Pharmacology Lecture 5. Anticoagulants

Transcription

1 Pharmacology Lecture 5 Anticoagulants

2 General overview Anti-thrombotic Drugs Antiplatlets Anticoagulants Fibrinolytics

3 Anticoagulants Indirect Thrombin Inhibitors Anti-thrombotic effect is exerted by interaction with antithrombin Examples Unfractionated Heparin Low molecular weight Heparin Fondaparinux Bind to anti-thrombin, anti thrombin is a protien in plasma tat prevents the action of thrombin and therefore prevents the formation of a fibrin clot by stopping the conversion of fibrinogen to fibrin

4 Heparin and indirect thrombin inhibitors Heparin - action dependent on the endogenous volume of anti-thrombin Anti-thrombin inhibits clotting factors IIa, IXa, and Xa, in the presence of heparin, this reaction rate is increased 1000 fold Effect is monitored by APTT in Heparin, and weight based dosing in LMWH Pharmaco-kinetics A: IV so 100% bioavailability D: Volume of distribution close to plasma volume, half life about 1.5 hours M: uncertain E: uncertain? reticuloendothelial cells metabolise and degrade the compound

5 Heparin Toxicity: Bleeding Allergy Reversible alopecia Osteoporosis and fractures Heparin induced thrombocytopenia - antibodies against heparin and platelet factor 4 compound, usually an IgG compound so takes at least 5 days to form Occurs in 1-4% of patients treated with unfractionaed heparin for a minimum of 7 days Surgical patients are at greatest risk Rates lower with LMWH Thrombotic event: Venous thrombosis most common Treatment is: discontinue heparin and use direct thrombin inhibitor

6 Heparin Administration and dosage: Aim for APTT times that of control in patients For LMWH, 1mg/kg BD or 1.5mg/kg Daily Reversal: Discontinue Antagonist: Protamine Sulphate Effect on LMWH is limited with Protamine

7 Direct Thrombin Inhibitors Exert their anticoagulant effect directly binding to the active site of thrombin and thus inhibiting its downstream effects HIRUDIN/BILVARUDIN Used for patients with HITS A: IV administration, rapid onset of action D: Small VD M: Short half life E: Clearance is 20% renal and the remainder is metabolic

8 NAOCs Rivaroxoban - Direct Xa inhibitor Apixaban - Direct Xa inhibitor Dabigatran - Direct thrombin inhibitor Pharmacokinetics: A: Apixaban: generally well absorbed, bioavailibility approximately 50% Dabigatran: poor bioavailability D: M: Apixaban: No need for activation via first pass, half life around 12 hours Dabigatran: Needs to be activated by first pass metabolism E: Apixaban: Renal excretion of of unchanged drug, Dabigatran: 80% really excreted, dose alteration in renal failure

9 WARFARIN Pharmacokinetics A: PO, 100% bioavailibility D: Low Vd, and long half life (36 hours), highly bound to albumin M: Hepatic metabolism via CYP enzyme system E: minimal excretion of unchanged drug in serum Mechanism of action: Blocks the gamma-carboxylation of several glutamate residues in prothrombin and factors VII, IX and X as well as protein C and S (endogenous anticoagulants). Protien carboxylation reaction is coupled to the oxidisation of Vitamin K Warfarin prevents recycling of Vitamin K by blocking the enzyme VITAMIN K EPOXIDE REDUCTASE 8-12 hours delay in the action of warfarin Anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four Vitamin K dependent clotting factors S isomers and R isomers - S isomer is 4 times more potent than the R isomer

10 WARFARIN Drug Interactions: Pharmacokinetic effects Enzyme induction Enzyme inhibition Reduced plasma protein binding Pharmacodynamic effects Synergism - hemostasis and reduced clotting factor synthesis as in liver disease Competitive antagonism (Vitamin K)

11 WARFARIN Most serious interactions are those than prolong anticoagulation PYRAZOLONES - both augment hypo prothrombinemia and inhibit platelet function Metronidazole, fluconazole and Bactrim - steroselectively inhibit metabolic transformation of the more potent S isomer Amiodarone, disulfram and cimetidine inhibit metabolism of both isomers Asprin, hepatic disease and hyperthyroidism augment warfarin pharmacodynamically Third generation cephalosporins eliminate bacteria in the GI that produce Vitamin K Decrease in effect by induction of hepatic enzymes Barbituates and rifampicin Pharmacodynamic reductions occur with Vitamin K, spironolactone and hypothyroidism

12 Fibrinolytic agents Catalyse the formation for plasmin from plasminogen PHARMACOLOGY: Streptokinase - a protein produced by streptococci that combines with plasminogen - this enzymatic complex catalyses the conversion of inactive plasminogen to plasmin Urokinase - Human enzyme synthesised by the kidney that directly converts plasminogen to plasmin Plasminogen can also be activated endogenously by TPA - it preferentially activates plasminogen that is bound to fibrin which confines fibrinolysis to the formed thrombus and avoids systemic activation There can be recombinant versions of this (ALTEPLASE, RETEPLASE)

13 Fibrinolytic agents Indications and dosage PE with instability Phlegmasia AMI with ST elevation Acute ischemic stroke

14 Anti Platelet Agents Platelet function is regulated by three categories of substances Agents generated outside the platelet that interact with the platelet membrane Agents generated within the platelet that interact with membrane receptors (ADP, prostaglandin) Agents generated within the platelet that act within the platelet (Thromboxane A2)

15 Aspirin - COX inhibitor, inhibits the synthesis of Thromboxane A2 Clopidogrel - Inhibits the ADP pathway in platelets and inhibits platelet aggregation Irreversible blockade Antithrombotic effects are dose dependent - after loading dose of 300mg 80% of platlets will be inhibited Glycoprotien IIb/IIIa Used in patients with ACS The IIb/IIIa receptor receptor complex acts as a receptor mainly for fibrinogen but also for vwf Activation of this pathway is the common pathway for platelet aggregation