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BIOPHARMACEUTICAL ASPECT OF

DRUGS USE IN
VENOUS THROMBOEMBOLISM

Dheni Krisnawati

POST GRADUATED HOSPITAL PHARMACY SPECIALIST PROGRAMME


AIRLANGGA UNIVERCITY
PEBRUARY 2009

Pharmacotherapy Handbook,Joseph T Dipiro 1


Venous thromboembolism
Venous thromboembolism (VTE) comprises
DVT & PE

DVT (deep vein thrombosis) is a thrombus


composed of cellular material (red, white
cells, platelet) bound together with fibrin
strands, which form in the venous

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 PE (pulmonary embolism) is a thrombus that
arise from the systemic circulation and lodges
in pulmonary, causing obstruction of
pulmonary blood flow.

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Trigger of coagulation cascade :

 Intrinsic pathway : it is activated by contact of


factor XII with expose collagen from damage
subendothelial vessels.
 Extrinsic pathway :it is activated by the
exposure of blood to tissue thromboplastin, a
tissue factor released after vescular wall
damage.

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FORMATION OF A CLOT

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Pathophysiology
3 PRIMARY COMPONENT (VIRCHOW TRIAD)
 Venous stasis :
 reduce blood flow from immobility, hypovolemia
 venous obstruction, varicose veins
 heart failure
 late stage pregnancy
 shock or severe myocardial infarction.
 Vascular wall /endothelial damage:
 mechanical ( venipuncture, fracture )
 chemical (potassium, hypertonic glucose)
 trauma (phlebitis) .
 Hypercoagulability or excessive activation :
 activated protein C resistance,
 deficiencies of protein C,
 deficiencies of protein S
 deficiencies of antithrombin III
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RISK FACTOR
INHERITED FACTOR DISEASE
APC resistance-FV Leiden Cancer
AT deficiency Auto-immune (ex : lupus)
Protein C deficiency Post operative (knee and hip surgery)
Protein S deficiency
Prothrombin Mutation

ACQUIRED FACTOR Hyperhomocystenemia


Age Elevated level of FVIII,IX,XI
Malignancy Immobilisation
Trauma
Post OP
Estrogen use
Antiphospolipid antibodi
Long distance flight
Hematologi disease
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Clinical presentation
 pain, tenderness, swelling, discoloration (from
cyanosis)
 Edema or vascular inflammation because of
swelling.
 Physical : palpable cord and a positive Homan’s
sign (a nonspecific and insensitive test)
 Dyspnea, cough, tachypnea, tachycardia, pleuritis
chest pain, anxiety or feeling of impending doom,
diaphoresis, chest pain, hemoptysis (which indicated
pulmonary infarction or congestion atelecstasis )
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Diagnosis
 Visualize :
 contrast venography(as GOLD STANDART)
 ultrasound
 magnetic resonance imaging.
 Measure obstruction to venous outflow :
 Impedance plethysmography
 Doppler ultrasound
 Detect the incorporation of radiolabeled
protein into the developing thrombus :
 I-fibrinogen scan
 Monoclonal antibodies
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Protein C deficiency
Classification of protein C deficiency :
 Type I : the function is normal, the amount is
not adequat

 Type II :the amount is normal, but the


molecule is defect.

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Classification of protein C deficiency :

 Type I : the function is normal, the amount is


not adequat

 Type II :the amount is normal, but the


molecule is defect.

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Protein C deficiency type I & II

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Treatment of deficiency of
Protein C
 Heparin
 Warfarin
 LMWH
 The treatment are generally continued for 3-
6 months

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Deficiency of protein S
Classification Protein S deficiency :
 Type I : The function is normal, the amount is
insufficient.
 Type II : the amount is normal , unable to
interact with other molecules.
 Type III : low amount of protein S, but overall
is normal .

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Deficiency of protein S

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Treatment of deficiency
of Protein S
 Heparin or LMWH
 Warfarin
 The treatment are generally continued for 3-
6 months

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Antithrombin / antithrombin III
deficiency:
Classification of antithrombin deficiency :
 Type I : the amount is inadequate, the fuction
is normal.
 Type II : the amount is normal, the function is
improper.

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Treatment of antithrombin
deficiency :

 Heparin or LMWH
 Warfarin
 Antithrombin concentrated

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Treatment of antithrombin
deficiency (in pregnancy) :
 Heparin or LMWH
 Antithrombin concentrated

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Desired outcome
 To prevent pulmonary embolism and the
postphlebitic syndrome, to reduce morbidity,
achieve the objective with minimum of
adverse effect and cost.
 Restore potency to venous circulation while
maintaining normal venous valve function

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The Effect of Medicine on Clotting

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ANTIPLATELET AGENT
 Aspirin,NSAID:
Inhibit an enzyme COX1 that cause platelet aggregation.
Aspirin is the longest anti platelet action

 Dypiridamol:
Mechanism is not clear,use as combine to aspirin,
Side effect:
bleeding,dizziness,hypotension,headache,nausea,flushing,abdo
minal discomfort

 Ticlopidine,clopidogrel:
Inhibit ability of ADP to bind to platelet,so inhibit platelet
aggregation. Side effect Clopidogrel :nausea,upset,
stomach,diarrhea,itching,rash,fatique,headache,flu like
symptom,TTP (thrombotic thrombocytopenic purpura).
Ticlopidine side effect like clopidogrel,nephritic
syndrome,hyponatremia,low blood cells
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HEPARIN
 A natural subtance in the liver
 Mechan. enhance the effect of antithrombin
 2 kind:
 Unfractionated inhibit FIIa & Xa heparin,IV
Side effect fever, runny nose,itching,irritation in the site of
infusion,,chills,osteoporosis,thrombocytopenia.
Poor absorbed through GIT IV
Monitoring every 6 hours.
 LMWH (low molecular weight heparin) inhibit Xa,SC.
Example:enoxaparin,dalteparin,tinzaparin,nadropin,revipari
n,certoparin.
Not require regular monitoring. Antidote protamine sulfate
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UF heparin versus LMW Heparin
• Elimination primarily • Elimination mainly
through cellular through a renal
uptake mechanism
• Bioavailability ~ 30% • Bioavailability ~ 90%
• Half-life 1 – 3 hours • Half-life ~ 4 hours
• Accelerates primarily • Accelerates primarily
the inhibition of the inhibition of FXa
thrombin and FXa • Cannot be measured
• Can be measured by by APTT assays
APTT assays

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Warfarin (coumadin)
 Inhibit the effect of vitamin K dependent
clotting factor
(FII/protrombin,FVII,FIX,FX,protein C,protein
S)
 Side effect rash,diarrhea, hepatitis,abdominal
pain,nausea, skin necrosis,
 Antidote : vitamin K or FFP (fresh frozen
plasma).
 Has a long t1/2 & duration of action-drug
accumulation possible and can cause internal
bleeding
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Thrombolitic medication/clot
buster
 Break the fibrin clot
 3 primary agent :
 Streptokinase
 Urokinase-type plasminogen activator(UPA)
 Tissue-type plasminogen activator(TPA)

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Streptokinase
 Large protein that produced from streptococci.
 Bind to and activate plasminogen breakdown the
formed fibrin.
 Administration : IV
 Side effect :
 Hemorhage
 antigenic  anaphylactic reaction.
 Hypotension
 Resistence to drug.
Tissue plasminogen activator
 Developed using recombinant DNA
technology
 Used when streptokinase less effective
Prevention DVT
 Nonpharmacologic : early ambulation, leg
elevation, exercises, elastic compression, calf
compression,
 Low dose unfractionated heparin therapy

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References

 www-admin.med.uiuc.edu/hematology
 Pharmacotherapy Handbook 2rd.,Joseph
T.Dipiro.,1998
 A manual of laboratory and diagnostic test 7th
edition (juli 2003): by France T Fisbach
RN,BSN,MSN
 Cherry & Merhats’s complication of pregnancy 5th
edition : by Wayne R Cohen (jan 2000)

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