Anti-thrombotic Drugs Flashcards
What is the life cycle of a thrombus?
Damage Vessel --> Platelet Aggregation White Thrombus --> Coagulation Factors Red Thrombus --> Plasmin Fibrinolysis Fibrin Dissolution
What are the 3 types of anti-thrombotic Drugs?
- Anti-platelet Drugs
Aspirin
Clopidogrel
Fibrinogen Receptor Antagonists
2. Anti coagulants Unfractionated Heparin (UFH) LMW Heparin (LMWH) Warfarin Rivaroxaban, Apixaban, Dabigatran
- Fibrinolytics
Streptokinase
Urokinase
Tissue Plasminogen Factor
How does Aspirin work as an antiplatelet drug?
It is a irreversible cox inhibitor. It blocks more thromboxane (promotes platelet aggregation) in platelets than prostacycline (inhibits platelet aggregation) in endothelial cells, as the effect in platelets is more permanent due to platelets not being a full cell and having no nucleus hence being unable to synthesise new COX enzymes.
What are the uses of Aspirin?
To prevent arterial thrombosis (in myocardial infarction and stroke)
What is the dosage of aspirin used?
81mg/day
What are the side effects of Aspirin?
Peptic Ulcer, GI Bleeding (esp elderly), Allergy
What is the mechanism of action of clopidogrel (antiplatelet drug)
Clopidogrel (pro drug) is first converted in the liver by CYP2C19 enzymes into active metabolites. These active metabolites are P2Y12 Receptor Irreversible Antagonists, and inhibit ADP-induced platelet aggregation. This effect is active for the entire life-span of the platelet (7-10 days)
Why does Clopidogrel have a slow onset and variable effects?
This is because it is a pro drug and must first be metabolised by the liver
What are the uses of clopidogrel?
Prophylaxis of Arterial Thrombosis
Alternative to Aspirin
What are the side effects of clopidogrel?
Haemorrhage, Dypsnea (shortness of breath), Dizziness, Headache, Nausea
What are the different generation variations of clopidogrel?
1st gen: Ticlopidine - has more side effects eg. neutropenia, thrombotic thrombocytopenia purpura
Monitoring of WBC is necessary in the first 3 months
2nd gen: Clopidogrel (Pro-drug, slow onset)
3rd gen:
Prasugrel (Pro-drug, fast onset, irreversible)
Ticagrelor (Active drug, reversible)
What is an example of a fibrinogen receptor antagonist?
Abciximab
What is abciximab (fibrinogen receptor antagonist) used for?
Combination therapy in high risk patients undergoing angioplasty procedure (opening narrow blood vessel): Aspirin + Heparin + Abciximab
It helps to reduce ischaemic complications as well as prevent restenosis
What are the side effects of fibrinogen receptor antagonists?
Bleeding
Thrombocytopenia
What is a fibrinogen peptide analogue (Fibrinogen receptor antagonist)?
Eptifibatide
What is a non-peptide inhibitor (Fibrinogen receptor antagonist)?
Tirofiban
What is the mechanism of action of heparin?
- Binds and activates anti-thrombin III (through conformational change) which is a plasma protease inhibitor. This enhances anti-thrombin III interaction with clotting factors 2a, 9a, 10a by 1000 folds to form inactive complexes.
- Stimulates Tissue Factor Pathway Inhibitor (TFPI) release from endothelium.
How is Heparin given?
IV (immediate onset) Subcutaneous injection (20-60 mins)
In the hospital
What is the HMW Fraction of standard heparin?
5-30kDa
Does Heparin cross the placenta?
no hence can be used in pregnant women
What are the uses of Heparin (Anti-coagulant)?
- Treatment and prophylaxis of Venous Thromboembolism, Deep Vein Thrombosis (DVT) and Pulmonary Embolism
- Also used in arterial thrombosis: Myocardial Infarction
- Induces Anticoagulant therapy followed by oral anticoagulant (warfarin)
- Used in pregnant women at risk of thrombosis
What are the side effects of Heparin
- Narrow Therapeutic Window
- Bleeding (8-10%)
- Allergy - from animal sources
- Heparin-Induced Thrombocytopenia (HIT), transient (25%) and severe (5%)
Platelet counts should be performed
Causes paradoxical Thromboembolism
Long term use:
- Osteoporosis/Spontaneous Fractures
- Transient Reversible Alopecia (hair loss)
- Mineralocorticoid Deficiency
What is the management option for Heparin Induced Thrombocytopenia (HIT)/Allergy?
Discontinuation use of Heparin: Fondaparinux
New direct reversible thrombin 2a inhibitor (DTI): Argatroban
What is the MW of LMW heparin?
2-6 kDa by fractionation of UFH
What is the difference between LMW heparin and UFH?
- LMWH can be given as outpatient medication while UFH is given in the hospital
- LMWH is more homogenous than UFH
- Heparin Anti-thrombin III complex inhibits more factor 10a than 2a
- Greater bioavailability - LMWH: 90%
- Longer plasma half life - LMWH: 4hrs
What are the uses of LMWH?
Prophylaxis and treatment of deep vein thrombosis
What is an example of a LMWH?
Enoxaparin
What is the efficiency of LMWH?
Same as HMW Heparin (UFH)
What is the dosage/method of administration of LMWH?
Subcutaneous injection only (once or twice daily)
What are the side effects of LMWH?
- Similar risk of bleeding
LESS - thrombocytopenia
- osteoporosis
What is an Oral Anticoagulant?
Warfarin
What is Warfarin?
A Racemic mixture of 2 equal amounts of optical isomers (S-Warfarin (4x more potent) and R-Warfarin)
What are Direct Anticoagulants - Factor 10a Inhibitors?
Rivaroxaban, Apixaban
What are Direct Anticoagulants - Factor 2a Inhibitors?
Argatroban, Dabigatran
What is the mechanism of action of Warfarin?
It inhibits the Vitamin K Epoxide Reductase enzyme which is needed to convert KO (inactive epoxides) into KH2 (Active hydroquinones) which is needed to convert non-functional coagulation factors into functional coagulation factors with y-Carboxylase enzyme.
What is the onset, peak effect, plasma halflife and duration of action of Warfarin?
Onset: Slow (8-12 hrs)
Peak effect: 1-3 days
Plasma half life: 36 hrs
Duration of Action: 4-5 days
How is warfarin metabolised?
Hepatic Microsomal
S-Isomer is more rapidly metabolised than R isomer
Does warfarin cross the placenta?
Yes, hence it is contraindicated in pregnancy
What are the uses of warfarin?
- Maintenance of anticoagulant therapy
- Prophylaxis and treatment of venous thromboembolism (DVT and PE)
- Patients who suffered an MI, Stroke or transient ischemic attack (TIA)
- Potent Rodenticide
What are the side effects of warfarin?
- Narrow Therapeutic Window
- Bleeding
- Cutaneous necrosis and rarely infarction of breast, buttock, intestine, extremities
In babies: Teratogen: Fetal Warfarin Syndrome Severe Birth defects: Bone/CNS Hemorrhagic Fetus Abortion
What are some examples of drugs that cause enhanced anticoagulant effects?
- metronidazole
- fluconazole
- co-trimoxazole
- aspirin
- cephalosporin (3rd gen)
- heparin
What are some examples of drugs that cause reduced anticoagulant effects?
- barbituates (eg. thiopentone) –> GA
- phenytoin, carbamezapine, phenobarbitone
- rifampicin (antibiotic)
What is the treatment for overdose of anticoagulant?
Discontinuance
Heparin Antidote: Protamine Sulfate - highly basic peptide forming stable complex with heparin
Warfarin Antidote: Vitamin K1 (Phytonadione) re-establishes normal activity of clotting factors
What are 3 examples of Fibrinolytics?
Streptokinase, Urokinase, Tissue plasminogen Activator
What is the mechanism of action of Fibrinolytics?
It activates the conversion of Plasminogen to Plasmin
What is the route of administration of Fibrinolytics?
IV
What is the source of Fibrinolytics?
Streptokinase: Streptococci
Urokinase: Human Kidney
Tissue plasminogen activator: Human Recombinant
What is the type of plasminogen activation of fibrinolytics?
Streptokinase: free and fibrin bound
Urokinase: free and fibrin bound
Tissue plasminogen activator: fibrin bound
What is the side effects of fibrinolytics?
Haemorrhage
Allergy (Streptokinase)
What are the uses of fibrinolytics?
- Acute myocardial infarction
- Acute ischaemic stroke
- Acute pulmonary embolism
What are the efficacies of the fibrinolytics?
All are comparable in reperfusion rate, LVF preservation and overall survival
Tissue plasminogen activator lyses clots faster
