IVMS-CV Pharmacology- Drugs Affecting the Blood

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CV Pharmacology Drugs that Influence Coagulation :

CV Pharmacology Drugs that Influence Coagulation Presenter: Marc Imhotep Cray, M.D. Professor Pharmacology Recommended Reading: Management of Coagulation Disorders Formative Assessment Practice question set #1 Clinical: E-Medicine Article Disseminated Intravascular Coagulation Review Hemostasis Audiovisual Tutorial McGraw Hill

Lecture Outline:

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

Coagulation Physiology:

3 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)

Coagulation Physiology(2):

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

Coagulation Physiology(2):

5 Coagulation Physiology(2) 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

Review Hemostasis Audiovisual Tutorial McGraw Hill :

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

Thrombogenesis: Sequence and Characteristics:

7 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)

Thrombogenesis: Sequence and Characteristics:

8 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

Thrombogenesis: Sequence and Characteristics:

9 Fibrin reinforcement: damaged vessel exposed collagen + platelet content released Platelet degranulation releases aggregating substances: ADP TXA2 5-HT local thrombin production: platelet ADP release (ADP inducer of platelet aggregation) prostaglandin synthesis (derived from platelet membrane arachidonic acid) Thrombogenesis/vasoconstriction: thromboxane A2 , TXA2) Thrombogenesis inhibitor: prostacyclin Thrombogenesis: Sequence and Characteristics

See Notes for Explanation :

10 See Notes for Explanation From: http://en.wikipedia.org/wiki/Coagulation

Inactivation of coagulation proteins:

11 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

Clotting Factors: Drug Target Sites:

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

Anticoagulant Drugs: Pharmacology :

13 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

Anticoagulant Drugs: Pharmacology:

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

Anticoagulant Drugs: Pharmacology:

15 Anticoagulant Drugs: Pharmacology Heparin Contraindications: Heparin hypersensitivity Hematologic disease: hemophilia, thrombocytopenia, purpura Cardiovascular: severe hypertension, intracranial hemorrhage, infective endocarditis Active tuberculosis

Anticoagulant Drugs: Pharmacology:

16 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

Anticoagulant Drugs: Pharmacology:

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

Anticoagulant Drugs: Pharmacology:

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

Anticoagulant Drugs: Pharmacology:

19 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- R-warfarin Anticoagulant Drugs: Pharmacology

Anticoagulant Drugs: Pharmacology:

20 Anticoagulant Drugs: Pharmacology Mechanism of Action: Coumarin anticoagulants Blockade of g-carboxylation of glutamate residues in: prothrombin factors: VII, IX, X endogenous anticoagulant protein C g-carboxylation results in biologically inactive molecules Carboxylation reaction is coupled with oxidative deactivation of vitamin K

Anticoagulant Drugs: Pharmacology:

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

Anticoagulant Drugs: Pharmacology:

22 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

Anticoagulant Drugs: Pharmacology:

23 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

Anticoagulant Drugs: Pharmacology:

24 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)

Drug-Drug Interactions:

25 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…

Anticoagulant Drugs: Pharmacology:

26 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)

Anticoagulant Drugs: Pharmacology:

27 Drug-Drug Interactions: oral anticoagulants Aspirin, hepatic disease, hypothyroidism -- enhance Warfarin effects 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 Anticoagulant Drugs: Pharmacology

Anticoagulant Drugs: Pharmacology:

28 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

Anticoagulant Drugs: Pharmacology:

29 Anticoagulant Drugs: Pharmacology Pharmacodynamic -mediated reduction of anticoagulant effects: vitamin K -- {increased clotting factors synthesis} diuretics -- chlorthalidone, spironolactone {affect clotting factor concentration} genetics -- {molecular mutations of vitamin K reactivation cycle components} hypothyroidism -- {reduced clotting factors turnover rate}

Anticoagulant Drugs: Pharmacology:

30 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

Fibrolytic Drugs Pharmacology:

31 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

Fibrinolysis:

32 Fibrinolysis Major process: conversion plasminogen (inactive) plasmin (proteolytic enzyme, active) plasminogen activators: released from damaged cells Plasmin: limits thrombosis extension (by proteolytic fibrin digestion) Drug interventions: fibrinolytic system: Activators of fibrinolysis: tissue plasminogen activator (t-PA) urokinase (Abbokinase) streptokinase (Streptase, Kabikinase) Inhibitors of fibrinolysis: aminocaproic acid (Amicar)

Fibrinolysis:

33 Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition. From: http://en.wikipedia.org/wiki/Fibrinolysis See: Graphical representation of the fibrinolytic pathway Fibrinolysis

Fibrolytic Drugs Pharmacology:

34 Fibrolytic Drugs Pharmacology streptokinase , alteplase, tissue plasminogen activator , reteplase, urokinase

Fibrolytic Drugs Pharmacology:

35 Fibrolytic Drugs Pharmacology Streptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci) combines with plasminogen (proactivator) Enzymic complex catalyzes: plasminogen active plasmin

Fibrolytic Drugs Pharmacology:

36 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

Fibrolytic Drugs Pharmacology:

37 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

Fibrolytic Drugs Pharmacology:

38 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

Fibrolytic Drugs Pharmacology:

39 Fibrolytic Drugs Pharmacology Clinical Uses: Fibrolytic Drugs--- Multiple pulmonary emboli (not requiring surgery) Central deep venous thrombosis superior vena caval syndrome ascending thrombophlebitis (iliofemoral vein) Intra-arterial use -- peripheral vascular disease Acute Myocardial Infarction: careful patient selection (early intervention)

Antithrombotic / Antiplatelet Drugs Pharmacology:

40 Antithrombotic / Antiplatelet Drugs Pharmacology Antithrombotic -- Antiplatelet Drugs Overview: antithrombotic agents Regulation of platelet function – Three types of substances:…

Antithrombotic / Antiplatelet Drugs Pharmacology:

41 Antithrombotic / Antiplatelet Drugs Pharmacology Substances developed outside the platelet but interacts with platelet membrane receptors: catecholamines collagen thrombin prostacyclin

Antithrombotic / Antiplatelet Drugs Pharmacology:

42 Antithrombotic / Antiplatelet Drugs Pharmacology Agents generated internal to the platelet and interact with membrane receptors: ADP prostaglandin D2 prostaglandin E2 serotonin

Antithrombotic / Antiplatelet Drugs Pharmacology:

43 Antithrombotic / Antiplatelet Drugs Pharmacology Agents generated internal to the platelet and interact within the platelet: prostaglandin endoperoxidases thromboxane A2 cAMP cGMP Ca2+

Antithrombotic / Antiplatelet Drugs Pharmacology:

44 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

Antithrombotic / Antiplatelet Drugs Pharmacology:

45 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

Antithrombotic / Antiplatelet Drugs Pharmacology:

46 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 anti-inflammatory drugs

Antithrombotic / Antiplatelet Drugs Pharmacology:

47 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

Antithrombotic / Antiplatelet Drugs Pharmacology:

48 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

Antithrombotic / Antiplatelet Drugs Pharmacology:

49 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

Blood Animations and Tutorials:

50 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

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