I hope to help me about structure activity relationship of argatroban and warfar
ID: 255136 • Letter: I
Question
I hope to help me about structure activity relationship of argatroban and warfarin and about interaction with imidapril and celecoxib Case Study#26 is a 78-year-old Asian woman who was admitted to the use she needs to have hip-replacement surgery because she fell in her house recently. Her significant medical history includes chronic renal failure (creatine clearance, 14 mL/min), osteoarth failure. Her current medication list includes furosemide 20 mg po daily, spironolactone 12.5 mg po daily, imidapril 2.5 mg po bid, and celecoxib 200 mg po bid. Unfractionated heparin therapy at a subcutaneous dosage of 5,000 units tid was initiated after surgery for deep vein thrombosis prophylaxis. Five days after surgery, DY complained of pain and swelling in her left leg. A compression ultrasound reading demonstrated superficial femoral and ritis, hypertension, and congestive heart popliteal vein thrombosis. A laboratory evaluation for heparin- induced thrombocytopenia (serotonin release assay) was ordered and yielded a positive result. Her physician wants to change her unfractionated heparin to a different anticoagulant and asks your opinion of the choices 1-3 Furosemide Arga troban Ceiecoxib wor Farin 1. Conduct a thorough and mechanistic SAR analysis of the three therapeutic options in the case. 2. Apply the chemical understanding gained from the SAR analysis to this patient's specific needs to make a therapeutic recommendation.Explanation / Answer
1)
1)Warfarinis a widespread anticoagulant used as medicine to prevent strokes. Racemic
warfarin [3-?-(acetonylbenzyl)-4-hydroxycoumarin], a synthetic 4-hydroxycoumarin
derivative and vitamin K antagonist [1], has been utilized for more than two decades as
an oral anticoagulant (OA) and as a rodenticide. Its two enantiomers (chiral center at C-9)
do not exhibit equivalent anticoagulant activity due to complex factors, including differ-
ent intrinsic activities as well as differences in pharmacokinetics, pharmacodynamics and
metabolism. Current interest in ligand-based molecular modeling, together with knowledge ac-
cumulated from experimentation are used to build and test potential models for pre-
dicting ligand-protein interactions and hence drug-drug interactions, the sites of drug
metabolism, toxicity, and other parameters. High affinity ligands for each P450 enzyme
can help define the enzyme in the form of a pharmacophore, improving the identification
of drug leads with the highest potential for drug-drug interactions based on their struc-
ture. In practice, this is a lofty goal because determining drug interaction potential in any
quantitative manner requires an accurate, universal binding model that can predict any
compound’s affinity for a given enzyme. Warfarin is one of the most widely used model
compounds in this field of research, besides its clinical importance and such risks as ICH
and narrow therapeutic range.
2) Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor.[1] In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it
3)Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparin.Clinically, it is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism
2) Fondaparinux is recommended therapeutically because the patient is suffering specifically from femoral and popliteal vein thrombosis