drugs related to clotting
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DRUGS RELATED TO
COAGULATION
Dong Ngoc Quang
OMFS Postgrad Student
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HEPARIN
MECHANISM
Combine with
antithrombin-III
Inactivate many clotting
factors (including
thrombin (II) and VIII
XII) Encourage the release of
tissue factor pathway
inhibitor (TFPI)
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UNFRACTIONATED HEPARIN
Half life 30 mins, unpredictable
Mainly metabolised by endothelial cells,
liver, kidney
Subcutaneous:
Low dose
Bioavailability: 30%
Takes effect after up to 1 hour
NOT for emergency
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UNFRACTIONATED HEPARIN
IV route:
Rapid (immediate)
Higher bioavailability
Can be used in emergency
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LMWH
Low Molecular Weight Heparin
More predictable dose response
Greater subcutaneous bioavailability(90%) more effective
Greater effect on Xa than IIa
Same anticoagulant effect as UFH
Reduce the risk of bleeding
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Heparin Side Effects
Haemorrhage, increase by alcohol
Osteoporosis (less w/ LMWH)
Thrombocytopenia (life
threatening):caused by Heparin induced antiplatelet
antibodies
Hyperkalemia: inhibition of aldosteronsecretion
Hypersensitivity
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aPTT
Activated Partial Thromboplastin Time
Heparin works on intrinsic pathway and is
measured by aPTT
Normal: 25 39 seconds
Prolonged when: using Heparin,
Haemophilia
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WARFARIN
Mechanism: inhibits enzymatic reduction
of Vitamin K to its active form
(hydroquinone).Vitamin K is required for
factor II, VII, IX, X, protein C and S
Half life average 40 hours
Crosses the placenta, tiatrogenic
Early stages: defect, Later stages: foetal
haemorrhage
DO NOT use in pregnancy
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WARFARIN
Metabolised by cytochrome P450 system,
interacts w/ many drugs
Monitored by Prothrombin time, expressed
in INR.
Dose of warfarin is adjusted to give INR of 2-4
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WARFARIN
Adverse effects: Haemorrhage: bowel and brain.
Treated by Vitamin K or fresh plasma
containing clotting factors
Teratogenicity
Necrosis of soft tissue (buttock, breast): rare
but serious
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WARFARIN
Things increase warfarin effects:
Liver disease
High metabolis states
Drugs:
Inhibit synthesis of Vitamin K
Inhibit hepatic metabolism
Inhibit platetlet Displace warfarin from its binding site on albumin
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WARFARIN
Things that decrease warfarin effects: State: pregnancy, hyperthyrodism
Drugs
Vitamin K, food rich of Vitamin K (broccoli)
Induce hepatic cytochrome P450 enzymes
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ASPIRIN
Antiplatelet
Mechanism: permanently inactivate COX
activity of prostaglandin H synthetase
1 and 2 (COX-1, COX-2)
These catalyze the process to convert
Arachidonic acid to PGH2
PGH2is the cursor of PGD2, PGE2, PGF2,
PGI2, TA2
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ASPIRIN
Platelet function and mechanisms of antiplatelet therapy. ADP=adenosine diphosphate;
Ecs=endothelial cells; Gi=inhibitory G protein; GP=glycoprotein; PG=prostaglandin; P2=type 2
platelet purinergic receptor; TX=thromboxane; HETE=hydroxyeicosatetraenoic acid;
HPETE=hydroperoxyeicosatetraenoic acid.
Source: Peter, J.M. et al (2005); Aspirin Resistance and
Atherothrombotic Disease,Journal of the American College of
Cardiology, 46(6), p. 987
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ASPIRIN
Rapidly absorbed in the stomach and
upper instestine
Inhibition of TXA2
dependent platelet
function by 1 hour.
Half-life 15 20 mins, inhibitory effect last
for the life span of platelet
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ASPIRIN
Doses: use lowest effective dose is the
best strategy
AF:
Effective but < warfarin
DVT:
Effective but better methods of
thrombophylaxis available (LMWH,
rivaroxaban, dabigatran)not
recommended
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ASPIRIN
Does not cause a generalized bleeding
abnormality unless used in patients w/
underlying hemostatic defect
Balance between preventing &
haemorrhage depends on absolute
thrombotic vs haemorrhagic risk
GI toxicity: even low dose
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NOVEL ANTICOAGULANTS
Focus on the selective inhibition of clotting
factors
Two main factors: Xa and IIa (thrombin)
block both pathways
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DABIGATRAN
Rapid absorbtion (onset within 2 hours)
Not metabolized by cytochrome P450
low risk of drug interaction
Bioavailability 6.5%, required high doses
80% excreted via kidney, contraindicated
in patient w/ renal failure Indication: VTE treatment/prevention,
Stroke prevention in AF
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RIVAROXABAN
Factor Xa inhibitor
High bioavailability
Rapid onset
Metabolized by liver, kidney
Can be administered in fixed dose w/o
coagulation monitoring Minimal drug interactions
Indications: VTE treatment/prevention,
Stroke prevention in AF, ACS
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APIXABAN
Factor Xa inhibitor
Bioavailabillity 50%
Excreted mainly in feces, 25% via kidney
Indications: VTE treatment/prevention,
Stroke prevention in AF, ACS
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NOVEL ANTICOAGULANTS
Dabigatran extexilate Rivaroxaban Apixaban
Target Thrombin Factor Xa Factor Xa
Prodrug Yes No No
Bioavailability 6.5 >80 >50
Time to peak level
(hours)
2-3 2-4 3
Half-life (hours) 14-17 9 9-14
Renal excretion (%) 80 33 (67% by liver) 25(~70% in feces)
Dosing Once or twice daily Once or twice daily Twice daily
Drug interactions Potent CYP3A4 and P-
glycoprotein inhibitors
Potent CYP3A4 and
P-glycoproteininhibitors
Potent CYP3A4 and
P-glycoproteininhibitors
Antidode No No No
Properties of dabigatran etexilate, rivaroxaban, and apixaban
Source: Lip. Y. G. et al (2013) Handbook of Oral Anticoagulation. 2ndend. Springer
Healthcare. [Online]
Available at: http://www.springerhealthcare.com
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THANK YOU
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