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12. Pharmacology > Anticoag/thrombotic drugs > Flashcards

Anticoag/thrombotic drugs Flashcards

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1
Q

Goal of tx

A

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

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2
Q

3 main types of agents

A

o Platelet inhibitors
o Anticoagulants
o Fibrinolytic agents

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3
Q

4 steps of thrombus formation

A

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

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4
Q

Essential components of thrombus formation

A

Tissue factor
Thrombin
Von Willebrand factor

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5
Q

What is tissue factor

A

Cell surface glycoprotein

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6
Q

Tissue factor expression is increased w/

A

 ↑ expression in damaged endothelial cells and exposed subendothelial cells
 Derived from microparticles released in plaque rupture

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7
Q

Tissue factor activation leads to

A

o Form a complex/activate factor VII
 Factor VIIa → activate directly factor X and indirectly by factor IX
 Factor Xa convert prothrombin → thrombin

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8
Q

Role of thrombin and effect

A

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

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9
Q

Role of intrinsic pathway

A

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

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10
Q

Von Willebrand factor: normal

A

o Normally present in high levels but inactive in plasma

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11
Q

Von willebrand factor activation

A

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

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12
Q

Propagation of clot mechanism: other substances

A

o Secretion of plasminogen activator inhibitor (PAI-1)
 ↑ clot resistance to lysis
o Secretion of thromboxane A2 (TXA2)
 Vasoconstriction

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13
Q

Platelet activation

A

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

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14
Q

Platelet shape change

A

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

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15
Q

What happens w/ platelet intracell Ca2+

A

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

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16
Q

Platelet rapid propagation

A

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

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17
Q

Antiplatelet agents

A

Aspirin
Clopidogrel/ticlopidine
Dipyridamole
Sulfinpyrazone
Prasugrel
Ticagrelor
Cangrelor
Vorapaxar
Atopaxar

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18
Q

Aspirin: molecule

A

acetylsalicylic acid

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19
Q

Aspirin: MOA

A

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

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20
Q

Aspirin: side effects

A

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

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21
Q

Aspirin resistance

A

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

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22
Q

Aspirin resistance mechanisms

A

 Platelet Gp polymorphism
 Activation of platelets by pathways other than COX
 ↑ inflammatory activity from ↑ COX-2 expression

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23
Q

Aspirin: clinical uses

A

o Prophylaxis: after previous myocardial infarction or stroke
o Effort unstable angina
o Coronary artery bypass sx

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24
Q

Aspirin: CI

A

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

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25
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
26
Clopidogrel/Ticlopidine: molecule
o Thienopyridine derivatives  1st generation = ticlopidine  2nd generation = clopidogrel
27
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
28
PharmacoK ticlopidine
 ↓ clearance on repeated dosing  4-7 days to achieve max inhibition of platelet aggregation
29
Metabolism ticlopidine
 Metabolism: liver, excretion: kidneys
30
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
31
Clopidogrel: metabolism
 Hepatic or intestinal metabolism: activation by cytochrome CYP3A4 and 2C19 * Atorvastatin and omeprazole inhibit hepatic activation → ↓ effect
32
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
33
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
34
Clopidogrel: drug interaction
o Statin and H+ pump inhibitors (omeprazole)  Inhibit hepatic activation (theory, not proven by studies)
35
Dipyridamole: MOA
bind prostacyclin R on platelets
36
Dipyridamole: MOA
prosthetic mechanical valves
37
Dipyridamole: drug interaction
adenosine
38
Sulfinpyrazone MOA
* Mechanism: inhibit COX o Similar effect to aspirin
39
Newer anti platelet drugs
* Prasugrel Ticagrelor Cangrelor Vorapaxar Atopaxar
40
Pasugrel: molecule
o Newer generation thienopyridine
41
Pasugrel: MOA
o Mechanism: Irreversible/noncompetitive inhibition of P2Y12 R  5-9x more potent vs clopidogrel
42
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
43
Pasugrel: side effects
risks of serious bleeding
44
Ticagrelor: molecule
o Cyclopentyl-triazolopyrimidine
45
Ticagrelor: MOA
reversible binding/noncompetitive inhibition of P2Y12 R
46
Ticagrelor: pharmacoK
 More rapid/consistent onset of action → 3-4 days * ½ life = 12h  More rapid offset of action  No hepatic activation needed
47
Ticagrelor: drug interaction
 Amlodipine, statins, diltiazem, verapamil: inhibit CYP3A → ↑ levels and reduce speed of offset
48
Ticagrelor: side effects
 Bleeding  Dyspnea  ↑ frequency of ventricular pauses  ↑ uric acid
49
Cangrelor: MOA
Potent competitive inhibitor of P2Y12 R
50
Cangrelor: pharmacoK
 Rapid acting: IV effect in 20min → 85% inhibition of ADP induced platelet aggregation
51
Vorapaxar MOA
o Mechanism: potent competitive PAR-1 antagonist
52
Atopaxar MOA
o Mechanism: reversible protease activated R-1 thrombin R antagonist  Interfere in platelet signaling
53
Vorapaxar side effects
o Significant ↑ risk of major bleeding, including intra cranial
54
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
55
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
56
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
57
Glycoprotein IIb/IIIa R-antagonist: CI
o Bleeding or ↑ risk for bleeding o Thrombocytopenia
58
Glycoprotein IIb/IIIa R-antagonist: drugs
Abciximab Tirofiban Eptifibatide
59
Abciximab: molecule
* Monoclonal antibody against platelet GpIIb/IIIa R
60
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
61
Abciximab: how to reverse action
* Reverse action by platelet transfusion
62
Abciximab: side effects
bleeding, thrombocytopenia, hypersensitivity
63
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
64
Tirofiban: pharmacoK
acute onset, ½ life 2h o 35% unbound in circulation o Clearance: 65% renal, 25% fecal
65
Tirofiban: side effects
bleeding, renal disease, thrombocytopenia
66
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
67
Eptifibatide: pharmacoK
½ life 2-3h, renal clearance 30%
68
Eptifibatide: side effects
bleeding, renal disease, thrombocytopenia
69
Oral anticoag: drugs
Warfarin
70
Warfarin: MOA
71
Warfarin: pharmacoK
o PO: high plasma albumin bound
72
Warfarin: onset
2-7 days, 1/2 life = 37h
73
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
74
Warfarin: decrease dose if
* CHF or liver failure * Malnutrition (↓vit K) * Thyrotoxicosis: ↑ vit K catabolism * Renal failure
75
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
76
Warfarin: side effects
few o Over anticoagulation: bleeding, risk of intracranial hemorrhage  Highest in 1st 1-3mo (10x ↑) o Skin necrosis: rare
77
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
78
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
79
Acute anticoagulant: drugs
Heparin (unfractionated heparin) Low molecular weight heparin Enoxaparin Dalteparin Bivalirudin Fondaparinux
80
Heparin: molecule
* Heterogenous mucopolysaccharide: molecular weight = 5000-30000 Da
81
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
82
Heparin: dosage
IV infusion or SQ BID to TID → MAX 24h
83
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
84
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
85
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
86
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
87
Low molecular weight heparin: molecule
* 1/3 of heparin molecular weight = mean 5000Da o Heterogenous size
88
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)
89
Low molecular weight heparin: pharmacoK
o > bioavailability o > ½ life = 4h
90
Low molecular weight heparin: dosage
SQ SID to BID
91
Low molecular weight heparin: side effect
bleeding o ↓ but not completely reversible with protamine o Residual anti-Xa activity remains
92
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
93
Enoxaparin: MOA
inhibit factor Xa o Some degree of thrombin inhibition
94
Enoxaparin: dosage
1mg/kg SQ injection q12h
95
Enoxaparin: drug combination
Can be combined with aspirin/clopidogrel or GpIIa/IIIb inhibitor
96
Enoxaparin: metabolism
o Renal excretion
97
Dalteparin: dosage
deep SQ
98
Bivalirudin: molecule
* Molecular weight = 2180Da
99
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
100
Bivalirudin: pharmacoK
o Linear kinetic o ½ life 25min o Not protein bound → few drug interactions o Elimination: proteolytic cleavage > renal excretion (20%)
101
Bivalirudin: dosage
IV infusion o No reversal agent but coagulation time normalize 1h after discontinuation
102
Bivalirudin: monitoring
aPTT, ACT → correlated w [plasma]
103
Fondaparinux: molecule
* Molecular weight = 1728Da o Similar to antithrombin-binding sequence in heparin
104
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
105
Fondaparinux: pharmacoK
o SQ injection: 100% bioavailability o ½ life 17h
106
Fondaparinux: reversal
rVIIa is partial antagonist
107
Fondaparinux: dosage
SQ SID o ↓ dose in older/ renal impair o No monitoring needed
108
Fondaparinux: CI
o Renal clearance < 30ml/min o BW <50kg
109
Direct thrombin inhibitors: drugs
Dabigatran
110
Anti factor Xa agents: drugs
Rivaroxaban Apixaban
111
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
112
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
113
Dabigatran: side effects
gastric discomfort
114
Dabigatran: CI
age, ↑ bleeding risk
115
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
116
Rivaroxaban: MOA
oral inhibitor of factor Xa
117
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
118
Rivaroxaban: dosage
once daily o Major advantage
119
Apixaban: MOA
direct factor Xa inhibitor
120
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
121
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
122
Fibrinolytic/thrombolytic therapy: drugs
Alteplase/tissue plasminogen activator (tPA) Tenecteplase (TNK) Reteplase (rPA) Streptokinase (SK)
123
Plasmin inhibitors: drugs
Tranexamic acid
124
Activation of coagulation: drugs
* Recombinant factor VIIa * Prothrombin complex concentrate (PCC)
125
Indication Recombinant factor VIIa
hemophilia
126
Prothrombin complex concentrate (PCC) indication
o Reverse anticoagulant effect of rivaroxaban
127
Tranexamic acid effect
* Reduced bleeding when administered w/I 3h after trauma
128
Alteplase/tissue plasminogen activator (tPA): molecule
* Natural enzyme
129
Alteplase/tissue plasminogen activator (tPA): MOA
bind to fibrin o > affinity vs strepto/urokinase o Once bound: convert plasminogen → plasmin
130
Alteplase/tissue plasminogen activator (tPA): pharmacoK
short ½ life <5min, duration 90min
131
Alteplase/tissue plasminogen activator (tPA): indication
acute thrombotic event
132
Alteplase/tissue plasminogen activator (tPA): side effect and CI
related to hemorrhage
133
Tenecteplase (TNK): molecule
* Mutant of native tPA: amino acid substitutions at 3 sites
134
Differences tPA vs TNK
o ↓ plasma clearance and longer ½ life o ↑ fibrin specificity o ↑ resistance to PAI-1
135
Reteplase (rPA): molecule
* Mutant of alteplase: o Deletion of kringle-1, finger and epidermal growth domain o Carbohydrate side chains
136
Reteplase (rPA): pharmacoK
* Prolonged plasma clearance
137
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
138
Streptokinase (SK): side effects
hypersensitivity, hypotension, bleeding

12. Pharmacology (10 decks)

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