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Drugs that affect Drugs that affect hemostasishemostasis
Ahmad Shihada Silmi Msc, FIBMSIUG
Faculty of SciencesMedical Technology Dep.
Drugs Affecting
Hemostasis
Drugs are categorized according to the process they target.
An injured blood vessel Contracts Forms a platelet plug (1º hemostasis) Forms a protein clot (2º hemostasis) Once healed, solubilizes the clot
(fibrinolysis)
Drugs that affect Drugs that affect hemostasishemostasis
Anticoagulants
Therapeutic overview
Heparin and heparin derivatives
Coumarins (warfarin)
Directly acting thrombin inhibitors
hirudin
bivalirudin
argatroban
arterial thrombosis
atrial fibrillation
cardiomyopathy
cerebral emboli
heart valve disease
hip surgery
vascular prostheses
Venous thromboembolism
Oral anticoagulants4-Hydrdroxycoumarin and indan-1,3-dione are the parent molecules.
MechanismDrugs Affecting Hemostasis
Warfarin
Interferes with the synthesis of the vitamin K-dependent clotting factors
Drugs Affecting
Hemostasis
Vitamin KVitamin K
Synthesis Synthesis of of
Functional Functional CoagulatioCoagulation Factorsn Factors
VIIVII
IXIX
XX
IIII
Mechanism of ActionMechanism of ActionInterferes with liver synthesisInterferes with liver synthesis
CC
SS
ZZ
Synthesis Synthesis of Anti- of Anti-
coagulatiocoagulation Proteinsn Proteins
Drugs Affecting
Hemostasis
Vitamin K ActionVitamin K Action
Drugs Affecting
Hemostasis
Warfarin Mechanism of Warfarin Mechanism of ActionAction
Drugs Affecting
Hemostasis
Warfarin Warfarin PharmacokineticsPharmacokinetics
ABSORPTION: Rapid, complete. Used orally.
DISTRIBUTION: Vd is small; plasma protein binding ≈ 99%.
[Maternal] = [Fetal]. Warfarin is not found in breast milk; other coumadins are!
ELIMINATION: T1/2 = 40 hr.
ONSET: 2-3 days.
DURATION: 2-5 days.
Drugs Affecting
Hemostasis
Warfarin: Adverse Warfarin: Adverse
ActionsActions BleedingBleeding is the is the mainmain concern concern
vitamin K, clotting factors, fresh vitamin K, clotting factors, fresh frozen plasmafrozen plasma
Crosses the placenta and is Crosses the placenta and is teratogenic during weeks 6-12teratogenic during weeks 6-12
Alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, anorexia, skin necrosis
Drugs Affecting
Hemostasis
Drug Interactions
Drug interactions are particularly important with oral anticoagulants, and the result may be either an increase or a decrease in the effect of the anticoagulant. Frequent monitoring of the prothrombin time is essential when administering another drug with warfarin, and changing the dose of warfarin may be necessary.
Drugs increase anticoagulation by
1. Displacement of protein bound warfarin. Because of the high degree of warfarin bound to plasma proteins, even a small decrease in the amount bound can lead to significant increases in free drug levels. Examples: salicylates such as aspirin.
2. Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the availability of warfarin. Example: quinidine.
3. Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma level of warfarin. Example: d-thyroxine.
4. Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives.
5. Inhibiting platelet function. Example, aspirin.
Drugs depress anticoagulation by
1. Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of warfarin. Example: barbiturates.
2. Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example: vitamin K, estrogens.
3. Inhibition of absorption. Example: cholestyramine.
Drugs Affecting
Hemostasis
HeparinHeparin 2-40 kDa MW, naturally occurring N- & O-
sulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells.
Drugs Affecting
Hemostasis
Heparin 2-40 kDa MW, naturally occurring N- & O-sulfated
sugars polymerized by glycoside bonds found in the secretory granules of mast cells.
Lower MW polymers possess most of the biological activity.
Active in vitro as well as in vivo.
The most acidic organic acid in the body.
Is not absorbed following oral administration.
Drugs Affecting
Hemostasis
Mechanism of ActionMechanism of Action
Accelerates the inactivation of factors IIa, Accelerates the inactivation of factors IIa, Xa, IXa, XIa and XIIa by the serine protease Xa, IXa, XIa and XIIa by the serine protease inhibitor, antithrombin III (AT III).inhibitor, antithrombin III (AT III).
Drugs Affecting
Hemostasis
Mechanism of ActionMechanism of Action Unique pentasaccharide sequence binds to Unique pentasaccharide sequence binds to
antithrombin III (AT III) with high affinity but a antithrombin III (AT III) with high affinity but a polysaccharide of at least 18 units is required polysaccharide of at least 18 units is required (5 for LMWH).(5 for LMWH).
Drugs Affecting
Hemostasis
AT III + HeparinAT III + Heparin
SerineSerineproteaseprotease
Ternary complexTernary complexInactiveInactive
Drugs Affecting
Hemostasis
LMW Heparin MW 4,000 - 6,000 Preferentially binds to factor Xa T1/2 2x > standard heparin Less bleeding Less effect on platelet activation
and factor XIII activation Clinically effective - e.g.,
enoxaparin
Drugs Affecting
Hemostasis
AT IIIAT III
Heparin
IIaIIa
HeparinHeparin
ATAT IIIIII
HeparinHeparin
LMWHLMWH
AT IIIAT IIIXaXa
< 18 monosaccharide units
> 18 monosaccharide units
Drugs Affecting
Hemostasis
Heparin Heparin PharmacokineticsPharmacokinetics
No oral absorption; IV or subQ.
Vd is small due to extensive binding. Binding can influence the effect of heparin.
Onset: IV, immediate; subQ, 20-60 min
Drugs Affecting
Hemostasis
Heparin Adverse ActionsHeparin Adverse Actions Bleeding is the main concern. Antidote: protamine sulfate.
Thrombocytopenia (<5%, within a few days). Disappears with cessation of therapy.
Rapid and profound thrombocytopenia (<5%, 8-10 days) with paradoxical arterial or venous thrombosis. Results from the formation of anti-heparin antibodies. Heparin-Ab bind to platelets causing inappropriate aggregation and thrombus formation. May be life-threatening.
Reversible osteoporosis (6 months). If it occurs, it is usually after 6 months therapy with >15,000 U/day.
Drugs Affecting
Hemostasis
Antiplatelet DrugsAntiplatelet Drugs
Therapeutic overviewPlatelet aggregation inhibitors
AspirinCerebrovascular accident, stroke, coronary bypass surgery, coronary angioplasty/stenting or thrombolysis, myocardial infarction, transient ischemic attack
ClopidogrelCoronary artery disease, cerebrovascular accident, stroke, peripheral arterial disease
Glycoprotein IIb/IIIa inhibitors
Acute coronary syndromes, after coronary artery stenting
Drugs Affecting
Hemostasis
Aspirin Mechanism of Aspirin Mechanism of ActionAction
Aspirin irreversibly inactivates cyclooxygenase by covalent acetylation.
Aspirin inhibits
Aspirin inhibits
Drugs Affecting
Hemostasis
Selectivity of aspirin for platelet COXSelectivity of aspirin for platelet COX
1. Platelet COX is acetylated in the portal circulation before aspirin is deacylated in the liver.
2. The systemic vasculature is unaffected because platelets are not affected by salicylate.
Drugs Affecting
Hemostasis
Aspirin PharmacokineticsAspirin Pharmacokinetics ABSORPTION: 70% DISTRIBUTION: at low doses most is
protein bound in plasma; at high doses a smaller percentage is bound and more is available to tissues
ELIMINATION: hepatic metabolites (75%) and parent compound excreted in urine. At low doses half-life is 4 hr and is 1st order. High doses show saturation kinetics and half-life is 15 hr. Faster in alkaline urine.
ONSET: 30 min DURATION: 7-10 daysDURATION: 7-10 days
Drugs Affecting
Hemostasis
Aspirin Adverse ActionsAspirin Adverse ActionsPrimarily gastrointestinal Epigastric pain, heartburn, nausea
GI blood loss
Gastric ulcer
Others: rash, tinnitus, nasal polyps, gout, acid-base disturbances
Drugs Affecting
Hemostasis
Aspirin Drug InteractionsAspirin Drug Interactions
Decreases the effectiveness of antihypertensives: usually not a problem with low doses.
Increases the effect of warfarin.
Attenuates the actions of uricosuric agents, e.g. probenecid.
Drugs Affecting
Hemostasis
Ticlopidine and ClopidogrelTiclopidine and Clopidogrel
P2Y2 purine receptor antagonists.
Drugs Affecting
HemostasisDaniel, J. L. et al. J. Biol. Chem. 1998;273:2024-2029
clopidogrel
P2Y1R
P2Y2R AC
Other Antiplatelet DrugsTiclopidine and Clopidogrel: P2Y2 purine
receptor antagonists
Drugs Affecting
Hemostasis
ClopidogrelClopidogrel Reduces the incidence of stroke and
myocardial ischemia.
Particularly effective combined with aspirin.
Currently the drug of choice in the prophylaxis of subacute stent thrombosis and post ischemic stroke treatment.
Drugs Affecting
Hemostasis
Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors
GP IIb/IIIa is a platelet surface integrin (IIb3)
GP IIb/IIIa is the receptor for fibrinogen and von Willebrand factor.
Thrombin, collagen, TXA2 activate platelets exposing binding sites for vWf and fibrinogen.
Basal platelet with GP IIb/IIIa
receptors in inactive state
AgonisAgonistt
Activated Activated platelet with platelet with functional GP functional GP
IIb/IIIa receptorsIIb/IIIa receptorsFibrinog
en
Fibrinogen mediated platelet
aggregation
GP IIb/IIIa antagonis
t ()
Fibrinogen binding to platelets blocked
by GP IIb/IIIa receptor antagonist
Drugs Affecting
Hemostasis
Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors
AbciximabAbciximab -- Fab fragment directed to the GPIIb/IIIa receptor. Can be used only once.
EptifibatideEptifibatide -- a cyclic peptide
TirofibanTirofiban -- a nonpeptide inhibitor
Drugs Affecting
Hemostasis
FibrinolyticsFibrinolytics
Restore blood flow to an injured area by lysing the thrombus into soluble fibrin degradation products.
Drugs Affecting
Hemostasis
Alteplase (rtPA)Urokinase
StreptokinaseAnistreplase
Site of action of drugs acting on the fibrinolytic system. Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products.
© 2005 Elsevier
Drugs Affecting
Hemostasis
Plasminogen tPA
L LL
Fibrin Clot
Plasmin
tPA
LL L
Fibrin Clot
Plasmin
PI
Soluble fibrin digestion products
Plasminogen tPA
Plasmin
tPA, tissue plasminogen activator
L, lysine binding sites
PI, plasmin inactivator
Drugs Affecting
Hemostasis
Treatment Goals
Rapid reperfusion of the infarcted area to preserve more tissue.
Drugs Affecting
Hemostasis
Fibrinolytic success is dependent upon the time lapse between the onset of symptoms and administration of the fibrinolytic.
• DVT: < 7 days
• Pulmonary embolism: < 2 days
• Myocardial infarction: 2 - 4 hr
• Stroke: < 3 hr
Drugs Affecting
Hemostasis
Fibrinolytics: Adverse Fibrinolytics: Adverse ActionsActions
Unwanted BLEEDING is the MAJOR side effect.
Drugs Affecting
Hemostasis
The The EndEnd
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