Drugs Used in Disorders of Coagulation Flashcards
Platelet Aggregation Inhibitor general MOA
Decrease synthesis or action of chemical signals that promote platelet aggregation
4 types:
- COX inhibitors
- ADP receptor blockers
- phosphodiesterase inhibitors
- blockers of platelet GPIIb/IIIa receptors
Aspirin MOA
Platelet Aggregation Inhibitor
TXA2 causes platelets to normally degranulate and aggregated –> Aspirin inhibits TXA2 synthesis by irreversible acetylation of COX enzyme –> Anulcear platelets cannot synthesise new enzyme during its 10-day lifetime
Aspirin Uses
1) Prophylatic treatment of transient cerebral ischemia
2) To reduce incident of recurrent MI
3) To decrease mortality in post MI patients
ADP receptor blockers
Clopidogrel
Ticlopidine
Clopidogrel MOA
Irreversible inhibition of P2Y12 - one of the two subtypes of ADP receptors on the platelet surface –> inhibits platelet aggregation
Clopidogrel is preferred over ticlopidine as it has fewer side effects
Clopidogrel PK
Prodrug - converted to active metabolite mainly by CYP2C19
Patients who are poor metabolisers have low plasma levels of the active metabolite so alternative treatment should be considered
Concurrent use of clopidogrel and CYP2C19 inhibitors (e.g. omeprazole) should be avoided as they will reduce the plasma level of active metabolite
Ticlopidine MOA and AE
Irreversible inhibition of P2Y12 - one of the two subtypes of ADP receptors on the platelet surface –> inhibits platelet aggregation
Clopidogrel is preferred over ticlopidine as it has fewer side effects
Most serious side effect is neutropenia
Clopidogrel Uses
Similar to those of aspirin:
To reduce rate of stroke, MI and death in patients with recent MI, stroke or acute coronary syndrome
Dipryidamole MOA and use
Phosphodiesterase inhibitor –> inhibits platelet aggregation
Used for stroke prevention
Cilostazol MOA and use
Phosphodiesterase inhibitor –> promotes vasodilation and inhibits platelet aggregation
Used for intermittent claudication
Abciximab, Eptibatide, Tirofiban MOA
Blocks platelet GP IIb/IIIa receptor –> inhibits platelet aggregation
Complex is a receptor for fibrinogen –> fibrinogen is a bivalent ligand which binds to two receptors and forms bridges between adjacent platelets activation of this receptor is the final common pathway for lately aggregation
Tirofiban MOA and use
Blocks platelet GP IIb/IIIa receptor –> inhibits platelet aggregation
Adjuncts to PCI (percutaneous coronary intervention) for prevention of cardiac ischemic complications
Indirect thrombin and factor Xa inhibitors
Unfractionated heparin (UFH)
Low-molecular-weight-heparins (LMWH)
Fondaparinux
Route of administration of heparins
Heparin is an injectable, rapidly acting anticoagulant
Can not be given orally
Heparins MOA
Heparin’s anticoagulant effect is a consequence of binding to antithrombin III.
Antithrombin III is an a-globulin. It inhibits clotting factor proteases, especially thrombin, IXa and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow.
Heparin acts as a catalyst to antithrombin III which which allows it to interact more rapidly with the clotting factors.
Structural differences between UFH and LMWH
Both are mixture of straight, chain, sulphated mucopolysaccharides isolated from bovine lung or porcine intestinal mucosa
UFH - molecular weight range of 5000-30000
LMWH (Enoxaparin) - produced by depolymerisation of UFH. Molecular weights range from 1000-5000
Difference in MOA of heparins
Both accelerate antithrombin III activity via binding of specific pentasaccharide sequence
UFH efficiency inactivated both thrombin (IIa) and factor Xa –> forms a ternary complex with ATIII and IIa
LMWH efficiently inhibit Xa only as they are too short to form ternary complex. Not very good at inhibiting thrombin but there is little acceleration of thrombin inactivation indirectly by ATIII.
Ternary complex not necessary to accelerate inactivation of Xa by ATIII
Monitoring heparin levels
Using aPTT assay –> activated partial thromboplastin time –> test of integrity of intrinsic and common pathways of coagulation
Dosing of LMWH results in predictable plasma levels so it is not usually necessary to monitor LMWH blood levels.
Potency of LMWH can be assessed by anti-factor Xa assays
Uses of heparins
Prevention and treatment of DVT, pulmonary embolism and MI
Drug of choice during pregnancy as it does not cross placenta and not associated with fatal malformations unlike warfarin
Heparin AE
Bleeding
Hypersensitivity reactions
Heparin-induced Thrombocytopenia (HIT)
Type II HIT:
Caused by antibodies that recognise complexes of heparin and a platelet protein, Platelet Factor 4. IgG binds to PF4/heparin complex forming immune complexes –> IgG binding to Fc receptors on platelets –> Fc activation leading to platelet degranulation and aggregation –> activated platelets release more PF4 –> new immune complexes form –> can result in thrombocytopenia and thrombosis that range from mild to life-threatening.
Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor (argatroban or bivalirudin) or fondaparinux.
Reversal of heparin action
Discontinuance of drug if excess anti-coagulation occurs
If bleeding occurs –> give protamine sulfate
Fondaparinux MOA
Smallest heparin –> synthetic pentasaccharide that binds to antithrombin III –> specific inhibitor of Xa
Has negligible activity against thrombin (IIa)
Fondaparinux Uses
Prevention and treatment of DVT
Warfarin MOA
Antagonizes cofactor function of vitamin K by inhibiting vitamin K epoxide reductase –> results in production of inactive clotting factors.
Factors II, VII, IX and X and proteins C and S undergo a vitamin K-dependent post- translational modification, whereby a number of their glutamic acid residues are carboxylated to form gamma-carboxy-glutamic acid residues –> enzyme gamma-glutamyl carboxyl required vitamin K in reduced form as co-factor.
Warfarin anticoagulant effects
Coagulation factors involved have half-lives ranging from 6-60 hours: 60 hours for factor II and 6 hours for factor VII
Anticoagulant effect is apparent within 24 hours of administration –> peak effect may take 72-96 hours
Duration of action of a single dose of warfarin is 2 to 5 days
Reversal of warfarin action
Anticoagulant effects can be overcome by giving vitamin K –> reversal takes approx 24 hours
Monitoring warfarin levels
Has narrow TI and many drug-drug interactions are involved –> effects must be monitored regularly (every 2-4 weeks)
Monitoring by assessing prothrombin time (PT) –> tests integrity of extrinsic and common pathways of coagulation –> results are expressed as INR
Warfarin uses
Prevention and treatment of DVT, pulmonary embolism , following an initial course of heparin
Prevention and treatment of thromboembolic complication associated with atrial fibrillation
Warfarin AE
Hemorrhage
Cutaneous necrosis: due to reduced activity of protein C –> is an anticoagulant factor –> in some people protein C levels drop faster than the clotting factors so there is over-coagulation –> blood clots block the blood vessels in skin and cause necrosis
Teratogenic: crosses placenta and can cause hemorrhagic disorder in fetus and serious birth defects
Warfarin contraindications
Pregnancy category X –> crosses placenta and can cause hemorrhagic disorder in fetus and serious brith defects
Many drug interactions that can potentiate or attenuate anticoagulant effects as it metabolised by P450 enzymes (more potent S-warfarin by CYP2C9)
Direct thrombin inhibitors MOA
Directly bind to active site of thrombin –> anticoagulant effect
Desirudin MOA and use
Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect
Monitered by aPTT assay
Indicated for thromboprophylaxis in patients undergoing elective hip replacement surgery
Bivalirudin MOA and use
Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect
Monitered by aPTT assay
Used in patient use going PCI
Argatroban MOA and use
Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect
Monitered by aPTT assay
Used in patient use going PCI
Dabigatran etexilate
Oral DTI –> directly binds to active site of thrombin –> anticoagulant effect
Prodrug converted to dabigatran (active metabolite)
Produces a predictable anticoagulant response so routine monitoring is unnecessary
Dabigatran etexilate use
Prevention and treatment of DVT and PE
Apixaban and rivaroxaban MOA and use
Oral direct factor Xa inhibitors –> newer drugs given now instead of warfarin
Do not require monitoring
Used for prevention and treatment of DVT and PE
Choice of oral anticoagulant
Direct oral coagulants dabigatran, apixaban and rivoraxaban have equivalent antithrombotic efficacy to warfarin and lower bleeding rates
Other advantages:
- have rapid onset of action
- predictable pharmacokinetics
- wider therapeutic window
- no monitoring needed
- fewer drug interactions
Are replacing warfarin for treatment of VTE or stroke and prevention of embolism in atrial fibrillation
Thrombolytics general MOA abd use
Thrombolytic agents act by converting the inactive zymogen plasminogen to the active protease plasmin. Plasmin is a relatively nonspecific protease that digests fibrin.
Anticoagulants can prevent formation of thrombi but are ineffective against pre-existing clots. Thrombolytic drugs lyse blood clots and restore the potency of obstructed vessels before distal tissue necrosis occurs.
Thrombolytic drugs reduce the mortality of acute myocardial infarction and are used in situations in which PCI (angioplasty) is not readily available.
Streptokinase MOA and use
Thrombolytic - activates plasminogen to plasmin which digests fibrin to break down clots
Protein produced by b-hemolytic streptococci
Rarely used since advent of newer agents
Urokinase MOA and use
Thrombolytic - activates plasminogen to plasmin which digests fibrin to break down clots
Human enzyme synthesised by the kidney and found in the urine
Approved for lysis of pulmonary emboli
Fibrin-selective thrombolytics
Alteplase
Reteplase
Tenecteplase
Alteplase, reteplase, tenecteplase MOA
Tissue plasminogen activator (t-Pa) is a serine protease produced by human endothelial cells –> activates plasminogen bound to fibrin in a thrombus –> is a fibrin-selective thrombolytics –> more selective at breaking down clots –> the selectivity of t- Pa for fibrin limits systemic formation of plasmin and the induction of a systemic lytic state
Alteplase - recombinant t-Pa
Reteplase, tenecteplase - recombinant variants t-Pa with longer half-lives
Alteplase use
recombinant t-Pa –> thrombolytic
Management of acute MI and acute ischemic stroke
Aminocaproic acid & tranexamic acid MOA and use
Inhibit plasminogen activation –> protect integrity of clot –> for treatment of bleeding disorders
Used as adjunctive therapy in haemophilia and therapy for bleeding from thrombotic therapy overdose
Protamine sulfate MOA and use
Chemical antagonist of heparin –> high in arginine –> cationic protein that interacts with anionic heparin to form a complex with no anticoagulant activity.
Protamine is most active against UFH and it can partially reverse the anticoagulant effects of LMWHs.
Inactive against fondaparinux.
Vitamin K uses
Used to correct the bleeding tendency or hemorrhage associated with its deficiency
Used for drug induced hypoprothrombineia:
Vitamin K is available in oral and parenteral forms –> onset of effect taken 6 hours and effect is complete by 24 hours.
If immediate homeostasis is required, fresh-frozen plasma should be infused in addition
Also given to prevent vitamin K deficiency bleeding in newborns –> all babies should receive standard vitamin K1 IM at birth
Plasma Fractions
Deficiencies in plasma coagulation factors can cause bleeding.
Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease or hemophilia B) account for most of the heritable coagulation defects.
