Lecture 9 - Anticoagulants - PDF

Lecture 9 Anticoagulants Pharmaceutical Practice Department Therapeutic I Course Code: 1804472-04 4th Year Pharmacy Students Semester 2 (1446) (2024-2025) Updated on Learning outcome Student should be able to:  Understand the Coagula...

Lecture 9 Anticoagulants Pharmaceutical Practice Department Therapeutic I Course Code: 1804472-04 4th Year Pharmacy Students Semester 2 (1446) (2024-2025) Updated on Learning outcome Student should be able to:  Understand the Coagulation Cascade:  Describe the intrinsic, extrinsic, and common pathways of the coagulation cascade.  Identify key clotting factors and their roles in the cascade.  Explain the physiological regulation of coagulation, including natural anticoagulants and fibrinolysis.  Recognize Anticoagulant Mechanisms of Action:  Differentiate between anticoagulant drug classes (e.g., heparins, warfarin, DOACs, thrombin inhibitors).  Correlate anticoagulant mechanisms to specific points in the coagulation cascade.  Compare and Contrast Anticoagulants:  Evaluate pharmacokinetic and pharmacodynamic properties of anticoagulant medications.  Discuss the indications, contraindications, and therapeutic uses for each class. Learning outcome Student should be able to:  Understand Dose Adjustments:  Recognize the importance of individualizing anticoagulant doses based on renal function, weight, or clinical factors.  Discuss dose adjustments for specific populations (e.g., elderly, pediatric, or pregnant patients).  Integrate Anticoagulation into Clinical Practice:  Identify reversal strategies for anticoagulant-related bleeding (e.g., protamine, vitamin K, idarucizumab).  Address Patient-Centered Care:  Educate patients on anticoagulant use, adherence, and bleeding risk management.  Incorporate patient preferences and comorbidities into anticoagulation decisions.  Vascular Endothelial Cell Role  Normal Endothelial Anticoagulant Phenotype: Vascular endothelial cells prevent adhesion of blood platelets and clotting factors under normal conditions.  Response to Vascular Injury: Injury transforms endothelial cells into a procoagulant phenotype. Exposed subendothelial matrix proteins (e.g., collagen and von Willebrand factor) promote platelet adherence and activation. 4  Vascular Endothelial Cell Role Platelet Activation & Secretion:  Thromboxane A2 (TXA2):  Synthesized from arachidonic acid.  Acts as a platelet activator and vasoconstrictor.  Platelet Granules Secretion:  Adenosine Diphosphate (ADP): Induces platelet aggregation.  Serotonin (5-HT): Stimulates aggregation and vasoconstriction.  Platelet Plug Formation:  Conformational change in αIIbβIII integrin (IIb/IIIa) receptors. 5  Fibrinogen binding facilitates cross-linking of platelets to form a platelet plug. Platelet and Fibrin Plug Arterial Thrombi (White Thrombi): Venous Thrombi (Red Thrombi): Form in high flow rate and high shear force Form in low flow rate environments (e.g., environments (e.g., arteries). veins). Composition: Platelet-rich. Composition: Pathological Effects: Fibrin-rich. Contain large numbers of trapped red blood Occlusive arterial thrombi can cause: cells. Downstream ischemia of extremities or vital organs. Pathological Recognition: Red thrombi under Limb amputation or organ failure. microscopic examination. 6 6 Blood coagulates  Cascade of proteolytic activations culminating in thrombin (Factor IIa) formation.  Initiation Pathway (TF-VIIa): Exposed tissue factor (TF) binds to Factor VIIa → Activates Factors X and IX. Prothrombinase complex (Xa & Va): Converts prothrombin to thrombin. Regulated by tissue factor pathway inhibitor (TFPI). 7 Blood coagulates Intrinsic Pathway of Coagulation  Activation Trigger: Contact with a negatively charged surface (e.g., collagen, glass in vitro) activates Factor XII (Hageman factor). Factor XIIa then activates Factor XI. Factor XI Activation Activation of Factor IX 8 Blood coagulates Intrinsic Pathway of Coagulation Factor X Activation: The tenase complex (IXa + VIIIa) activates Factor X into Factor Xa. Prothrombin Activation: Factor Xa, along with Factor Va (from the extrinsic or feedback pathways), forms the prothrombinase complex. Prothrombinase converts prothrombin (Factor II) into thrombin (Factor IIa). Thrombin Amplification: Thrombin further activates Factor VIII and Factor 9 XI, amplifying the intrinsic pathway. Blood coagulates Extrinsic Pathway of Coagulation  Initiation by Tissue Factor (TF):  When vascular injury occurs, tissue factor (TF) is exposed on damaged endothelial cells or subendothelial tissues.  TF binds to circulating Factor VII, forming the TF-VIIa complex.  Activation of Factor X:  The TF-VIIa complex activates Factor X into Factor Xa in the presence of calcium ions (Ca²⁺). 10 Blood coagulates Extrinsic Pathway of Coagulation  Formation of Prothrombinase Complex:  Factor Xa combines with Factor Va to form the prothrombinase complex.  This complex converts prothrombin (Factor II) into thrombin (Factor IIa).  Thrombin Generation:  Thrombin cleaves fibrinogen into fibrin, leading to clot formation.  Thrombin also amplifies coagulation by activating Factors V, VIII, and XI, linking to the intrinsic pathway for further thrombin production. 11 Anticoagulants Medication Anticoagulan ts Direct Oral Parenteral Vitamin K Anticoagulants Anticoagulati Antagonist (DOACs) on 12 13  Anticoagulants Direct Thrombin UFH LMWH Factor Xa Inhibitors Vitamin K antagonist Inhibitors Daltaparin Fondaparinux Bivalirudine Warfarin Enoxaparin Rivaroxaban Argatroban Tinzaparin Apixaban Dabigatran Edoxaban Betrixaban 14  Oral Anticoagulation 15 15 Dabigatran Inhibits both free and fibrin-bound thrombin as Mechanism of action well as thrombin-induced platelet aggregation Dose 150 mg twice daily Onset of action 0.5-2 hours Half-life 12-17 hours Absorption 6-7% Protein Binding 35 % Route of elimination 80% Renal Gastrointestinal symptoms (25% to 40%) Adverse reactions Hemorrhage (11% to 19%) Strengths 75 mg, 110 mg, 150 mg capsules 16 Rivaroxaban Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa Mechanism of action (FXa) in both the intrinsic and extrinsic coagulation pathways Dose 20 mg once daily Onset of action 2-4 hours Half-life 5-13 hours Absorption Rapid Protein binding 92% to 95% Route of elimination 66% Liver, 33% Renal Adverse reactions Hemorrhage (5% to 28%) Available strengths 2.5 mg, 10 mg, 15 mg and 20 mg tablets 17 Apixaban Inhibits platelet activation and fibrin clot formation via Mechanism of direct, selective and reversible inhibition of factor Xa (FXa) action in both the intrinsic and extrinsic coagulation pathways Dose 5 mg twice daily Onset of action 1-3 hours Half-life 9-14 hours Absorption 50% Protein binding 87% Route of 27% Renal elimination Adverse reactions Hemorrhage (1% to 12%) Available strengths 2.5 mg and 5 mg tablets 18 Edoxaban Inhibits platelet activation and fibrin clot formation via direct, Mechanism of selective and reversible inhibition of factor Xa (FXa) in both action the intrinsic and extrinsic coagulation pathways Dose 60 mg once daily Onset of action 1-2 hours Half-life 10-14 hours Absorption 62% Protein binding 55% 50% Renal Route of elimination 50% Hepatic Adverse reactions Hemorrhage (22%) Available strengths 15 mg, 30 mg and 60 mg tablets 19 General warnings regarding DOACs and special populations  Avoid DOACs:  Pregnancy and lactation due to limited safety  Moderate-severe hepatic dysfunction (Child-Pugh class B or C)  Antiphospholipid syndrome. (worsen the outcomes)  Patients undergoing bariatric surgery: All DOACs have unpredictable pharmacokinetics  Patients with low body weight (limited data) but most support apixaban and rivaroxaban > edoxaban and dabigatran 20 Warfarin* Coumadin® Clotting Cascade Interferes with hepatic Mechanism of synthesis of vitamin K Action dependent coagulation factors (II,VII,IX,X) Onset of action 36-72 hours Duration 2-5 days VII-6 hrs, IX-24 hrs, X-40 hrs, II- 60 hrs, Half-life Protein C-7 hrs, Protein S-30 hrs Protein Binding 99% Absorption Rapid and complete Route of Hepatically metabolized elimination Metabolism/ ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP CYP2C9, 1A2, 3A4 GUIDELINES D-D interactions Administration of Warfarin Take at the same time each day Food high in vitamin K inhibit anticoagulation effect Do NOT change dietary habits once stabilized on warfarin therapy Do NOT switching brands once desired therapeutic response has been achieved. Warfarin Dosing Initiation Day Therapy INR Dose Adjustment Value 5 mg daily Day 1 (2.5 mg daily if high sensitivity to warfarin identified) < 1.5 5 – 7.5 mg daily 1.5 – 1.9 2.5 – 5 mg daily In 2-3 day 2.0 – 2.5 2.5 mg daily after initiation 2.5 – 3.0 0 – 2.5 mg daily > 3.0 Hold warfarin, recheck in 1-2 days < 1.5 7.5 – 10 mg daily In additional 1.5 – 1.9 5 – 10 mg daily 2-3 days after 2.0 – 3.0 2.5 – 5 mg daily last INR check > 3.0 Hold warfarin, recheck in 1-2 days 23 Warfarin Dosing follow- up  INR values on a specific day are the result of warfarin doses taken over the previous 3–4 days.  Warfarin dosing changes on a specific day are not fully represented in the INR for 3–5 days.  If the INR is out of the therapeutic range the total weekly dose should be increased or decreased by 5%–20%, 24 Warfarin Dosing follow- up  INR> 4.0, hold one or two doses before resuming the agent at the reduced maintenance dose.  If the INR was stable and a single out-of-range INR is 0.5 or less above or below the range, current dosing can be continued; rechecked within 1–2 weeks.  No need to adjust dose if INR is within 0.1 of goal but monitor 25 Warfarin Sensitive Patients High Sensitivity Baseline INR ≥ 1.2 Age > 65 Actual body weight < 45 kg Malnourished /NPO > 3 days Hypoalbuminemia < 2d/dl Chronic diarrhea Thrombocytopenia : platelet 41.04 µmol/L End stage renal disease GI bleed within past 30 days Surgery within past 2 weeks Intracranial bleed within past 30 days 26 Warfarin Sensitive Patients, Cont. Low Sensitivity Baseline INR < 1.2 Age ≤ 55 Male gender Diet rich in Vitamin K Weight > 90 kg 27 Warfarin – Drug Interaction Penicillin Cephalexin Increase INR Ceftazidim Cefdinir Nafacillin Dicloxacillin Decrease INR Dicloxacillin Doxycycline Rifampin Metronidazol Carbamazepi e ne Macrolide Infliximab Quinolones Vitamin K Sulfamethax azole Antifungal Amiodarone 28 This is not comprehensive list Please check the Lexi interaction tool High Risk Medication Drug Name Suggested Dose Change / Recheck Decrease 30%-50% , recheck in 7-10 days Amiodarone from start date Sulfamethoxazole/ Decrease 30% , recheck in 7-10 days from Trimethoprim start date Clarithromycin/ Decrease 30% , recheck in 7-10 days from Erythromycin start date Decrease 30% , recheck in 7-10 days from Fluconazole start date Decrease 30% , recheck in 7-10 days from Metronidazole start date Increase dose and recheck INR every 7-10 days. Rifampicin Upon discontinuation of rifampin reduce dose of warfarin (up to … 50% reduction may be 29 needed) with close INR monitoring Genetic Factor with Warfarin A number of point mutations in the gene coding for the CYP2C9 have been identified. These polymorphisms, the most common of which: CYP2C9*2 CYP2C9*3 Polymorphisms are associated with an impaired ability to metabolize S-warfarin, resulting in a reduction in S- warfarin clearance and, as a result, an increased S- warfarin elimination half-life. Lower initial doses are needed Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 30 Clinical Practice Guidelines. 2012 Genetic Factor with Warfarin, Cont. Vitamin K epoxide reductase (VKORC1) Genetic mutations in the gene coding for the VKORC1often involve several mutations leading to various haplotypes that cause greater resistance to warfarin therapy. Five major haplotypes associated with different dose requirements for maintaining a therapeutic INR. Low dose of 2.7 mg High dose of 6.2 mg warfarin per day for the per day for the sensitive haplotypes resistant haplotypes Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 31 Clinical Practice Guidelines. 2012 Warfarin Monitoring Parameters Prothrom Hemoglo bin time bin (PT) Signs and INR symptom s of bleeding 32  Parenteral Anticoagulants 33 33 Heparin and Enoxaparin Heparin Enoxaparin  Initial bolus of 60 to 80 Prophylactic dose: units/kg (maximum: 5,000  40 mg SC daily units) Treatment dose: Dosing versus   1.5mg/Kg SC QD or 1mg/Kg Continuous infusion of 12 to Indicatn 18 units/kg/hour twice daily (maximum: 1,000 units/hour) CrCl 40 Prophylaxis dose of enoxaparin could be 40 mg every 12 hours or 60 mg once daily Treatment dose of enoxaparin 1 mg/kg every 12 hours (NOT exceed 100-120 unit per dose) OR Total dose of 1.5 mg/kg then divide it in two dose Prophylaxis dose of heparin 7500 unit every 12 hours 7500 unit every 8 hours ?? Fondaparinux and Bivalirudin Fondaparinux Bivalirudin VTE prophylaxis and ACS: During PCI:  Fixed dose 2.5 mg SC daily  Initial: 0.75 mg/kg bolus Treatment for DVT/PE: immediately prior to Dosing versus  100 kg: 10 mg once daily. mg/kg/hour for the duration of procedure for up to 4 hours. CrCl 50-80 mL/min.CrCl ≥30 mL/minute: 25% reduction in total drug 1.75 mg/kg/hour. clearance, consider dose CrCl