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How many pathways are there in the coagulation cascade and what are they?
What factors are associated with the extrinsic pathway of coagulation?
3, 7, (4)
What factors are associated with the intrinsic pathway of coagulation?
12, 11, 9 , 8 ,(4)
What factors are associated with the common pathway of coagulation?
5, 10, 1,2, 13
What laboratory test monitors the extrinsic pathway? Intrinsic?
Discuss the initiation of the clotting cascade and the role of TF-Factor VIIa.
- Tissue factor (factor III) is the physiologic initiator for the extrinsic pathway. Tissue factor activates factor VII (proconvertin), and when complexed with calcium (factor IV) on the surface of the platelet factor X is activated.
- Describe the role of antithrombin AT (antithrombin III) and Fibrinolysis.
- Fibrinolysis is the process of preventing blood clots. Antithrombin is a protein that binds several coagulation factors (II, IX, X, XI, XII) but its main target is II (thrombin). Hence the name �anti� thrombin. Antithrombin is a cofactor for heparin and when complexed together is 1000x more effective at anticoagulation. On its own it is a rather inefficient anticoagulant.
What pharmacological class does heparin belong to?
indirect thrombin inhibitors
Briefly, what is the mechanism of action of heparin?
inhibits thrombin & factor Xa
What are some clinical uses for heparin?
- DVT prevention & treatment
What can be measured to assess the clinical effectiveness of heparin?
aPTT & ACT
Name 3 contraindications for heparin therapy.
- bleeding (non DIC)
- severe low platelets
What medication can reverse heparin and what type of reaction is it?
- neutralization reaction
How much heparin does protamine reverse?
100 units of heparin for every 1 mg of protamine
Why should the infusion rate of protamine not exceed 50 mg in 10 min?
because it has an anticoagulant effect also
What medication is protamine not effective at reversing?
Describe the pharmacology of direct factor X inhibitors.
factor Xa catalyzes the reactions to convert prothrombin to thrombin. By blocking this common access point you can block the extrinsic and intrinsic at the same time.
Discuss the pharmacology of (IV/PO) direct thrombin inhibitors
reversibly binds to the thrombin active site. Does not require the co-factor antithrombin III for antithrombotic activity. Inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation
What condition would make the use of lepirudin most beneficial?
HIT (heparin induced thrombocytopenia)
What class of medication is Pradaxa?
direct thrombin inhibitor
What class of medication is Rivaroxaban?
direct factor X inhibitor
What class of medication is Heparin and LMWH?
indirect thrombin inhibitors
Lepirudin is the synthetic analogue of what substance and what animal does it come from?
Name 4 medications that when given together with Pradaxa cause an increased anticoagulant effect.
What is the antidote for pradaxa or lepirudin OD?
there is none. you can try recombinant factor VII or prothrombin complex concentrations for life-threatening bleeding
What is the MOA of coumadin?
vitamin K antagonist by inhibiting vitamin K epoxide reductase, thus preventing the recycling of vitamin K, and the carboxylation of the vitamin-K-dependent factors.
What are the Vitamin K dependent coagulation factors?
II, VII, IX, X, protein C & S
What medication category for pregnancy does Coumadin fall into and why?
- category X
- readily crosses the placenta causing hemorrhagic disorders of the fetus
- serious birth defects of bone formation
What test is used to assess therapeutic effect of Warfarin?
Why is not appropriate to use a loading dose or increase the daily dose of Warfarin to attempt therapeutic INR?
- because the 1/2 lives of vitamin K factors fairly long so it will take several days for the INR to reflect the change in dosage.
- (1/2 life of factor VII is about 4-6 hours)
Name 3 common medications that can INCREASE INR when taken with Warfarin.
Name 3 commmon medications that can DECREASE INR when taken with Warfarin.
- Vitamin K foods (green leafy vegetables)
How can you reverse the action of Warfarin?
- stop taking the medication
- Vitamin K (will need more than 1 dose due to long 1/2 life of warfarin)
Describe the pharmacology of fibrinolytic drugs
- Fibrinolytic drugs are plasminogen activators. Plasminogen is woven into thrombi as they are created. Once the zymogen, plasminogen, is activated it forms plasmin. Plasmin then can lyse or break down fibrin into fibrin degradation products.
- Name 4 common uses for fibrinolytic therapy.
- pulmonary embolism with hemodynamic compromise
- severe DVT
- ascending thrombophlebitis
- intra-arterially for PVD
In terms of anticoagulation, what type of medication is ASA?
How does ASA block platelet aggregation?
by inhibiting cyclooxygenase to inhibit thromboxane A2 and ADP which prevents fibrinogen receptors from being uncovered. This prevents platelets from linking together
In terms of platelet life span, how long does ASA effect last?
the entire life span of the platelet which is about 7-10 days
How does Ticlopidine differ from ASA in terms of MOA?
it does not block prostaglandin such thromboxane A2 like ASA does. It only blocks the ADP pathway
How do platelet glycoprotein receptor blockers work?
GPIIb/IIIa receptor blockers essentially block the receptor for fibrinogen and vitronectin. This is different from ASA because where thromboxane A2 and ADP uncover these receptors, the GPIIb/IIIa simply �cap� them.
A person that is lacking GPIIb/IIIa receptors on the surface fo their platelets has this condition?
Concerning the tendency to form thrombi, deficiency of these 3 natural anticoagulants is known as a loss of function mutation.
- protein C
- protein S
Name 3 gain of function mutations that can cause abnormal thrombi formation.
- factor V leiden
- prothrombin mutation
Describe the prevention vs treatment of established coagulation disorder. (thombus)
Prevention and treatment are essential with the same medications. To prevent thrombosis you can use heparin, LMWH, or warfarin. With treatment, LMWH or UFH is used for the initial 5-7 days and then warfarin is overlapped. Once therapeutic effects have been achieved the patient is on warfarin for a minimum of 3-6 months and if the thrombi are recurrent, treatment could be indefinite.
What class of medication is Abciximab?
GP IIb/IIIa receptor blocker
Name 4 adverse effects of infusing Vitamin K to rapidly?
- chest/back pain
How does DDAVP enhance coagulation?
it causes the release of von Willebrand's factor from subendothelial stores that will enhance platelet aggregation
What clotting factors does FFP contain?
all of them except for platelets
Of all the coagulation factors, which one does not require treatment for a deficiency?
Hageman factor (XII)
Regarding statin therapy, what is the mechanism of action?
inhibit the HMG-CoA reductase enzyme which is the RATE LIMITING step in cholesterol production
What is the mechanism though to cause muscle cell damage by statin?
inhibit production of coenzyme Q-10
Which form of statin is associated with less myopathy?
Concerning food and drug interactions, which population of CYP enzymes is often implicated?
What classification of pregnancy medication do statins fall into?
Niacin is also known as what B vitamin?
Name the 3 MOA for Niacin.
- inhibit VLDL secretion, thus lowering LDL
- increase VLDL clearance via lipoprotein lipase, thus reducing triglycerides
- decreased HDL breakdown
Name 4 adverse reactions associated with Niacin use.
- Flushing (prostaglandin mediated)
- Liver enzymes elevated
- Elevated blood glucose
What receptor do Fibrates activate?
peroxisome proliferation-activated receptor alpha (PPAR-a)
By activating the PPAR-a receptor, what 2 effects do fibrates have on LPL activity?
- LPL is upregulated
- increased LPL breakdown of triglycerides
Name 5 adverse reactions associated with fibrate therapy.
- increased liver enzymes
- DEC renal function
- Rhabdo with statin use (gemfibrozil)
- GI symptoms
How do bile acid sequestrants work?
bind with bile acids to form an insoluble compound that is then excreted in the feces
Name 2 pros for bile acid sequestrants.
- can be used in children
- no drug metabolism interactions
What medication adminstration adjustments need to be taken when on bile acid sequestrant therapy?
take other medications 1 hour before the bile acid seq. or 4 hours after
BAS can bind other drugs and compounds decreasing their absorption. Name 3.
- vitamins A, D, E, K, Folic acid
- Lipophilic medications
What class of medication is Zetia?
sterol absorption inhibitor
What is the MOA for the sterol absorption inhibitors?
inhibits intestinal absorption of cholesterol in the small intestines via the sterol transporter; Niemann-Pick C1-like-1. It also upregulates LDL receptors that enhances uptake of LDL out of the plasma.
Name 4 adverse effects associated with Zetia use.
- elevated liver enzymes
- rhabdo with statin use (rare)