Anticoag/thrombotic drugs Flashcards
Goal of tx
protect against risk of bleeding
o Coronary endothelial damage → feature of ischemic heart disease
Constant risk of antiaggregatory forces < proaggregatory forces
Risk of further vascular damage → thrombosis
3 main types of agents
o Platelet inhibitors
o Anticoagulants
o Fibrinolytic agents
4 steps of thrombus formation
a) Exposition of subendothelial tissue factor (endothelial damage)
b) Activation of coagulation factors → generate thrombus
o Conversion of fibrinogen → fibrin
c) Platelet adhesion, activation, aggregation → action of thrombin
o Platelet activation: shape and conformational changes
o Activated platelet R → promote aggregation → formation of primary platelet plug
o Thrombin generated by platelets and coag factors
Stimulate further platelet activation/aggregation
Forms fibrin → stabilized platelet plug
o Platelet release substances further promoting activation and aggregation
d) Thrombus formation
o Fibrin forms polymer cross-link
o Aggregated platelets tightly combine
Essential components of thrombus formation
Tissue factor
Thrombin
Von Willebrand factor
What is tissue factor
Cell surface glycoprotein
Tissue factor expression is increased w/
↑ expression in damaged endothelial cells and exposed subendothelial cells
Derived from microparticles released in plaque rupture
Tissue factor activation leads to
o Form a complex/activate factor VII
Factor VIIa → activate directly factor X and indirectly by factor IX
Factor Xa convert prothrombin → thrombin
Role of thrombin and effect
o Thrombin activate protease activated R on platelets → rapid platelet activation
o Positive feedback on coag pathway → activate factor V, VIII, XI, XIII
XIIIa: necessary for full stabilization of fibrin clot
Role of intrinsic pathway
o Start with activation of several factors: XII, XI, IX, X
o Xa: Acts on prothrombin to form thrombin
Convergence of intrinsic and extrinsic pathways → common pathway
Von Willebrand factor: normal
o Normally present in high levels but inactive in plasma
Von willebrand factor activation
o Immobilized and activated at site of injury
Interact with platelet R glycoprotein Ib-α (GpIbα)
* Tether platelets to the site of injury
Release Ca2+ from endoplasmic reticulum
* Helps activate platelets
Propagation of clot mechanism: other substances
o Secretion of plasminogen activator inhibitor (PAI-1)
↑ clot resistance to lysis
o Secretion of thromboxane A2 (TXA2)
Vasoconstriction
Platelet activation
o Transition from low to high affinity binding state
Inside-outside activation
o Thrombin: potent activator
Release of more thrombin by platelets
Release of adenosine diphosphate (ADP)
Release of TXA2
o Bind to respective platelet-R → promote further activation = self amplification
Activated-R bind more vWF, subendothelial collagen and fibrinogen
Platelet shape change
o Activated platelets have activated contractile prots
o Formation of new actin filaments
o TXA2 + thrombin R binding → activation of MLCK → platelet conformation change
↑ surface membrane available for platelet activation
Promotion of R conformational change → further activate platelets
Release of ADP, TXA2, thrombin → activate other platelets
What happens w/ platelet intracell Ca2+
o ↑ intracell [Ca2+] during activation
Stimulate formation of TXA2
Activate platelet contraction/shape change
* Conformational activation of GpIIb/IIIa
* Adhesive prot + fibrinogen interlink platelets
↑ADP release from platelet granules
Platelet rapid propagation
o ↑ local [thrombin] → local fibrin → polymerize in end-to-end or side-to-side reaction → fibrin clot
Changes factor XIII → XIIIa which cross link fibrin units
Antiplatelet agents
Aspirin
Clopidogrel/ticlopidine
Dipyridamole
Sulfinpyrazone
Prasugrel
Ticagrelor
Cangrelor
Vorapaxar
Atopaxar
Aspirin: molecule
acetylsalicylic acid
Aspirin: MOA
Irreversible acetylation of cyclooxygenase (COX)
o Isoform COX-1 inhibition
↓ TXA2 synthesis → ↓ thrombin formation
No strong effect on COX-2 → prostaglandin production pathway
* Contribute to inflammatory response
o Inhibition for complete life span of platelet: 8-10 days
Effective until new platelets form
o Vascular COX: can be reformed w/I hours
Aspirin: side effects
o Bleeding = most serious
o GI side effects: indigestion, nausea, vomiting
Gastric irritation and ulcerations → related to dose
* Can give w food or coated to ↓ risk (may also ↓ bioavailability)
* H+ pump inhibitors: ↓ risk of side effects
Aspirin resistance
o Defined as: failure of suppression of TXA2 generation
↑urinary TXA2 metabolite
Recurrent vascular event despite adequate tx dose
* 50% of cats after 1st vascular event
o 5-20% of patients will experience recurrence of thrombotic event
Continuous spectrum
Aspirin resistance mechanisms
Platelet Gp polymorphism
Activation of platelets by pathways other than COX
↑ inflammatory activity from ↑ COX-2 expression
Aspirin: clinical uses
o Prophylaxis: after previous myocardial infarction or stroke
o Effort unstable angina
o Coronary artery bypass sx
Aspirin: CI
o Aspirin tolerance
o Hx of GI bleeding/peptic ulcer
o Renal disease: retard urine excretion of create and uric acid
o Hemophilia: not absolute if strong CV indication
o Relative: gout, indigestion, iron-deficiency anemia
Aspirin: drug interactions
o Warfarin: ↑ risk of bleeding
o NSAIDs with dominant COX-1 activity
Ibuprofen and naproxen: ↑ risk of GI bleeding
o Corticosteroids: ↑ risk of GI bleeding
o ACEi: opposite effects on renal hemodynamics
Aspirin inhibit vs ACEi promote vasodilatory PGs
o Phenobarbital, phenytoin, rifampin: ↓ efficacy by induction of hepatic enzymes
o Thiazides: ↓ urinary excretion of uric acid → ↑ risk of gout
Clopidogrel/Ticlopidine: molecule
o Thienopyridine derivatives
1st generation = ticlopidine
2nd generation = clopidogrel
Clopidogrel/Ticlopidine: MOA
o Irreversible binding to the P2Y12 R
ADP released by platelets during activation → interact with
* P2Y1 R → platelet shape change + GpIIb/IIIa activation
* P2Y12 R → perpetuate GpIIb/IIIa activation + stabilize platelet aggregation
* Activate IV tissue factor indirectly
Inhibition of P2Y12 R =prevent transformation and activation of GpIIb/IIIa
PharmacoK ticlopidine
↓ clearance on repeated dosing
4-7 days to achieve max inhibition of platelet aggregation
Metabolism ticlopidine
Metabolism: liver, excretion: kidneys
Clopidogrel: pharmacoK, onset of action
Onset of action: hrs after oral dose
* Steady state inhibition requires 3-7 days
* ↓ clearance with repeated dosing
Takes 5 days to generate new platelets and reduce bleeding after stopping
Variation in platelet reactivity to clopidogrel: can cause clinical resistance
* ↑ compared to newer drugs
Clopidogrel: metabolism
Hepatic or intestinal metabolism: activation by cytochrome CYP3A4 and 2C19
* Atorvastatin and omeprazole inhibit hepatic activation → ↓ effect
Clopidogrel side effects
Low rate of myelotoxicity (0.02% of cases)
↓ GI bleeding compared to aspirin
Major side effect: ↑ major bleed w/o ↑ intracranial bleed
Ticlopidine side effects
rarely used because of side effects compared to clopidogrel
Neutropenia: 1st 3mo of tx (2.4% of cases)
Liver abnormalities
Thrombotic thrombocytopenic purpura
Clopidogrel: drug interaction
o Statin and H+ pump inhibitors (omeprazole)
Inhibit hepatic activation (theory, not proven by studies)
Dipyridamole: MOA
bind prostacyclin R on platelets
Dipyridamole: MOA
prosthetic mechanical valves
Dipyridamole: drug interaction
adenosine
Sulfinpyrazone MOA
- Mechanism: inhibit COX
o Similar effect to aspirin
Newer anti platelet drugs
- Prasugrel
Ticagrelor
Cangrelor
Vorapaxar
Atopaxar
Pasugrel: molecule
o Newer generation thienopyridine
Pasugrel: MOA
o Mechanism: Irreversible/noncompetitive inhibition of P2Y12 R
5-9x more potent vs clopidogrel
Pasugrel: pharmacoK
Prodrug: hydrolyzed in GI → thiolactone → converted in liver by CYP3A4 and CYP2B6
* CYP inhibitors (diltiazem, verapamil): not alter activity but ↓ peak [plasma]
Onset of action 5-10 days
½ life = 7h
Pasugrel: side effects
risks of serious bleeding
Ticagrelor: molecule
o Cyclopentyl-triazolopyrimidine
Ticagrelor: MOA
reversible binding/noncompetitive inhibition of P2Y12 R
Ticagrelor: pharmacoK
More rapid/consistent onset of action → 3-4 days
* ½ life = 12h
More rapid offset of action
No hepatic activation needed
Ticagrelor: drug interaction
Amlodipine, statins, diltiazem, verapamil: inhibit CYP3A → ↑ levels and reduce speed of offset
Ticagrelor: side effects
Bleeding
Dyspnea
↑ frequency of ventricular pauses
↑ uric acid
Cangrelor: MOA
Potent competitive inhibitor of P2Y12 R
Cangrelor: pharmacoK
Rapid acting: IV effect in 20min → 85% inhibition of ADP induced platelet aggregation
Vorapaxar MOA
o Mechanism: potent competitive PAR-1 antagonist
Atopaxar MOA
o Mechanism: reversible protease activated R-1 thrombin R antagonist
Interfere in platelet signaling
Vorapaxar side effects
o Significant ↑ risk of major bleeding, including intra cranial
Dual anti-platelet therapy
- Aspirin + clopidogrel
o 20% reduction in ↓ vascular events
o Different mechanism of action → should create strong combination - Aspirin + newer anti platelet
Glycoprotein IIb/IIIa R-antagonist MOA
inhibition of platelet adhesion R GpIIb/IIIa
o Block final platelet activation and cross-linking by fibrinogen and vWF
Glycoprotein IIb/IIIa R-antagonist: side effects
acute thrombocytopenia and ↑ risk of delayed thrombocytopenia
o Risk range from 0.3 to 6%
o Secondary to drug dependent anti bodies
Glycoprotein IIb/IIIa R-antagonist: CI
o Bleeding or ↑ risk for bleeding
o Thrombocytopenia
Glycoprotein IIb/IIIa R-antagonist: drugs
Abciximab
Tirofiban
Eptifibatide
Abciximab: molecule
- Monoclonal antibody against platelet GpIIb/IIIa R
Abciximab: pharmacoK
o IV: maximal platelet aggregation inhibition at 2h
o Duration 12h
o ½ life 10-30min
o Remain platelet bound in circulation for 15 days
Abciximab: how to reverse action
- Reverse action by platelet transfusion
Abciximab: side effects
bleeding, thrombocytopenia, hypersensitivity
Tirofiban: molecule
- Highly specific nonpeptide peptidomimetic GpIIb/IIIa inhibitor
o Inhibition of fibrinogen and vWF binding to R
o ↓ risk of hypersensitivity to monoclonal antibody
Tirofiban: pharmacoK
acute onset, ½ life 2h
o 35% unbound in circulation
o Clearance: 65% renal, 25% fecal
Tirofiban: side effects
bleeding, renal disease, thrombocytopenia
Eptifibatide: molecule
- Synthetic cyclic heptapeptide
o Structural differences w Tirofiban
o Bind at different site on GpIIb/IIIa R → same end result
Lower affinity compared to others
Eptifibatide: pharmacoK
½ life 2-3h, renal clearance 30%
Eptifibatide: side effects
bleeding, renal disease, thrombocytopenia
Oral anticoag: drugs
Warfarin
Warfarin: MOA
Warfarin: pharmacoK
o PO: high plasma albumin bound
Warfarin: onset
2-7 days, 1/2 life = 37h
Warfarin: metabolism
hepatic cytochrome CYP2C9 and vit K epoxide reductase (VKORC1)
Inactive metabolites → excreted in urine and stools
Genetic variation in enzymes → individual dosage variability
Warfarin: decrease dose if
- CHF or liver failure
- Malnutrition (↓vit K)
- Thyrotoxicosis: ↑ vit K catabolism
- Renal failure
Warfarin: monitoring tx
international normalized ration (INR) → aim is moderate intensity
o High intensity warfarin (INR 3-4) → more effective vs aspirin
More bleeding associated and close monitoring needed
o Moderate intensity warfarin (INR 2-3) → ↓ bleeding risks, better vs aspirin
Warfarin: side effects
few
o Over anticoagulation: bleeding, risk of intracranial hemorrhage
Highest in 1st 1-3mo (10x ↑)
o Skin necrosis: rare
Warfarin: drug interaction
many drugs
o Barbiturates, phenytoin → accelerate degradation by liver
o Allopurinol, amiodarone, cephalosporins → potentiate effects by inhibiting vit K formation
o Antibiotics (ie metronidazole and others) → ↓ warfarin degradation → ↑ anticoag effect
o Aspirin, clopidogrel, NSAID may potentiate bleeding
Warfarin: CI
o Recent stroke
o Uncontrolled hypertension
o Hepatic cirrhosis
o Potential GI/genitourinary bleeding points: hiatus hernia, peptic ulcer, gastritis, gastric reflux, colitis…
o Renal impairment
o Pregnancy
Acute anticoagulant: drugs
Heparin (unfractionated heparin)
Low molecular weight heparin
Enoxaparin
Dalteparin
Bivalirudin
Fondaparinux
Heparin: molecule
- Heterogenous mucopolysaccharide: molecular weight = 5000-30000 Da
Heparin: MOA
Interact w antithrombin and thrombin (factor IIa)
o Binds to antithrombin (Penta saccharide segment of heparin molecule)
Heparin-antithrombin → inhibit factor Xa > factor XIa
o Binds to thrombin by 13 additional saccharide units
Inhibit thrombin induced platelet aggregation
o Binds to variety of plasma proteins, endothelial , macrophages
Some inactivation of molecule
Heparin: dosage
IV infusion or SQ BID to TID → MAX 24h
Heparin: dose effect relationship
o Dose-effect relationship hard to predict
Heterogeneous group of molecules extracted by variety of procedures
Strength varies from batch to batch
Heparin: dose adjustment
o Dose adjusted based on aPTT
Should be 1.5 to 2.5x normal (higher ↑ risks of cerebral bleeding)
Monitored at 6, 12, 24h
Some patients are resistant → high doses, monitor q4h
Heparin: side effects
o Risks of thrombocytopenia (3-5% of patients): IM
4T’s clinical score
* Thrombocytopenia: <50% count drop
* Timing: 5-10days after initiation
* New thrombosis
* Other causes of thrombocytopenia
Thrombocytopenia-thrombosis syndrome: prothrombotic condition
* Immunoglobulin bridge platelets causing ↓ counts and thrombosis
o ↑ risk of hemorrhage: subacute bacterial endocarditis, hematologic disorders (hemophilia, hepatic diseases), GI ulcerations
o Allergic reactions: derived from animal tissue
Heparin: advantages compared to LMWH
o Effect stops rapidly after discontinuing the drug
o Completely reversed by protamine
o Not cleared by kidneys → safe with renal failure
Low molecular weight heparin: molecule
- 1/3 of heparin molecular weight = mean 5000Da
o Heterogenous size
Low molecular weight heparin: MOA
- Mechanism: bind to
o Antithrombin (factor IIa) activity
o Anti factor Xa activity
o Some direct inhibition of thrombin (less powerful than heparin)
Low molecular weight heparin: pharmacoK
o > bioavailability
o > ½ life = 4h
Low molecular weight heparin: dosage
SQ SID to BID
Low molecular weight heparin: side effect
bleeding
o ↓ but not completely reversible with protamine
o Residual anti-Xa activity remains
Low molecular weight heparin: advantages vs UFC
< expensive
No need for monitoring
* Can measure antiXa levels if renal failure, severe obesity, pregnancy
Lack of complete antidote: partially reversible w protamine
Inability to monitor degree of anticoagulation
Enoxaparin: MOA
inhibit factor Xa
o Some degree of thrombin inhibition
Enoxaparin: dosage
1mg/kg SQ injection q12h
Enoxaparin: drug combination
Can be combined with aspirin/clopidogrel or GpIIa/IIIb inhibitor
Enoxaparin: metabolism
o Renal excretion
Dalteparin: dosage
deep SQ
Bivalirudin: molecule
- Molecular weight = 2180Da
Bivalirudin: MOA
direct binding to thrombin (factor IIa)
o Inhibit thrombin induced conversion fibrinogen → fibrin
Both soluble and clot bound thrombin
o Inhibit thrombin induced platelet aggregation
Bivalirudin: pharmacoK
o Linear kinetic
o ½ life 25min
o Not protein bound → few drug interactions
o Elimination: proteolytic cleavage > renal excretion (20%)
Bivalirudin: dosage
IV infusion
o No reversal agent but coagulation time normalize 1h after discontinuation
Bivalirudin: monitoring
aPTT, ACT → correlated w [plasma]
Fondaparinux: molecule
- Molecular weight = 1728Da
o Similar to antithrombin-binding sequence in heparin
Fondaparinux: MOA
specific conformational change in antithrombin
o High affinity reversible binding to antithrombin → promote antithrombin inhibition of factor Xa
o Strong and selective inhibition of factor Xa
Fondaparinux: pharmacoK
o SQ injection: 100% bioavailability
o ½ life 17h
Fondaparinux: reversal
rVIIa is partial antagonist
Fondaparinux: dosage
SQ SID
o ↓ dose in older/ renal impair
o No monitoring needed
Fondaparinux: CI
o Renal clearance < 30ml/min
o BW <50kg
Direct thrombin inhibitors: drugs
Dabigatran
Anti factor Xa agents: drugs
Rivaroxaban
Apixaban
Dabigatran: MOA
- Mechanism: direct competitive thrombin inhibitor
o Thrombin → conversion fibrinogen → fibrin
o Effective on free and clot-bound thrombin
o Inhibit thrombin induced platelet aggregation
Dabigatran: pharmacoK
o Bioavailability 6.5
Dabigatran etexilate mesylate absorbed as ester → hydrolyzed → dabigatran
Maximal [plasma] w/I 1h
½ life 12-17h
o Excretion: 80% kidneys
Dabigatran: side effects
gastric discomfort
Dabigatran: CI
age, ↑ bleeding risk
Dabigatran: advantages vs warfarin
o Rapidly effective
o Not interact w food or drugs
o Not require monitoring
o ↓ risk of ischemic stroke or intracranial bleed
Rivaroxaban: MOA
oral inhibitor of factor Xa
Rivaroxaban: pharmacoK
o Bioavailability: 100%
No metabolites
Rapid absorption, maximal [plasma] after 2-4h
½ life = 5-13h
High plasma protein bounding: 92-95%
o Metabolism: hepatic by CYP3A4 and CYP 2J2
o Excretion: 2/3 liver, 1/3 kidneys
Rivaroxaban: dosage
once daily
o Major advantage
Apixaban: MOA
direct factor Xa inhibitor
Apixaban: pharmacoK
o Bioavailability: 50%
Max [plasma] after 3-4h
½ life 8-15h
o Metabolism: liver 75% by CYP3A4
25% excreted unchanged in urine
o Dosage: BID
Fibrinolytic/thrombolytic therapy goals
- Thrombolytic therapy goal: formation of plasmin → clot lysis
o Plasminogen activator system: form plasminogen → bind clot surface → clot lysis
o Plasminogen activator inhibitor (PAI-1): inhibit plasmin formation
Made by adipose tissue - Fibrinolysis: goals is to achieve early reperfusion and patency = critical 1st 2-3h
o ↑ myocardial salvage
o Preserve LV fct
o ↓ mortality
Fibrinolytic/thrombolytic therapy: drugs
Alteplase/tissue plasminogen activator (tPA)
Tenecteplase (TNK)
Reteplase (rPA)
Streptokinase (SK)
Plasmin inhibitors: drugs
Tranexamic acid
Activation of coagulation: drugs
- Recombinant factor VIIa
- Prothrombin complex concentrate (PCC)
Indication Recombinant factor VIIa
hemophilia
Prothrombin complex concentrate (PCC) indication
o Reverse anticoagulant effect of rivaroxaban
Tranexamic acid effect
- Reduced bleeding when administered w/I 3h after trauma
Alteplase/tissue plasminogen activator (tPA): molecule
- Natural enzyme
Alteplase/tissue plasminogen activator (tPA): MOA
bind to fibrin
o > affinity vs strepto/urokinase
o Once bound: convert plasminogen → plasmin
Alteplase/tissue plasminogen activator (tPA): pharmacoK
short ½ life <5min, duration 90min
Alteplase/tissue plasminogen activator (tPA): indication
acute thrombotic event
Alteplase/tissue plasminogen activator (tPA): side effect and CI
related to hemorrhage
Tenecteplase (TNK): molecule
- Mutant of native tPA: amino acid substitutions at 3 sites
Differences tPA vs TNK
o ↓ plasma clearance and longer ½ life
o ↑ fibrin specificity
o ↑ resistance to PAI-1
Reteplase (rPA): molecule
- Mutant of alteplase:
o Deletion of kringle-1, finger and epidermal growth domain
o Carbohydrate side chains
Reteplase (rPA): pharmacoK
- Prolonged plasma clearance
Streptokinase (SK): MOA
- Original thrombolytic agent
- Mechanism: bind plasminogen to form 1:1 complex
o No direct effect on plasminogen
o Complex → become active enzyme convert plasminogen → plasmin
o Can ↑ levels of activated prot-C → ↑ clot lysis
Streptokinase (SK): side effects
hypersensitivity, hypotension, bleeding
