Anticoagulant & Antiplatet Drugs Flashcards
General characteristics of normal thrombus formation
- exposure of circulating blood elements to thrombogenic material (e.g. unmasked sub-endothelial collagen after plaque rupture)
- activation and aggregation of platelets
- triggering of the coagulation cascade –> fibrin clot formation
Intrinsic pathway summary and common drug targets
- Factor XIIa -> XIa -> IXa + VIII -> Xa.
- Heparin inactivates: XIIa, XIa, IXa, Xa
- Warfarin inhibits synthesis: IX, X
Extrinsic pathway summary and common drug targets
- tissue factor + VIIa -> Xa.
- Heparin inactivates: VIIa
- Warfarin inhibits synthesis: VII
Common pathway summary and common drug targets
Common: Xa + Va –> IIa (Thrombin) -> Ia (Fibrin) + XIII -> clot.
- Heparin inactivates: Xa, Thrombin (IIa)
- Warfarin inhibits synthesis: X, Prothrombin (II)
- Rivaroxaban & LMWH-ATIII/Fondaparinux inhibit: Xa
- Dabigatran & Hirudin/Bivalirudin inhibit: Thrombin
Thrombin inhibitors
- Dabigatran
- Hirudin/Bivalirudin
- Warfarin
- Heparin
Factor Xa inhibitors
- Rivaroxaban
- LMWH-ATIII/Fondaparinux
- Warfarin
- Heparin
Coagulation cascade summary/drug targets (diagram)
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Examples of anticoagulant drugs
- Heparin
- low MW heparins [enoxaparin]
- warfarin
- dabigatran
- rivaroxaban
Examples of thrombolytic agents
- streptokinase
- tissue plasminogen activator and variants
Examples of antiplatet agents
- Aspirin
- clopidrogel
- dipyridamole
- abciximab/epifibatide/tirofiban
Venous vs. aterial thrombi
- venous = composed mainly of fibrin and trapped red blood cells with relatively few platelets
- arterial = composed mainly of platelet aggregates held together by small amounts of fibrin
Anticoagulant agents general characteristics
- prevention and treatment of venous thromboembolism
- prevention of cardioembolic events in patients with atrial fibrillation
- also effective for arterial thrombosis and their effects can be additive with antiplatelet agents
Antiplatet agents general characteristics
- primarily for prevention and treatment of arterial thrombosis
- primary and secondary prevention and treatment of acute coronary syndrome
General mechanisms of blood coagulation
- emerging blood increases mechanical pressure and helps limit blood loss; vessel damage exposes collagen of subendothelium
- vessels constrict
- platelets adhere
- platelets activate
- blood coagulates via coagulation cascade
- blood flow returns to normal
Warfarin inhibits:
- vit K factors:
- II
- VII
- IX
- X
Heparin inactivates:
- w/antithrombin III (ATIII):
- IIa
- IXa
- Xa
- XIa
- XIIa
Low molecular weight heaparins (LMWH)/Fondaparinux inactivates
- w/ATIII:
- Xa
Hirudin, Dabigatran inactivates
-directly inactivates IIa (thrombin)
Rivaroban inactivates:
-directly inactivates Xa
PT test
- tests extrinsic pathway –> prolonged = defect @ extrinsic
- used to monitor oral (warfarin) anticoag therapy
- INR=patient PT/mean normal PT –> allows comparison between labs
aPTT test characteristics
- tests intrinsic pathway –> prolonged = defect @ intrinsic
- used to monitor heparin therapy
- not significantly affected by LMWH
Ecarin Clotting Time (ECT)
-monitors therapy w/direct thrombin (IIa) inhibitors = hirudin & dabigatran
Factors that normally limit clot formation
- prostacyclin (PGI2) and nitrous oxide=vasodilate and inhibit platelet agg.
- Antithrombin III & Protein C/Protein S
- fibrinolysis via plasmin
Fibrin inhibition mechanisms
-Antithrombin: protease inhibitor that inactivates IIa, IXa, Xa, XIIa less activated of X
Heparin: MOA
- inhibits activated clotting factors
- accelerates ATIII activity –> inhibits clotting factors
- inhibits: IIa (thrombin), IXa, Xa, XIa, XIIa, XIIIa
Heparin: Pharmacokinetics
- IV or SC
- loading dose needed for anticoagulant effect
- continuous infusion preferred for heparin
- renal elimination
- safe in pregnancy
Heparin: Uses
- treatment of coronary occlusion in unstable angina/acute MI
- prophylaxis tx of venous thromboembolism (VTE)
- prevent cerebral thrombosis in stroke
- prophylaxis tx for post-op thromboembolism
Heparin: Adverse Rxns
- bleeding risk
- hypersensitivity
- thrombocytopenia: mild or severe (immune-mediated)
- osteoporosis
Parenteral anticoagulants
-heparin
-LMWH (Enoxapirin)
-Fondaparinux
Direct thrombin (IIa) inhibitors
LMWH: drug example
-Enoxapirin
LMWH: MOA
-Binds to ATIII to inactivate factor Xa, but not IIa (thrombin)
LMWH: Pharmacokinetics
- IV or SC
- longer t1/2
- first-order renal elimination
- safe in pregnancy
LMWH: Uses
- equal efficacy as regular heparin for VTE
- less bleeding complications & thrombocytopenia
- PTT not affected –> no monitoring needed
LMWH: Overdose sx/signs and tx
- bleeding is chief sign nosebleed, hematuria, bruising
- tx: protamine –> neutralizes hepearin w/in 5 min
Warfarin: MOA
- Acts in liver to prevent synthesis of clotting factors
- Blocks vit-K dependent factors (II, VII, IX, X)
- Increases prothrombin time
Warfarin: Pharmacokinetics
- Oral
- Onset delayed until turnover of existing clotting factors
- Reaches max effect @ 3-5 days
- Metabolized by CYP2C9
- Genetic polymorphisms
Warfarin:Uses
- Afib: prevent thromboembolic complications
* Prophylaxis/treatment of vneous thromboembolism
Warfarin: Adverse Rxns
- Hemorrhage
- GI upset
- Contraindicated in pregnancy
Warfarin: overdose signs/sx & management
- Sx: Hematuria, gum bleed, excessive menstrual bleeding
- INR < 4.5: reduce or skip dose
- INR 4.5-10: hold 1-2 doses
- INR > 10 w/out bleed: hold, administer vit K
- Major bleed: hold, slow vit K infusion + Prothrombin complex concentrate (better than fresh frozen plasmin) or recombinant factor VIIa
Dabigatran: MOA
• Acts in plasma to directly inhibit the activity of thrombin (IIa)
Dabigatran : Pharmacokinetics
- Oral = rapidly absorbed as prodrug
- Renal excretion
- Requires frequent monitoring and dosage adjustments
Dabigatran :Uses
• Reduce risk of systemic embolism w/non-valvular afib (not VTE)
Dabigatran : Adverse Rxns
- Bleeding
- GI complaints
- Fewer drug interactions
Warfarin vs. Dabigatram in aFib
- Warfarin=long history of use, once-daily dosing, reversal w/vitK, but requires INR monitoring, drug interactions
- Dabigatran=lower rates of strokes/intracranial complications, no INR monitoring or diet restrictions, fewer drug rxns, but no good monitoring tool, no specific antidote, twice-daily dowing, storage challenges, and renal adjustment
Rivaroxavan/Apixaban: MOA
• Acts in the plasma to directly inhibit the activity of factor Xa
Rivaroxavan/Apixaban : Pharmacokinetics
- Oral
* Hepatic metabolism and renal excetrion
Rivaroxavan/Apixaban :Uses
- Reduce risk of systemic embolism in patients w/non-valvular aFib
- Approved for prevention and tx of DVT/VTE
Rivaroxavan/Apixaban : Adverse Rxns
- Bleeding
* No antidote for rapid reversal
Warfarin vs. Rivaroxavan/Apixaban in aFib
- Adv of Riv/Apix: lower rates of stroke/bleeding, no INR, no dietary restrictions, once-daily dosing (Riv)
- Disadv: no monitoring tool, no specific antidote, bid dosing (Apix), renal dosing
Main antiplatelet agents
- Aspirin
- Clopidogrel
- Dipyridamole
- Abciximab, Eptifibatide, Tirofibanm
Aspirin: MOA
• Inhibition of COX-1 synthesis of thombroxane (COX-1 inhibit > COX-2 @ endothelial cells)
Aspirin : Pharmacokinetics
- Oral
* Low-dose daily dosing
Aspirin :Uses
- Acute MI (STEMI) (w/ADP antagonist)
- Unstable angina/NSTEMI
- Percutaneous coronary interventions (w/ADP antagonist)
- Secondary prevention of MI/ischemic stroke
Aspirin : Adverse Rxns
- Rare w/low-dose therapy
* GI complaints or bleeding
Clopidogrel (Plavix): MOA
- ADP receptor antagonists → interferes w/ADP-induced platelet aggregation via irreversible inhibition
- Synergistic actions w/aspirin
Clopidogrel (Plavix): Pharmacokinetics
• Once-daily dosing w/loading dose
Clopidogrel (Plavix):Uses
- Acute MI (STEMI) (w/aspirin)
- Sometimes: Unstable angina/NSTEMI
- Percutaneous coronary interventions (w/asprin)
Clopidogrel (Plavix)/Other ADP antagonists: Adverse Rxns
- Clopidogrel: GI upset, headache, dizziness, URI, bleeding
- Prasugrel: bleeding
- Tricagrelor: bleeding
Dipyridamole: MOA
• Blocks phosphodiesterase breakdown of cAMP → prostacyclin anti-aggregatory effect
Dipyridamole : Pharmacokinetics
- Oral
* 3-4x before meals
Dipyridamole :Uses
• ischemic stroke: dipyridamole + aspirin
Dipyridamole : Adverse Rxns
• minimal and transient
Abciximab: MOA
• blocks IIb/IIIa receptors on platelet → prevents integrin and fibrinogen binding
Abciximab : Pharmacokinetics
• continuous IV infusion
Abciximab :Uses
• Percutaneous coronary interventions (PCI): aspirin + ADP antagonists + GIIb/IIa inhibitors
Abciximab : Adverse Rxns
• Bleeding
Thrombolytics: MOA
- Increased formation of plasmin from plasminogen
- Streptokinase = activates free and fibrin-bound plasminogen
- tPA = activates bound plasminogen
Streptokinase characteristics
• systemic activation of plasmin
Tissue Plasminogen Activator (tPA) characteristics
• recombinant tPA → binds to fibrin and activates bound plasminogen
Reteplase/Tenecteplase characteristics
- given bolus w/prolonged duration of action
* less fibrin-specific than tPA
Thrombolytics: Uses
- Acute MI → coronary artery thrombosis
- DVT
- Multiple PE
Thrombolytics: Adverse Effects
• hemorrhage
