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29 Cards in this Set
- Front
- Back
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What is the MOA of Warfarin?
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Vitamin K antagonist
Inhibits the activation of the coagulation cascade Finely tuned therapy (NTI) requires careful monitoring |
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What is the SAR of Coumarin/Warfarin?
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Mimics the structure of Vitamin K
Water insoluble lactones 3- and 4- substitution required for activity 4-hydroxyl (-OH) allows Formation of Na+ salts-water solubility Hemiketal conformation: enhances enzyme binding 3- substitution affects kinetics |
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What is the metabolism of Warfarin?
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S-isomer is the active isomer (4:1)
Significant patient variability (CYP2C9, VKORC1) Significant DDI-Bleeding/Vitamin K |
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What enzymes metabolize Warfarin?
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S isomer: CYP 2C9
R isomer:CYP 3A4 CYP1A, CYP1A2 |
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What is the VKORC1 variability in Warfarin?
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(Vitamin K epoxide reductase enzyme)
AA: less activity enzyme (asians) (decrease dose) AB: intermediate activity BB: highest activity (blacks) (increase dose) Need to adjust dose of warfarin based on their phenotype |
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What is the pharmokinetics of Warfarin?
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100% bioavailability, hepatic metabolism (different metabolic enzymes for the isomers)
-Excreted renally -Dosage forms-Tablets, IM, IV, Supp -Onset of action is related to the turnover of coagulation factors -High protein binding (95-99%) because it is weakly ACIDIC -Significant DDI with CYP2C9 inhibitors |
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High molecular weight Heparin (Unfractionated) chemistry
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- made up of sulfates
- acidic - negatively charged - 5 to 30 kDa - Na+, Ca++, Li+ help with water solubility - not oral due to instability in gastric acid |
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What is the MOA of unfractionated Heparin?
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- Binds to Antithrombin (III) which inactivates Thrombin (IIa) and Factor Xa
- enhances Antithrombin binding by 1000 fold - (-) Heparin binds to (+) amines in Antithrombin - Forms stable 1:1 complex with Xa and IIa |
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What is the pharmokinetics of unfractionated Heparin?
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~ 30% dose is absorbed by SC route
Non-specific binding to proteins (this decreases the bioavailability, so not 100% even when IV) Metabolized into inactive depolymerized and desulfated analogues Excreted by kidneys |
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What is the advantages of LMWH (fractionated) compared to Heparin (unfractionated)?
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-Better absorption (30-90%)
-More specific interactions (10a binding) -decrease toxicity -More predictable longer T1/2 (renal). |
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What is the antidote for Heparin overdose and how does it work?
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Protein isolated form salmon sperm
Specific antagonist to heparin VERY STRONG + charge: made up of many amine groups with (+), can bind to the (-) on heparin Foreign protein –anaphylaxis |
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What are the advantages of Fondaparinux (synthetic LMW Heparin)?
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-critical 5 sugar unit
1. Consistent dosage form due to smaller structure 2. Specific for Factor Xa (has the MOST selectivity for 10a of any LMWH) 3. Better pharmacokinetics 4. SC dosage form, 5. LONG duration of action (1 day) due to 94% binding to antithrombin 3 6.Fondaparinux 100% absorbed (selective for 10a) -Renal excreted |
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What is Idraprinux and how is it different from Fondaparinux?
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Idraparinux – methylether (-OCH3) derivative of Fondaparinux
Various –OH and -OSO3- groups in Fondaparinux replaced with –OCH3 groups Increase in lipophilicity: increases T½ from17 hours to 80 hrs, 1x /week dosing -Fonaparinux is only 1/day dosing. |
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How do Heparins differ from one another?
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Vary in selectivity for Factor Xa
Fondaparinux> LMWHs > Unfractionated heparin |
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What are the 3 PEPTIDE based Direct Thrombin (IIa) Inhibitors?
What is the 1 peptidomimetic DTI? |
Lepirudin
Desirudin Bivalirudin 1. Argatroban |
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Argatroban : IV DTI
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-Parenteral IV only Direct Thrombin Inhibitor
-Binds selectively to catalytic site of thrombin -S- isomer is two times more potent than R- isomer -Metabolized by CYP 3A4 - Not given by itself, always given with another thrombotic agent |
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Dabigatran Etexillate: Oral DTI
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-Prodrug (active drug called Dabigatran): given as prodrug because Dabigatran is zwitterionic and won't work in GI due to poor absorption, so prodrug enhances absorption.
-Orally active (~ 6% oral bioavailability). That's why its made into a prodrug first (the prodrug is orally active) -Substrate of PGP: have to worry about PGP inhibitors and inducers -metabolized by esterases - No CYP enzymes |
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Which antiplatelet drug inhibits Cyclooxygenase-1
(COX-1) and TXA2? |
Aspirin
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Which 2 antiplatelet drugs inhibit PDE-3?
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Dipyridamole
Cilostazole |
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Which 3 antiplatelet drugs are P2Y Purinergic receptor antagonists?
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1. Ticlopidine (Ticlid®)
2. Clopidogrel (Plavix®) 3. Prasugrel (Effient™) **P2Y12 is sustained platelet aggregation, so you want to inhibit this** |
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Which 4 antiplatelet drugs are Glycoprotein IIb/IIIa receptor antagonists?
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Abciximab
Eptifibatide Tirofiban Defibrotide |
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Aspirin
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-Thromoxane A2 (TXA2) stimulates platelet aggregation
-Aspirin reduces TXA2 production, thus antiplatelet effect -Irreversibly inhibits COX -Highly bound to plasma proteins -Acidic drug -Cause gastric upset/bleeding (because prostaglandin is decreased from COX1 inhibition) |
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Dipyridamole
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- PDE-3 inhibitor
Generally used in combination (ex: used with aspirin) PgP inhibitor Highly bound to plasma protein |
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Cilostazol
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Has more selectivity for PDE-3 (than Dipyridamole)
Highly bound to plasma protein Metabolized by CYP3A4 and CYP2C19 into 2 ACTIVE metabolites Parent drug Cilostazol is also ACTIVE |
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MOA of P2Y Purinergic Receptor Antagonists
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Antagonists (Thienopyridines) irreversibly inhibit the P2Y12 receptor
-The duration of action reflects the lifetime of the platelets (7 days)because IRREVERSIBLE Most of them are prodrugs (that contain sulfur pyridine group, this has to turn into a -SH (thiol group) in order to be active -Bioactivated in the LIVER ***The thiol group -SH is what makes the bond to the receptor. Ex: DRUG- S-S - Receptor |
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**Clopidogrel (Plavix) Metabolism**
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Prodrug
Irreversible antagonist Metabolized by hepatic esterase and CYP 450 DDI with PPIs (omeprazole, nexium), and other CYP2C19 inhibitors (so the dose of clopidogrel has to be reduced) Metabolism could be affected by the patient phenotype (2C19) (ex: Hispanics are POOR metabolizers of 2C19, which means they have less active drug in their blood and drug doesn't work to decrease platelet aggregation) Ungergoes 2 metabolic pathways: 1. CYP3A4, CYP2C19 to ACTIVE Drug 2. Hepatic esterases to INACTIVE Drug (major portion goes to inactive) (First pass inactivation) |
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Parsugrel
What is the advantage of it over Clopidogrel? |
- it's also a P2Y irreversible prodrug antagonist
1. More Potent than Clopidogrel (cuz no inactivation pathway--all to active drug) 2. No inactivation pathway 3. No polymorphisms (by C219) 4. No PPI (omeprazole,nexium) DDI 5. Metabolized by CYP3A4 and CYP2B6, and hepatic esterases 6. similar therapeutic activity as clopidogrel |
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Anti-Platelet Drugs: Glycoprotein IIb/IIIa Recetor Antagonists
What is the difference between the 4? |
All IV: because the S-S bond becomes cleaved in the GI and then the drug becomes inactive for IIb/IIIa antagonism
1. Abciximab: monoclonal ANTIBODY, IRREVERSIBLE, binds more tightly, more favorable kinetics 2. Eptifibatide: cyclic heptapeptide, synthetic drug, less favorable kinetics 3. Tirofiban: Peptidomimetic Fibans |
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What are the 1st, 2nd, 3rd generation Thrombolytics?
Which one is more selective? |
**Thrombolytics (Fibrinolytic drugs): ACTIVATE plasminogen and INCREASE plasmin levels (break down clot)
-all these drug IV and are enzymes - 3rd generation are most selective to activate plasminogen, than 2nd, then 1st. -Remember that 3rd, 2nd are more CLOT specific (they are t-PA recombinant analogues) - 1st Gen are not clot specific and will break down anything 3rd Gen: Reteplase (t-PA), Tenecteplase 2nd Gen: Alteplase (t-PA), Prourokinase 1st Gen: Streptokinase, Urokinase, Anistreplase |
