SPPS 249 Anticoagulation 3-28-2011

SPPS 249 Anticoagulation 3-28-2011 - Anticoagulation David...

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Unformatted text preview: Anticoagulation David S. Adler , Pharm.D. Professor of Clinical Pharmacy University of California UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences Objectives The goal of this session is to discuss the pharmacological principles of treatment and prevention of arterial and venous thromboembolism and the current drugs used in treatment/prevention and promising drugs in clinical trials. At the completion of this unit the student will be able to: 1. Discuss the pathophysiology of thrombus formation and dissolution 2. Discuss the indications for anticoagulation therapy 3. Discuss the Absorption, Distribution, Metabolism and Elimination of anticoagulants 4. Identify the anticoagulant drug targets, coagulation cascade, extrinsic, intrinsic and common pathways, and the role of the clotting factors 5. Describe the initiation of anticoagulation therapy 6. Describe dosing of the various antithrombotic drugs and their antagonists 7. Identify the laboratory parameters for monitoring anticoagulation therapy 8. Know the different types of drug interactions and their mechanism 9. Identify patient education issues essential for safe patient anticoagulant use Thromboembolism • Thrombosis – a disturbance in the fibrinolytic system resulting in a mass of platelets, clotting factors and other cellular elements forming an obstruction within a blood vessel (artery, vein, heart chamber) with potentially fatal consequences. • Embolism – a clot or clot fragment dislodging from its site of origin and traveling to another vessel causing an obstruction at that site with potentially fatal consequences. Etiology • Abnormalities in blood flow causing venous stasis • Intracardiac blood flow stasis • Abnormalities of blood vessel walls from trauma or cellular injury • Vascular foreign bodies such as artificial heart valves, catheters • Hypercoagulable states Common Consequences of Thrombosis and Embolism • Deep Vein Thrombosis (occlusive , non-occlusive) • Pulmonary Embolism • Myocardial Infarction • Cerebral Vascular Accident, (CVA),Stroke Transient Ischemic Attack(TIA) Deep Vein Thrombosis with Pulmonary Embolus Pulmonary Embolism V/Q Scan --- Ventilation-Perfusion Classification of Hypercoagulable Conditions Primary (inherited) Antithrombin deficiency (AT III) Protein C deficiency Protein S deficiency Factor V Leiden (resulting in APC resistance) Prothrombin 20210 mutation Hyperhomocystinemia Elevated factor VIII levels Dysfibrinogenemia Factor XII deficiency Disorders of plasmin generation Classification of Hypercoagulable Conditions Secondary (acquired) Pregnancy Immobility Trauma Postoperative state Use of oral contraceptives, estrogen, tamoxifen Antiphospholipid syndrome Hyperhomocystinemia Other disease states Malignancy Nephrotic syndrome Myeloproliferative disorders Congestive heart failure Heparin-induced thrombocytopenia with thrombosis Paroxysmal nocturnal hemoglobinuria Behçet's disease Table 2. Estimated prevalence of various thrombophilic defects Defect General population Venous Thromboembolism population Antithrombin 0.3% 3% Protein C 0.3% 3% Protein S 0.3% 3% Factor V Leiden 5% 10%­20% Hyperhomocystinemia 5% 10%­20% Prothrombin 20210 2%­3% 6%­18% Antiphospholipid 2% 14% Factor VIII 6%­8% 10%­15% Adapted from Lensing et al (3) and Ginsberg et al (22). Hemostasis A complex series of actions and reactions of pro- and anti- coagulant events that regulate hemostasis, preventing hemorrhage and thrombosis. Normal hemostasis is a physiologic interaction and regulation between the following: 1. Vessel wall (artery, vein, heart) 2. Platelets 3. Coagulation cascade 4. Fibrinolytic system This is a dynamic process Background: The Coagulation Cascade Initiation of Thrombosis • • • • Injury to the blood vessel Immediate vascular constriction Platelet contact with subendothelial surface Tissue Factors Activate - from monocytes, neutrophils, macrophages • Triggered by Extrinsic side of cascade Targets for prevention/tx of VTE/PE • Vitamin K - associated factors VII, IX, X, II • Thrombin (IIa) • Xa Current FDA-Approved Therapies for Venous Thromboembolism • Oral Agents Vitamin K Antagonist • Injectable Agents Indirect Thrombin Inhibitors Unfractionated Heparin Low-Molecular Weight Heparins Coumadin Dalteparin - Fragmin Multiple generics Enoxaparin - Lovenox Tinzaparin - Innohep Direct Thrombin Inhibitor(DTI) Selective Indirect Xa Inhibitor Dabigatran - Pradaxa Fondaparinux – Arixtra Warfarin Xa Inhibitor *Rivaroxiban – Xarelto * in FDA Review Direct Thrombin inhibitors Lepirudin – Refludan Bivalirudin - Angiomax Argatroban - Argatroban Indirect Thrombin Inhibitors Heparins Unfractionated Heparin (UFH) Low Molecular Weight Heparins: Enoxparin - Lovenox Dalteparin - Fragmin Tinzaparin - Innohep Fondaparinux - Arixtra Chemical Structure Unfractionated Heparin Glycosaminoglycan composed of chains of alternating residues of D-glucosamine and an uronic acid. (~15,000Da) Chemical Structure Enoxaparin – Lovenox Depolymerization of porcine mucosal heparin (~4500Da) Chemical structure Tinzaparin - Innohep Depolymerization of heparin from porcine mucosa (~5500-7500 Da) Indirect Thrombin Inhibitors Action Half-life Excretion Monitoring Administration Unfractionated Heparin (UFH) Catalyzes ATIIIthrombin Inhibits Xa 30-90 min Dose Dep 1h,2.5h, 5h Reticuloendothelial system aPTT SC, IV IV infusion Enoxaparin Lovenox Catalyzes ATIII Inhibts Xa>IIa 119-139 min Renal Monitor Anti-Xa in CrCl< 30ml/ min Anti-Xa SC < 1% But w/ Cancer ~ 6% Protamine 1mg/100u UFH Dalteparin Fragmin Catalyzes ATIII Inhibts Xa>IIa 139-180 min Renal Monitor Anti-Xa in CrCl< 30ml/ min Anti-Xa SC < 1% But w/ Cancer ~6% Protamine 1mg/100u UFH Tinzaparin Innohep Catalyzes ATIII Inhibts Xa>IIa 111-234 min Renal Monitor Anti-Xa in CrCl< 30ml/ min Anti-Xa SC < 1% Protamine 1mg/100u UFH Fondaparinux Catalyzes ATIII- 17 – 21 Renal None SC 0.2%** None Drug HIT* Risk 1-3% To 6% Neutralization Protamine 1mg/100u UFH Unfractionated Heparin Dosing Heparin Infusion Indication Deep Vein Thrombosis Pulmonary Embolism Loading Dose Initial Infusion Rate 5000 -7500 units bolus or 1200u -1600u /hr with infusion pump or Wgt-Based*: 17-20 units/kg/hr (Maximum of 1,000units/hr) with infusion pump Wgt-based*: 80-100units/kg (Maximum of 10,000 units) Acute Coronary Syndrome Wgt-Based*: 60-70units/kg (Maximum of 5000 units) Wgt-Based*:12-15 units/kg/hr (Maximum of 1000 units/hr) [Infusion rate is adjusted per algorithm based on aPTT] •Wgt-based dosing protocols increased the proportion of patients reaching therapeutic levels within 24 hours. •Achieving a therapeutic response within 24 hours decreases the rate of recurrent VTE. Indirect Thrombin Inhibitors: Low Molecular Weight Heparin Dosing Deep Vein Thrombosis Pulmonary Embolism Drug Dose Enoxaparen (Lovenox) Indication 1 mg/kg SC every 12 hours or 1.5 mg/kg SC every 24 hours Dalteparin (Fragmin) Tinzaparin (Innohep) Deep Vein Thrombosis Pulmonary Embolism DVT/PE Prophylaxis Fondaparinux 5mg SC daily < 50kg 7.5mg 50-100kg 10mg >100kg 2.5mg SC daily > 50kg CI in patients <50Kg Heparin: mode of action Indirect effect on thrombin via AT. Acts like a catalyst in an enzymatic reaction. 2 Heparin AT Thrombin 1 Pentasaccharide sequence X/BR//255.a.1 29 Heparin’s limitations The heparin:AT complex inhibits only soluble thrombin… not fibrin-bound thrombin 2 Heparin Thrombin AT 1 2 2 Thrombin Thrombin 1 1 Fibrin • Heparin increases the affinity of thrombin for fibrin. X/E//257.a.1 30 Biomaterials Research - Manfred Maitz Effect of Antithrombin III/Heparin Intrinsic Pathway Extrinsic Pathway Surface Contact Collagen FXII activator F XII Tissue/Cell Defect F XIIa F XI F IXa Ca2+ F VII F III (Tissue Thromboplastin) F VIIIa Platelet Factor 3 Factor F X Factor Xa Ca2+ F Va Prothrombin II F XIIIa Crosslinked Fibrin Meshwork Ca2+ F XIa Ca2+ F IX F VIII F VIIa Ca2+ Ca2+ Factor F X FV Thrombin F XIII Fibrin polymers Fibrin monomers Fibrinogen Unfractionated Heparin (UHF) • Mechanism of Action – 1. Highly charged polyanion w/ chain of 18-50 saccharide units 2. Binds to Antithrombin(AT) and induces confirmation change 3.Promotes interaction of AT with thrombin and Xa by 1000-fold 4. In presence of UFH, AT neutralizes IXa, XIa, XIIa, Little activity against VIIa Unfractionated Heparin (UHF) Indications: • • • • Deep Vein Thrombosis (occlusive , non-occlusive) Pulmonary Embolism Myocardial Infarction Cerebral Vascular Accident, (CVA),Stroke Clinical Effects: 1. Low-dose/Full-dose heparin tx inhibit thrombus formation in presence of stasis 2. Full-dose heparin tx prevents extension of existing thrombi 3. UFH has NO fibrinolytic activity and does not lyse established thrombi Heparin - Adverse Effects • Common: – Dermatologic: Local erythema, Injection site ulcer, following subcutaneous injection – Hematologic: Hematoma – Neurologic: Pain (Mild) • Serious: – Hematologic: Hemorrhage, Heparin-induced thrombocytopenia (HIT) – Hepatic: Increased liver aminotransferase level – Immunologic: Anaphylaxis, Immune hypersensitivity reaction, HIT – Musculoskeletal: Osteoporosis,With longterm, high-dose administration Unfractionated Heparin (UHF) Monitoring parameters: Full dose heparin produces prolongation of the following tests: aPTT, PT, ACT, TT, WBCT aPTT – activated Partial Thromboplastin Time - is most reliable, available and is sensitive to the inhibitory effect of heparin on Thrombin and Anti-factor IIa and Anti-factor Xa activity. Determine baseline aPTT and dose adjust to 1.5-2.5 X baseline for therapeutic effect With initiation of a heparin infusion monitor aPTT at 6 hours The ACT is more useful for HIGH dose heparin infusions. Unfractionated Heparin (UHF) Reversal of Heparin: Drug of Choice – Protamine Sulfate (polypeptide –source is salmon sperm) MOA – combines immediately with heparin & binds the heparin moiety neutralizing the heparin effect Dose: 1mg Protamine/ 100 units heparin (based on heparin given the previous 4 hours). Administer IV at a slow rate of 50mg/10 minutes. Protamine - Adverse SE to consider: Hypotension Vasodilation Bradycardia Dyspnea Bleeding complications of excess Protamine Low Molecular Weight Heparins Indications: Treatment of DVT Prevention of DVT/PE THA – Total Hip Arthroplasty - Hip replacement TKA – Total Knee Arthroplasty - Knee replacement Abdominal surgery pts with PE risk Bridging OAC patients with pending invasive procedures Potential Advantages of Treatment Doses: More predictable dose response Longer duration of action Routine monitoring w/ aPTT is not useful Low Molecular Weight Heparins MOA: Heparin and AT complex to inactivate Xa and IIa Xa Inactivation –Requires binding only AT component of the H-AT complex to Xa Occurs with both UFH and LMWH IIa Inactivation – Requires binding both the Heparin & AT components of H-AT complex to IIa LMWH have decreased ability to inactivate IIa Anti-Xa:Anti-IIa activity is greater for LMWHs than for UFH aPTT not elevated w/ LMWH, rather anti-Xa activity may be assayed anti-Xa assay is not easily available, generally LMWH not monitored.* *Exceptions –morbid obesity, renal failure, pregnancy Fondaparinux---- Arixtra Indications: Prophylaxis against Venous Thrombosis and PE following THA, Hip Fracture and TKA initiated 6hrs post-operatively X 10d Extended Prophylaxis of 28-35 days post-op high risk gp Treatment and 2o prevention of DVT in conjunction with warfarin Treatment and 2o prevention of PE conjunction with warfarin Reports in literature of treatment or prophylaxis in Heparin induced thrombocytopenia {However Random Controlled Trials are necessary] Administration: Fondaparinux must be administered SC(subcutaneously), Not IM Fondaparinux---- Arixtra MOA: 1. Synthetic Factor Xa inhibitor 2. Chemically, a pentasaccharide 3. Analog of the minimum saccharide chain length for ATIII anticoagulation activity 4. Accelerates the rate at which ATIII neutralizes thrombin, Xa 5. Result is inhibition of Prothrombin to Thrombin conversion 6. No current drug available to reverse bleeding in presence of Fondaparinux Fondaparinux (pentasaccharide) Biomaterials Research - Manfred Maitz Effect of Antithrombin III binding Xa Intrinsic Pathway Extrinsic Pathway Surface Contact Collagen FXII activator F XII Tissue/Cell Defect F XIIa F XI F IXa Ca2+ F VII F III (Tissue Thromboplastin) F VIIIa Platelet Factor 3 Factor F X Ca2+ Factor F Xa F Va Prothrombin II F XIIIa Crosslinked Fibrin Meshwork Ca2+ F XIa Ca2+ F IX F VIII F VIIa Ca2+ Ca2+ Factor F X FV Thrombin F XIII Fibrin polymers Fibrin monomers Fibrinogen Direct Thrombin Inhibitors Bind to both Free/Bound Thrombin Indications (FDA Approved) Lepirudin Refludan HIT- Heparin Induced Thrombocytopenia Bivalirudin Angiomax HIT- Heparin Induced Thrombocytopenia ACS w/ PCI* as alternative w/ possible HIT** Argatroban Argatroban HIT- Heparin Induced Thrombocytopenia ACS w/ PCI* as alternative w/ possible HIT** * Percutaneous Coronary Intervention ** See Clinical Pharmacology and ACCP Chest Guidelines Chemical Structure Recombinant hirudin derived from yeast cells Lepirudin . Chemical Structure Bivalent analog of hirudin. a natural anticoagulant secreted in leech saliva Chemical Structure N2-substituted derivative of arginine Direct Thrombin Inhibitors Action Half-life Excretion Lepirudin Recomb , yeast derived DTI Irreversible 1.3 h Renal Bivalirudin DTI Reversible 20-30 min DTI Reversible 40 min Drug Recom- semi-syn Argatroban Semi-synthetic Arginine derivative Dose Monitoring Administration Neutralization *0.4mg/kg Bolus, 0.15mg/kg/h Infusion, <110kg aPTT or ECT IV, SC None 20% Renal, Proteolytic cleavage **0.75mg/kg bolus 1.75mg/kg/hr aPTT ACT IV, SC Hepatic, renal ***0.002mg/kg/min Infusion aPTT ACT IV EndogenousThrombin Short half-life None Key: aPTT, activated partial thromboplastin time; DTI, direct thrombin inhibition; ECT, ecarin clotting time., ACT, Activated Clotting Time *Renal failure and hemodialysis dose adjustment necessary, do not wgt base dose >110Kg ** Renal failure dose adjustment necessary ***Hepatic disease dose adjustment necessary to 0.0005mg/kg/min & weight. Monitoring of INR required with concommitant warfarin therapy. Bivalirudin: Properties • Direct thrombin inhibitor • Inhibits clot-bound and circulating thrombin • Does not activate platelets • Reliable pharmacokinetics • 25-minute half-life A/BR//292.a.1 49 Bivalirudin: Mechanism of Action Specific, reversible binding 2 Thrombin Gly-Pro-Arg-Pro (active-site-binding portion) (Gly)4 2 Thrombin 1 Bivalirudin 1 C-terminal dodecapeptide (Exosite 1-binding portion) 50 Bivalirudin: Mechanism of Action Bivalirudin inhibits both fibrin-bound and circulating thrombin Fibrin-bound thrombin Circulating thrombin 2 2 1 2 2 1 1 1 Fibrin A/E//263.a.1 51 WARFARIN & OTHER ORAL ANTICOAGULANTS Structure Activity Relationship of the Coumarins • a non-planar lactone ring carbon substituted at C3/C4 is necesssary for activity • Derivatives are water insoluble lactones • Weakly acidic due to 4’OH substitution, allows for water soluble sodium salt providing 100% bioavailability • Forms vary in their PK parameters based on onset, DOA, t ½ and peak plasma concentration Phenprocoumn - Markumar (Europe) Acenocoumarol – Sintrom (Latin America) Inandione vs coumarin • Anisindione (Miradon) Warfarin • Racemic mixture of R(+) and S(-) enanitomers • S isomer is 4 - 5 X > potency then R isomer, Influence of DI Inhibits hepatic Vitamin K Epoxide Reductase activity influencing Factors VII, IX X and II Protein C and S Vitamin K-dependent clotting factors deplete per own t1/2 Thrombus prevention requires adequate depletion of X, II Prothrombin Time/ INR as measure of effect is most sensitive to VII Warfarin Isomers • S(-) Isomer • R (+) Isomer Warfarin Metabolism • Hepatic • CYP2C9 S-Warfarin R-Warfarin CYP1A2 minor CYP2C19, CYP3A4 • Inactive metabolites: 6 and 7-hydroxywarfarins • Active metabolites (minor): a pair of 2’-hydroxywarfarins by reductive metabolism of the C3 ketone side chain • No drug is excreted in the urine unchanged Pharmacokinetics Parameter Parameter Value Value Bioavailability Bioavailability 100% for Oral/IV/IM/Rectal 100% for Oral/IV/IM/Rectal Peak Plasma Concentration Peak Plasma Concentration 3 hours 3 hours Protein Binding Protein Binding 95-99% ** 95-99% ** Volume of Distribution (VD) Volume of Distribution (VD) 0.1-0.2 L/kg 0.1-0.2 L/kg Active Part Active Part Free Drug Free Drug Background: The Coagulation Cascade Vitamin K Dependent Clotting Factor Degradation Protein Half-Life Factor VII 4-6 hr Factor IX 24 hr Factor X 27-48 hr Factor II 60 hr Protein C 8 hr Protein S 30 hr Initiating Warfarin Therapy in Complex Patients • Importance of 4-Ds: Diet, Dose, Drugs, Disease • Additional considerations: Age Nutritional status Surgical status Liver Function Thyroid status Cardiac status Malignancy Baseline INR Ethnicity Initiation of Warfarin Therapy • History of Loading Dose Theory – abandoned • Avg daily dose for caucasians 4.5-5.5mg Asians including Pacific Islanders 2.5mg First 30 days greatest risk for adverse events including bleeding and recurrent thrombosis Uncomplicated patient - INR increases and generally reaches steady state at 5-7 days Complex or complicated patient requires careful review prior to initiating warfarin therapy Warfarin Risks of Loading Dose 1. Induces rapid and excessive reduction of Factor VII 2. In Protein C Deficiency may lead to warfarin necrosis 3. Increased risk for hemorrhagic complications 4. Does not achieve more rapid reduction in Vitamin-K dependent clotting factors, IX, X and II. 5. Clotting Factor depletion is the rate limiting step, not plasma levels of warfarin. Warfarin Necrosis Warfarin Necrosis (after debridement) Warfarin Necrosis Warfarin Necrosis Patient with Protein S Deficiency Warfarin Monitoring Optimal Duration of Anticoagulant Therapy for Symptomatic Venous Thrombosis: Recommendations Indication Calf-vein Duration thrombosis: reversible cause 6 weeks to 3 months Idiopathic calf-vein thrombosis 6 months to 1 year Proximal thrombosis: reversible cause 3 to 6 months Idiopathic proximal vein thrombosis 6 months to >1 year Patient Counseling • • • • • • • • • • • Warfarin Action Drug interactions, starting and stopping medications Diet Alcohol Dose schedule, changes, missed doses Analgesic use, treating H/A and fever Compliance, dose and clinic visits Laboratory monitoring Falls, Fall avoidance Bruising/Bleeding Pregnancy – Teratogen exposure risk Direct Thrombin Inhibitor Value Bioavailability Oral 3-7% Peak Plasma Concentration Cmax 1 hour Protein Binding 35% T1/2 12-17 hours Volume of distribution Dabigatran etexilate (Pradaxa) Parameter 50-70 L/Kg Substrate of eflux P-glycoprotein transporter Metabolism as 4 active acylglucuronides Elimination - primarily renal as dabigatran ~ 75% Dose with CrCl > 30 ml/min: 150mg 2X/day Dose with CrCl 15-30 ml/min: 75mg 2X/day Monitoring - None recommended Benzamidine based thrombin inhibitor 10 - 40% NR (aPTT, ECT, TT) FDA Pregnancy category “C” Animal ADE data Breast milk data Unknown Shelf life –once opened Toxicity 30 days No antidote Direct Xa Inhibitor Bioavailability 60- 80+% Peak Plasma Concentration Cmax 2-4 hour Protein Binding ~ 90% 7-11 hours Volume of distribution (in Europe/Canada in use, in US under FDA Review) Value T1/2 Rivaroxaban(Xarelto) Parameter 1.36L/Kg Substrate of eflux P-glycoprotein transporter Metabolism CYP3A4, CYP2J2 & CYP-independ 2/3 hepatic CYP3A4 - inhibtors oxazolidinone carboxamide D-DI inc CPss CYP3A4 - inducers D-DI dec CPss Elimination 2/3 hep, 1/3 renal Dose with CrCl ,<15 ml/min: Not recommended Dose with CrCl 15-49 ml/min 15mg; >50ml/min 20mg Inc bleeding risk Hepatic disease-moderate Monitoring - None recommended Inc bleeding risk NR (PT, aPTT) FDA Pregnancy category TBD Mechanisms for Warfarin Interactions • • • ·Pharmacodynamic – -interfering with platelet aggregation (i.e. aspirin, clopidogrel) – -hypoprothrombinemia caused by increased thyroid function (i.e. levothyroxine) – -decreased liver function (i.e. acetaminophen) – -changes in dietary vitamin K intake ·Pharmacokinetic – -decreased absorption (i.e. cholestyramine) – -displacement from albumin binding sites – -increased hepatic metabolism (i.e. phenobarbital, rifampin) – -decreased hepatic metabolism (i.e. sulfa, amiodarone) Pathophysiologic – -Pneumonia – -Stress – -Illness – -Cellelular damage to GI mucosa (NSAIDS) ALCOHOL - WARFARIN • ACUTE vs CHRONIC – Regular (chronic) alcohol consumption induces hepatic cytochrome P450 enzymes and increases warfarin dose requirements – Acute drinking of excessive alcohol (binge) leading to intoxication causes a substantial increase in the prothrombin time/INR, hepatic cellular injury, and causes excessive anticoagulation and increases the risk of hemorrhage. Fall risks from significant alcohol are substantial. WARFARIN DRUG INTERACTIONS • Over 250 documented interactions with warfarin • Antimicrobials, Analgesics, Anticonvulsants, Antiarrhythmics, Alcohol are biggest risk and • • OTC medications are sources for drug interactions Patients need to be taught to inform their anticoagulant clinician when ANY changes in drug therapy are made. • The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected to cause an interaction to patients on coumarin therapy. Clinical Pharmacokinetics 1996 Jun; 30(6):417. Case # 1 A 41 yo female developed deep vein thrombosis during pregnancy. Which anticoagulant drug would be best for her and why? What side effects should you be on the lookout for? Warfarin Teratogenicity Case # 2 A 68 yo male is a diabetic in end stage renal failure. He was admitted to the ER with severe chest pain and was found to have sustained an MI. Which anticoagulant should he be started on and on which one should he placed when he is discharged? ...
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SPPS 249 Anticoagulation 3-28-2011 - Anticoagulation David...

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