Pharmacology of Anticoagulation Therapy Flashcards
Name the anticoagulant drugs that interfere with the coagulation cascade and prevent formation of thrombin, which converts fibrinogen to fibrin.
Heparin and oral anticoagulants
What agent promotes lysis of clots by increasing formation of plasmin, a serine protease that degrades fibrin?
Fibrinolytic agents
What drug inhibits the formation of platelet products or blocks platelet adhesion thus preventing platelet aggregation and clot formation?
Anti-platelet agents
What are the three forms of Heparin?
- Unfractionated Heparin
- Low molecular weight heparins
- Fondaparinux
Describe unfractionated heparin.
- Proteoglycans containing covalently linked sulfated polysaccharide chains
- 12,000 Daltons
- Highest negative charge density
Describe low molecular weight heparins like
- lovenox
- enoxaparin
- dalteparin
- nadroparin
- produced by chemical or enzymatic depolymerization of heparin
- 4,500 Daltons
Describe Fondaparinux (Arixtra)
Synthetic pentasacharide
Minimal sequence in heparin for binding antithrombin
What is the mechanism of action of heparin?
Heparins bind antithrombin III
Antithromin III is a natural protease inhibitor that inactivates coagulation factors
Heparin accelerates the rate of decay of IXa, Xa, and XIIa by antithrombin III
Which type of heparin is able to bind to the antithrombin/thrombin complex?
Unfractionated
LMWH and Fondaparinux can only bind AT-III
Which drug does not absorb well from the GI tract and can’t be given orally. This drug also has poor bioavailability and relatively short half-life?
Hint: Requires careful monitoring in hospital but can be given to pregnant women.
Unfractionated heparin
What drug is given SQ, has a long half life, requires less monitoring, and has a better bioabailability than unfractionated heparin?
Low molecular weight heparins and fondaparinux
What conditions would you use heparins to treat?
-Venous thrombosis and pumonary embolism
-management of unstable angina or acute myocardial infarction
-During and after coronary angioplasty or stent placement
During surgery requiring cardiopulmonary bypass
-Kidney dialysis
What drug can you use to reverse the toxic affects of heparin?
Protamine sulfate, a positively charged compound that neutralizes heparin
Name three toxic effects of heparin.
- Bleeding
- Heparin-induced thrombocytopenia syndrome (HIT)
- Allergic Events
Describe the onset of heparin-induced thrombocytopenia syndrome.
Platelet cound decreases 5-10 after heparin
Caused by development of antibodies that bind to and activate platelets resulting in a prothrombotic state
What is the treatment for patients who have heparin-induced thrombocytopenia syndrome?
TX with direct thrombin inhibitors:
- Argatroban (Novastan): a small molecule inhibitor
- Lepirudin (Refludan): recombinant form of hirudin, the antivoagulant from leeches
Allergic reactions are sometimes seen in patients on Heparin. What is the root cause of thos allergic reaction?
Contaminant over sulfated chondroitin sulfate
What drug is a derivative of dicumarol and is a vitamin K analogue?
Warfarin
What is the mechanism of action of warfarin?
Warfarin inhibits reductases that reduce vitamin K.
Reduced vitamin K is used as a cofactor for certain enzymes
These enzymes undergo vitamin K-dependent gamma carboxylation of N-terminal glutamate
What are the pharmacokinetic characteristics of warfarin?
It is readily absorbed
Good bioavailability
Does not achieve affect until 2-3 days
What are the clinical uses of warfarin?
Used to prevent:
- Venous thromboembolism
- Systemic embolism in patients with prosthetic heart valves or atrial fibrillation
- Stroke, recurrent infarction, or death in patients with acute myocardial infarction
What are some of the adverse effects of warfarin?
Hemorrhage
TX: Drug stopped, Vitamin K administered, Plasma can be transfused to replace coag. factors
Teratogenic
What drugs can increase the action of warfarin?
- Drugs that inhibit platelet function (aspirin)
- Drugs that decrease vit. K synthesis by intestinal microbes (antibiotics)
- Drugs that replace warfarin from plasma proteins (clofibrate, phenytoin)
- Drugs that reduce the metabolism and elimination of warfarin in the liver
What drug decrease the effect of warfarin?
- Drugs that increase the metabolism by inducing metabolic enzymes in the liver (barbiturates, rifampin)
- Drugs that decrease warfarin absorption from the GI tract (cholestyramine)
There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name some advantages of these drugs.
- Rapid onset of action
- Absence of food interactions
- Do not require monitoring
There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name some disadvantages of these drugs.
- Contraindicated with kidney disease
- Greater GI bleeding than with warfarin
- Short half-life
- Cost
- No antidote available to reverse effects
There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name three of these new drugs.
- Dabigatran etexilate: Prodrug, lowers rate of stroke and systemic embolism, less intracranial hemorrhage. More myocardial infarctions
- Apixaban
- Rivaroxaban- Synthetic, lower rates of strokes and emboli for the TX or atrial fibrillation
All three have been approved for the treatment of atrial fibrillation
What is the mechanism of action for fibrinolytic agents?
Convert plasminogen to plasmin, a protease that degrades fibrin clots.
What is tissue plasminogen activator and what is its mechanism of action?
- Serine protease
- Fibrinolytic drug that binds to fibrin, which increases cleavage of plasminogen to plasmin.
What is urokinase (u-PA)?
Enzyme obtained from renal cells in culture that converts plasminogen to plasmin
DOES NOT BIND FIBRIN
What is streptokinase?
Non-enzymatic protein obtained from beta-hemolytic streptococci.
-forms a complex with plasminogen which becomes activated and converts plasmin
What are fibrinolytic agents used in the the treatment for?
-Acute myocardial infarction
-Ischemic stroke
-Deep vein thrombosis
Pulmonary embolism
What are some adverse effects of fibinolytic agents?
Hemorrhage
Induced systemic lytic state
Allergic reaction due to antibodies against Streptokinase
What are antiplatelet drugs used to treat?
Acute coronary syndrome
What are the three classes of anti-platelet drugs?
- Those that inhibit formatio of platelet products (Aspirin)
- Those that prevent activation/aggregation (ADP receptor antagonist)
- Those that block adhesion proteins (Glycoprotein IIb/IIIa Inhibitors)
What is the mechanism of action of aspirin?
Irreversibly inactivates cyclooxygenase preventing thromboxane A2 formation by platelets
Permanent- for the lifespan of the platelet 7-10 days
Used in prevention of AMI of patients with artherosclerosis
What are two ADP receptor antagonist?
Thienophyridines
- Clopidogrel (Plavix)-used in pts. w/ aspirin intol.
- Ticlopidine
- Prasugrel- most potent
What is the mechanism of action of ADP receptor antagonists?
They block platelet activation by ADP which inhibits secretion of alpha granules and blocks expression of adhesion proteins GPIIb/IIa
What is the pharmacokinetics of ADP receptor antagonists?
slow onset of action because they are prodrugs that have to be metabolized by the liver
Is the action of ADP receptor antagonists permanent?
Yes so for the lifespan of that platelet
What is ADP receptor antagonist used to treat?
Preventing cardiac events in patients with atherosclerosis
Describe Ticagrelor.
Oral ATP analogue that binds reversibly to ADP receptor
Rapid action
Greater platelet inhibition
Reduced rate of death from MI without increasing major bleeding
What are glycoprotein IIb/IIIa inhibitors?
Adhesion protein on the surface of platelets that is a receptor for fibrinogen
Inhibitors block the receptor and prevent platelet aggregation
Name three glycoprotein IIb/IIIc inhibitors.
Abciximab-Monoclonal antibody agains the glycoprotein receptor. Used in coronary angioplasty. Prevents restenosis, recurrent AMI
Eptifibatide- Cyclic peptide inhibitor used for unstable angina
Tirofiban- small molecule inhibitor used or treatment of unstable angina
What are the adverse affects of glycoprotein IIb/IIIc inhibitors?
Bleeding and thrombocytopenia
Reverse by platelet infusion
