Flashcards in L27. Drugs Affecting Coagulation Deck (27):
What are the three major steps of normal clot formation?
1. Coagulation (fibrin formatin)
2. Platelets (adhesion and activation)
3. Fibrinolysis (dissolving the clots)
What is a major inherent difficulty in coagulation medications?
Getting the right amount of medication right
Clot vs. Bleeding
What are the three major types of drugs that affect fibrin formation?
1. Procoagulant drugs
2. Injectable anticoagulant: Heparin and LMW Heparins
3. Oral anticoagulants: Warfarin
What is Vitamin K important for (in terms of the coagulation cascade)?
The formation of clotting factors: II, VII, IX and X
- require gamma carboxylation after synthesis which is done by a reduced vitamin K
What is the mechanism of action of Heparin?
Draw the pathway
It binds to and activates anti-thrombin III which is a natural inhibitor of factor Xa and Thrombin thus preventing the formation of thrombin (less coagulation cascade, less fibrin formation and less platelet activation)
It also has the power to inhibit the action of all the other major factors in the cascade XII, XI and IX
What is the structure of Heparin? What does this mean for the drug?
It is a very large compound (60-100kD), negatively charged
- thus it is not orally available (must be given by IV)
What are the low molecular weight Heparins?
The are much smaller (2-9kD)
Still not orally available
Have the same effects on Xa (not on thrombin) and has a longer elimination half life.
Why must patients taking Heparin be monitored closely? How is this done?
The very serious side effects of the drug and the 'swinging' effect of thrombosis vs. bleeding.
Done by monitoring the Activated Partial Thromboplastin Time (APTT) that measures the time for clot formation in plasma after addition of calcium.
What are the side effects of Heparin?
Thrombocytopaenia (platelet deficiency)
Osteroporosis (not a well known mechanism)
In what settings is Heparin used?
Usually only in the ICU in dire and heavily monitored situations due to the serious side effects.
Only used Acutely and once out of the dire situation, the patients are switched to oral warfarin.
What are the oral anticoagulants?
Derivatives of Coumarin which all inhibit the reduction of Vitamin K and thus inhibit the gamma carboxylation of factors II, XII, IX and X
What is the mechanism of action of Warfarin?
It competes with vitamin K and thus inhibits its action to gamma carboxylation (Activation) of Factors in the coagulation cascade.
Does the drug act on already active factors?
What is the impact of this?
No. It acts on the next 'generation' of factors by affecting their development/activation and has no affecting already activated ones.
This means there is a DELAYED onset of action of the drug and so the dosages must be titrated accordingly
What is the administration and distribution of the drug warfarin?
It is orally available
Rapidly absorbed drug
What are the adverse effects of warfarin?
Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
Chest pain or discomfort
How is warfarin overdose combated?
Vitamin K (oral), phytomedadione natural vitamin K (by IV) or fresh frozen plasma
Why is warfarin called a 'moody drug'?
It is difficult to control
99% Strongly bound to plasma and only 1% unbound (active portion)
= Any changes in plasma proteins have an effect on warfarin activity
EG. dietary changes in Vitamin K, Hepatic disease, hypermetabolic states, drug interactions
What drug interactions occur with Warfarin?
Aspirin impairs platelet aggregation and leads to increased warfarin activity
NSAIDS compete with the same plasma binding protein as warfarin
Competition for the cytochrome p450 pathway with cimetidine (anti-H2) or alcohol, decreases warfarin clearance
What states affect warfarin activity?
Pregnancy and Drug interactions
How and why is careful monitoring of patients on warfarin required?
Because the drug is highly labile
PT and INR monitoring
Because side effects are important and because the dosages constantly change (difficult to have compliance)
What kind of drugs (give examples) are commonly used adjunctly with anti-coagulants or used in other less severe states and why?
Drugs that affect platelet activation and adhesion eg. Aspirin as prevention for clots
For long term anticoagulation
For patients with not a high enough risk to use warfarin
What are the three main types of anti-platelet drugs?
1. ADP receptor antagonists: eg. Clopidegrel
2. Thromboxane synthesis inhibitors eg. aspirin
3. Glycoprotein IIb/IIIa receptor antagonists eg. abciximab
4. Increased production of prostacyclin eg. Dypiradamoles
How do the ADP receptor antagonists work?
Prevent adenosine diphosphate binding (ADP) to the platelet receptor. This inhibits formation of the Glycoprotein IIb/IIIa complex and thus prevents binding to fibrinogen and platelet AGGREGATION
How to the thromboxane inhibitors work
Thromboxanes normally activate platelets and aspirin acts on COX which inhibits the ability of the platelet to produce thromboxane
How does an increase in prostacycline lead to anti-platelet activity?
Dipyridamoles increase the levels of prostacyclin from endothelial cells) which have anti-platelet activity.
They also inhibit phosphodiesterases PDE, which also leads to a decrease in the GP IIa/IIIb formation.
How to the glycoprotein IIb/IIIa receptor angatonigs work?
They are monoclonal antibodies raised against the complex (very expensive) - IV use and only used when other drugs are not working