CV PharmacologyDrugs that Influence Coagulation : CV PharmacologyDrugs 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 : 3/6/2010 2 Lecture Outline Review of Hemostasis /Coagulation/ Thrombogenesis / Fibrinolysis
Anticoagulant Drugs Pharmacology
Fibrolytic Drugs Pharmacology
Antithrombotic / Antiplatelet Drugs Pharmacology
Coagulation Physiology : 3/6/2010 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) : 3/6/2010 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) : 3/6/2010 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 : 3/6/2010 6 Review Hemostasis Audiovisual Tutorial McGraw Hill Pathway of Thrombogenesis
Click to read source:
http://www.heartzine.com/170.pdf
Thrombogenesis: Sequence and Characteristics : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 10 See Notes for Explanation From:http://en.wikipedia.org/wiki/Coagulation
Inactivation of coagulation proteins : 3/6/2010 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 : 3/6/2010 12 Clotting Factors: Drug Target Sites
Anticoagulant Drugs: Pharmacology : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 25 Drug-Drug Interactions See:American Family Physician Vol. 61/No. 6 (March 15, 2000)
Clinical PharmacologyClinically Significant Drug InteractionsPAUL 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 34 Fibrolytic Drugs Pharmacology streptokinase,
alteplase,
tissue plasminogen activator,
reteplase,
urokinase
Fibrolytic Drugs Pharmacology : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 40 Antithrombotic / Antiplatelet Drugs Pharmacology Antithrombotic -- Antiplatelet Drugs
Overview: antithrombotic agents
Regulation of platelet function –
Three types of substances:…
Antithrombotic / Antiplatelet Drugs Pharmacology : 3/6/2010 41 Antithrombotic / Antiplatelet Drugs Pharmacology Substances developed outside the platelet but interacts with platelet membrane receptors:
catecholamines
collagen
thrombin
prostacyclin
Antithrombotic / Antiplatelet Drugs Pharmacology : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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 : 3/6/2010 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