Anti-Coagulants, Anti-Platelets, Fibrinolytics

Anti-Coagulants
Parenteral (Rapid acting)
Oral (Delayed acting)
Standard Heparin
Warfarin
Low Molecular Weight Heparin
Fondaparinux (Pentasaccharide)
Inhibits Function of Clotting
Inhibit Synthesis of Clotting
Factors
Factors
Help prevent thrombus formation
No direct effect on a thrombus already formed
Standard Heparin (Unfractionated Heparin, Conventional Heparin)
Available in Mast Cells of Human Tissues
Commercially from Porcine Intestinal Mucosa, Bovine Lung
MOA
Inhibit Clotting Factor Protease XIIa, XIa, IXa, IIa, Xa (12,11,9,2,10)
(through action on Antithrombin III)
Binds to AT III, cause conformational change
(for more rapid interaction with proteases)
AT III Inhibits Clotting Factor Proteases by forming complexes with them
Pharmacokinetics
Not absorbed from GIT (large molecule) (therefore given Parentally)
IV
IM
SC
Immediate
Avoided
Bioavailability varies
onset action
(Cause Hematoma)
(onset action delayed 1-2 hours)
Cleared from circulation by RES, Metabolised by Liver
Half Life - (1-1 hours)(effect disappears within hours)
Do not cross Placenta (big molecule) (can be given in Pregnancy)
Does not enter Breast Milk
Clinical Application (Venous Thrombosis)
Therapy
Prophylaxis
DVT, Pulmonary Embolism, Arterial
Risk (Immobilized, Surgical
Thrombus & Embolism, MI
pt)
No direct effect on Thrombus that has
DVT
been formed
Pulmonary Embolism
Does not guarantee Thrombosis
Prevent Further Extension, Embolisation
does not occur
of Formed Clot
( Risk 60-80%)
Dose than Prophylaxis
Subcutaneous Administration
Monitor Anticoagulant Activity
aPTT
Adverse Effects
Bleeding (epistaxis, hematuria, melena,
ecchymosis)
Heparin Induced Thrombocytopenia
(HIT)
Excess Anticoagulant Managed by
Heparin Induced
Dose/ Discontinue Heparin
Thrombocytopenia
Antidote Protamine Sulfate
Low Molecular Weight Heparin (LMWH) (Enoxaparin, Dalteparin, Nadroparin)
Fragments 1/3 of UFH size
All Porcine based
MOA
Inhibit Protease Xa (via Anti-thrombin)
Pharmacokinetics
Smaller molecular size (compared to standard heparin)
Better subcutaneous bioavailability (compared to standard heparin)
Half-Life - (less frequent dosing required)
Cleared Renally (Half-life in Renal Failure require dose reduction)
Clinical Application
Therapy
Prophylaxis
Adverse Effects
Bleeding (especially if overdose)
Heparin induced thrombocytopenia ( incidence compared to standard heparin)
Warfarin
Vitamin K Antagonist
MOA
Inhibit synthesis of active Vitamin K dependent clotting factors by liver (Factor VII,
IX, X, II)
Vitamin K Cofactor in gamma carboxylation (needed for activation) of these factors
during synthesis (these factors ineffective in coagulation)
Pharmacokinetics
Good GIT Absorption (100% Bioavailability)
Half-Life - ( >36 hours) (daily dosing is adequate)
Transformed to Inactive Metabolite by Liver
Liver Disease (enhance anticoagulant effect, start dose in liver failure)
Duration of Action after drug discontinued persist to 4-5 days
Clinical Application
Long term anticoagulant (eg. after Venous Thrombosis)
No effect on clotting factors already in circulation
Full Therapeutic Effect Delayed 4-5 days
(time balance between degradation of existing clotting factors, inhibited synthesis of
new factors)
Monitor Anticoagulant Effects
Prothrombin Time
International Normalised Ratio (INR) (INR = Patient PT/ Control PT)
Adverse Effects
Bleeding (related to intensity of anticoagulation)(Antidote Vitamin K)
Necrosis, Gangrene of Skin, Soft Tissues
Teratogenic (passes Placenta)(should not use in pregnancy)
Drug Interactions
Diet ( in Vitamin K content - Warfarin effect), Compliance, Drugs, Herbs, Alcohol
Pharmacokinetic
Pharmacodynamic
Enzyme induction, Enzyme Inhibition,
Synergism Hepatic Disease
Plasma Protein Binding
Drugs Aspirin
Drugs
Enzyme

Anti-Platelets
CycloADP Receptor
oxygenase
Inhibitors
Inhibitors
Aspirin
Clopidogrel

Fibrinolytics/ Thrombolytics
Streptokinase (widely used)
Urokinase

Inhibit Platelet Aggregation

Increase Fibrinolysis

Clinical Application
Prevent 2 CVS events with history of
vascular events (eg. Post MI, Stroke)

Fibrinolytic System
Dissolves Intravascular Clot
(due to action of Plasmin, an enzyme that
digest Fibrin)

Better at preventing Arterial Thrombosis

(not effective in preventing venous
thrombosis)
Thromboxane A2, ADP significant platelet
aggregators
Antiplatelets
COX Inhibitors
Inhibit platelet
Thromboxane A2
production
Aspirin

ADP Inhibitors
Inhibit ADPinduced Platelet
aggregation
Ticlopidine
Clopidogrel

Cyclooxygenase Inhibitors (eg. aspirin)

(Orally)

In Platelet, major COX product is TxA2

(induce platelet aggregation)
Aspirin
Inhibit Cyclooxygenase enzyme Irreversibly
Inhibit synthesis of Thromboxane A2

Tissue Plasminogen Activator (tPA)

Plasminogen
(inactive Precursor)

Plasmin

Enzyme that Digest Fibrin Clots

Fibrinolytics
Promote Plasmin Formation (from
Plasminogen)
Clinical Application
Pulmonary Embolism
Myocardial Infarction (MI) (best within 6
hours)(ASAP)
All given Intravenously
Contraindication
Recent Surgery
Bleeding
Streptokinase
Protein produced by haemolytic
streptococci
Adverse Effects
Bleeding
Allergic reactions (antigenic)
Anaphylaxis (rarely)
Fever (rarely)
Tissue Plasminogen Activator
Endogenously released from Endothelial cells

Bleeding Time Prolonged

Given Orally Daily
ADP-Inhibitors (eg. Clopidogrel,
Ticlopidine) (Orally)
Aspirin Alternative
Unable to Tolerate Aspirin
(GI Intolerance, Hypersensitivity)
Use with Aspirin (synergism)
MOA
Inhibit ADP Induced Platelet Aggregation
Adverse Effects
BM Suppression (eg. Neutropenia,
Thrombocytopenia)
GI Disturbances
Haemorrhage

Differences - UFH, LMWH

UFH
Structure
Large Molecular
Weight
MOA
Inhibit Proteases
XIIa, XIa, IXa, IIa, Xa
via Antithrombin
Monitor
aPTT
Effects
Kinetics
Half-Life (about 1
hour)
Do not cross placenta
Not absorbed orally
Antidote
Protamine Sulfate
Kinetics
Differences Heparin, Warfarin
Heparin
Parenteral (IV, SC)
Half-Life
Monitoring by aPTT
Rapid Anticoagulant effect
Inhibit Proteases by action on
Antithrombin III
Fetal Warfarin Syndrome

LMWH
Smaller Molecular Size
Mainly Inhibit Protease Xa
via Antithrombin
aPTT not useful
Half-Life (3-4 hours)( frequent
dosing)
Do not cross placenta
Not absorbed orally
No specific antidote
SC Bioavailability better

Warfarin
Oral
Half-Life
Monitoring by INR
Delayed effects (days)
Impair synthesis of
Vitamin K dependent clotting factors

Inhibiting
Metabolism
Plasma conc.
Enhance Effect

Inducers
Plasma conc.
Decrease Effects

Fondaparinux
Synthetic Pentasaccharide
MOA
Selective Inhibitor of Activated Factor X
Works by binding to AT III, Potentiates Neutralisation of Factor Xa
Interupts Blood Coagulation cascade, Inhibit Thrombin, Thrombus development
Pharmacokinetics
Excreted in Urine
Half-Life - (17-21 hours) (prolonged in Renal Impairment)
Clinical Indication
Similar to LMWH, Heparin

Infant with
Hypoplastic nose
Flat face
Low nasal bridge
Altered Calcification