PHARMACOLOGY - Oral Anticoagulants


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PHARMACOLOGY - Oral Anticoagulants

  1. 1. PHARMACOLOGY: Oral AnticoagulantsnianderthalNOTES
  2. 2. ORAL ANTI-COAGULANTSWARFARIN:-Chemistry: -synthesized as a derivative of 4- hydroxycoumarin -with asymmetrical carbon
  3. 3. ORAL ANTI-COAGULANTSWARFARIN:-Mechanism of Action: -antagonists of Vitamin K -coagulation factors affected: II, VII, IX, X -anticoagulants affected: protein C and S -decreased the total amount of each Vitamin K-dependent coagulation factor by 30-50%
  4. 4. ORAL ANTI-COAGULANTSWARFARIN:-Mechanism of Action: -the time required for the activity of each factor in the plasma to reach a new steady state after therapy is based on its individual rate of clearance. The approximate half-lives are: FACTORS Half-life (t1/2) II 50 hours VII 6 hours IX 24 hours X 36 hours Protein C 8 hours Protein S 30 hours
  5. 5. ORAL ANTI-COAGULANTSWARFARIN:-Mechanism of Action: -the full antithrombotic effect of warfarin is not achieved for several days, even though the PT may be prolonged soon after administration due to more rapid reduction of factors with shorter t1/2 (VII)
  6. 6. ORAL ANTI-COAGULANTSWARFARIN:-Dosage: -warfarin (Coumadin) is 5mg/day for 2-4 days -followed by 2-10mg/day as indicated by measurements of the INR -lower dose for elderly, pts at risk for bleeding -can be given IV BUT NOT IM due to risk of hematoma formation
  7. 7. ORAL ANTI-COAGULANTSWARFARIN:-Absorption: -bioavailability nearly complete when drug is administered PO, IV or rectally -FOOD DECREASES the rate of absorption -detected in plasma within 1 hour and peak concentrations in 2-8 hours
  8. 8. ORAL ANTI-COAGULANTSWARFARIN:-Distribution: -almost completely bound to plasma proteins, principally albumin -concentration in fetal plasma approach maternal values -active warfarin is not found in milk compared to other coumarins and indandiones
  9. 9. ORAL ANTI-COAGULANTSWARFARIN:-Biotransformation and Elimination: -transformed into inactive metabolites: - weak warfarin (R) – by CYP1A2, CYP2C19, CYP3A4 potent warfarin (S) – by CYP2C9 -inactive metabolites are excreted in urine and stool -t1/2: 25-60 hours (mean: 40 hours) -duration of action: 2-5 days
  10. 10. ORAL ANTI-COAGULANTSWARFARIN:-Drug and other Interactions: -patients must be educated to report the addition or deletion of any medication -any substance or condition is potentially dangerous if it alters: 1. the uptake or metabolism of the oral anticoagulant or vitamin K 2. the synthesis, function, or clearance of any factor or cell involved in hemostasis or fibrinolysis 3. the integrity of any epithelial surface
  11. 11. ORAL ANTI-COAGULANTSWARFARIN:-Drug and other Interactions: -factors that DECREASE the effects of oral anticoagulants: 1. reduced absorption of drug caused by binding to CHOLESTYRAMINE in the GI tract 2. increased volume of distribution and a short t1/2 secondary to HYPOPROTEINEMIA 3. increased metabolic clearance of the drug secondary to induction of hepatic enzymes, especially CYP2C9 4. ingestion of large amounts of Vitamin K rich foods or supplements 5. increased levels of coagulation factors during pregnancy
  12. 12. ORAL ANTI-COAGULANTSWARFARIN:-Drug and other Interactions: -factors that INCREASE the effects of oral anticoagulants (risk for hemorrhage): 1. decreased metabolism due to CYP2C9 inhibition (e.g. amiodarone, cotrimoxazole, clopidogrel, isoniazin, metronidazole) 2. displacement from protein binding sites caused by loop diuretics or valproate 3. relative deficiency of vitamin K 4. low concentration of coagulation factors
  13. 13. ORAL ANTI-COAGULANTSWARFARIN:-Sensitivity to warfarin: - <1.5 mg/day of warfarin to achieve an INR of 2-3
  14. 14. ORAL ANTI-COAGULANTSWARFARIN:-Toxicities: 1. Bleeding -MAJOR TOXICITY OF ORAL ANTICOAGULANTS -risk increases with: a. intensity & duration of therapy b. use of other meds that interfere with hemostasis c. presence of potential anatomic source of bleeding -INR >4 = risk for intracranial hemorrhage -INR 5-9 = 1-2.5 mg vitamin K is given -INR >9 = 3-5 mg vitamin K is given - INR >20 = consider FFP transfusion w/ 10 mg vitamin K
  15. 15. ORAL ANTI-COAGULANTSWARFARIN:-Toxicities: 2. Birth Defects -if administered during pregnancy, warfarin can cause birth defects and abortion -CNS abnormalities if given in 2nd/3rd trimester 3. Toxicities -PURPLE TOE SYNDROME – REVERSIBLE bluish discoloration of the plantar surfaces and sides of toes that blanches with pressure and fades with elevation  d/t release of cholesterol emboli -alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, anorexia
  16. 16. ORAL ANTI-COAGULANTSWARFARIN:-Clinical Use: -prevent the progression or recurrence of DVT -prevent venous thromboembolism -given concurrently with heparin; heparin is halted 4-5 days after initiation - systemic embolization -INR is calculated from the patient’s PT is used to monitor efficacy and compliance (TARGET INR: 2-3 but higher for pts with mechanical prosthetic hearts valves 2.5-3.5) -Daily INR at onset of Rx, then lengthened gradually to weekly then monthly for pts on long-term Rx
  17. 17. ORAL ANTI-COAGULANTSPHENPROCOUMON:-has longer plasma t1/2 than warfarin: 5 days-slower onset of action-longer duration of action: 7-14 days-daily maintenance dose: 0.75-6 mg
  18. 18. ORAL ANTI-COAGULANTSACENOCOUMAROL:-has shorter t1/2: 10-24 hours-more rapid effect on PT-shorter duration of action: 2 days-daily maintenance dose: 1-8 mg
  19. 19. ORAL ANTI-COAGULANTSXIMELAGATRAN:-novel drug that is readily absorbed after oral administration-rapidly metabolized to melagatran, a direct thrombin inhibitor