Pharmacology

• Anticoagulants


  The mainstay of treatment for stroke and systemic embolism prevention in patients with atrial fibrillation (AF) or flutter. They can be used as well for prevention and treatment of venous thromboembolism (VTE) and treatment of thrombus formation in other places.
• Indications for anticoagulants


  • Deep vein thrombosis
  • Pulmonary embolism
  • Prophylaxis of embolization in rheumatic heart disease and atrial fibrillation
  • Prophylaxis after insertion of prosthetic heart valves
  • Short-term anticoagulation in acute coronary syndrome
  • Patients undergoing major orthopedic surgery should receive short-term anticoagulation
• Anticoagulants in use


  • Unfractionated heparin (UFH)
  • Low molecular weight heparin (LMWH)
  • Fondaparinux
  • Warfarin
  • Direct oral anticoagulants (DOAC; apixaban, rivaroxaban, dabigatran)

  
• Unfractionated heparin (UFH)


  Repeating polymer of sulfated glycosaminoglycans. Present in granules of mast cells. Produces its effects mainly by increasing the rate of antithrombin iii – thrombin complex formation 1000 fold causing instantaneous inactivation of thrombin. Also inhibits factor Xa and others. Inhibits platelet function.

  
• Unfractionated Heparin


  • Not absorbed orally, given subcutaneously or intravenously. Highly protein bound. Clearance by endothelial cells and macrophages, not affected by renal or liver disease at standard therapeutic concentrations. Rapid onset of action with short half life. Does not cross placenta.

  
• Adverse effects of UFH


  • Haemorrhage
  • Thrombocytopaenia : Heparin-induced thrombocytopenia (HIT type 1 - benign, probably dilutional effect; HIT type 2 - antibody formation against heparin-platelet factor 4 complex, can be severe)
  • Osteoporosis with long-term use
  • Hypersensitivity reactions and skin necrosis
• Unfractionated heparin


  Highly negatively charged, binds to blood components, pharmacokinetics poorly predictable, degree of anticoagulation must be monitored by aPTT. Only a fraction metabolized by kidneys, can be neutralized with protamine sulfate.

  
• LMWH


  Smaller fractions of the heparin molecule, administered subcutaneously, inactivates factor Xa to a greater extent than thrombin, comparable in safety and efficacy to unfractionated heparin, does not cross placenta.

  
• LMWH


  • Less protein and cellular binding, more predictable pharmacokinetics allowing fixed weight based dosing, high bioavailability at low doses, renally cleared, longer half-life for once/twice daily dosing, lower frequency of HIT.

  
• Adverse effects of LMWH


  • Bleeding
  • Local affects at injection site : e.g. haematoma
  • Lower incidence of HIT type 2 but still some risk
• Advantages of LMWH over UFH


  • Higher bioavailability by subcutaneous route
  • Longer T1/2, allowing once or bd dosing and out patient treatment
  • Predictable pharmacokinetics and pharmacodynamics not requiring routine monitoring except in renal dysfunction
  • Low to moderate inhibition of platelet function
• Fondaparinux


  Exerts almost no thrombin inhibition and indirectly inhibit factor Xa through binding to antithrombin. Almost exclusively metabolized by the kidneys and should be avoided in renal failure. Predictable pharmacokinetics allow for weight based dosing. Long half life. No effective neutralizing agent.

  
• Warfarin


  Vitamin K antagonist. Inhibits the activity of vitamin K dependent carboxylase that is important for posttranslational modification of coagulation factors II, VII, IX and X. Taken orally. Periodic monitoring with INR is needed. Interact with drugs that induce/ inhibit hepatic P450 microsomal enzyme system. Cross the placenta.

  
• Warfarin pharmacokinetics


  • 100% bioavailable, >99% bound to plasma, small Vd, long T1/2, lack of urinary excretion of unchanged drug. Time for anticoagulant effect depends on the T ½ of clotting factors inhibited, usually 8 – 12 hours.

  
• Warfarin therapy


  Commenced with small doses (5-10mg), usually along with heparin which is continued until INR has been therapeutic for 2 days. Needs close monitoring with regular INR to maintain at target level.
• Drug interactions with warfarin


  • Can increase or decrease INR through pharmacokinetic mechanisms (enzyme induction/inhibition, reduced plasma protein binding) or pharmacodynamic mechanisms (synergism, competitive antagonism)
• Side effects of warfarin


  • Bleeding
  • Skin necrosis
• NOACs


  Non-vitamin K antagonist oral anticoagulants, include dabigatran, rivaroxaban, apixaban, and edoxaban. Designed to overcome the limitations of warfarin. As effective as warfarin, but more convenient to administer without routine coagulation monitoring. Associated with significantly less intracranial bleeding than warfarin.
• Fibrinolytic drugs


  Lyse thrombi by catalyzing the formation of plasmin from plasminogen. Conversion of Plasminogen (proenzyme) to plasmin (active enzyme) resulting in clot lysis. Plasmin is a nonspecific protease capable of breaking down fibrin & other proteins – fibrinogen, factors V & VIII.

  
• Currently available thrombolytic agents


  • Streptokinase
  • Alteplase
  • Reteplase
  • Tenecteplase
  • Urokinase
  • Prourokinase
  • Anistreplase(APSAC)

  
• Fibrin-specific fibrinolytic agents


  Need the presence of fibrin for the conversion, bind preferentially to plasminogen at fibrin surface (non circulating) not plasminogen in circulation, activity is enhanced upon binding to fibrin, selective in action – clot specific, risk of bleeding is less. Eg: Alteplase, Reteplase, Tenecteplase.

  
• Non-fibrin-specific fibrinolytic agents


  Do not need fibrin presence for the conversion, activate plasminogen in both the blood (systemic circulation) as well as on the clot surface, produce systemic fibrinolysis - increased tendency to bleed. Eg: Streptokinase.

  
• Streptokinase


  The first historical thrombolytic agent extracted from certain streptococcal strains. It is not a plasminogen activator, but after binding with free circulating plasminogen, it forms a complex that converts additional plasminogen to active plasmin. It is the most widely used fibrinolytic agent worldwide due to its relatively low cost, reasonable efficacy and safety, though lower efficacy than alteplase. Re-administration within 6 months is not considered safe due to high antigenicity and associated high antistreptococcal antibody titer. Often exerts febrile reactions.

  
• Tenecteplase


  Non-fibrin-specific agents that do not need fibrin presence for the conversion, activate plasminogen in both the blood and on the clot surface, produce systemic fibrinolysis and increased tendency to bleed

  
• Streptokinase


  The first historical thrombolytic agent extracted from certain streptococcal strains, it is not a plasminogen activator but forms a complex with free circulating plasminogen that converts additional plasminogen to active plasmin, it is the most widely used fibrinolytic agent worldwide due to its relatively low cost, reasonable efficacy and safety, but has lower efficacy than alteplase and the risk of intracranial hemorrhage is less, re-administration within 6 months is not considered safe due to its high antigenicity and associated high antistreptococcal antibody titer, it often exerts febrile reactions and other allergic reactions, and dose dependent hypotension is another potential caution

  
• Alteplase


  The recombinant plasminogen activator (rtPA) identical to native tPA, more fibrin specific with a plasma half-life of 46 minutes, the most often used fibrinolytic in the treatment of acute cardiovascular events, pulmonary embolism, and acute ischemic stroke, theoretically only active on the surface of a fibrin clot but in reality exhibits systemic fibrinolysis with a moderate risk of bleeding, not antigenic and seldom associated with any allergic manifestations

  
• Tenecteplase (TNK-tPA)


  A commonly used fibrinolytic agent with higher fibrin specificity, longer plasma half-life with final clearance mostly through hepatic metabolism, as efficient as alteplase while exerting a lower risk of non-cerebral bleeding, lacks antigenicity, and more comfortable to administer

  
• Indications for fibrinolytics


  • Acute MI
  • Acute ischaemic stroke
  • Massive PE with haemodynamic instability
  • Limb threatening venous thrombosis
  • Acute peripheral arterial occlusion
• Fibrinolytic therapy in Acute MI


  • Proven treatment in ST-elevation myocardial infarctions, widely available, can be administered by qualified health care professionals even in prehospital setting, greater the time to deliver the therapy after the AMI lessens its efficacy, should be given within 12 hours of onset of chest pain as soon as possible, reduces death rate following AMI, available agents - tPA, Tenecteplase, Alteplase, Streptokinase
• Tenecteplase administration in Acute MI


  Single IV bolus, dose depends on patient's body weight
• Streptokinase administration in Acute MI


  1.5 million units in 100ml 0.9% NaCl over 30-60 min, preceded or followed by Heparin
• Acute Ischemic Stroke (AIS)


  • Ischaemic penumbra is a severely hypoperfused, non-functional, but still viable cortex that surrounds the irreversibly damaged ischaemic core, with elapsing time, more penumbra gets recruited into the core, tissue reperfusion is able to stop this deleterious process until a certain point in time, saving the penumbra should improve clinical outcome

  
• Treatment Options for Acute Ischemic Stroke


  • Fibrinolytics/thrombolytics
  • Thrombectomy
• Fibrinolytic therapy in Acute Ischemic Stroke


  • To break up blood clots that prevent blood flow to brain and restore blood flow to areas of brain that have not yet suffered an infarct - penumbra, large clots less likely to dissolve with fibrinolytics, trial evidence from NINDS (1995) - 3 hours, ECASS (2008) - 4.5 hours, inclusion & exclusion criteria, all patients with AIS should receive treatment with intravenous alteplase (tPA) who present within a 4.5-hour window from their last known well time without any absolute contraindications, mainstay of thrombolysis in AIS significantly improves functional outcome

  
• Intravenous thrombolysis with Alteplase in Acute Ischemic Stroke


  Door to needle time should be < 60 mins, earlier the treatment given greater the benefit, very short half life (4-5 min), dose of r-tPA calculated according to body weight (estimated) Dose-0.9mg/kg (maximum 90 mg), 10% of the total dose given as an IV bolus over 1-2 min, 90% is given as an IV infusion, aspirin/heparin should not be given before or within first 24 hrs of thrombolysis
• Mechanical thrombectomy in Acute Ischemic Stroke


  • Beneficial when an AIS results from a proximal intracranial arterial occlusion and large thrombus
• Monitoring of patients receiving thrombolytic therapy


  Constant neurologic and cardiovascular evaluation, BP monitoring every 15 minutes during and after tPA infusion for at least 2 hours, then half-hourly for 6 hours and hourly for the next 16 hours after injection, thrombolytic therapy should be stopped urgently with any signs of neurologic deterioration, patient should receive an emergency computed tomography (CT), fibrinolytic agents or any anticoagulants stopped immediately with any bleeding complications, supportive measures should be instituted, including volume correction and blood factor transfusion, if on concomitant heparin, protamine sulfate can reverse the heparin effect
• Adverse Effects of fibrinolytic agents


  • Bleeding, hypotension, allergic reactions, angioedema, and reperfusion arrhythmias (when used in acute MI), streptokinase is the most antigenic and most frequently complicated by allergic reactions and hypotension
• Bleeding/hemorrhagic complications of thrombolytic therapy


  • The most frequent complication, can occur in puncture sites or spontaneously anywhere inside the body, intracranial hemorrhage or hemorrhagic stroke is the greatest concern, risk factors include elderly patients, uncontrolled hypertension, recent stroke or surgery, presence of bleeding diathesis, and concurrent use of anticoagulants, overdose most often occurs when administered in a non-body-weight adjusted manner and can cause severe hemorrhagic complications
• Absolute contraindications for thrombolytic therapy


  • Previous Intra-Cranial Hemorrhage (ICH)
  • Stroke of unknown origin at any time
  • Ischemic stroke < 6 months
  • CNS - Malignant intracranial neoplasm, aneurysm or AVM
  • History of closed head or facial trauma < 3 months
  • Major trauma/surgery < 3 weeks
  • Suspected aortic dissection
  • Active bleeding or known bleeding diathesis
  • Gastrointestinal bleeding < past 1 month
  • Non-compressible punctures < 24 hours (e.g. liver biopsy, lumber puncture)