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