drugs related to clotting

8/11/2019 Drugs Related to Clotting

1/23

DRUGS RELATED TO

COAGULATION

Dong Ngoc Quang

OMFS Postgrad Student


2/23

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)


3/23

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


4/23

UNFRACTIONATED HEPARIN

IV route:

Rapid (immediate)

Higher bioavailability

Can be used in emergency


5/23

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


6/23

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


7/23

aPTT

Activated Partial Thromboplastin Time

Heparin works on intrinsic pathway and is

measured by aPTT

Normal: 25 39 seconds

Prolonged when: using Heparin,

Haemophilia


8/23

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


9/23

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


10/23

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


11/23

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


12/23

WARFARIN

Things that decrease warfarin effects: State: pregnancy, hyperthyrodism

Drugs

Vitamin K, food rich of Vitamin K (broccoli)

Induce hepatic cytochrome P450 enzymes


13/23

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


14/23

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


15/23

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


16/23

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


17/23

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


18/23

NOVEL ANTICOAGULANTS

Focus on the selective inhibition of clotting

factors

Two main factors: Xa and IIa (thrombin)

block both pathways


19/23

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


20/23

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


21/23

APIXABAN

Factor Xa inhibitor

Bioavailabillity 50%

Excreted mainly in feces, 25% via kidney

Indications: VTE treatment/prevention,

Stroke prevention in AF, ACS


22/23

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


23/23

THANK YOU

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