6. Anticoagulants, Thrombolytics, Antiplatelet Agents, and Antifibrinolytics

Question 1

5. 4. What are the key points of anticoagulants?
      - What is inhibited?
      - Immediate or delayed effect?
      - High or low risk of drug drug interaction?

Answer 1

Anticoagulants all inhibit the action or formation of one or more of the clotting factors

Create an immediate defect (minutes for IV, hours for orally) in the clotting mechanism and should be treated with caution

High risk of DDI - a large number of unrelated drugs affect the dose of the anticoagulant needed to produce a desired effect

Question 2

5. 4 What are the key points of anticoagulants?
   - Narrow or wide range between sufficient therapy and hemorrhagic risk? Consistent patient outcome?
   - How important are individual treatment and frequent laboratory tests?

Answer 2

Narrow range between sufficient therapy and risk. Patient outcome can vary considerably.

Individual treatment and frequent laboratory tests are imperative

Question 3

5.5 What are the four categories of anticoagulants?

(Bonus points - divide the four into old and new!)

Answer 3

Old:

1. indirect thrombin inhibitors (like Heparin)
2. Coumarin anticoagulants (like Warfarin)

New:

3. Direct thrombin inhibitors
4. Direct factor x inhibitors

Question 4

5. 6 Heparin
   - What is it comprised of?
   - What are the two most common preparations?

Answer 4

Heparin is comprised of a mixture of heparins (protein molecules) with a wide range of molecular weights.

The two most common preparations are:

1. Unfractionated heparin (UFH) – Heparin Sodium
2. Low-mol. weight heparin (LMWH) – Fragmin, Innohep, Lovenox

Question 5

5. 7 Heparin
   - Mechanism
   
   • What protein is stimulated by heparin?
     - What kind of category of anticoagulant is heparin?

Answer 5

Heparin stimulates antithrombin III, which neutralizes factor X and other clotting factors.

Without factor Xa, prothrombin canot be converted to thrombin (prevents fibrinogen into fibrin).

Heparin also stimulates heparin cofactor II, which inhibits thrombin

An “Indirect” thrombin inhibitor

Question 6

5. 9 Unfractionated Heparin (UFH)
   - How is it adminstered?
   - What is tricky about dosage?

Answer 6

Given IV (bolus or infusion) - cannot be given orally (heparin proteins destroyed by stomach acidity)

UFH binds to plasma proteins in addition to its normal intended affect, reducing its anticoagulation activity and causing a large variability of anticoagulant response among patients. UFH also binds to endothelial cells and macrophages.

Dosage of UFH is adjusted and effect is monitored with APTT (normal is 25-36 and UFH will be 2-2.5 times that value).

Question 7

5.11 What form of heparin can be administered either in hospital or out of hospital?

Answer 7

Either in-hospital or out of hospital because they can be administered via syringe on a body weight basis without the need for lab monitoring.

Question 8

5.12 What is the only major coumarin anticoagulant in the USA?

Answer 8

Warfarin (Coumadin)

Side note - rat poison

Question 9

5. 13 What is Warfarin’s mechanism?

- Which clotting factors does it target?

Answer 9

Inhibits blood clotting mechanisms by interfering with the hepatic synthesis of vitamin-K dependent clotting factors (II, VII, IX, and X)

Question 10

5.14 What are the main indications for treatment with warfarin?

Answer 10

1. Long-term treatment of venous thrombosis or pulmonary embolism
2. Post-MI and post-op (after cardiac or vascular surgery) patients
3. Prevention of systemic thromboembolism in patients with prosthetic heart valves or atrial fibrillation

Question 11

5.15 How is Warfarin therapy monitored?

Answer 11

It is defined in terms of the international normalized ratio (INR).

For most patients, an INR of 2.0 to 3.0 is desired.

Question 12

5.16 What are key drug-drug interactions with Warfarin?

Answer 12

1. Cimetidine (Tagamet)
2. Acetaminophen (Tylenol)
3. High dose, acute alcohol
4. Many antibiotics
   - Azithromycin (Zithromax)
   - Ciprofloxacin
   - Clarithromycin
   - Erythromycin

Synthetic thyroid hormones increase the catabolism of many clotting factors and can potentiate (increase) the effects of warfarin.

Question 13

5.17 What can stimulate warfarin metabolism, diminishing the desired effects?

Answer 13

Chronic alcohol use

Phenytoin (dilantin)

Question 14

5.17 How do oral contraceptives interact with warfarin?

Answer 14

Oral contraceptives increase the synthesis of many clotting factors, reducing the effects of warfarin.

Question 15

5. 18 What foods can decrease warfarin effects?
   - How?
   - What are some examples of these foods?

Answer 15

Foods rich in Vitamin K

They stimulate the synthesis of vitamin K dependent clotting factors (II, VII, IX, X)

Cabbage, cauliflower, spinach, and other green leafy vegetables, as well as cereals

Question 16

5.18 How are warfarin overdoses typically treated?

Answer 16

Treated with vitamin K and transfusion

Question 17

5.19 What is the most common side effect of warfarin and where does this occur?

Answer 17

Most common side effect is bleeding

Occurs most often from the mucous membranes of the GI tract and the genitourinary tract

Question 18

5.19 Why is warfarin contraindicated during pregnancy (category X)?

Answer 18

It cross the placenta and is teratogenic (affects development of the fetus).

Breast feeding should also be avoided.

Question 19

5.20 What is the first oral Direct Thrombin Inhibitor that came to market?

• How is this anticoagulant administered?
• Does it require frequent INR tests?

Answer 19

Dabigatran (Pradaxa)

Orally administered anticoagulant

Does not require frequent blood tests for INR

Question 20

5.22 What are the four types of drugs affecting hemostasis?

Answer 20

1. Anticoagulants - prevent coagulation/thrombi
2. Thrombolytics/Fibrinolytics - dissolve clots/thrombi
3. Antiplatelets - reduce adhesion/aggregation of platelets
4. Antifibrinolytics - formation of clots/excess bleeding

Question 21

5.23 What do thrombolytics/fibrinolytics do?

Answer 21

Thrombolytics rapidly lyse thrombi when adminstered intravenously by catalyzing the formation of plasmin from plasminogen

Question 22

5.23 What are examples of thrombolytics/fibrinolytics?

Answer 22

Streptokinase
Urokinase
Synthetic tPA
Others

Question 23

5.23 What are indications for use of thrombolytics/fibrinolytics?

When are thrombolytics/fibrinolytics best used?

Answer 23

Indications include acute MI, acute ischemic stroke, and pulmonary embolism

Best used as soon as possible from the onset of the event

Question 24

5.24 What are the three main classes of antiplatelets?

Answer 24

1. Thienopyridines (ADP inhibitors)
2. Cyclooxygenase inhibitors (mainly aspirin)
3. GP IIb/IIIa inhibitors)

Question 25

5.25 How does aspirin (cyclooxygenase inhibitor) act on platelets?

Answer 25

It inhibits the synthesis of TXA2 - a substance that helps make the platelets sticky and more likely to aggregate. (TXA2 normally acts on other platelets)

Question 26

5. 26 How do thienopyridines (ADP inhibitors) work?

- What is an example of this drug?

Answer 26

These drugs act by preventing the binding of ADP to its receptors on platelets, inhibiting the pathway towards platelet aggregation.

Clopidogrel (Plavix)

Question 27

5. 27 GP IIb / IIIa Inhibitors
   - Mechanism?
   - An example?
   - How are they administered?

Answer 27

Inhibit activation of glycoprotein IIb/IIIa receptors on platelets, inhibiting the “final common pathway” for platelet aggregation.

Example is abciximab (ReoPro)

Administered IV with an initial bolus followed by constant infusion

Question 28

5. 28 Antifibrinolytics
   - What is an example?
   - Mechanism?
   - Use in dentistry?

Answer 28

Tranexamic acid

Inhibits activation of plasminogen to plasmin

Used in dentistry as a 5% mouth rinse after extractions or surgery in patients with prolonged bleeding time (from acquired or inherited disorders).