Anticoagulants

Question 1

What are Anticoagulants?

Answer 1

Prevent thrombus formation and extension by inhibiting clotting factors e.g. heparin, low molecular weight heparin, coumarins/ warfarin.

Question 2

What are Antiplatelet drugs?

Answer 2

reduce risk of clot formation by inhibiting platelet functions e.g. aspirin and ticlopidine.

Question 3

What are Fibrinolytic agents?

Answer 3

dissolve thrombi already formed e.g. streptokinase.

Question 4

List all 13 coagulation factors and their names

Answer 4

I Fibrinogen
II Prothrombin
III Tissue Factor or thromboplastin
IV Ca++
V Proaccelerin
VII Proconvertin
VIII Antihemophilic A factor
IX Antihemophilic B factor or Christmas factor
X Stuart or Stuart- Prower factor
XI Plasma thomboplastin antecedent
XII Hageman factor, contact factor
XIII Fibrin stabilizing factor
Prekallikrein factor
High-molecular-weight kininogen

Question 5

What are 3 endogenous Inhibitors of Coagulation?

Answer 5

1. Antithrombin III, is a plasma protein that inhibits activated thrombin (factor IIa) and Xa, it is the site of action of heparin
2. Prostacyclin ( PGI2), is synthesized by endothelial cells and inhibits platelet aggregation
3. Protein C and Protein S: degrading Factor VIIIa and Va preventing coagulation

Question 6

Types of anticoagulants

Answer 6

Parenteral anticoagulants:
Direct e.g hirudin, lepirudin
Indirect e.g heparin and heparin related agents

Oral Anticoagulants:
Vitamin K antagonists e.g. warfarin

Question 7

Anticoagulants are indicated in

Answer 7

Myocardial infarction (MI)
Deep venous thrombosis (DVT)
Peripheral arterial emboli, pulmonary embolism (PE) and many other conditions
Anticoagulants are also useful in dialysis procedures

Question 8

What is Heparin (Unfractionated Heparin)?

Answer 8

Normally occurs as macromolecule in mast cells with histamine ( its physiological role is unknown )

Commercial preparations are extracted from beef lung or pig intestine (can cause hypersensitivity reaction)

Heparin stops the expansion of a thrombus and prevents the formation of new thrombi but it does not dissolve an existing thrombus

Question 8

What is Heparin’s Mechanism of action

Answer 8

Indirect Thrombin Inhibitor

It acts indirectly by increasing the activity of the endogenous anticoagulant “antithrombin III” (1000 folds) which inhibits activated clotting factors mainly thrombin (factor IIa) and Xa

When Heparin binds to antithrombin III, it causes conformational changes that accelerates its rate of action 1000 fold

Heparin binds to both antithrombin III and thrombin to form a ternary complex

Heparin dissociates leaving the thrombin bound to its inhibitor
Once dissociated, Heparin is free to bind to another antithrombin molecule and subsequently inhibits more thrombin

Question 9

Discuss the Pharmacokinetics of UFH

Answer 9

• Heparin is not absorbed from the GIT
• It should be administered by IV or SC injection.
• Not injected IM as it causes haematomas at injection site
• Once in the blood stream, UFH binds to plasma proteins, endothelial cells and macrophages
• Heparin does not cross the placenta; therefore it is the drug of choice as anticoagulat during pregnancy
• Close monitoring of the activated partial thromboplastin time (aPTT) is necessary in patients receiving UFH.

Question 10

Therapeutic uses of heparin

Answer 10

Due to its rapid onset of action, it is used to initiate immediate anticoagulation in thromboembolic disease (PE, DVT, MI) mainly as induction for oral vitamin K antagonists (VKAs)

Prevention of postoperative DVT (in patient undergoing hip replacement)

Prevention of coagulation during renal dialysis or cardiac surgery

Question 10

Disadvantages of UFH

Answer 10

The inconvenience of administration by injection

The need for regular monitoring (aPTT)

UFH carries a risk of heparin-induced thrombocytopenia (HIT), a fall in the platelet count and increased risk of thrombosis due to binding to platelets

Generally, if the number of platelets is too low, excessive bleeding can occur

If the number of platelets is too high, blood clots can form thrombosis

However, there are disorders that reduce the number of platelets, such as heparin-induced thrombocytopenia (HIT) that typically cause thrombosis, or clots, instead of bleeding

Question 11

Adverse effects of UFH

Answer 11

The major adverse effect of heparin is bleeding

Allergic reactions (chills, fever, urticaria) as heparin is of animal origin and should be used cautiously in patients with allergy

Long-term heparin therapy is associated with osteoporosis

Heparin-induced thrombocytopenia (HIT )

Question 11

Heparin-Induced Thrombocytopenia

Answer 11

Generally, if the number of platelets is too low, excessive bleeding can occur

If the number of platelets is too high, blood clots can form thrombosis

However, there are disorders that reduce the number of platelets, such as heparin-induced thrombocytopenia (HIT) that typically cause thrombosis, or clots, instead of bleeding

Question 12

Contraindications of Heparin

Answer 12

Bleeding disorders, hemophilia
Patients with hypersensitivity to the drug
Recent surgery of the brain, eye or spinal cord, threatened abortion

Question 13

Examples of LMWH

Answer 13

Heparin fragments (e.g. Enoxaparin, Dalteparin)
Synthetic pentasaccharide (Fondaparinux) are used increasingly in place of unfractionated heparin
LMWHs increase the action of antithrombin III on factor Xa but not its action on thrombin, because the molecules are too small to bind to both enzyme and inhibitor

Question 14

Difference between UFH and LMWH

Answer 14

1. IV life: UFH-2hrs LMWH-4hrs
2. Biolavailabilty after SC injection: UFH-20%, LMWH-90%
3. Anticoagulant response: UFH variable, LMWH-predictable
4. Major adverse effect: UFH-HIT, high blood loss and osteoporosis, LMWH: Low blood loss and low HIT
5. Specific antagonist: UFH-Protamine sulfate, LMWH-incomplete
6. Setting for therapt: UFH-Hospital, LMWH-Hospital, OPC
7. Lab monitoring: UFH-needed for aPTT, LMWH-not needed

Question 15

Advantages of LMWHs over UFH

Answer 15

The theoretical pharmacologic advantages ofLMWHover UFH arise from the preferential binding ratio to factor Xa over thrombin

The convenience of once- or twice- daily subcutaneous injections without regular coagulation monitoring due to:

• More predictable response
• Long plasma half-life and improved bioavailability
• Less plasma protein binding
• Less platelet activation and lower risk of re-thrombosis and thrombocytopenia

Question 16

Direct thrombin inhibitors (DTIs)
What is their unique characteristic?

Answer 16

DTIs exert their anticoagulant effect by direct binding to thrombin
This direct effect is rapid and potent

DTIs are not associated with the development of thrombocytopenia

Question 17

What are some examples of Direct thrombin inhibitors (DTIs)?

Answer 17

Parenteral direct inhibitors of thrombin activity are FDA-approved:
lepirudin, desirudin, bivalirudin and argatroban
Dabigatran

Question 18

Sources of Vit k
Required for synthesis of
Causes of deficiency

Answer 18

Source of vitamin K: Green vegetables Synthesized by intestinal flora

Required for synthesis of Factors II, VII, IX ,X Protein C and S (endogenous anticoagulants)

Causes of deficiency
Malnutrition, Malabsorption, Antibiotic therapy

Question 19

What are the Vit k dependent clotting factors

Answer 19

Factors 2,7,9 ans 10

Question 20

Warfarin: Mechanism of action

Answer 20

Warfarin Inhibits synthesis of Vitamin K-dependent coagulation factors II, VII, IX, & X as well as anticoagulant proteins C & S

3-4 days until effect is seen

Does not have any effect on already-synthesized coagulation factors; therefore, the therapeutic effects are not seen until these factors are depleted

Question 21

Disadvantages of Warfarin therapy

Answer 21

• Variable, unpredictable effect necessitating regular INR monitoring and dose adjustment
• Narrow therapeutic window leading to increased risk of severe bleeding
• Slow onset and offset of action
• Numerous interactions with foods containing vitamin K and drugs
• Skin necrosis if low protein C

Question 22

What are some Drug interactions with oral anticoagulants?

Answer 22

1. Inhibition of Vit. K synthesis by intestinal flora; oral antibiotics
2. Inhibition of Vit K absorption; liquid paraffin
3. Decrease in drug metabolism by microsomal enzyme inhibitors; chloramphenicol, & cimetidine
4. Displacment of the drug from protein binding sites; phenylbutazone & salicylates
5. Co-administration of drugs that increase bleeding tendency by; inhibiting platelet function; NSAIDs, heparin
6. Inhibition of drug absorption from GIT; cholystyramine, colestipol
7. Increase in synthesis of clotting factors; Vit K, oral contraceptives
8. Increase in drug metabolism by microsomal enzyme inducers; Carbamazepine; barbiturates, rifampicin

Question 23

Why is Warfarin is contraindicated during pregnancy?

Answer 23

Warfarin is contraindicated during pregnancy as it can cross the placental barrier and cause:
Abortion
Hemorrhagic disorder in the fetus
Birth defects

Question 24

What should a pateint do if they experince bleeding due to warfarin?

Answer 24

Discontinue the drug
Administer Vitamin K (its antagonist)
Administer fresh frozen blood

Question 25

What is Dabigatran etexilate?

Answer 25

Dabigatran etexilate is a new oral direct thrombin inhibitor and the prodrug of dabigatran
Dabigatran is a small molecule that reversibly inhibits both free and clot-bound thrombin by binding to exosite 1 and/or the active site of thrombin

Question 26

What is Rivaroxaban?

Answer 26

Rivaroxaban is an orally available, small-molecule, active site-directed factor Xa inhibitor
There are no significant interactions between food, antacids, digoxin, aspirin, naproxen and rivaroxaban have been noted suggesting that dose adjustment of rivaroxaban would not be required when these agents are concurrently administered

Question 27

Adverse effects of warfarin

Answer 27

Bleeding, skin necrosis (if low protein C), drug interactions, teratogenic (bone dysmorphogenesis)

Question 28

Advantages of oral drugs

Answer 28

Advantages:

1. Convenience: Oral administration is easy and convenient for patients.
2. Cost-effective: Oral medications

are generally less expensive than injectable or topical forms.

3. Non-invasive: No needles or invasive procedures required.
4. Self-administration: Patients can take oral medications independently.
5. Wide availability: Oral medications are widely available.
6. Flexibility: Various dosage forms (tablets, capsules, liquids, etc.).
7. Patient compliance: Easier to adhere to treatment regimens.

Disadvantages:

Question 29

Disadvantages of oral drugs

Answer 29

1. Variable absorption: Absorption rates may vary depending on factors like stomach pH, food

intake, and gut motility.
2. First-pass metabolism: Drugs may be metabolized by the liver before reaching systemic circulation.

3. Gastrointestinal side effects:
   Nausea, vomiting, diarrhea, stomach upset.
4. Delayed onset: Effects may be delayed due to absorption and digestion times.
5. Limited bioavailability: Some drugs may have poor oral bioavailability.
6. Food interactions: Food can affect drug absorption or efficacy.
7. Gastric irritation: Some drugs can irritate the stomach lining.
8. Hepatic toxicity: Some oral drugs can cause liver damage.
9. Interpatient variability: Responses may vary between individuals.