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