Term
coumarins are competitive inhibitors of vitamin K in the biosynthesis of prothrombin.
Vit K is a necessary cofactor for the posttranslational carboxylation of glutamic acids on the N terminal portions of the clotting factors.
This gamma glutamyl carboxylation results in a new amino acid, gamma-carboxyglutamate, which through chelation of Ca ions causes conformational changes in the proteins.
In turn, these changes make the vit K dependent clotting factors become activated. |
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warfarin
coumarin derivative
inhibits the vitamin K cycle enzyme controlling regeneration of reduced vit K, vitamin K epoxide reductase complex 1. |
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acenocoumarol
coumarin derivative
inhibits the vitamin K cycle enzyme controlling regeneration of reduced vit K, vitamin K epoxide reductase complex 1. |
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phenprocoumon
coumarin derivative
inhibits the vitamin K cycle enzyme controlling regeneration of reduced vit K, vitamin K epoxide reductase complex 1. |
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dicoumarol
coumarin derivative
inhibits the vitamin K cycle enzyme controlling regeneration of reduced vit K, vitamin K epoxide reductase complex 1. |
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tioclomarol
coumarin derivative
inhibits the vitamin K cycle enzyme controlling regeneration of reduced vit K, vitamin K epoxide reductase complex 1. |
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Definition
coumarin is water insoluble
[image]
4-hydroxy-coumarin has weakly acidic properties which makes the molecule water soluble under ( ) conditions
[image] |
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indandiones derivatives
similar MOA as coumarins
rarely used due to hepatic toxicity
anisindione fewer side effects, still preference to warfarin |
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Definition
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water insoluble lactones
mostly substitutions at C3 and C4 of lactone ring
[image]
4-OH substitution makes them weakly acidic, salt formation
chiral center present. Two diastereometic cyclic hemiketal and open chain conformers in solution
[image]
S is 4x as potent as R-warfarin. Administered drug is racemic |
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S-warfarin metabolism
both are para hydroxylations |
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Definition
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mechanism of action of heparin
In the absence of heparin, the rate of thrombin inactivation by antithrombin (AT) is low.
After a conformation change induced by heparin, AT irreversibly binds to and inhibits the active site of thrombin.
Heparin induces a conformational change to antithrombin by exposing AT's active site.
The heparin-AT complex cannot bind fibrin-bound thrombin. |
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Definition
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Term
heparin
The hydroxyl groups can be sulfated, thus resulting in a polymer that is highly negatively charged.
Heparin is a polysaccaride with a MW ranging from 5K to 30K daltons.
It is built up from alternating glucosamine and uronic acid (D-glucuronic or L-iduronic) residues, which are highly functionalized
[image] [image]
O-sulfation at position 2 of uronic acids
O-sulfation at postitions 3 and 6 of glucosamine
[image]
amino functionalities can be sulfated, acylated, or unsubstituted
[image]
linked by alpha-1,4 bonds
b/c it is a polysulfate, it is administered as a salt (Na, Ca) |
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Definition
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| The binding of a heparin pentasaccharide to antithrombin induces a conformational change involving the expulsion of the hinge region (circled) from the central β-sheet A (red), and extension (yellow) of the A and D helices (green and cyan, respectively). The expulsion of the hinge region liberates the Arg (green ball-and-stick). (b) Representation of the crystal structure of the ternary complex between antithrombin (colored as above), thrombin (magenta) and heparin (stick, with blue electron density contour). Thrombin is docked toward the heparin-binding site of antithrombin, and makes several exosite interactions. |
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Definition
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Term
The key structural unit of heparin is the pentasaccaride sequence, consisting of 3 D-glucosamine and 2 uronic acid residues.
The central D-glucosamine residue contains a unique 3-O-sulfate moiety that is rare outside of this sequence.
[image]
4 sulfate groups on the D-glucosamines are found to be critical for retaining high anticoagulant activity. Elimination of any of them results in dramatic reduction in the anticoagulant activity.
Removal of the unique 3-O-sulfate group results in complete loss of activity.
Removal of sulfate groups other than the critical ones seems to not affect anticoagulant activity. |
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Definition
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Term
depolymerization
desulfation
heparin's half life is prolonged in patients with hepatic dysfunction |
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Definition
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Term
similar MOA as heparin, but binding more selective against activation factor Xa, and less against thrombin
the antithromin/LMWH complex is not sufficient length to bind to and inhibit both thrombin and Xa
So, all inactivate Xa, but only 25-50% inactivate thrombin as well
they are in the 4-6 kDa MW range
they are isolated as fractions from heparin using gel filtration chromatography or differential precipitation with ethanol |
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Definition
| MOA of low molecular weight heparin |
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Term
synthetic heparin
no effect on thrombin
advantage: it is synthetic, thus its composition does not change, predictable pharmacokinetics
metabolism: none
protein binding to antithrombin (94%) and nothing else |
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Definition
MOA of fondaparinux
[image] |
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Term
direct thrombin inhibitors
bivalent binding - interact with the active (catalytic) site of thrombin and with the fibrinogen binding site (exosite 1)
thrombin specific
hirudin analogs |
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Definition
| MOA of lepirudin and desirudin |
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Term
direct thrombin inhibitor
bivalent - interacts with the active (catalytic) site of thrombin and with the fibrinogen binding site (exosite 1)
***binds reversibly***
a 20 aa peptide as opposed to 65 with the others
unites the C-terminal docapeptide from native hirudin with an active side binding N-terminal tetrapeptide and 4 glycines bridging the 2.
[image]
is thrombin specific |
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Definition
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Term
metabolism of bivalirudin
this cleavage makes bivalirudin a competitive inhibitor of thrombin (reversible) |
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Definition
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Term
direct thrombin inhibtor
univalent - only interacts with the active (catalytic) site of thrombin
binds reversibly
it is a mixture of 2 diastereomers (S is 2x as potent as R)
***thrombin selective*** (can bind to other things unlike the other DTIs)
[image]
peptidomimetic
peptide bonds are replaced with sulfonamide (except for circled bond, but this is not labile b/c is part of a cyclic moiety.) |
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Definition
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Definition
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1) reduced bioavailibility of aspirin: Inadequate intake of aspirin (poor compliance), Inadequate dose of aspirin, Concurrent intake of certain non steroidal anti-inflammatory drugs (for example ibuprofen, indomethacin), possibly preventing the access of aspirin to cyclo-oxygenase-1 binding site
2) alternate pathways of platelet activation: Platelet activation by pathways that are not blocked by aspirin (for example, red cell induced platelet activation: stimulation of collagen, adenosine diphosphate, epinephrine, and thrombin receptors on platelets), Biosynthesis of thromboxane by pathways that are not blocked by aspirin
3) genetic polymorphisms: Polymorphisms of cyclo-oxygenase-1, cyclo-oxygenase-2, Factor XIII Val34Leu polymorphism, leading to variable inhibition of factor XIII activation by low dose aspirin, Polymorphism of platelet glycoprotein IIb/IIIa |
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Definition
| possible mechanism for aspirin resistance |
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Term
aspirin
COX 1 and 2 are responsible for the production of PGs
both isoforms are targets of NSAIDS
there is a 60% homology between the 2, aspirin bind and selectively acetylates the hydroxyl group of one serine residue
acetylation leads to irreversible inhibition.
side effects are due to the functions of COX: COX 1 has a house-keeping role and COX 2 produces PGs for inflammatory response |
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Definition
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Definition
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Definition
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Term
| tetrazole, imidazole, carboxyl, sulfate, phosphinic group |
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Definition
| what functional groups can coordinate with Zn? |
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Term
dipyridamole
PDE3 inhibitor
contains a piperidine and a pyrimidine |
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Definition
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Term
cilostazol
PDE3 inhibitor
contains a tetrazole |
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Definition
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Term
ticlodipine
irreversibly inhibits P2Y receptor, inhibiting platelet aggregation and delay clot retraction |
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Definition
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Term
clopidogrel
irreversibly inhibits P2Y receptor, inhibiting platelet aggretation and delaying clot retraction |
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Definition
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Term
| metabolism of clopidogrel |
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Definition
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Term
eptifibatide
glycoprotein IIb/IIIa receptor inhibitor
cyclic heptapeptide with six amino acids and one mercapto-proionyl group
Lys-Gly-Asp specific |
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Definition
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Term
tirofiban
glycoprotein IIb/IIIa receptor inhibitor
peptidomimetic |
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Definition
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