華法林鈉
華法林（Warfarin）是一種香豆素類抗凝血劑，主要用於貓、狗或馬的血栓性疾病的長期治療或預防。由於其治療指數狹窄、具有致命性出血的潛在風險，且需要頻繁且昂貴的凝血功能監測，其在獸醫學中的應用存在一定爭議，通常僅在其他抗凝血劑不可行時使用。
作用機制: Warfarin acts as an indirect anticoagulant by antagonizing Vitamin K. * It competitively inhibits the enzyme **Vitamin K epoxide reductase (VKORC1)**. * This inhibition prevents the conversion of inactive Vitamin K epoxide back into its active form (Vitamin K hydroquinone). * Active Vitamin K is an essential cofactor for the γ-carboxylation (activation) of **coagulation factors II, VII, IX, and X**, as well as the endogenous anticoagulant proteins C and S. * **Pathway:** VKORC1 inhibition → Depletion of active Vitamin K → Production of inactive, undercarboxylated clotting factors (PIVKA) → Prolonged clotting times and anticoagulation.
各物種劑量
- Adjunctive maintenance therapy for venous thrombosis with or without pulmonary thromboembolism (PTE) · 0.5 mg (total dose per cat) · PO · once daily · Initially, then adjusted to achieve a PT prolongation of 1.25 to 1.5 times the pretreatment value.
- Maintenance therapy for feline arterial thromboembolism · 0.06 to 0.09 mg/kg/day · PO · once daily · Heparinization is recommended during the first 5 to 7 days that warfarin is administered.
- Long-term thromboprophylaxis · 0.06-0.09 mg/kg per day · PO · once daily · Initially. Tablets should be crushed and mixed well due to unequal drug distribution. Overlap heparin and warfarin therapy by at least 4-5 days.
- Adjunctive therapy of thromboembolism · 0.25-0.5 mg (total dose) per cat · PO · once daily · Initially. Adjust dosage to prolong PT to twice normal value, or INR to be between 2-3. Overlap therapy with heparin.
- Cardiogenic arterial thromboembolism · 0.25-0.5 mg total dose per cat · PO · q24h · Heparin (150-250 Units/kg SC q8h) should be administered concurrently during the first 4-6 days. Target PT range is 1.3-1.6 times baseline, or INR 2.0-3.0.
- Adjunctive treatment of laminitis · 0.0198 mg/kg · PO · once daily · Monitor OSPT (one-step prothrombin time) until prolonged 2-4 seconds beyond baseline.
- Anticoagulant · Initially, 0.018 mg/kg PO once daily and increase dose by 20% every day until baseline PT is doubled. Final dose rates may be from 0.012 mg/kg to 0.57 mg/kg daily. · PO · once daily · ARCI UCGFS Class 5 Drug.
- Adjunctive maintenance therapy for venous thrombosis with or without pulmonary thromboembolism (PTE) · 0.22 mg/kg · PO · q12h · Initially, then adjusted to achieve a PT prolongation of 1.25 to 1.5 times the pretreatment value.
- Adjunctive therapy of thromboemboli · 0.22 mg/kg · PO · q12h · Target dosage to prolong PT by 1.25-1.5 times the pretreatment value.
- Prophylactic use in patients with glomerular disease and severe proteinuria · 0.22 mg/kg · PO · once daily · Initially. Monitor PT and adjust dose so that PT is maintained at 1.5 times normal.
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給藥途徑
禁忌症
- Preexistent hemorrhagic tendencies or diseases
- Patients undergoing or contemplating eye or CNS surgery
- Major regional lumbar block anesthesia
- Surgery of large, open surfaces
- Active bleeding from the GI, respiratory, or GU tract
- Aneurysm
- Acute nephritis
- Cerebrovascular hemorrhage
- Blood dyscrasias
- Uncontrolled or malignant hypertension
- Hepatic insufficiency
- Pericardial effusion
- Pregnancy (Teratogenic - FDA Category X / Papich Class D)
- Visceral carcinomas
不良反應
- Dose-related hemorrhage (primary adverse effect)
- Anemia
- Thrombocytopenia
- Weakness
- Hematomas and ecchymoses
- Epistaxis (nosebleeds)
- Hematemesis (vomiting blood)
- Hematuria (blood in urine)
- Melena (dark, tarry stools)
- Hematochezia (fresh blood in stools)
- Hemarthrosis (bleeding into joints)
- Hemothorax
- Intracranial hemorrhage
- Pericardial hemorrhage
- Death
藥物相互作用
- Acetaminophen, NSAIDs, Salicylates · May increase anticoagulant response (via protein displacement or platelet inhibition); increases bleeding risk.
- Fluoroquinolones, Macrolides (Azithromycin, Erythromycin), Chloramphenicol, Sulfonamides, Co-trimoxazole · May increase anticoagulant response (often via inhibition of hepatic metabolism).
- Cimetidine, Cisapride, Fluoxetine, Metronidazole, Sertraline · May increase anticoagulant response.
- Amiodarone, Allopurinol, Danazol, Diazoxide, Ethacrynic acid, Pentoxifylline, Propylthiouracil, Quinidine, Zafirlukast · May increase anticoagulant response.
- Anabolic Steroids, Thyroid Medications · May increase anticoagulant response.
- Heparin · Increases anticoagulant response; often used concurrently during the initial overlap phase but requires careful monitoring.
- Barbiturates (e.g., Phenobarbital), Rifampin, Griseofulvin · May decrease anticoagulant response (via induction of hepatic metabolizing enzymes).
- Corticosteroids, Estrogens, Mercaptopurine, Spironolactone, Sucralfate · May decrease anticoagulant response.
- Vitamin K · Directly antagonizes warfarin, decreasing its anticoagulant response (used as an antidote for overdose).
監測
- Prothrombin Time (PT) - Target usually 1.25 to 1.5x (or up to 2x) normal depending on protocol
- International Normalized Ratio (INR) - Target usually 2.0 to 3.0 (Note: not fully validated for veterinary patients)
- PIVKA (Proteins Induced by Vitamin K Antagonists) - May be more sensitive than PT
- Platelet counts and hematocrit (PCV)
- Occult blood in stool and urine
- Physical observations for bleeding (mucous membranes, bruising, epistaxis)
- Clinical efficacy (resolution/prevention of thromboembolism)
過量
Acute overdosages of warfarin may result in life-threatening hemorrhage. * **Toxic Doses:** In dogs and cats, single doses of 5-50 mg/kg have been associated with toxicity. Cumulative toxic doses are reported as 1-5 mg/kg for 5-15 days in dogs, and 1 mg/kg for 7 days in cats. * **Lag Time:** A lag time of 2-5 days may occur before clinical signs of toxicity manifest. Animals must be monitored closely during this period. * **Treatment:** If detected early, prevent absorption from the gut using standard decontamination protocols (emesis, activated charcoal). If clinical signs of bleeding are noted, treat with blood products (plasma/whole blood to replace active clotting factors) and **Vitamin K1 (phytonadione)**.
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