L7 Anti-coagulant drugs.pdf

Academic logo Anti-coagulant drugs • • • • • • EDITING FILE Main text Male slide Female slide Important Dr, notes Extra info Drugs and Coagulation Drugs & Coagulation Antiplatelet Agents/Drugs Anticoagulants Fibrinolytic Agents ● Molecules that do not allow platelets to aggregate and thus pr...

Academic logo Anti-coagulant drugs • • • • • • EDITING FILE Main text Male slide Female slide Important Dr, notes Extra info Drugs and Coagulation Drugs & Coagulation Antiplatelet Agents/Drugs Anticoagulants Fibrinolytic Agents ● Molecules that do not allow platelets to aggregate and thus prevent clotting, especially in the arteries. ● Reduce risk of clot formation by inhibiting platelet functions. ● Molecules that prevent blood from clotting by inhibiting the chemical process of formation of the fibrin polymer. ● Prevent thrombus formation & extension by inhibiting clotting factors. ● Heparin ● Low molecular weight heparin ● Coumarins / Warfarin ● Molecules that disintegrate a pre-formed clot. ● Dissolve thrombin already formed. ● Aspirin ● Ticlopidine ● Streptokinase Coagulation Cascade Intrinsic Pathway Extrinsic Pathway All clotting factors are within blood Clotting: slower | accessed by aPTT Initiating factor is outside the blood Clotting: rapid (sec.) | accessed by PT BV Injury / Exposed Collagen XII Tissue Injury / Damaged cells Tissue Factors XIIa XI (prot & phospholipid) XIa IX Coumarins (Warfarin) Both converge to a common pathway. Picture + Ca++ VIIa 13 soluble factors [normally circulate in an inactive state] are involved in clotting & must be activated to form a Fibrin Clot. VII Coumarins (warfarin) IXa +VIIIa + Ca++ +PF X Heparin XII I Thrombin IIa XIIIa Xa Prothrombin II Prothrombinase Fibrinogen Fibrin Monomer (soluble) Fibrin Polymer (insoluble) Cross-Linked Fibrin Anticoagulants Thanks to 441 team Dr.Fouda PLEASE BE AWARE THAT NOT ALL THE ANTIDOTES WORKS ON ALL THE ANTICOAGULANT DRUGS YOU HAVE TO BE SPECIFIC. Anticoagulants Oral Parenteral ● Act as thrombin inhibitors either in a direct or an indirect way. ● Coagulation factors inactivation [XIIa - XIa - IXa Xa - IIa]. ● Rapid / Variable “emergency use” “inactivate previously formed factors” ● Monitor by: - APTT (1.5 - 2.5 times normal [30sec]) ( APTT = activated partial thromboplastin time ) - CT (2-3 times normal [5-7 min) ● Antidote: - Protamine Sulphate IV 1mg / 100 units UFH - +/ Fresh blood Indirect thrombin inhibitors : Unfractionated Heparin (UFH): - 3000 - 30000 - > AT III “more active on AntiThrombin III ” Low Molecular Weight Heparin (LMWH): - < 800 - > Xa ”more active on factor Xa” - Enoxaparin - Dalteparin Direct Thrombin inhibitors: - IIa - Reversible (R): Bivalirudin - Argatroban Dabigatran - Irreversible (IR): Lepirudin Factor Xa inhibitors: Pentasaccharide - Xa - Indirect: Fondaparinux - Direct: Rivaroxaban - Act as Vitamin K antagonist. ↓ Coagulation factor synthesis [II VII - IX - X]. Slow / Latency / Variable ”Needs time to work - long term tx, not emergency” Monitor by: - PT (2 times) - INR (2.5) ● Antidote: - Vit. K1 infusion +/ Fresh blood - + Needs de novo synthesis Coumarins: Warfarin potency: > 40x than Dicumarol Anticoagulant Endogenous Coagulation Inhibitors - Physiological coagulation inhibitors synthesised inside the body , 3 types: Antithrombin III: plasma protein, inactivates thrombin (factor IIa) & other coagulation factors [IXa - Xa - XIa - XIIa] by forming complex with these factors. - Site of action of heparin (heparin like molecules enhances these interactions). Prostacyclin (PGI2): synthesized by endothelial cells , inhibits platelet aggregation. Protein C & S: vitamin K dependent proteins, slow coagulation cascade by inactivating factor Va & VIIIa. Anticoagulants Indications 1 Myocardial infarction (MI) 4 Blood transfusion & dialysis. 2 Deep venous thrombosis (DVT) 3 Pulmonary embolism (PE) 5 Peripheral arterial emboli. 6 Many other conditions. 1.A. Direct Thrombin Inhibitors (DTIs) Females’ Slides MOA exert their anticoagulant effect by direct binding to thrombin. Effect rapid and potent. Advantage Drug Lepirudin not associated with thrombocytopenia development. ● recombinant hirudin, a polypeptide. ● Used as IV anticoagulant in patients with HIT Binds directly to active site of thrombin. ● 1.B. Indirect Thrombin Inhibitors: I. Unfractionated Heparin (UFHs) Drug Heparin (Unfractionated Heparin) M.O.A. ● Indirect Thrombin Inhibitor. ● ↑ Activity of endogenous anticoagulant [Antithrombin III] → inhibits activated clotting factors: thrombin (factor IIa - essential for clot formation) & VIIa - IXa - particularly Xa. ● Heparin (co-factor) binds to antithrombin III and thrombin → conformational changes (ternary complex) → ↑ rate of action 1000x. (no heparin → slow inactivation). ● Heparin dissociates → thrombin bound to inhibitor + free heparin → inhibit more thrombin. ● “You could simply say that it increases the activity of Antithrombin III by 1000 folds” P.K. ● Administration: injectable (IV or SC | Not IM → haematomas at injection site). ● Absorption: not absorbed from GIT. ● Onset of action: rapid. Drug Heparin (Unfractionated Heparin) cont.. ● ● ● ● Uses ● [Drug of choice] anticoagulant during pregnancy (doesn’t cross the placenta). Stops the expansion of a thrombus + prevents formation of new thrombi. Does not dissolve an existing thrombus. Initiates immediate (rapid onset of action) anticoagulation in thromboembolic disease (PE - DVT - MI) as induction for oral vitamin K antagonists. Prevents postoperative DVT (hip replacement) + renal dialysis/cardiac surgery coagulation. No predictable anticoagulant effects: inter-patient & intra-patient variability in response to a given dosage in hospital setting, repeated close monitoring of aPTT is necessary. ● Re-thrombosis: activates platelets as it does not neutralize fibrin-bound IIa “thrombin”. ● Heparin Induced Thrombocytopenia (HIT) [4%]: heparin binds to platelets → ↓ platelet count + ↑ thrombosis risk (instead of bleeding). - Generally: ↓ platelets → excessive bleeding | ↑ platelets → blood clot → thrombosis. - Latency: 5-10 days after 1st exposure or 2-3 day after re-exposures. - Venous > Arterial thrombosis. - Management: - Heparin discontinuation. - Give DTIs (Direct thrombin inhibitors). - 🚫 Packed platelets → ↑ thrombosis [do NOT do this]. - 🚫 Warfarin → precipitate venous gangrene [do NOT do this]. ● Inconvenience of administration by injection. ● Limitations ● ● Pathophysiology Of HIT ● Picture ● ADRs # C.l. Female slide Origin of the drug Platelet Factor 4 (PF4) bind to heparin → immunogenic complex → ↑ IgG antibody production. IgG → triggers production of PF4/Heparin/IgG complex (ternary complex). Ternary complex bind to platelets → activated platelets → microparticles + more PF 4 → accelerated system. - Microparticle → ↑ thrombin release. IgG/PF4 complex bind to heparin → endothelial release tissue Femalecells slide factor → ↑ thrombin generation. ● Bleeding (major ADR). ● Allergic reactions (chills - fever urticaria) → caution in allergic patients. ● Long-term therapy → osteoporosis ● HIT ● ● ● ● Reversal of Action Bleeding disorders - hemophilia. Hypersensitivity to drug. Recent surgery of the brain, eye or spinal cord. Threatened abortion. ● Normal macromolecule in mast cells with histamine (unknown physiological role). ● Commercial preparations: extracted from beef lung or pig intestine → can cause hypersensitivity reaction. Extra UFH & DTIs ● Discontinuation of drug. ● IV protamine sulfate (strong base protein) + Heparin (strong acid) → neutralized stable complex [no anticoagulant activity]. ● ● Anticoagulant activity of heparin: able to generate a ternary heparin-thrombin-antithrombin complex. - MOA: conformational change → antithrombin irreversibly binds to and inhibits active site of thrombin → anticoagulation. - Heparin-antithrombin complex cannot bind fibrin-bound thrombin. Anticoagulant activity of DTIs: independent of the presence of antithrombin - related to direct interaction of DTIs with the thrombin molecule. 1.B. Indirect Thrombin Inhibitors II. Low Molecular-Weight Heparins (LMWHs) Heparin fragments Synthetic pentasaccharide (Enoxaparin - Dalteparin) (Fondaparinux) Drug Derived from the chemical or enzymatic degradation of UFH into fragments. ● ↑ Action of antithrombin III on factor Xa but not its action on thrombin (molecules are too small to bind to both enzyme and inhibitor). M.O.A. ● P.K. Inhibits factor Xa by antithrombin but does not inhibit thrombin. ● Size: 1/3 the size of UFH. ● Plasma half-life (t ½): longer → ↑ bioavailability. ● Duration of action: longer → ↓ frequency of administration. ● Administration: SC, once- or twice- daily. ● Given once a day at a fixed dose without coagulation monitoring. Uses ● Used increasingly in place of unfractionated heparin. ADR’s ● Less likely to trigger HIT. Advantages of LMWHs over UFH Advantages of LMWH over UFH arise from the preferential binding ratio to factor Xa over thrombin. ● Equal efficacy to UFH. ● ↑ Predictability of anticoagulant response: ↓ inter-patient & intra-patient variability in response to a given dosage → no need for laboratory monitoring → suitable for outpatient therapy. ● ↑ Bioavailability: ↓ binding to plasma proteins, endothelium & macrophages. ● ↓ Incidence of thrombocytopenia: seldom (rarely) sensitive to PF4. ● ↓ Incidence of bleeding tendency: ↓ effect AT III & ↓ platelet interactions /activation & ↓ binding with osteoblasts. ● Much better tolerability. ● ↓ Risk of re-thrombosis and thrombocytopenia. 1.B. Indirect Thrombin Inhibitors: Heparin (UFH) Drug P.K ● ● ● Male slide IV ½ life: 2 hours Bioavailability after SC: 20% Non-Specific Binding: more LMWH ● ● ● IV ½ life: 4 hours Bioavailability after SC: 90% Non-Specific Binding: little “↑bioavailability” ● ● ● ↑ anti-Xa activity ↑ inhibition of thrombin generation Work directly on Xa → inhibits thrombin generation better than when working on AT3 indirectly "UFH" M.O.A ● ↓ anti-Xa activity ● ↑ antithrombin activity ● ↓ inhibition of thrombin generation Male slide Sensitive Resistant “rethrombosis is not a risk” Variable Predictable ”used more often” ● Frequent bleeding ● HIT ● Osteoporosis ● Less frequent bleeding ● Less HIT. ● Less osteoporosis. PF4 Female slides Response ADRs Antagonist Therapy setting Monitoring Protamine sulphate Hospital Needed aPPT Incomplete Hospital & OPC Not needed Vitamin K: Fat Soluble Vitamin Vitamin K Source ● Green vegetables. ● Synthesized by intestinal flora. Required for ● Functional coagulation factors II, VII, IX ,X synthesis. ● Protein C & S synthesis (endogenous anticoagulants). Deficiency Causes ● Malnutrition. ● Malabsorption. ● Antibiotic therapy. Drugs In Modulating Response to VKAs (Oral Anticoagulants): Female slide 01 Increase the actions of anticoagulants Oral antibiotics: inhibition of Vit K synthesis by intestinal flora Liquid Paraffin: inhibition of Vit K absorption chloramphenicol, & cimetidine: ↓ Drug Metabolism by Microsomal Enzyme Inhibitors phenylbutazone & salicylates: displacement of the drug from protein binding sites NSAIDs & heparin: Co-administration of drugs that increase bleeding tendency by inhibiting platelet function and coagulation factors ,respectively. 02 Decrease the actions of anticoagulants cholestyramine, colestipol: inhibition of drug absorption from GIT Vit K, oral contraceptives: increased synthesis of clotting factors Carbamazepine; barbiturates, rifampicin: Increase in drug metabolism by microsomal enzyme inducers 2. Vitamin K Antagonists: Coumarin: Warfarin Coumarin (Warfarin) Important 1. 2. 3. M.O.A 4. Precursors of factors II, VII, IX & X require carboxylation of their glutamic acid residues to bind to phospholipid surfaces. Carboxylation of glutamic acid residues is provided by Vitamin K [changes from oxidized to reduced form]. Reduced Vitamin K recycles back to oxidized form by Vitamin K by epoxide reductase. Epoxide reductase is blocked by VKA → lost functioning ability of coagulation factors. Picture i.e ● Inhibits biologically active forms of vitamin K-dependent clotting factors [II - VII - IX - X] , and anticoagulant proteins C and S synthesis. ● No effect on already-synthesized coagulation factors → therapeutic effects are not seen until these factors are depleted. Inactive clotting factors [II - VII - IX - X] Vitamin K ylase Carbox Active clotting factors Vitamin K Epoxide Form Warfarin Epoxide Reductase ● ● P.K ● ● ● ● ● Limitations Active only in vivo. In bloodstream: 98% bound to plasma proteins (albumin) “when taken with Phenylbutazone & Salicylates (high protein binding) → displace Warfarin from binding sites → ↑ free Warfarin in blood → ↑ effect”. Bioavailability: 100% Onset of action: starts when already-synthesized factors are eliminated. Effect takes 3 - 4 days to develop because of the time taken for degradation of circulating functional clotting factors. Monitoring anticoagulant effect by measuring PT [International Normalized Ratio (INR)]. Offset of action: slow due to time required for synthesis of new, functional factors. ● Variable, unpredictable effect → required regular INR monitoring + dose adjustment. ● Narrow therapeutic window → any change in that level can be hazard + ↑ risk of severe bleeding. ● Slow onset (not given in emergency) & offset of action. ● Many interactions with drugs + foods containing vitamin K → toxicities / under use. ● Polymorphisms in CYT P450 isoforms that metabolize warfarin → ↑ nonpredictable response → toxicities / under use. 2. Vitamin K Antagonists: Coumarin: Warfarin Important Coumarin (Warfarin) Female slide ADRs Bleeding (major ADR). Female slide ● Stop the drug. ● IV Vitamin K. ● Fresh frozen blood. Reversal of Action # ● Pregnancy [Cross placental barrier → abortion - hemorrhagic disorder in fetus - birth defects]. - Give heparin or LMWH instead. Heparin Vs. Warfarin Important Heparins Drug Chemical Nature M.O.A. P.K. ● Large polysaccharide ● Water soluble ● Small molecule ● Lipid soluble derivative of Vit. K ● ↑ activity of Antithrombin III → inactivation of coagulation factors IIa - IXa - Xa - XIa - XIIa. ● Action in vivo and vitro ● Rapid / variable ● ↓hepatic synthesis of Vitamin Kdependent factors II, VII, IX, X cournarins prevent their γ-carboxylation. ● Has no effect on factors already present. ● Action in vivo only. ● Slow / latency / variable. ● Administration: parenterally (IV/SC). ● Half-life: 2 h ● Elimination: hepatic & reticuloendothelial. ● No placental access. ● ● ● ● ● ● ● Partial thromboplastin time (PTT) 1.5-2.5 times normal (30 sec) Monitoring ● Clotting time 2-3 times normal (5-7 min) Antagonist (Anti-dote) Uses Toxicity Coumarin (Warfarin) Administration: orally. 98% protein bound. PO Metabolism: liver. Half-life: 30+ h Placental access. ● Prothrombin time (PT) ● Expressed as International Normalized Ratio (INR) ● Protamine sulfate I.V (1mg/100 units UFH) (chemical antagonism, fast onset) ● + Fresh blood ● ↑ Vit K cofactor synthesis (slow onset) ● Fresh frozen plasma (fast onset) ● Fresh blood + needs de novo synthesis - Has clotting factors → manage bleeding fast. ● Rapid anticoagulation (intensive, emergency) for: - Thromboses - Emboli - Unstable angina - Disseminated intravascular coagulation (DIC) - Open heart surgery ● Long term anticoagulation (controlled, prophylaxis) for: - Thromboses - Emboli - Post MI - Heart valve damage - Atrial arrhythmias ● ● ● ● Bleeding Osteoporosis Thrombocytopenia (HIT) Hypersensitivity ● ● ● ● Bleeding Skin necrosis (if low protein C) Drug interactions Teratogenic (Bone dysmorphogenesis) Class MOA Pharmacological action Uses ADRs