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Drugs for Coagulation disorders
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• There are a number of different categories of drugs which modify the coagulation process:
• I. Anticoagulants
• II. Antiplatelet agents
• III. Thrombolytics
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I. AnticoagulantsA. The coagulation cascade
• The coagulation cascade begins when injured cells release thromboplastin.
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• Thromboplastin converts the clotting factor prothrombin to thrombin.
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• Thrombin then converts the plasma protein fibrinogen to long strands of fibrin and activates several clotting factors (V, VIII, XIII, and protein C)
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• The fibrin strands form an insoluble web
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B. Types of anticoagulants
• The mechanism of action of anticoagulant medications involves either the inactivation of various existing coagulation factors, or
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• preventing the synthesis of coagulation factors (the vitamin K antagonists)
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• Anticoagulant medications do NOT dissolve clots.
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1. heparins
• a. standard heparin
• b. low molecular weight (LMW) heparins
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• Heparins are indicated for the treatment of:
• deep vein thrombosis (DVT)
• prophylaxis and treatment of venous thrombi, alone
• prophylaxis and treatment of venous thrombi in conjunction with pulmonary emboli
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• Heparins are NOT direct thrombin inhibitors.
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• Instead, heparins prevent thrombin formation by binding to clotting factors in the circulation.
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• These clotting factors then bind to and inactivate thrombin, the major enzyme in the clotting pathway.
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• The main commercial sources of standard heparin are the lungs and intestines of cattle (bovine) and pigs (porcine).
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• LMW heparins are derived from porcine heparin.
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• They are smaller in size as they only contain the anticoagulant fraction of heparin, and not the additional saccharide chains that standard heparin has.
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a. Standard heparin
• Standard heparin has an immediate onset of action if administered IV, it peaks within 5-10 minutes, and its duration is 2-6 hours.
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• Standard heparin has an onset of action of 20 minute – 1 hour if administered SC, it peaks within 2 hours, and its duration is 8-12 hours.
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• Standard heparin IV administration: bolus of 10,000 – 12,000 units followed by 5,000-10,000 units every 4-6 hours
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• Standard heparin SC administration: bolus of 10,000 – 12,000 units followed by 15,000-20,000 units every 12 hours
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b. Low molecular weight (LMW) heparins
• LMW heparins are ONLY administered SC, have a rapid onset of action, generally peak within 3-6 hours, and have a duration of 12-24 hours depending on the agent. Specific LMW heparins include:
•
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• i. dalteparin (Fragmin):
• Indicated for prophylaxis of Deep Vein Thrombosis (DVT) in patients undergoing abdominal surgery or hip replacement surgery.
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• ii. enoxaprin (Lovenox):
• Indicated for prophylaxis of DVT in patients undergoing abdominal, hip, or knee surgery.
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• iii. fondaparinux (Arixtra):
• Indicated for both the treatment of and prophylaxis of DVT and pulmonary embolism (PE).
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• iv. tinzaparin (Innohep):
• Indicated for both the treatment of and prophylaxis of DVT.
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• LMW heparins have certain advantages over standard heparin:
• 90% bioavailability (standard heparin has 30%)
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• LMW heparin can be dosed based on body size without coagulation test monitoring (if patient has normal kidney function)
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• Adverse effects of heparins:
• hemorrhage
• anemia in elderly with Lovenox, due to decreased clearance
• fever
• hair loss
• thrombocytopenia (↓ in no. of platelets)
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• Black box warning for LMW heparin use in patients concurrently receiving epidural or spinal anesthesia as it increases the risk for epidural or spinal hematomas
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2. thrombin inhibitors
• Unlike the heparins, these drugs bind directly to thrombin. They are all administered IV.
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• a. argatroban (Argatroban)
• indicated for patients with, or at risk for thrombocytopenia who are undergoing percutaneous coronary intervention (PCI).
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• b. bivalirudin (Angiomax): used, along with aspirin, in patients with unstable angina who undergo PCI. This treatment is intended to reduce the risk of acute ischemic complications
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• c. lepirudin (Refludan): derives from the natural product hirudin, found in leech saliva.
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• Leeches have been used for bloodletting since the times of the ancient Greeks.
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3. anticoagulants which prevent the synthesis of coagulation factors
• This category of anticoagulant is significantly different from the heparins in that it can be administered orally.
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• This type of anticoagulant has a longer onset because of the time required to clear the normal clotting factors from the circulation before an effect can be observed.
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• The only drug in this class is warfarin sodium (Coumadin): 2-10 mg
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• Its onset of activity is about 12-72 hours.
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• However, its duration of action is longer (2 to 10 days) even after drug administration has been discontinued.
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• Coumadin is indicated for the treatment of DVT and prevention of myocardial re-infarction
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• Adverse effects include:
• GI disturbances
• hypotension
• hair loss
• headache
• hemorrhage (most serious)
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• A black box warning indicates that there is an ↑ risk of hemorrhage in:
• patients over 65
• patients with a history of GI bleeding
• INR > 4
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• INR (international normalized ratio) is a test used to monitor coagulation status.
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• People not on anticoagulants have an INR of 1
• An INR of 2 – 3 is needed for a therapeutic effect with warfarin
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II. Antiplatelet agents
• Antiplatelet agents exert an anticoagulant effect by interfering with various aspects of platelet function.
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• Antiplatelet agents are indicated for the treatment of :
• thrombocytopenia
• acute coronary syndrome
• prevention of myocardial re-infarction
• and reducing coronary events
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• The 2 subclasses of antiplatelet agents are:
• A. nonselective COX inhibitors
• B. adenosine diphosphate (ADP) receptor blockers
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A. nonselective COX inhibitors
• Normally, the cyclooxygenase enzyme pathway in platelets results in the production of thromboxane A2, a potent platelet aggregator.
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• Aspirin, in doses from 81 mg (baby aspirin) to 325 mg (adult analgesic dose) irreversibly blocks a step in this pathway, preventing the synthesis of thromboxane A2.
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• Therefore, thromboxane will not be active until new platelets are formed.
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B. ADP receptor blockers
• These drugs interfere with a receptor on the membrane of platelets, preventing them from aggregating.
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• Adenosine diphosphate (ADP) normally binds to these membrane receptors in platelets, resulting in the coagulation of the platelets.
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• The drugs in this class block the receptor so that ADP cannot bind.
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• All of the drugs in this class are administered orally.
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• 1. ticlopidine (Ticlid): 250 mg, bid
• 2. clopidogrel (Plavix): 75 mg
• 3. cilostazol (Pletal): 100 mg, bid
• 4. prasugrel (Effient): 5 – 10 mg with food
• 5. anagrelide (Agrylin): 1.0 mg, bid
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III. Thrombolytics
• Thrombolytics are enzymes used to dissolve blood clots.
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• They convert plasminogen to plasmin, which is then able to degrade the fibrin present in clots.
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• Their primary functions are: to break apart pulmonary emboli and coronary artery thromboses during acute MI.
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• They need to be administered as soon as possible once it has been established that a clot or infarct has occurred.
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• Other disorders for which they may be indicated are:
• DVT
• stroke
• occluded central venous access devices
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• For the treatment of acute MI: administer the drug within 1-6 hours of the onset of symptoms.
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• There is a longer window of opportunity for use of these drugs in treating a pulmonary embolism. Here the time for initiation of therapy may be up to a few days.
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• All drugs in this class are enzymes that must be administered IV.
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A. streptokinase
• Streptokinase (Streptase, Kabbikinase): generally, 250,000 IU over 30 minutes, then 100,000 IU/hour for up to 72 hours
• Larger doses may be used in the treatment of MI
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B. urokinase
• urokinase (Abbokinase): IV 4400-6000 IU administered over several minutes to 12 hours
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• A symptomatic ulnar artery occlusion before and after urokinase infusion therapy.
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C. thrombolytics produced via recombinant DNA
• alteplase (Activase, Cathflo), reteplase (Retavase) and tenecteplase (TNKase) are thrombolytic enzymes produced through recombinant DNA technology
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• alteplase: based on patient weight, not to exceed 100 mg. Generally, a 15 mg bolus, followed by 50 mg over next 30 minutes then 35 mg over the next 60 minutes
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• reteplase: 10 unit bolus over 2 minutes, wait 30 minutes, repeat
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• tenecteplase: a single bolus, over 5 seconds based on body weight, not to exceed 50 mg
• Generally used in conjunction with aspirin and heparin therapy
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• Adverse effects of the thrombolytics:
• hemorrhage
• rash/itching
• headache
• nausea
• bronchospasm
• cardiogenic shock or arrhythmias with the recombinants