Anti-coagulants Flashcards
Steps of hemostasis
1) Local vasoconristion
2) Formation of primary hemostatic plug
3) Formation of thrombus due to coagulation
4) Fibrinolysis- degradation of blood clot
Primary hemostasis stepns
1) vascular injury (exposes reactive subendothelial proteins)
2) Platelet adhesion and activation
a) Thromboxane A2 (TXA2)synthesized from arachidonic acid by COX-1, potent vasoconstrictor and platelet activator
b) Conformational change in the integrin receptor, resulting in fibrinogen binding
3) platelet granule release
a) ADP activates integrin receptor
b) TXA2
c) Calcium release- important for clotting factors
Thrombosis risk factors
- Endothelial injury
- surgical procedure
- Hypercoagulability
- oral contraceptives
types of drugs to treat thrombosis
- Antiplatelet drugs (prevents primary plug)
- Anticoagulant drugs (inhibits fibrin clotting cascade)
- Thrombolytic drugs( dissolve an existing clot)
Aspirin pharmacology
- Inhibits thromboxane A2 via irreversible acetylation of COX-1
- rapid absorption
- Better at lower doses
- Effect lasts for the lifespan of a platelet (7-10d)
- nothing more effective
- Adverse effects: increased hemorrhagic stroke; GI bleeding
Clopidogrel (pharmacology, adverse effect and therapy)
- Irreversible inhibits P2Y12 ADP receptor
- ADP receptor blockade inhibits activation of the glycoprotein IIb/IIIa pathway (final common pathway for platelet aggregation
- Therapeutic uses reduction of rate of stroke, MI, heart attack, unstable angina and death in patients with recent MI, peripheral artery disease, or acute coronary syndrome
- Equivalent to aspirin in prevention of stroke
- Adverse effects: prolonged bleeding, thrombotic thrombo cytopenic
Integrin receptor GP IIb/IIIa inhibitors (pharmacology, adverse effect and therapy)
Fab fragment of humanized monoclonal antibody against the GFPIIb receptor long duration (10hrs)
- therapeutic uses: used with aspirin and heparin to treat coronary thrombosis or during coronary angioplasty, reduces restenosis , recurrent MI
- Adverse effect: major hemorrhagic event 1% to 10% of patients
Dental considerations of anti platelet drugs
Antiplatelet can cause excessive bleeding
- Aspirin/clopidogrel when used prophylactically can be discontinued for dental procedure
- patient with recent stent should not stop or with hold aspirin or clopidogrel
HMW Heparin Pharmacology
- catalyzes inhibition of clotting factors IXa, Xa and thomin by enhancing antithombin III activity causing conformational change in ATIII exposing it reactive site
- testing required to determine does effect on coagulation
- not absorbed by GI tract due ti large molecular weight so either IV or SC injection
- in log term treatment it is used until warfarin takes effect
HMW heparin therapy and adverse effects
Threputic use: venous thrombosis and pulmonary embolism , angina, acute MI
- Does not cross placenta, perfect for pregnancy - Adverse effects: hemorrhage, osteoporosis and spontaneous fracture, 1-4% get heparin induced thrombocytopenia - antagonist: protamine sulfate
Monitoring HMW heparin
- Activated partial thromboplastin time (aPTT) 25-39s
- Threputic range 2-2.5x aPPT normal
- Given IV every 6 hrs and monitored
- SC injection usually not monitored
LMW heparin (pharmacology and therapy)
- Fractioned form of HMW heparin(Dalteparin)
- Inhibit factor Xa by antithrombin, too short to inhibit thrombin
- Therapeutic uses: Venoous thrombolism, thrombosis, pulmonary embolism and unstable angina
- protamine incompletely neutralizes LMW heparin
Advantages of LMW heparin over HMW
- Longer half-life(4 hrs) and faster absorption
- much lower risk of thrombocytopenia and osteoporosis
- once daily SC injection administered in outpatient setting
- Less frequent monitoring required due to predictable PK
Warfarin(Coumadin) pharmacology
Most widely used oral anticoagulant with predicable PK, bioavailability, and anticoagulant response.
- blocks the carboxylation of glutamate residues in prothrombin and factors VII, IX and X.
- The enzyme Vitamin K epoxide reductase is inhibited by warfarin preventing reductive metabolism of the inactive vitamin K epoxide to its active hydroquinone form
- slow onset( 8-12hrs) existing clotting factors must be depleted maximal effect 3-5 day after administration.
Warfarin monitoring
Initiate: 5-10mg for one week to reach maintenance level, maintaince dose is 5-7 mg/d
-monitor prothrombin time to calculate INR
INR=((PT of patient)/(normal PT))^ISI
What is normal and therapeutic INR?
Normal INR= 1.0
Therapeutic INR= 2-3 times normal , 2.5-3.5 for tilting disk heart valves
Warfarin Therapeutic uses and adverse effect.
- Therapeutic uses: acute DVT, pulmonary embolism, venous thromboembolism, following acute MI, prosthetic heart valve placement, chronic atrial fibrillation
- Adverse effects: hemorrhage, risk increases with intensity and duration. readily crosses the placenta
warfarin drug interactions
- increase effects : ASA, Anabolic steroids, antibiotics, tamoxifen, oral hypoglycemics, vitamin K deficiency.
- Decrease effects: chronic alcohol abise, oral contraceptives, corticosteroids, barbituates, increased hepatic synthesis of clotting factors, increased vitamin K intake, Cholestyramine reduced bioavailability
- Phytonadione(vitamin k1) used to reverse warfarin associated bleeding
Warfarin dental considerations
- May be continued for dental extractions
- discontinue for oral surgery
- Always check with MD before recommending discontinuation of warfarin
Dabigatran etexilate pharmacology, therapeutic use and adverse effects
Direct Thrombin inhibitor
- Standard oral twice-daily dose
- Low molecular weight pro-drug, rapidly(1hr) converted to active form Dabigatran which binds to exosite 1 on thrombin preventing fibrinogen cleavage
- Therapeutic effect : stroke prevention in atrial fibrillation- equal to warfarin
- adverse effect: hemorrhage, heartburn, stomach upset, increase risk of MI
Benfits and issues with Dabigatran etexilate
Benefit: no patient monitoring/ titration as with warfarin, rapid onset, no adverse drug reactions
-Issues: cost 10x more than warfarin in Europe . Approx. 30 million warfarin prescriptions in USA
Thrombolytics pharmacology
- Combine with plasminogen to make an active complex for conversion to plasmin
- Or Directly convert plasminogen to plasmin
Thrombolytics Theraputic uses, side effects, and inhibitors
- therapeutics uses- in hospital : acute ischemic stroke, MI, Pulmonary embolism, severe deep venous thrombosis, ascending thrombophlebitis
- Inhibitors: aminocaproic acid- inhibits the conversion of plasminogen to plasmin
- Side effect- Hemorrhage
- contraindicated for brain tumors or aneurysms, stroke, major surgey within last 2 weeks, active bleeding in GI or urinary tract, severe platelet shortage or coagulation disorder, severe uncontrolled hypertension
Streptokinase Pharmacology
- First thrombolytic available
- Catalyzes the conversion of inactive plasminogen to active plasmin
- Acts through the circulation, not just at the clot
- Given IV ASAP after heart attack to dissolve clots in the arteries of the heart wall. only used in 1st heart attack
