50 - Drugs Affecting Coagulation Flashcards
Clot vs thrombus
Thrombus forms in vivo, clot in vitro
Factors released by activated platelets, upon binding to damaged endothelium
5-HT, ADP. Powerful vasoconstrictors.
Mechanism of platelet activation and adhesion 1) 2) 3) 4) 5)
1) ADP released from platelets causes others to activate, change shape
2) Platelets release granule contents (ADP, 5-HT)
3) Mediators synthesised (EG: thromboxane)
4) Platelets aggregate, adhere via fibrinogen bridging between GPIIb, GPIIIa receptors
5) Soft plug formed
Some stimuli for platelet activation 1) 2) 3) 4)
1) Collagen
2) Thrombin
3) Thromboxane
4) ADP
Mechanism of fibrin deposition
1)
2)
1) Thrombin cleaves fibrinogen to fibrin
2) Thrombin is produced through activation of prothrombin
Two pathways that can result in activation of prothrombin
1) Intrinsic - Exposed collagen or foreign material, negative charges
2) Extrinsic - Damaged tissues release thromboplastin
Important aspects of the coagulation cascade 1) 2) 3) 4)
1) A small signal (EG: factor XII) leads to a large amount of product (fibrin)
2) Each step leads to the formation of more product (amplification)
3) The factors are proteases
4) The extrinsic pathway is faster than the intrinsic (intrinsic has more steps)
Function of thromboplastin
Initiates the extrinsic pathway.
Converts factor VII to VIIa.
Point of convergence between intrinsic and extrinsic pathways
Conversion of factor X to Xa
Common pathway of intrinsic and extrinsic pathways
1)
2)
3)
1) X–>Xa
2) Xa/Va complex convert prothrombin to thrombin
3) Thrombin converts fibrinogen to fibrin, which forms a stable clot
What converts X to Xa from extrinsic pathway?
VIIa
What converts X to Xa from intrinsic pathway?
IXa, with Ca2+ and VIII as cofactors
Example of a clotting cascade inhibitor
Antithrombin III.
Fibrinolysis by plasmin mechanism 1) 2) 3) 4) 5) 6)
1) Thrombomodulin binds to thrombin.
2) Thrombomodulin/thrombin complex activates protein C
3) Activated protein C inactivates factors VIIIa, Va
4) Activated protein C inactivates inhibitor of tissue plasminogen
5) Plasminogen becomes plasmin.
6) Plasmin fibrolyses
Examples of where blood stasis can lead to a thrombus
DVT, atrial fibrillation
Targets for anti-coagulant drugs
1)
2)
3)
1) Coagulation (fibrin formation)
2) Platelets
3) Fibrinolysis
Example of a procoagulant drug
Vitamin K
Examples of injectable anticoagulant drugs
Heparin, low molecular weight heparins
Short-term anticoagulants
Heparin, low molecular weight heparins
Long-term anticoagulants
Warfarin
Antithrombin III effect
Inhibits Xa and thrombin
Heparin function
Enhances activity of antithrombin III by binding, exposing active site.
This increases antithrombin III inhibition of Xa and thromibn
Low molecular weight heparins action
Enhances antithrombin III activity, has same effect on factor Xa as heparin, less effect on thrombin
Differences between heparin and LMW heparins
1)
2)
3)
1) Heparin is much larger molecule (60-100 kD vs 2-9kD)
2) LMW heparins have a much longer elimination half life
3) Both are not orally available
How is anti-coagulant activity of heparin monitored?
Activated partial thromboplastin time.
Measure of intrinsic pathway
Pathway of coagulation that heparin mostly interferes with
Intrinsic pathway
Adverse effects of heparin
1)
2)
3)
1) Haemorrhage
2) Thrombocytopaenia (platelet deficiency)
3) Osteoporosis (mechanism unknown)
Role of vitamin K
Factors II, VII, IX and X require gamma carboxylation of glutamate on them for function.
Vitamin K is a cofactor in this process.
What is warfarin derived from?
Coumarin
How does warfarin work?
Inhibits reduction of vitamin K, which is required for gamma carboxylation of II, VII, IX and X.
Inhibits vitamin K reductase
Aspects of warfarin function
1)
2)
3)
1) Only active in vivo
2) Delayed onset of function
3) Doesn’t affect already activated factors II, VII, IX and X
Adverse effects of warfarin
Haemorrhage
Why is warfarin a ‘moody’ drug?
1)
2)
3)
Anticoagulant activity is very labile:
1) Dietary levels of vitamin K change potency a lot.
2) Hepatic disease can impair synthesis of clotting factors
3) Hypermetabolic states can increase metabolism of clotting factors
How is warfarin poisoning reversed?
Vitamin K administered (oral or IV).
Fresh frozen plasma
Pharmacokinetics of warfarin
1) Orally available
2) Rapidly absorbed
3) Strongly bound to plasma proteins (over 99%)
Drug interactions that increase activity of warfarin
1)
2)
3)
1) Aspirin (decreased platelet aggregation)
2) NSAIDs compete for plasma protein binding
3) Drugs can compete for cytochrome p450 metabolism pathway, reducing warfarin clearance (EG: acute alcohol consumption)
What can decrease warfarin activity?
1)
2)
3)
1) Pregnancy
2) Induction of liver enzymes (EG: with barbiturates, chronic alcohol consumption)
3) Vitamin K supplements
How is warfarin activity monitored?
Prothrombin time.
Measure of the extrinsic pathway.
Coagulation test of the intrinsic pathway
Activated partial thromboplastin time.
Coagulation test of the extrinsic pathway
Prothrombin time
New anticoagulant drugs
1)
2)
3)
1) Indirect factor Xa inhibitors
2) Direct factor X inhibitors
3) Direct thrombin inhibitors
Drugs affecting platelet aggregation and adhesion
1)
2)
3)
1) ADP receptor antagonists
2) Thromboxane synthesis inhibitors (EG: aspirin)
3) Glycoprotein GPIIb,GPIIIa inhibitors (prevents fibrin binding, stops platelet aggregation)
When are platelet inhibitors used?
As adjunctive therapy with aspirin
In patients intolerant of aspirin
Example of GPIIb/IIIa inhibitor
Abciximab.
For IV use in acute risk coronary syndromes
Effect of ADP receptor antagonists
Prevent platelet activation
Fibrinolytic drugs
1)
2)
1) Streptokinase
2) Alteplase
Proportion of aspirin dose inactivated in first-pass metabolism
90%
Streptokinase 1) 2) 3) 4)
1) Fibrinolytic
2) IV administration
3) Activates plasminogen
4) Streptococcus-derived, so can only be used once (antigenic)
Alteplase 1) 2) 3) 4) 5
1) Human recombinant tissue plasminogen activator
2) Non-antigenic
3) IV-administered (short half-life)
4) More active on fibrin-bound plasminogen, so clot-selective.
5) Extremely expensive
