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47 Cards in this Set
- Front
- Back
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ADP Receptor Blockers
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-Concentration dependent inhibition of platelet activation
-Delayed 2-3 days for clinical effect, maximal effect 8-11 days -Active metabolites -Synergistic with aspirin -Indicated to prevent stroke, MI, PAD, angioplasty -Includes ticlopidine and clopidogrel |
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Ticlopidine
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-Prodrug (hepatic activation)
-Forms disulfide bridge with P2Y12 receptor cytosine and sulfur- prolonged effect -Adverse effects: -Hemorrhage <2% -Neutropenia 2.4% -TTP: immunological component -N/V, diarrhea -Rash 5% -Use limited to those who cannot tolerate ASA |
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Clopidogrel
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-Prodrug
-Binds sulfur on P2Y12 receptor -Synergistic with ASA -Hepatic activation- loading dose -Adverse effects: -Hemorrhage <2% -Neutropenia 0.4% -TTP (0.00035%, much smaller than with ticlopidine) -N/V, diarrhea -Rash 4% |
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GP IIb/IIIa blockers
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-Abciximab
-Eptifibatide -Tirofiban |
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Abciximab
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-Given by infusion, t1/2: 30 minutes (protein type structure)
-Humanized monoclonal antibody -Immediate onset, stays bound 18-24 hrs after infusion stopped -Expensive -Angioplasty with ASA and heparin, prevent restenosis, acute MI -Adverse effects: -Bleeding (1-10%) -Thrombocytopenia -Immunogenic 3-5% develop antibodies |
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Eftifibatide
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-Given by infusion
-Peptide inhibitor of fibrinogen binding to GPIIb/IIIa -infusions up to 96 hrs -given with ASA and heparin -Angioplasty and acute coronary events -Adverse effects: -Bleeding 10% -Thrombocytopenia 1% -Less immunogenicity (peptide<protein) |
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Tirofiban
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-Given by infusion with heparin
-Non-peptide inhibitor -Renal elimination -Angioplasty and acute coronary events -Adverse effects: -Bleeding 10-12% -Bradycardia -Dizziness |
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Heparin
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-Glycosaminoglycan found in mast cells
-10-15 glycosaminoglycan chains containing ~200-300 monosaccharide units, given SC or IV -Chains attached to core protein -MW from 3K-30K (average 12-15K) |
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General Information on UFH
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-Extracted from porcine intestinal mucosa or bovine lung
-Not absorbed -Given IV or SC -Immediate onset with IV -1-2 hr delay with SC -Doesn't cross placenta or BBB, not in breast milk, plasma protein bound -Dose dependent t1/2, may increase in cirrhosis and renal failure |
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MOA of UFH
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-Antithrombin III suicide substrate of activated factors:
- IIa > Xa > IXa > XIa > XIIa -Provides platform for binding of thrombin to antithrombin -Increases inhibitory activity x 1000 -Antithrombin + thrombin = 18 units -Antithrombin + Xa = 5 units -Heparin released after antithrombin and thrombin bound together -Sulfated-O-glucosamine specific binding site only found on ~30% molecules |
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Monitoring parameters for UFH
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-aPTT, or activated partial thromboplastin time
-aPTT ratio: patient's aPTT/normal aPTT control -Test dependent on reagent and instrument -Therapeutic ratio 1.5 - 2.5 -Indicated for: -Venous thrombosis -Pulmonary embolism -MI -Coronary angioplasty |
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Toxicity of UFH
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-Bleeding (major 1-5% IV)
-reversed with protamine sulfate (binds heparin), may have some anticoagulant effect by binding other factors- use smallest amount IV -HIT 0.5% - 5-10 days after initiation of therapy -Antibodies to heparin and platelet factor 4- activate platelets -D/c IMMEDIATELY and give direct thrombin inhibitor (such as Lepirudin, Argatroban, or Danaparoid) -Avoid LMWH and warfarin until thrombosis (clumped platelets) resolves -Abnormal hepatic function tests |
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General information on LMWH
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-Glycosaminoglycans of lower MW (1-10K, mean 5K)
-15 monosaccharide units -Chemically or enzymatically derived -Fragments 1/3 size of UFH -Preparations: -Enoxaparin (most frequently used) -Dalteparin, Tinzaparin -Not used in US: Nadroparin, Reviparin |
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MOA of LMWH
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-Minimal effect on thrombin (IIa)
-Lacks sequence to bind thrombin -Both inhibit factor Xa to same extent Ratio of Xa to IIa activity: -UFH: 1:1 -LMWH: 2-4:1 |
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Monitoring and Toxicity of LMWH
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-Given SC as fixed, or weight adjusted, dose ONCE or TWICE daily
-T1/2: 3-6 hrs -No effect on aPTT -decrease the dose in renal failure and the elderly -Monitoring not done routinely -Anti-factor Xa assay in renal failure and weight < 50 kg and > 80 kg -Toxicity: -Less bleeding than heparin -May cause HIT |
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Fondaparinux
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-Synthetic pentasaccharide based on antithrombin binding region of heparin
-Selective Xa inhibitor- no monitoring (no binding; activates antithrombin III which goes and finds factors Xa or IIa) -SC ONCE daily -t1/2: 17-21 hrs -Not used in renal failure -Low incidence of HIT -Indicated for: -Knee, hip replacement, pulmonary embolism, venous thrombosis |
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Direct Thrombin Inhibitors
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Based on Hirudin, natural product from salivary glands of medicinal leech inhibit thrombin catalytic site directly
-Includes: Lepirudin Bivalirudin Argatroban Danaproid Drotrecogin Dabigatran |
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Lepirudin
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-Recombinant derivative
-Used in HIT, aPTT 1.5 - 2.5 x normal -IV -Renal excretion |
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Bivalirudin
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-Synthetic 20 amino acid peptide
-Binds catalytic site of thrombin -Coronary angioplasty -IV -Renal excretion |
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Argatroban
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-Based on L-arginine
-Binds catalytic site of thrombin -Used in HIT, aPTT 1.5 - 3x normal -Hepatic excretion |
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Danaproid
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-Nonheparin saccharides
-Inhibits factor Xa -Venous thrombosis and HIT |
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Drotrecogin alfa
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-Recombinant form of protein C
-Inhibits factors Va and VIIIa -Used to treat severe sepsis -96 hr infusion |
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Dabigatran
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-Phase 3 clinical trials
-For VTE in hip and knee replacements similar to Enoxaparin (lower dose than usually used) -Also looking at atrial fibrillation, stroke, and MI -Orally active thrombin (IIa) inhibitor which requires no coagulation monitoring |
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Adverse effects of Dabigatran
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-Bleeding 1.3%
-N/V -Constipation -Hypotension -Elevated liver enzymes 2% *Similar drug Melagatran withdrawn because of liver toxicity |
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MOA of Warfarin
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-Racemic mix
-S warfarin 2-5x anticoagulant activity of R warfarin -Vitamin K antagonist -Factors II, VII, IX, X, protein C and S: synthesized in liver and require 9-13 carboxylated terminal glu residues requiring reduced vitamin K -Warfarin inhibits this (vitamin K epoxide reductase) -2 steps: Vitamin KO -> Vitamin K -> Vitamin KH2 -Warfarin inhibits FIRST enzyme at much LOWER doses than the second |
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Information on Warfarin
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-Therapeutic levels decrease vitamin K dependent synthesis of cofactors by 30 - 50%
-Decrease activity of those synthesized by 10 - 40% -No effect on existing carboxylated factors -Delay in onset |
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Coagulation factors affected by Warfarin
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t1/2 of:
-Factor VII: 4 - 6 hrs -Factor IX: 21 - 30 hrs -Factor X: 27 - 48 hrs -Factor II: > 60 hrs -Protein C: 4 - 6 hrs -Protein S: 40 - 60 hrs -Anticoagulant begins in first 24 hrs -Antithrombotic effect 5 - 7 days -Initial hypercoagulable state for first 24 - 48 hrs due to depletion of protein C. -So cover with heparin in high risk patients |
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What happens to Warfarin in the body?
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-Given orally, 100% absorption
-t1/2: 36 hrs -Steady state in 3 - 5 days -Highly protein bound 99% to albumin -Metabolized in liver -S warfarin: CYP2C9 -R warfarin: CYP 1A2 and 3A4 -Crosses placenta, so CONTRAINDICATED in pregnancy -Not present in breast milk -Do not give loading doses |
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Things that decrease the action of Warfarin
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Agents altering:
1) Uptake and metabolism of oral drugs or vitamin K (green leafy vegetables) 2) Synthesis, function, or clearance of clotting factors 3) Integrity of epithelial surface |
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Things that increase the actions of Warfarin
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1) CYP2C9 inhibition
2) Protein binding 3) Vitamin K, decrease due to antibiotics (gut bacteria important source of vitamin K) 4) Liver function, low levels of factors 5) Elderly |
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Monitoring Parameters of Warfarin
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-PT and INR
-PT measured value (factors II, VII, and X) -PT varies from lab to lab -INR calculated value that normalizes PT for international sensitivty index for each -INR: (PT pt / PT ref) ^ ISI -Target INR: 2 - 3.5 -Higher levels in high risk patients (mechanical heart valves, warfarin resistance) |
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Warfarin Sensitivity
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-10% of patients
-CYP2C9 alleles -much less efficient metabolism -CYP2C9*2 and *3 -10 - 20% of Caucasians -<5% of African Americans |
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Warfarin Toxicity
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-Bleeding: know signs and symptoms
-Less than 5% with INR of 2 - 3.5 -INR > 4, increase cranial hemorrhage -INR > 5, give Vitamin K1 (Phytonatdione) PO or SC (Aquamephytoin, Mephytoin, Konakion) -INR > 20, fresh frozen plasma and vitamin K -Birth defects -Skin necrosis in protein C or S deficiency |
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Direct Factor Xa Inhibitors
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Rivaroxaban:
-Orally active factor Xa -direct inhibitor for VTE and PE in hip and knee replacements comparable to Enoxaparin (lower dose than usually needed) -No coagulation monitoring -Adverse effects: Bleeding 5%, N/V, elevated liver enzymes, CV events -require more information |
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Fibrinolytics
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-All act directly or indirectly to activate the conversion of plasminogen to plasmin
-Plasminogen inactive in circulation, converted to plasmin by tPA -Plasmin lyses fibrin, fibrinogen, factors II, V, VII |
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a2 antiplasmin
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Glycoprotein forms stable complex with plasmin-> inactive
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Plasminogen activator inhibitors
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PAI 1,2: bind circulating tPA released from endothelial cells
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tPA
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-tissue plasminogen activator
-binds plasminogen bound to fibrin and converts to plasmin -lyses clot |
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Adverse effects of Fibrinolytics
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-Bleeding
-Allergic reactions: -Fever, chills, skin rash mainly with streptokinase and urokinase -Anaphylaxis -Ventricular arrhythmias |
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Contraindications in Fibrinolytics
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1) Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious head/facial trauma, CPR
2) Serious GI bleeding within 3 mos. 3) History of HTN (diastolic pressure >110 mmHg) 4) Active bleeding/hemorrhagic disorder 5) Previous CVA or active intracranial process (tumors) 6) Aortic dissection 7) Acute pericarditis 8) STK prior exposure or allergic reaction 9) Pregnancy |
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Streptokinase
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-Forms stable 1:1 complex with plasminogen, which exposes catalytic site and converts plasminogen to plasmin
-Beta-hemolytic streptococci -Acts on both fibrin bound and circulating plasminogen -1:1 complex, indirect activator -Antigenic -Some patients refractory due to preexisting streptococci antibodies -Re-thrombosis: 10 - 20% -Used with aspirin -Used mainly in Europe |
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Alteplase
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-Recombinant DNA technology
-Chinese hamster ovary cells -527 amino acids -Directly activate fibrin bound plasminogen -Very expensive |
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Reteplase
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-E Coli cells recombinant 355/527 amino acids
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Tenecteplase
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-Chinese hamster ovary cells
-Recombinant substituted amino acids -Reteplase, Tenecteplase: increased t1/2 over tPA -Relatively resistant to PAI-1 -Increased affinity for fibrin |
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Antifibrinolytics
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Aprotinin, Tranexamic acid, aminocaproid acid
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Aprotinin
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-Kallikrein antagonist
-Inhibits plasmin -Prevents clot breakdown -Used to prevent bleeding during CABG -FDA warning about renal impairment (to be withdrawn) |
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Aminocaproid acid
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-Lysine analogs block lysine binding site in plasminogen and plasmin preventing interaction with fibrin
-Ised to prevent bleeding in hemophiliacs during tooth extractiong and surgery, CABG |
