Anticoagulant Pharmacology Flashcards
Anticoagulants
- heparin, low molecular weight heparin (LMWH)
- warfarin
- direct thrombin inhibitors
- direct factor Xa inhibitors
Heparin
- natural sulfated glycosaminoglycan (from porcine intestines)
- unfractionated heparin (UFH)
- low molecular weight heparin (LMWH)
- mechanism: enhances inhibition of clotting factors by antithrombin (ATIII or AT)
Molecular targets of heparin (UFH)
- factors IXa, Xa, IIa
Size difference b/w UFH & LMWH
- UFH 3X larger than LMWH
Effect of UFH on inactivation of thrombin and factor Xa
- thrombin: template mechanism (binds AT & thrombin)
- factor Xa: conformation mechanism (only binds AT) which increases affinity for Xa binding
Effect of LMWH on inactivation of thrombin & factor Xa
- thrombin: conformation mechanism (WEAK)
- factor Xa: conformation mechanism (STRONG)
- *must use conformation mechanism b/c too small to be able to bind another molecule besides AT**
UFH mechanism
- enhances ability of antithrombin, a serine protease inhibitor (serpin), to inhibit thrombin, factor Xa, and other activated clotting factors
UFH facts
- parenteral administration (IV or SC) – bolus followed by continuous infusion
- rapid onset of actin & short half life (1-2hrs)
- requires monitoring by APTT
- effect can be REVERSED by protamine
- can be used during pregnancy
Molecular targets of LMWH
- MORE Xa inhibition
- some IIa (thrombin) inhibition
LMWH facts
- SC administration
- rapid onset w/ short half life (6-12 hrs)
- monitored by specialized assay, NOT APTT
- partially reversed by protamine
- can be used safely during pregnancy
LMWH metabolism
- cleared by kidney
- should not be used in patients w/ impaired renal function
Adverse effects of heparins
- bleeding
- osteoporosis
- heparin induced thrombocytopenia: can cause THROMBOSIS
Heparin induced thrombocytopenia (HIT)
- prothrombotic condition mediated by IgG antibodies that bind to platelet factor 4 when complexed w/ heparin
- surgical patients have higher risk
- UFH higher risk than LMWH
- occurs 5-10 days after initiation of heparin
Treatment of HIT
- immediately discontinue all heparins
- start non heparin anticoagulant drug: fondaparinux (synthetic LMWH), direct thrombin inhibitor (argatroban, lepirudin, bivalirudin)
- warfarin should not be used until platelet count has recovered to at leas 150,000 per uL
Warfarin
- vitamin K antagonist
- inhibits glutamate carboxylation of vitamin K dependent clotting factors
Molecular targets of warfarin
- activated clotting factors IIa, VIIa, IXa, Xa
Warfarin administration
- ORAL
- slow onset of action b/c long half lives of clotting factors in plasma
- action reversed by vitamin K
- metabolized by liver and kidney
- monitored by INR of PT
Warfarin drug interactions
- pharmacokinetics: changes absorption, protein binding, or metabolism–metabolism/elimination via cytochrome P450 system
- pharmacodynamic: alter risk of bleeding or clotting by either effect on platelet aggregation of vitamin K catabolism
Warfarin pharmacogenetics
- R-warfarin & S-warfarin (CYP2C9)
- S warfarin more effective at vitamin K inhibition
Warfarin & genotyping
- genotyping appears to allow you to get INR into the proper range sooner but has not been shown to improve clinical outcomes
Adverse effects of warfarin
- bleeding
- teratogenicity (contraindicated in pregnancy)
- warfarin induced skin necrosis
- purple toe syndrome (cholesterol emobilization)
Limitations of warfarin
- narrow therapeutic index
- requires frequent monitoring
- pharmacogenetic testing has not been proven to improve clinical outcomes
- slow onset–so heparin overlap necessary
Direct thrombin inhibitors
- parenteral: argatroban, lepirudin, bivalirudin
- oral: dabigatran
Molecular target of direct thrombin inhibitors
- FACTOR IIa – thrombin
Argatroban
- approved for treatment of heparin induced thrombocytopenia
- administration: continuous IV
- short half life (1 hour)
- monitoring: APTT
- metabolism: HEPATIC
Lepirudin & Bivalirudin
- approved for treatment of HIT
- administration: continuous IV
- short half life (1-2 hours)
- metabolism: RENAL
- *derived from the medicinal leach**
New oral target specific anticoagulant drugs
- direct thrombin inhibitors: dabigatran
- direct factor Xa inhibitors: rivaroxaban, apixaban
Look at table on page 45
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Important features of new oral anticoagulants
- faster onset than warfarin: ~2 hours
- shorter half life: 7-17 hours
- monitoring: NOT NEEDED
Efficacy of new oral anticoagulants
- stroke prevention in non valvular Afib
- prevention of VTE in orthopedic surgery
- treatment of VTE
New oral anticoagulants: antidote
- NO ANTIDOTE
- under development: anti dabigatran monoclondal antibody, inactive Xa analogues (decoys) to neutralize factor Xa inhibitors
Anti platelet drugs
- aspirin
- P2Y12 receptor antagonist (receptor on platelets for ADP)
- glycoprotein IIb/IIIa antagonists
- dipyridamole
Aspirin: mechanism
- irreversibly inhibits COX 1&2, decreasing synthesis of TXA2 (potent platelet agonist)
- inhibits platelet function for life of platelets (7-10 days)
- administration: oral
Aspirin: adverse effects
- bleeding
- GI ulceration
- allergy/bronchospasm
- interstitial nephritis, papillary necrosis, proteinuria, renal failure
- reye’s syndrome (rapidly progressive encephalopathy & hepatic dysfunction) in children w/ viral illness*
Aspirin COX inhibition: platelet & endothelial cell
- platelet: inhibits COX1 decreasing TXA2 (platelet aggregator)
- endothelial cell: inhibits COX1/2 decreasing PGI2 (inhibits aggregation)
P2Y12 receptor antagonist: mechanism
- block activation of platelets by reducing ADP activation of P2Y12 receptor
Administration of P2Y12 inhibitors
ORAL
P2Y12 receptor antagonist drugs
- thienopyridines: clopidogrel, ticlopidine, prasugrel–IRREVERSIBLE binding
- cyclopentyltriazolopyrimidine: ticagrelor–noncompetitive inhibitor (REVERSIBLE)
P2Y12 receptor antagonists: adverse effects
- bleeding
- GI irritation
- thrombocytopenia, neutropenia
Glycoprotein IIb/IIIa antagonists: mechanism
- inhibit binding of fibrinogen to glycoprotein IIa/IIIb (integrin a2bB3)
Glycoprotein IIb/IIIa antagonist: drugs
- abciximab: Fab fragment of a monoclonal antibody
- tirofiban: small molecule
- eptifibitide: cyclic heptapeptide
Administration of glycoprotein IIb/IIIa antagonists
IV
Adverse effects of glycoprotein IIb/IIIa
- bleeding
- thrombocytopenia (esp. with abciximab)
Dipyridamole: mechanisms
- stimulates prostacyclin synthesis, inhibits adenosine deaminase and phosphodiesterase
Dipyridamole
- anti platelet drug
- also has vasodilatory effects
- oral or IV
- adverse effects: headache
- *often used in combination with aspirin**
Fibrinolytic agents
- mechanism: promote activation of plasminogen to generate plasmin, which then degrades fibrin
- streptokinase
- urokinase (u-PA)
- tissue plasminogen activator (t-PA)
Streptokinase
- derived from beta hemolytic stretococcus
- bind plasminogen, forming complex that gets allosterically active
- administration: IV or catheter directed
- NOT fibrin specific (also cleaves fibrinogen)
Streptokinase: adverse effects
- bleeding
- allergic reactions (anti step antibodies)
- hypotension
Urokinase (u-PA)
- isolated from human urine or kidney cells
- protease that directly cleaves plasminogen to form plasmin
- NON-antigenic
- administration: IV
- NOT fibrin specific (also cleaves fibrinogen)
Tissue plasminogen activator (t-PA)
- recombinant t-PA (alteplase), variants (reteplase, tenecteplase)
- proteases that directly cleave plasminogen to form plasmin
- fibrin SPECIFIC (more localized fibrinolytic activity)
- short half life (minutes): must be used w/ heparin
- administration: IV
Catheter directed thrombolytic therapy
- localized therapy w/ less bleeding risk
Apixaban vs. warfarin
Apixaban shown to be just as effective with no need for monitoring
Mechanism of action of antithrombotic drugs
- anticoagulants: inhibit proteases in the coagulation cascade
- anti-platelet drugs: inhibit platelet activation or aggregation
- fibrinolytic agents: promote generation of plasmin, degrading clots
Major problem with warfarin
many more drug, dietary, pharmacogenetic interactions than other antithrombotic drugs
Important adverse effects of antithrombotic drugs
- bleeding: all antithrombotic drugs
- immunological reactions: HIT, anaphylaxis
- teratogenicity: warfarin
Antithrombotic Drugs
- anticoagulants
- ani platelet drugs
- fibrnolytic drugs
