Anticoagulants Flashcards
What are Anticoagulants?
Prevent thrombus formation and extension by inhibiting clotting factors e.g. heparin, low molecular weight heparin, coumarins/ warfarin.
What are Antiplatelet drugs?
reduce risk of clot formation by inhibiting platelet functions e.g. aspirin and ticlopidine.
What are Fibrinolytic agents?
dissolve thrombi already formed e.g. streptokinase.
List all 13 coagulation factors and their names
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
What are 3 endogenous Inhibitors of Coagulation?
- Antithrombin III, is a plasma protein that inhibits activated thrombin (factor IIa) and Xa, it is the site of action of heparin
- Prostacyclin ( PGI2), is synthesized by endothelial cells and inhibits platelet aggregation
- Protein C and Protein S: degrading Factor VIIIa and Va preventing coagulation
Types of anticoagulants
Parenteral anticoagulants:
Direct e.g hirudin, lepirudin
Indirect e.g heparin and heparin related agents
Oral Anticoagulants:
Vitamin K antagonists e.g. warfarin
Anticoagulants are indicated in
Myocardial infarction (MI)
Deep venous thrombosis (DVT)
Peripheral arterial emboli, pulmonary embolism (PE) and many other conditions
Anticoagulants are also useful in dialysis procedures
What is Heparin (Unfractionated Heparin)?
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
What is Heparin’s Mechanism of action
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
Discuss the Pharmacokinetics of UFH
- 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.
Therapeutic uses of heparin
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
Disadvantages of UFH
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
Adverse effects of UFH
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 )
Heparin-Induced Thrombocytopenia
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
Contraindications of Heparin
Bleeding disorders, hemophilia
Patients with hypersensitivity to the drug
Recent surgery of the brain, eye or spinal cord, threatened abortion
Examples of LMWH
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
Difference between UFH and LMWH
- IV life: UFH-2hrs LMWH-4hrs
- Biolavailabilty after SC injection: UFH-20%, LMWH-90%
- Anticoagulant response: UFH variable, LMWH-predictable
- Major adverse effect: UFH-HIT, high blood loss and osteoporosis, LMWH: Low blood loss and low HIT
- Specific antagonist: UFH-Protamine sulfate, LMWH-incomplete
- Setting for therapt: UFH-Hospital, LMWH-Hospital, OPC
- Lab monitoring: UFH-needed for aPTT, LMWH-not needed
Advantages of LMWHs over UFH
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
Direct thrombin inhibitors (DTIs)
What is their unique characteristic?
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
What are some examples of Direct thrombin inhibitors (DTIs)?
Parenteral direct inhibitors of thrombin activity are FDA-approved:
lepirudin, desirudin, bivalirudin and argatroban
Dabigatran
Sources of Vit k
Required for synthesis of
Causes of deficiency
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
What are the Vit k dependent clotting factors
Factors 2,7,9 ans 10
Warfarin: Mechanism of action
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
Disadvantages of Warfarin therapy
- 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
What are some Drug interactions with oral anticoagulants?
- Inhibition of Vit. K synthesis by intestinal flora; oral antibiotics
- Inhibition of Vit K absorption; liquid paraffin
- Decrease in drug metabolism by microsomal enzyme inhibitors; chloramphenicol, & cimetidine
- Displacment of the drug from protein binding sites; phenylbutazone & salicylates
- Co-administration of drugs that increase bleeding tendency by; inhibiting platelet function; NSAIDs, heparin
- Inhibition of drug absorption from GIT; cholystyramine, colestipol
- Increase in synthesis of clotting factors; Vit K, oral contraceptives
- Increase in drug metabolism by microsomal enzyme inducers; Carbamazepine; barbiturates, rifampicin
Why is Warfarin is contraindicated during pregnancy?
Warfarin is contraindicated during pregnancy as it can cross the placental barrier and cause:
Abortion
Hemorrhagic disorder in the fetus
Birth defects
What should a pateint do if they experince bleeding due to warfarin?
Discontinue the drug
Administer Vitamin K (its antagonist)
Administer fresh frozen blood
What is Dabigatran etexilate?
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
What is Rivaroxaban?
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
Adverse effects of warfarin
Bleeding, skin necrosis (if low protein C), drug interactions, teratogenic (bone dysmorphogenesis)
Advantages of oral drugs
Advantages:
- Convenience: Oral administration is easy and convenient for patients.
- Cost-effective: Oral medications
are generally less expensive than injectable or topical forms.
- Non-invasive: No needles or invasive procedures required.
- Self-administration: Patients can take oral medications independently.
- Wide availability: Oral medications are widely available.
- Flexibility: Various dosage forms (tablets, capsules, liquids, etc.).
- Patient compliance: Easier to adhere to treatment regimens.
Disadvantages:
Disadvantages of oral drugs
- 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.
- Gastrointestinal side effects:
Nausea, vomiting, diarrhea, stomach upset. - Delayed onset: Effects may be delayed due to absorption and digestion times.
- Limited bioavailability: Some drugs may have poor oral bioavailability.
- Food interactions: Food can affect drug absorption or efficacy.
- Gastric irritation: Some drugs can irritate the stomach lining.
- Hepatic toxicity: Some oral drugs can cause liver damage.
- Interpatient variability: Responses may vary between individuals.
