IVMS-CV Pharmacology- Drugs Affecting the Blood


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Individualized Webcam facilitated and e-Classroom USMLE Step 1 Tutorials with Dr. Cray. Starting at $50.00/hr., depending on pre-assessment. 1 BMS Unit is 4 hr. General Principles and some Organ System require multiple units to complete in preparation for the USMLE Step 1 A HIGH YIELD FOCUS IN Biochemistry / Cell Biology, Microbiology / Immunology and the 4 P’s-Phiso, Pathophys, Path and Pharm. Webcam Facilitated USMLE Step 2 Clinical Knowledge and Clinical Skills diadactic tutorials /1 Unit is 4 hours, individualized one-on-one and group sessions, Including all Internal Medicine sub-sub-specitialities. For questions or more information.. drcray@imhotepvirtualmedsch.com

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IVMS-CV Pharmacology- Drugs Affecting the Blood

  1. 1. CV Pharmacology Drugs that Influence Coagulation Review Hemostasis Audiovisual Tutorial McGraw Hill Recommended Reading: Management of Coagulation DisordersPrepared and Presenter: Marc Imhotep Cray, M.D. Formative Assessment Professor Pharmacology Practice question set #1 Clinical: E-Medicine Article Disseminated Intravascular Coagulation
  2. 2. Lecture Outline Review of Hemostasis /Coagulation/ Thrombogenesis / Fibrinolysis Anticoagulant Drugs Pharmacology Fibrolytic Drugs Pharmacology Antithrombotic / Antiplatelet Drugs Pharmacology 2
  3. 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) 3
  4. 4. Coagulation Physiology(2)Platelet activation1. Damage to blood vessel walls exposes subendothelium proteins, most notably collagen, present under the endothelium2. Circulating platelets bind collagen with surface collagen-specific glycoprotein Ia/IIa receptors 4
  5. 5. Coagulation Physiology(2)3. 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.4. This adhesion activates the platelets 5
  6. 6. Review Hemostasis Audiovisual Tutorial McGraw Hill Pathway of Thrombogenesis Click to read source:http://www.heartzine.com/170.pdf 6
  7. 7. Thrombogenesis: Sequenceand 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
  8. 8. Thrombogenesis: Sequenceand 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 8
  9. 9. Thrombogenesis: Sequenceand Characteristics 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 9
  10. 10. See Notes for Explanation From:http://en.wikipedia.org/wiki/Coagulation 10
  11. 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 11
  12. 12. Clotting Factors: Drug Target SitesFactor/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) Christmas factor, plasma thromboplastin IX Heparin (IXa); Warfarin (synthesis) component (PTC) X Stuart-Prower factor Heparin (IXa); Warfarin (synthesis) XI Plasma thromboplastin antecedent (PTA) XII Hageman factor XIII Fibrin-stabilizing factorProteins C and S ------- Warfarin (synthesis) Plasminogen ------- Thrombolytic enzymes, aminocaproic acid 12
  13. 13. Anticoagulant Drugs: PharmacologyHeparin 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
  14. 14. Anticoagulant Drugs: PharmacologyHeparin 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 thromboplastin time (PTT)  osteoporosis  Factors predisposing to hemorrhage:  spontaneous  elderly fractures  renal failure patients 14
  15. 15. Anticoagulant Drugs:PharmacologyHeparin Contraindications: Heparin hypersensitivity Hematologic disease:  hemophilia, thrombocytopenia, purpura Cardiovascular:  severe hypertension, intracranial hemorrhage, infective endocarditis Active tuberculosis 15
  16. 16. Anticoagulant Drugs:PharmacologyHeparin 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
  17. 17. Anticoagulant Drugs:PharmacologyReversal of Heparin Effects: drug discontinuation Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect) 17
  18. 18. Anticoagulant Drugs: PharmacologyWarfarin & Coumarin Chemistry/Pharmacokinetics: Warfarin & Coumarin Coumarin: produces plasma prothrombin deficiency active agent --: bishydroxycoumarin (synthesis - - dicumarol) Uses:  rodenticide  humans: antithrombotic agent 18
  19. 19. 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- R- warfarin 19
  20. 20. Anticoagulant Drugs:PharmacologyMechanism 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 20
  21. 21. Anticoagulant Drugs: PharmacologyMechanism of Action: Coumarin anticoagulants Anticoagulant effect dependent on two considerations1. Partially inhibited synthesis of the four vitamin K-dependent clotting factors and2. Altered degradation rates of these factors Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis 21
  22. 22. Anticoagulant Drugs: PharmacologyToxicity: 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
  23. 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 23
  24. 24. Anticoagulant Drugs: PharmacologyDrug-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
  25. 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… 25
  26. 26. Anticoagulant Drugs:PharmacologyDrug-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
  27. 27. Anticoagulant Drugs: PharmacologyDrug-Drug Interactions: oral anticoagulants Aspirin, hepatic disease, hypothyroidism -- enhance Warfarin effectspharmacodynamic:  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 27
  28. 28. Anticoagulant Drugs:PharmacologyDrug-Drug Interactions: oral anticoagulantsDecrease of anticoagulant action: Barbiturates & rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin. Cholestyramine: promotes intestinal Warfarin binding 28
  29. 29. Anticoagulant Drugs: PharmacologyPharmacodynamic -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
  30. 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 30
  31. 31. Fibrolytic DrugsPharmacologyOverview: 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
  32. 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) 32
  33. 33. Fibrinolysis See: Graphicalrepresentation of the fibrinolytic pathway Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition. From: http://en.wikipedia.org/wiki/Fibrinolysis 33
  34. 34. Fibrolytic Drugs Pharmacology streptokinase, alteplase, tissue plasminogen activator, reteplase, urokinase 34
  35. 35. Fibrolytic Drugs PharmacologyStreptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci)  combines with plasminogen (proactivator)  Enzymic complex catalyzes: plasminogen active plasmin 35
  36. 36. Fibrolytic Drugs PharmacologyUrokinase (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
  37. 37. Fibrolytic Drugs PharmacologyAnistreplase (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
  38. 38. Fibrolytic DrugsPharmacologyTissue 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
  39. 39. Fibrolytic DrugsPharmacologyClinical Uses: Fibrolytic Drugs---1. Multiple pulmonary emboli (not requiring surgery)2. Central deep venous thrombosis  superior vena caval syndrome  ascending thrombophlebitis (iliofemoral vein)3. Intra-arterial use -- peripheral vascular disease4. Acute Myocardial Infarction:  careful patient selection (early intervention) 39
  40. 40. Antithrombotic / AntiplateletDrugs PharmacologyAntithrombotic -- Antiplatelet Drugs Overview: antithrombotic agents  Regulation of platelet function –  Three types of substances:… 40
  41. 41. Antithrombotic / AntiplateletDrugs Pharmacology1. Substances developed outside the platelet but interacts with platelet membrane receptors: catecholamines collagen thrombin prostacyclin 41
  42. 42. Antithrombotic / AntiplateletDrugs Pharmacology2. Agents generated internal to the platelet and interact with membrane receptors: ADP prostaglandin D2 prostaglandin E2 serotonin 42
  43. 43. Antithrombotic / AntiplateletDrugs Pharmacology3. Agents generated internal to the platelet and interact within the platelet: prostaglandin endoperoxidases thromboxane A2 cAMP cGMP Ca2+ 43
  44. 44. Antithrombotic / AntiplateletDrugs PharmacologyPharmacological 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
  45. 45. Antithrombotic / AntiplateletDrugs PharmacologyAspirin: 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
  46. 46. Antithrombotic / Antiplatelet Drugs PharmacologyMechanism 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 46
  47. 47. Antithrombotic / AntiplateletDrugs PharmacologyaspirinClinical Use --antithrombotic effects Possible primary prophylaxis of myocardial infarction FDA approval for this indicationAdverse Effects: aspirin increased gastrointestinal bleeding increased frequency of peptic ulcer disease 47
  48. 48. Antithrombotic / Antiplatelet Drugs PharmacologyTiclopidine: Inhibits ADP platelet pathway: reduces platelet aggregation no effect on prostaglandin metabolismClinical Use-Ticlopidine: Efficacy in prevention:  completed strokes  unstable angina  transient ischemic attacks 48
  49. 49. Antithrombotic / AntiplateletDrugs PharmacologyAdverse Effect: ticlopidine gastrointestinal disturbance: frequency = 20% hemorrhage: frequency = 5% leukopenia (serious): frequency: = 1%  requires blood testing during first three months of ticlopidine treatment 49
  50. 50. Blood Animations and Tutorials Red Blood Cells Wisconsin  Atlas of Hematology by Online Nivaldo Medeiros M. D. White Blood Cells Wisconsin  Blood Typing Game Online Nobel e-Museum Rh Factor and ABO Compatibility  Hemophilia Your Genes Baltimore Community College Your Health Genetic Immune Deficiency called SCID-X1 Sumanas Inc.  Hemostasis McGraw Hill Hemostasis and Platelet Info  Blood Type Waynes platelet-research.org Word Interpreting Hematology Lab  Blood Tutorials Results Wisconsin Online GetBodySmart Clotting of Blood Cold Spring  Blood Groups Wisconsin Harbor Laboratory Online 50