Anticoagulants

Anticoagulants

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  ANTICOAGULANTS Dr. ZIKRULLAH
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  ANTICOAGULANT – GENERALOVERVIEW  Drugs that help prevent the clotting (coagulation) of blood.  Coagulation will occur instantaneously once a blood vessel has been severed.
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  BLOOD CLOTTING Vascular Phase PlateletPhase Coagulation Phase Fibrinolytic Phase
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  VASCULAR PHASE  Afterinitial injury a brief period of arteriolar vasoconstriction occurs.  As a result of reflex neurogenic mechanisms.  Augmented by the local secretion of factors such as endothelin (a potent endothelium-derived vasoconstrictor).  The effect is transient.
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  PLATELET PHASE  Bloodvessel wall (endothelial cells) prevent platelet adhesion and aggregation.  Platelets contain receptors for fibrinogen and von- Willebrand factor.  After vessel injury Platelets adhere and aggregate.  Release permeability increasing factors (e.g. vascular permeability factor, VPF).  Loose their membrane and form a viscous plug.
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  COAGULATION PHASE  Twomajor pathways  Intrinsic pathway  Extrinsic pathway  Both converge at a common point.  13 soluble factors are involved in clotting.  Biosynthesis of some factors are dependent on Vitamin K.  Normally inactive and sequentially activated.
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  FIBRINOLYSIS  Enhance degradationof clots.  Activation of endogenous protease.  Plasminogen (inactive form) is converted to plasmin (active form).  Plasmin breaks down fibrin clots.
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  CLASSIFICATION A. Parenteral Anti-Coagulants 1.Indirect Thrombin Inhibitors a) Heparins i) High Molecular Weight Heparin -Unfractionated Heparin (UFH) ii) Low Molecular Weight Heparins -Enoxaparin -Dalteparin -Tinzaparin -Reviparin -Danaparoid
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  2. Direct ThrombinInhibitors -Hirudin -Lepirudin -Bivalirudin - Argatroban B. Oral Anti-Coagulants 1. Coumarins -Warfarin -Dicumarol 2. Indanediones -Phenindione
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  C.NEW ORAL ANTICOAGULANTS -Dabigatran -Rivaroxaban -Apixaban -Endoxaban -Betrixaban
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  HEPARIN  It isa mixture of straight chain anionic (negative charge) glycosaminoglycan with a wide range of molecular weights.  It is strongly acidic because of presence of sulfate and carboxylic acid groups.  Commercial heparin is extracted from porcine intestinal mucosa and bovine lung.
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  HEPARIN-KINETICS  Half life:1to 1.5 hours  Heparin is highly charged, thus crosses cell membranes very poorly, hence given Parenterally.  Dose : - Bolus :80 units/kg or 5000 units - Maintenance :15 units/kg /hr or 700 to 2000 units/day  Low dose: Subcutaneous  High Dose: Subcutaneous or IV Injection.  Metabolized by liver, half life depends on dose.
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  MECHANISM OF ACTION Activated, factors IXa, Xa, XIa, XIIa and IIa are neutralized by Anti- thrombin III (AT III).  Heparin accelerates the interaction of the active clotting factors with ATIII.  Once antithrombin-clotting factor complex is formed, heparin is released for renewed binding to more antithrombin.
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   High molecular weight Heparins acceleratesthe inactivation of clotting factors IIa and Xa.  Low molecular weight heparins accelerate the inactivation of only Factor Xa.
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  MONITORING HEPARIN  ActivatedPartial Thromboplastin Time (aPTT)  Normal range: 25-40 seconds  Therapeutic Range: 55-70 seconds  Timing:  4-6 hours after commencing infusion  4-6 hours after changing dosing regimen
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  ASRA COMMENDATIONS For minidose prophylaxis:  No contraindication: Hold morning dose.  Check platelet count. In a patients with combined neuraxial block and intraoperative anticoagulation:  Avoid RA in patients with medication of clotting inhibitors in combination.  Delay heparin dose up to one hour after needle placement.
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   Remove catheter4 hours stopping the dose and start the dose again after 1 hour.  Check for motor and sensory blockade.  Consider minimal dose of local anaesthetics for early detection of spinal hematoma.
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  Combining neuraxial techniquewith full anticoagulation of cardiac surgery:  Insuffcient data and experience to determine the risk of hematoma.  Postoperative monitoring of neurological function.  Selection of solution to minimize sensory and motor blockade.
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  LMW HERARIN  Mechnismof action:inhibit clotting factor Xa more than IIa.  Examples : - Deltaparin - Enoxaparin -Tinzaparin
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   Half life:3to 4 times than Heparin  Doses : - Deltaparin :2500-5000 unit/day -Enoxaparin :30-40 mg/day -Tinzaparin:175 unit/day
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  ASRA RECOMMENDATIONS  Monitoringof anti-Xa level is not recommended.  No RA in patients taking other clotting inhibition in addition.  In the presence of blood during needle and catheter placement.  Delay LMWH therapy for 24 hours  Should be discussed with the surgeon.
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   Preoperative LMWH: Thromboprophylaxis :needle placement should up to 10-12 hours.  Treatment doses:a delay of at least 24 hours is recommended.  No RA if the dose is given in morning preoperatively.
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   Postoperative LMWH: May undergo RA technique, but removal of the catheter depends upon total daily dose and timing.  (A ) Twice daily dose:  Increased risk of spinal hematoma  First dose of LMWH should not be administered 24 hours postoperatively.  Catheter should be removed prior to initiation of thromboprophylaxis.  LMWH dose should be started after 2 hours removing the catheter.
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  (B)Single daily dose: First dose should be administered 6-8 hours postoperatively.  Second dose after 24 hours and catheters may be safely maintained.  Catheter should be removed after 12 hours of last LMWH dose.  LMWH dose can be started after 2 hours.
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  FOR GENERALANAESTHESIA  Isit not contraindicated for patient with anticoagulant.  Precaution should be consider:  Avoid IM/S.C. drug administration.  If IM administration is necessary,the arm should be used(since local haemorrage is easier to detect and treat).  All venopuncture/arterial puncture should be carried out meticulosly.
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   CVL bysubclavian/int.jugular route is contraindicated.  If CVL is necessary, used anticubital fossa.  Ext.jugular can be used as hematoma formation can be treat with ext.pressure.  Atraumatic laryngoscopy and tracheal intubation.  Avoid nasal intubation /NG tube.  No precaution are necessary for patient receiving prophylactic low dose heparin.
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  ADVANTAGES OF LMWHOVER UFH  Better subcutaneous bioavailability(70-90%) compared to UFH(20-30%).  Longer and more consistent half life: once daily subcutaneous administration.  Since aPTT/clotting times are not prolonged, lab. monitoring is not needed.  Lower incidence of haemorrhagic complications.
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  USES OF HEPARIN 1.Treatment& Prevention of Deep Venous Thrombosis in :  Bedridden (Immobilized patients)  Old people  Post-operative  Post-stroke patients  Leg fractures  Elective Surgery
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  2. Ischemic HeartDisease Unstable angina After MI After angioplasty CABG, stent replacement 3. Rheumatic Heart Disease/ Atrial Fibrillation 4. Cerebrovascular Diseases Cerebral Emboli (Prevention of recurrence) 5. Vascular Surgery, Prosthetic heart valves, Hemodialysis To prevent thromboembolism 6. DIC Abruptio placenta, malignancies, infections; increased consumption of clotting factors
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  ADVERSE EFFECTS 1.Bleeding(most common) 2.Allergy and Anaphylaxis 3. Increased hair loss, alopecia 4. Long term-Osteoporosis, spontaneous fractures 5. Thrombocytopenia
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  CONTRAINDICATION 1. Hypersensitivity 2. BleedingDisorders like Hemophilia 3. Thrombocytopenia 4-. Intracranial Hemorrhage 5. GIT Ulcerations 6. Threatened abortion 7. Advanced renal or hepatic disease
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  HEPARIN AND PREGNANCY Heparin does not cross the placenta, therefore it must be used instead of warfarin in cases of requiring anticoagulant therapy in pregnancy.  Warfarin crosses the placenta and induces changed in the fetus to produce the fetal warfarin syndrome .
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  HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)  2ndmost common side effect after bleeding.  Occurs in 3-5% of patients 5 to 10 days after initiation of standard heparin therapy.  Lower incidence in low molecular wt. heparin.  Can be life-threatening.  Due to production of IgG against complexes of heparin with platelet.  The complexes activate more platelets with the release of more platelet factor 4 or other cytokines.
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   This stimulatesthe formation of more IgG.  This snow-ball effect uses up platelets and also leads to thrombosis. Systemic bleeding and localized infarction (due to thrombosis) occur.  Once thrombocytopenia is determined, heparin must be stopped. Direct thrombin inhibitor should be given  Platelets must NOT be given because they will react with antibody already being produced against them, causing greater chance of thrombosis.
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  ANTIDOTE –PROTAMINE SULFATE Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity.  Hemorrhage – can be reversed by protamine sulfate titrated so that 1 mg of protamine sulfate is administered for every 100 U of heparin.  Protamine sulfate is also an anticoagulant because it interacts with platelets, fibrinogen, and other clotting factors – so it can make hemorrhage worse if more is given than necessary.
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  WARFARIN Wisconsin Alumni ResearchFoundation Coumarin Warfarin-Pharmacokinetics : 1. Rapidly and completely absorbed after oral administration 2. 100% Bioavailability 3. Highly plasma protein bound (99%) 4. Crosses the placenta (teratogenic)
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  5. Appears inmilk; 6. Variable but slow clearance;depends on hepatic cytochrome P450s 7. Biotransformation by the liver: Oxidation, Glucuronidation 8.Half life:40 hours . 9.Doses :2-15mg/day. 10.Monitering :PT and INR
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  Warfarin No Synthesis of Functional Coagulation Factors Antagonism of VitaminK WARFARIN MECHANISM OF ACTION Vitamin K VII IX X II
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  USES  Same asHeparin and other Anticoagulants.  Monitoring necessary because of its low therapeutic index.  PT (Prothrombin time is noted; time taken for blood to clot).  Patients on Heparin are shifted to oral warfarin after 3-5 days
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  ADVERSE EFFECTS 1. Bleeding Mostcommon and most serious adverse effect; Epistaxis, hematuria, GIT Bleeding, internal hemorrhages 2. Cutaneous Necrosis This is due to decreased activity of Protein C Protein C and Protein S found in bone & other tissues also require Gamma carboxylations 3. Infarction of breast, fatty tissues, intestine and extremities due to venous thrombosis caused by again decreased activity of Protein C
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  ANTIDOTE OF WARFARIN Stop Warfarin  Give Vitamin K (Antidote)  Also Fresh frozen plasma, Prothrombin complex concentrates and Recombinant factor VIIa can be administered.
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  CONTRAINDICATIONS 1.Pregnancy Fetal protein inbone and blood affected -Causes birth defects including abnormal bone formation, bone hypoplasia. -CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal death may occur. 2. Other contraindications same as heparin.
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  PHYSIOLOGICAL/PATHOLOGICAL FACTORS AFFECTING WARFARIN ACTION 1.Increased warfarin action  Malnutrition, debility (Decreased Vit. K)  Liver disease, chronic alcoholism (Decreased clotting factors)  Hyperthyroidism (Increased degradation of Clotting factors)  Newborns (Decreased vitamin K)
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  2. Decreased WarfarinAction  Pregnancy (Increased clotting factors)  Nephrotic syndrome  Warfarin resistance (Genetic)
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  ASRA RECOMMENDATIONS  Cautionshould made in performing neuraxial block in patients recently discontinued warfarin therapy.  The anticoagulant therapy must be stopped(ideally 4-5 days before performing the block).  Moniter PT / INR prior to initiation of block.
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   No RAif in combination of other drugs affecting the clotting.  If the first dose given 24 hours eariler-check PT/INR.  Patients receiving warfarin during epidural analgesia- do PT/INR on daily basis.  Check PT/INR before catheter removal if initial doses of warfarin are given more than 36 hours preoperatively.
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   Epidural cathetercan be removed if INR is<1.5  Neurological testing of the motor and sensory functions should be done.  Minimize the degree of motor and sensory block.  If INR>3,hold warfarin in patients with enhanced drug response.
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   Stopping warfarinbefore operation  Check INR: - INR 2-3 :discontinue warfarin 5 days before operation - INR 3-4.5:discontinue 6 days before operation  Target preop.INR<1.2 - Elderly ass.with slower rate of decrease in INR  If INR >1.5(1-2 days before surgery)to give 1-2 mg oral vit.K  Warfarin need not be stopped for all procedure
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   Starting heparinbefore the operation  Assesment of the patient which require bridging therapy based on individual risk factors  Recommandation for perop.bridge therapy:  High risk gr.: bridging anticoagulation with therapeutic dose of s.c. LMWH/ i.v. UFH  Moderate risk gr.: therapeutic dose of LMWH/UFH or low dose s.c.LMWH  Low risk:low dose s.c.LMWH or no bridging
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   After surgery: Minor surgery(high risk group): -Reinitiate LMWH at full dose 24hrs.after surgery  Major surgery/high risk of bleeding: -Use prophylactic dose on the first 2 post operative day than full dose of LMWH OR -Delay the initiation of therapeutic dose for 48-72hrs post operative.
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   Discuss withsurgeon regarding reinitiation of anticoagulant  Restart warfarin as previous dose 1 day post op.(12- 24hrs)when haemostasis are adequate  Daily PT/INR till discharge and periodically after discharge till INR reach therapeutic range  Discontinue LMWH when INR is between 2-3 for 2 consecutive day
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  DIRECT THROMBIN INHIBITORS (DTIS) The DTIs bind thrombin without additional binding proteins, such as anti-thrombin, and they do not bind to other plasma proteins such as platelet factor 4.  Hirudin and Bivalirudin bind at both the catalytic or active site of thrombin as well as at a substrate recognition site.  Argatroban bind only at the thrombin active site
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  LEPIRUDIN  Monitored byaPTT.  Action independent of antithrombin.  Use in thrombosis related to heparin induced thrombocytopenia.  No antidote.  Adverse effect: Antibody formation against thrombin- lepirudin complex.
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  Bivalirudin Inhibits platelet activation Usein percutaneous coronary angiography. Argatroban Used in heparin induced thrombocytopenia with or without thrombosis Monitored by aPTT Dose reduction in liver disease
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  THANK YOU……