Barbiturates & rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin. Cholestyramine: promotes intestinal Warfarin binding
28

Anticoagulant Drugs: Pharmacology

Pharmacodynamic -mediated reduction of anticoagulant effects: 1. vitamin K -- {increased clotting factors synthesis} 2. diuretics -- chlorthalidone, spironolactone {affect clotting factor concentration} 3. genetics -- {molecular mutations of vitamin K reactivation cycle components} 4. hypothyroidism -- {reduced clotting factors turnover rate}

29

Anticoagulant Drugs: Pharmacology

Reversal of Warfarin anticoagulant effects: discontinue drug administration administer vitamin K1 (phytonadione) & fresh-frozen plasma or factor IX concentrates Objective of intervention: establishing normal clotting factor activity

serious bleeding: large amounts of vitamin K1 (intravenous administration), factor IX concentrates, and possibly whole blood transfusion
30

Fibrolytic Drugs Pharmacology

Overview: fibrolytic drugs Lyse thrombi by catalyzing plasmin (serine protease) formation from plasminogen (the zymogen precursor) Lytic state induced following IV administration Note: both target thromboemboli and hemostatic thrombi are dissolved
31

Fibrinolysis

Major process: conversion plasminogen (inactive) plasmin (proteolytic enzyme, active) plasminogen activators: released from damaged cells Plasmin:

limits thrombosis extension (by proteolytic fibrin digestion) Activators of fibrinolysis:

Drug interventions: fibrinolytic system:

tissue plasminogen activator (t-PA) urokinase (Abbokinase) streptokinase (Streptase, Kabikinase) aminocaproic acid (Amicar)
32

Inhibitors of fibrinolysis:

Fibrinolysis

See: Graphical representation of the fibrinolytic pathway

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition. From: http://en.wikipedia.org/wiki/Fibrinolysis 33

Fibrolytic Drugs Pharmacology

streptokinase, alteplase, tissue plasminogen activator, reteplase, urokinase

34

Fibrolytic Drugs Pharmacology

Streptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci)

combines with plasminogen (proactivator) Enzymic complex catalyzes: plasminogen active plasmin

35

Fibrolytic Drugs Pharmacology

Urokinase (Abbokinase):(human enzyme; renal) Catalyzes: plasminogen active plasmin Note: Plasmin cannot be directly used because of endogenous inhibitors;

endogenous antiplasmins do not affect urokinase or streptokinase-proactivator complex Urokinase (and streptokinase-proactivator complex) promote plasmin formation inside the thrombus lyse thrombus from within
36

Fibrolytic Drugs Pharmacology

Anistreplase (APSAC, Eminase) (anisoylated plasminogen streptokinase activator complex; APSAC) purified human plasminogen - bacterial acylated streptokinase complex {upon administration deacylation activates streptokinase-proactivator complex} rapid IV injection enhanced clot selectivity -- more plasminogen activity clot-associated than associated with free blood plasminogen more thrombolytic activity
37

Fibrolytic Drugs Pharmacology

Tissue Plasminogen Activators (t-PA) Plasminogen activator preferential activation of fibrin-bound plasminogen Human t-PA: recombinant DNA technology Alteplase: unmodified human t-PA Reteplase: modified human t-PA
38

Fibrolytic Drugs Pharmacology

Clinical Uses: Fibrolytic Drugs--1. Multiple pulmonary emboli (not requiring surgery) 2. Central deep venous thrombosis

3. 4.

Intra-arterial use -- peripheral vascular disease Acute Myocardial Infarction:

careful patient selection (early intervention)

superior vena caval syndrome ascending thrombophlebitis (iliofemoral vein)

39

Antithrombotic / Antiplatelet Drugs Pharmacology

Antithrombotic -- Antiplatelet Drugs Overview: antithrombotic agents

Regulation of platelet function Three types of substances:

40

Antithrombotic / Antiplatelet Drugs Pharmacology

1. Substances developed outside the platelet but interacts with platelet membrane receptors: catecholamines collagen thrombin prostacyclin
41

Antithrombotic / Antiplatelet Drugs Pharmacology

2. Agents generated internal to the platelet and interact with membrane receptors: ADP prostaglandin D2 prostaglandin E2 serotonin
42

Antithrombotic / Antiplatelet Drugs Pharmacology

3. Agents generated internal to the platelet and interact within the platelet: prostaglandin endoperoxidases thromboxane A2 cAMP cGMP Ca2+
43

Antithrombotic / Antiplatelet Drugs Pharmacology

Pharmacological Targets: antithrombotic agents Inhibition of prostaglandin metabolism: aspirin inhibition of ADP-induced platelet aggregation: ticlopidine blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab(ReoPro)& integrelin
44

Antithrombotic / Antiplatelet Drugs Pharmacology

Aspirin: Mechanism of Action: aspirin

Prostaglandin thromboxane A2 (arachidonate product) causes:

platelet aggregation platelet shape changing platelet degranulation

inhibition of this process inhibits platelet aggregation, prolonging in vivo bleeding time
45

Antithrombotic / Antiplatelet Drugs Pharmacology

Mechanism of Action: aspirin Aspirin inhibits thromboxane A2 synthesis by: irreversible acetylation of cyclooxygenase new cyclooxygenase cannot be synthesize during the 10-day lifespan of the platelet Other cyclooxygenase inhibitors are reversible and therefore have shorter duration of action, e.g. other salicylates & other nonsteroidal antiinflammatory drugs
46

Antithrombotic / Antiplatelet Drugs Pharmacology

aspirin Clinical Use --antithrombotic effects Possible primary prophylaxis of myocardial infarction FDA approval for this indication Adverse Effects: aspirin increased gastrointestinal bleeding increased frequency of peptic ulcer disease
47

Antithrombotic / Antiplatelet Drugs Pharmacology

Ticlopidine: Inhibits ADP platelet pathway: reduces platelet aggregation no effect on prostaglandin metabolism Clinical Use-Ticlopidine: Efficacy in prevention:

completed strokes unstable angina transient ischemic attacks

48

Antithrombotic / Antiplatelet Drugs Pharmacology

Adverse Effect: ticlopidine gastrointestinal disturbance: frequency = 20% hemorrhage: frequency = 5% leukopenia (serious): frequency: = 1%

requires blood testing during first three months of ticlopidine treatment

49

Blood Animations and Tutorials

Red Blood Cells Wisconsin Online White Blood Cells Wisconsin Online Rh Factor and ABO Compatibility Baltimore Community College Genetic Immune Deficiency called SCID-X1 Sumanas Inc. Hemostasis and Platelet Info platelet-research.org Interpreting Hematology Lab Results Wisconsin Online Clotting of Blood Cold Spring Harbor Laboratory

Atlas of Hematology by Nivaldo Medeiros M. D. Blood Typing Game Nobel e-Museum Hemophilia Your Genes Your Health Hemostasis McGraw Hill Blood Type Wayne's Word Blood Tutorials GetBodySmart Blood Groups Wisconsin Online

50