Cardio L19 Antocoagulants 1 Flashcards
Haemostasis
prevention of bleeding due to vessel damage
Haemostasis a result of 3 componenets:
- Formation of platelet plug – to block hole
- Formation of fibrin clot from proteins present in plasma-reinforces plug (fibrin mesh)
- Contraction of blood vessels – to limit blood flow
Drugs used in clotting and bleeding disorders: to reduce clotting
Anticoagulants
Antiplatelet drugs
Thrombolytics
To facilitate clotting
Replacement factors 9VIII, IX)
Plasminogen inhibitors
Thrombosis:
an unwanted haemostatic plug in blood vessel or heart
Venous → thrombosis
predominantly fibrin/associated with blood flow stasis (anticoagulants).
Arterial thrombosis
predominantly platelets/ associated with atherosclerosis/causes ischemia tissue infarction (antiplatelet drugs).
Blood coagulation:
- Conversion of fluid blood to solid gel or clot.
- Conversion of soluble fibrinogen to fibrin
- Insoluble meshwork of fibrin traps blood cells stabilizing clots
Clotting cascade endpoint →
thrombin converts fibrinogen to fibrin monomers and then into fibrin polymers
2 pathways of blood coagulation
- In vivo (extrinsic) pathway) → Tissue damage
2. The invitro (intrinsic pathway) → Contact (e.g. with exposed collagen)
Pathways:
Intrinsic pathway →
Contact (e.g. with collagen/damaged surface)
- T Factor XII converted to XIIa via contact (e.g. via exposed collagen) (12 → 12a)
- Factor XIIa converts factor XI to Xia (11 to 11a)
- Factors Xia converts factor Ix to IXa
- Factor VIIA, phosphlopids and Calcium ions aid to convert factor X to XA
- Factor X via Va, phospholipis and Calcium ions convert prothrombin (factor II) to Factor IIA (Thrombin)
- Thrombin converts fibrinogen to fibrin and thrombin also converts XII via calcium ions to initiate the stabilisation of fibrin.
Extrinsic pathway:
- Tissue Damamge/Trauma causes the release of TF VIIa, phospholipids and Calcium to covert:
- Converts X to Xa and follows steps above.
- Prothrombin to thrombin
- Fibrinogen to fibrin
Clotting Cascade: Important points:
- Inactive precursors activated in series by proteolysis
- Two distinct pathways:
- Both pathways converge and activate factor X
- Calcium ions and –vely charged phospholipids (PL) required for three steps:
- PL provided by activated platelets
- Some factors promote coagulation by binding to PL, calcium and serine protease (i.e. Factor II activation of X required calcium/PL and protease factor Va
End point fibrinogen to Fibrin
caused by the conversion of Tissue factor IIa (Thrombin) from its inactive precursor (TF II (Prothrombin)
- Platelet activated
a. Changes shape and expresses negatively charged phospholipid → allows calcium to bind
i. TF can bind to activated platelets (with calcium) e.g. TF10
ii. TF I → prothrombin
b. Expression to TF5a
c. Leads to downstream activation of clotting cascade above and thrombin formation therefore fibrin clot.
TF binding requires →
- Negative phospholipids
- Calcium
- Gamma-carboxyglutamic acid residues on surface of TF’s → critical for binding to activated platelets
Carboxylation of factors II, VII, IX and X in liver →
How
• Tissue factors when made are uncarboxylated.
• In the liver TF 2,7,9,10 are convert to the gamma form
• How:
o Involves cyclic reaction using vit K via vitamin K reductase.
o Allows TF to bind to activated platelets properly
warfarin Mechanism of action
Inhibit carboxylation of Factors II, VII, IX and X (2,7,9,10)
Blocks vit K reductase action
warfarin Administration
Oral, rapidly absorbed by GI tract
warfarin Pharmacokinetics
- Binding power
- Binding strength
- Metabolisation
- Measurement of action
• Rate of onset – depends on factor half-life: I.e. shortest half-life is factor VII at 6 hrs.
→ Start 12-16 hr Duration 4-5 days
• Strongly binds to plasma proteins → makes drug interaction complex
• Metabolized in liver (t0.5 ~40 hrs)
• Measurement of action – measure prothrombin time (PT)
Prothrombin time (PT): clotting time
- Clotting time of plasma from patient following addition of calcium/ hromboplastin (standardised reference amount)
Prothrombin time (PT): expressed as
ratio (International normalized ratio) of clotting time compared with healthy subjects.
Prothrombin time (PT): INR values
a. 2-2.5 for prophylaxis of deep vein thrombosis
b. 2.5 treatment of DVT/ pulmonary embolism
c. 3.5 for recurrent DVT/ PE
Prothrombin time (PT): 4. INR Determined:
a. Daily initially
b. Then at longer intervals
c. Then upto every 12 weeks
Warfarin actions Potentiated by
Drugs which displace it from plasma proteins (Aspirin)
Drugs which interfere with liver function (sulphonamides)
Drugs which interfere with platelet functions (NSAID)
Liver disease (decreases factor production and warfarin clearance)
Decreased Vit K availability
Warfarin actions Decreased by
Drugs which induce metabolized enzymes (Barbituates)
Promoted clotting factor synthesis (Vitamin K)
Reduced warfarin absorption (colestipol)
Warfarin actions Unwanted side effects
Haemorrhage – bowel or brain
Warfarin actions Side effects Major bleeding action
- Stop warfarin administration
- Give Vit K
- Give replacement tissue factors
Warfarin actions Side effects INR 8.0
- Stop warfarin until <5.0
5. Give Vit K
Warfarin actions Side effect INR 6.0-8.0
Stop warfarin until < 5.0
Teratogenic
Contraindicated ui pregnancy
Injectable anticoagulants: examples
Heparin
LMW Heparin
Heparin: Mechanism of Action
→Binds to antithrombin III and changes the structure which allows it to bind to IIa
→Binds to IIa directly
→ Antithrombin III can bind to Xa
Forms a tight complex making it a potnet complex in the removal of TF IIa and antithrombin III, which removes IIa from the blood stream.
Heparin then dissociates and repeats the process else where.
Heparin: Potent action
More potent at Factor IIa than factor Xa
Heparin: Use
In vivo or (in virtro to clear blocked IV catheter)
Heparin: Limitations
Activity modified by platelet factor 4 release from platelets inhibits heparin activity
If factor Xa already bound to fibrin cannot interact with ATIII/heparin complex
Heparin: Administration
Due to charge and large size not absorbed in gut.
IV or SC (LMW heparin)
Heparin: Pharmacokinetics
- Complex due to plasma protein binding
- Initial rapid removal due to binding to endothelial/ macrophage cells (therefore big bolus initially and then an infusion (for renal excretion)
- Slower subsequent removal by renal excretion
Heparin: Onset of action
Immediate if IV
Heparin: Unwanted effects
- Haemorrhage (treat with heparin antagonist protamine sulphate – strong basic protein binds heparin)
- Thrombosis – rare (associated with antibodies against heparin causing endothelial tissue damage
- Occasional osteoporosis, Hypersensitivity and hypoaldosteronism
Heparin: Examples
Heparin
Calciparine
Minihep
Monoparin
LMW heparin: MOA of LMW Heparin
Cannot get antithrombin III to interact with IIa and therefore doesn’t inhibit IIa but it can inhibit Xa
LMW heparin: Pharmacokinetics
LMW does no bind to plasma proteins so kinetics simpler
LMW heparin: Problem
Only acts on Factor X
LMW heparin: Good
Not neutralised by platelet factor 4/ Can administer subcutaneously
Much less complex pharmacokinetics
LMW heparin: Examples
Certoparin
Dalteparin
Enoxaparin
Antithrombin III – independent: Hirudin
From leech, inhibits thrombin by binding to active site
Antithrombin III – independent: Hirugen
Synthetic peptide derived from hirudin
Antithrombin III – independent: Bivalirudin (angiomax)
Bivalirudin (angiomax)
Antithrombin III – independent: Actions/benefits of bivalrudin
• Potent arterial and venous antithrombotic with fewer bleeding problems (like heparin)
• Clinical trials showed no greater efficacy over pre-existing therapies therefore limited clinical uptake
• Still may prove useful in patients with hepain antibody production
Usage in percutaneous coronary intervention (coronary angioplasty) on the increase due to rapid on/off effects.
Clinical use of anticoagulants:
- Heparin → acutely (shortterm therapy)
- Warfarin → prolonged therapy
- Prevention of DVT (peri-operatively)
- In treatment of DVT/ prevention of PE
- Prevention of thrombosis on prosthetic heart valves.
