anticoagulants Flashcards
what is the maintenance of blood fluidity by?
the endothelial lining is non-thrombogenic.
balace between procoagulants:
Thrombin Tissue factor Thromboxane Adenosine diphosphate (ADP) Serotonin (5-hydroxytryptamine)
and
Anticoagulants: Heparan sulfate Prostacyclin Nitric oxide Antithrombin Proteins C and S
Heparan sulfate is found on the surface of endothelial cells and in the extracellular matrix - Interacts with circulating antithrombin to provide a natural antithrombotic mechanism
what are the drug targets for this?
platelets clump (initial clot) (prevention of this is by antiplatelet drugs) —coagulation cascade—> fibrin forms a mesh around platelet clot (prevent coagulation by blocking a single or multiple steps in the coagulation cascade with anticoagulant drugs (parenteral and oral) —–> clot dissolves (firbinolysis)(prevent ischemic damage by dissolving the clot with fibrinolytic drugs (emergency treatment)
what are the 4 drug classes?
- Antiplatelet agents
aspirin, clopidogrel - Heparin & derivatives
stimulate natural inhibitors of coagulant proteases (antithrombin) - Oral anticoagulants
warfarin, newer oral anticoagulants (e,g, dabigatran)
block single or multiple steps in the coagulation cascade - Fibrinolytic agents
streptokinase, tissue plasminogen activator
lyse (break) formed thrombi
what intiates the coagulation cascade?
tissue factor
what is the platelet function?
disruption of endothelium —> platelet adhesion —> platelet activation (proaggregatory mediationes: thrombin (from prothrombin)—-> platelet release -(serotonin, ADP, thromboxane, Con Willebrand factor, platelet factor 4) ——> platelet aggregation
clopidogrel and ticlopidine do?
Clopidogrel and ticlopidine block the platelet purinergic P2Y receptors for ADP and increase cyclic AMP (which prevents clotting)
what does Aspirin do?
Aspirin irreversibly inhibits platelet cyclooxygenase and prevents formation of thromboxane from arachidonic acid
Eptifibatide, Abcixmab, Tirofiba do what?
Eptifibatide, abciximab and tirofiban block the GpIIb-IIIa receptor for fibrinogen on platelets and prevent platelet aggregation
what does dipyridamole do?
inhibits phosphodiesterase and prevents breakdown of cAMP.
what is a good summary for actions of anti-platelet drugs?
Aspirin irreversibly inhibits platelet cyclooxygenase and prevents formation of thromboxane from arachidonic acid
Clopidogrel and ticlopidine block the platelet purinergic P2Y receptors for ADP and increase cyclic AMP
Dipyridamole inhibits platelet phosphodiesterase and prevents breakdown of cyclic AMP
Eptifibatide, abciximab and tirofiban block the GpIIb-IIIa receptor for fibrinogen on platelets and prevent platelet aggregation
what are the therapeutic uses of aspirin? what are the contraindications?
Prophylaxis for myocardial infarction (MI) - 80 mg/day
Post MI – 160 to 325 mg/day
Prophylaxis for transient ischemic attacks (TIA) or post TIA – 80 to 325 mg/day
Aspirin – Contraindications (not to be used in these conditions): Vitamin K deficient patients Hemophilia of any type Hypoprothrombinemia Pregnancy & Childbirth
for the coagulation cascade: sites of action of anticoagulant drugs, what does heparin do?
Heparin activates antithrombin III (ATIII) which then:
inhibits XIIa, XIa, IXa, X.
It also inhibits low molecular weight heparins which stops Xa, and it inhibits hirudin which stops it from forming IIa.
what is heparin?
Heparin is a negatively charged molecule
Cannot cross cell membranes easily (therefore safe during pregnancy)
Avg mol. wt – 13,500 daltons
Found in mast cells - storage of histamine & proteases
what’s the mechanism of action of heparin?
Antithrombin III circulates in the plasma - rapidly inhibits activated clotting factors: IIa (thrombin), Xa, IXa, XIa and XIIa. This reaction goes 1000 to 3000 times faster with heparin (acts as a catalyst).
what is the worry with heparin toxicity?
Hemorrhage – especially in patients with recent surgery, trauma, peptic ulcer disease, platelet dysfunction
Severe bleeding – antidote - protamine sulfate (original source sperm of salmon, now produced by recombinant technology) - administered by slow iv infusion
what is heparin-induced thrombocytopenia (HIT)?
Thrombocytopenia – more than 50% decrease in platelet count (<150,000/μl) due to an antigen antibody reaction
Occurs in 3-5% of patients, 5 to 10 days after starting heparin therapy
Lower incidence with low mol wt heparin
Can be life-threatening
Stop heparin immediately
Alternative anticoagulants – direct thrombin or factor Xa inhibitors (Avoid low molecular weight heparins)
what are the therapeutic uses of heparin?
Not absorbed orally - administered by i.v. infusion or s.c.
In venous thrombosis and pulmonary embolism - rapid onset of action, anticoagulation maintained by oral anticoagulants
Some conditions treated: coronary angioplasty, stent placement, cardiopulmonary bypass surgery
Drug of choice for anticoagulation during pregnancy – does not cross the placenta
A thrombus is a clot attached to the vessel wall
An embolus is a free travelling clot that can lodge in certain organs and obstruct blood flow
what is the mechanism of action of low molecular weight heparins?
LMWHs are smaller molecules than heparin (produced by fragmentation of heparin molecules) and have no space to bind thrombin.
LMWHs do not inactivate thrombin (IIa)
However, LMWHs bind to antithrombin III and can inactivate factor Xa which binds directly to antithrombin III
MAJOR DIFFERENCE BETWEEN HEPARAIN AND LMWHs IS THAT THE LMWH DOES NOT INACTIVATE THROMBIN.
what are the advantages of LMWHs over heparin? disadvantages?
Advantages of LMWHs over heparin:
Better absorbed - higher bioavailability
Can be given subcutaneously without lab monitoring in an outpatient setting
Lower risks of thrombocytopenia and bleeding
Disadvantages:
More expensive than heparin
Cleared unchanged by kidney (do not use in renal failure!) rather than by the mononuclear phagocyte system
for oral anticoagulants, what does coumarins (warfarin) do?
Inhibit vitamin K epoxide reductase in the liver where clotting factors are synthesized
Takes 4-5 days to become effective – active carboxylated factors in plasma need to be cleared before inactive factors from the liver predominate
Small Vd, steep D-R curve – small increase in dose can easily become toxic
Warfarin crosses placenta – is teratogenic – causes birth defects and abortion
Uses: To prevent and treat various thrombo-embolic conditions
for warfarin and drug interactions what should I know and what is INR ?
Coumarins (warfarin) are metabolized by CYP1A and CYP2C9
Watch out for drug interactions and bleeding episodes ! Warfarin (Coumarin) overdose - Antidote - excess vitamin K
Efficacy of treatment is measured by INR (International Normalized Ratio), the patient’s PT divided by the PT in pooled plasma
target is 2 - 3
comparison of warfarin and newer oral anticoagulants (know this there’s a qusetions about this slide)
warfarin
Slow onset and offset of action – need a rapidly acting anticoagulant at the start
Interindividual variability in anticoagulant effect – variability in dose requirements
Narrow therapeutic index – need to monitor anticoagulant effect
Food and drug interactions – need for anticoagulant activity lab tests
Reduce synthesis of all vitamin K dependent proteins – risk of many side effects
Newer oral anticoagulants
Rapid onset of action – no need for bridging anticoagulant
Predictable anticoagulant effect – no need for frequent lab tests for anticoagulant effect
Specific coagulation enzyme target – low risk of off-target side effects
Low potential for food interactions – no dietary precautions
Low potential for drug interactions – few drug restrictions
WITH WARFARIN YOU NEED TO CONTINUALLY MONITOR THE PROTHROMBIN TIME, EVERY MONTH OR SO.
the new oral anticoagulants (NOAs) have increased therapeutic options and work independent of the vitamin K pathway.
NOAs are limited by their high cost, lack of specific antidotes, and lack of long-term safety data.
what is the fibrinolytic process, what does streptokinase do? what does tPA (tissue type plasminogen activator) do?
Streptokinase binds to plasminogen and converts it into active plasmin
tPA binds to fibrin plus plasminogen and converts plasminogen into active plasmin
these lead to fibrin fragmentation (degraded) and lysis of the clot.
The tissue or endothelium releases this tPA
what are the indications for streptokinase, when should you not use it?
Indications: Dissolve clots after myocardial infarction, deep vein thrombosis, massive pulmonary emboli
Streptokinase is believed to cause systemic plasmin formation (and not only at sites of clot formation) – this may cause increased bleeding as a side effect
Side effects: Bleeding, allergic reactions, hypotension, fever
DO NOT USE IN: Patients with prior intracranial injuries, known brain vessel lesions, brain tumors, previous stroke, aortic lesions, bleeding tendencies, recent injuries etc.
what is tissues plasminogen activator (t-PA)- (alteplase,ACTIVASE) doing?
Activates fibrin bound plasminogen (less systemic plasmin formation) – therefore theoretically it is believed to act only at sites of clot formation and more specific than streptokinase
Clinical trials do not show it to be more specific than streptokinase
Indications: Same as streptokinase
More expensive than streptokinase
Contraindications (do not use): same as with streptokinase
