Lecture 12- Anti-coagulation, Thrombolytics, Antiplatelet - Sheet1 Flashcards
Actions of thrombin
- Transforms fibrinogen to fibrin (involving conversion of 13-13a for cross linking)
- Promotes platelet aggregation by thrombin specific receptors on platelets (protease activated receptors, PAR1/PAR4 by cleaving receptor at N terminus causing conformational change allowing activation of G protein
- Activates V, VIII,
- Anti-coag fxn by A.) Binding thrombomodulin on endothelial cells. B.) Elicits activation of protein C to Ca. C.) Protein Ca with cofactor protein S degrades factors Va and VIIIa. ALSO decreases rate of activation of prothrombin and limits further production of thrombin
How to test for heparin
Activated partial thromboplastin time (aPTT) a test of the intrinsic and common pathway
Blood sample collected with citrate to inactivate calcium and prevent clotting
Add negatively charged phospholipids, a particulate substance like aluminum sulfate, and calcium. Normal clotting in 26-33 seconds.
(heparin is therapeutic when aPTT is 1.5-2.5x normal mean=50-80 seconds)
Antagonist for heparin in order to controll bleeding/hemorrhage
Protamine sulfate
Low molecular weight heparins (LMWH)
Examples: Enoxaparin/Dalteparin
Fragment of standard MW Heparin.
Administered subcutaneously, with longer half life than heparin so advantage in hospital setting.
Poorly catalyze inhibition of thrombin by ATIII because it can no longer ALSO bind to the thrombin (in addition to the ATIII). You end with somewhat more specificity for 10a,9a,11a,12a.
Therapeutic Use: Acute DVT Prophylaxis of DVT Hip replacement surgery, during, and following hospitalization Acute unstable angina and MI
SE:
Risk in patient with renal disease due to renal elimination
Less risk of bleeding compared to heparin
Lower risk of thrombocytopenia compared to heparin
CI: Active bleeding Severe uncontrolled hypertension Recent surgery for eye, brain, spinal cord Renal impairment
Enoxaparin/Dalteparin
LMWH
Lepirudin/Bivalirudin
Direct thrombin inhibitor
Mechanism: Inactivates thrombin by blocking the substrate binding site 1:1 complex. Bind to both the catalytic site and exosite 1
IV administration (as compared to dabigatron, which is oral)
Renal excretion
Therapeutic use: alternative to heparin in patients with heparin-induced thrombocytopenia
Fondaparinux
Direct Factor 10a inhibitor
Synthetic pentasaccharide
Subcutaneous administration (as compared to rivaroxaban, which is oral) Renal excretion
Therapeutic use:
Prevention of DVT in patients undergoing surgery
Treatment of acute PE
Treatment of acute DVT w/o PE
Protamin sulfate
Heparin antagonist Low MW, + charged.
1:1 binding with heparin
SE:
Weak anticoagulant properties in high doses or when alone
Anaphylactic reaction from fish hypersensitivity and previous exposure from insulin products
Severe pulmonary hypertension
Therapeutic use:
Heparin overdose with acute bleeding that cannot be controlled by stopping heparin
Reverse heparin following cardiopulmonary bypass
Warfarin
Oral anticoagulant
Structural analog of Vitamin K. 3 types, racemic/S/R…
Administered as racemic but S is more active form.
Metabolized differently KNOW MORE FOR S: (S uses CYP2C9) (R uses CYP1A1, 1A2, 3A4)
Mechanism: (Moreso S-warfarin) Blocks VKORC1 (vitamin K reductase), preventing the recycling of oxidized Vitamin K (epoxide) to the reduced form (hydroquinone). This results in preventing the gamma-carboxylation of several glutamate residues in
prothrombin, 7,9,10, and endogenous anticoagulalant proteins C and S.
This is a competitive inhibition because Vit K administation will displace warfarin.
Therapeutic effect not seen for several hours to days
Peak plasma at 24 hours
CI: same as heparin, also CYP2C9 polymorphisms Genetic variations in VKORC1 Pregnancy/teratogenic, boen metabolism is vit k dependent Liver, kidney disease, vit k deficiency
Adverse reactions that are rare
Purple toe syndrome
Skin necrosis/gangrene
How to test for warfarin function
PT, prothrombin time
- Blood sample collected with citrate to inactivate calcium and prevent clotting
- Add thromboplastin, a saline extract of brain containing tissue factor and phospholipids
NORMAL CLOTTING in 12-14 seconds
Tests extrinsic and common pathway.
*There is a variability in thromboplastin, so ratio of patient PT to a control PT is obtained by standard method using WHO primary standard thromboplastin. So you actually measure INR
Normal INR between 0.8-1.2
Warfarin is therapeutic when PT betwen 15-26
INR usually 2-3
*Therapeutic effect of warfarin delayed because… blocks synthesis of clotting factors. The circulating factors are not inhibited by warfarin. so These active factors are still aorund while no longer able to synthesize any more active factors
How to reverse warfarin
If INR at therapeutic 2-3: Stop drug
If INR>5: give Vitamin K
For immediate reversal: transfusion with fresh frozen plasma
Why might the dosage of warfarin be varied among individuals
- CYP2C9*2 and *3 have decreased activity so wafarin not inactivated so use less warfarin
- VKORC1 variants. If produce less, then use less warfarin. If produce more, use more warfarin
Dabigatran
Oral anticoagulant.a direct thrombin inhibitor.
Lepirudin is the IV equivalent
Given as a pro-drug, metabolized to active dabigatran
Mechanism: interacts with active site of thrombin thus potent, reversible, competitive direct thrombin inhibitor that inhibits BOTH FIBRIN-BOUND AND FREE THROMBIN
Pharmacokinetics: Predictable Oral Rapid onset (2 hours peak plasma) Short half life (14-17 hr) Not substrate for CYP450 Excreted by kidney Must be carefully stored since administered as pro-drug can breakdown if exposed to moisture (30 days of stability)
P-glycoprotein can limit oral absorption of drugs by transporting them back into GI.
SE:
Less for bleeding compared to warfarin
No antidote!! Depends on excretion with plasma halflife of 14 hr
Upset GI
CI:
Renal impairment
Advanced liver disease
Valvular heart disease (bioprosthetic heart valves). More dangerous than with warfarin.
Drug interactions with P-glycoprotein efflux transporters. (If used with P-gp inducer, plasma conc and half life reduced. If used with P-gp inhibitor, increased plasma concentration)
Therapeutic Use:
Patients with nonvalvular atrial fibrillation at risk for stroke or systemic embolism
Prophylaxis in patients with knee or hip replacement
Rivaroxaban
Oral anticoagulant, a direct 10a inhibitor
Fondaparinux is the subcutaneous equivalent
(notice the Xa in the name..)
Good because Xa is primary site of amplification (1000 cul thrombin per 1 cul Xa)
Also good because you wouldn’t affect existing thrombin levels
Unlike heparin, capable fo gaining access to clotbound factor 10a. Inhibits both free factor 10a and factor 10a in the prothrombinase complex. This prevents extension of the thrombus by blcoking further generation of thrombin within the clot
Pharmacokinetics: 1/3 renal eliminated unchanged 2/3 metabolized in liver, half of which renal half of which hepatobiliary route CYP450 metabolized. Substrate for P-glycoprotein
No significant between group difference in risk of major bleeding ALTHOUGH INTRACRANIAL AND FATAL BLEEDING OCCURRED LESS FREQUENTLY WITH RIVAROXABAN GROUP
SE:
Bleeding
Drug interactions with CYP3A4 inhibitors/inducers AND P-glycoprotein inhibitors/inducers
No good monitoring
Therapeutic Use:
Similar to dabigatran
(patients with nonvalvular atrial fibrillaiton at risk for stroke or systemic embolism)
(Prophylaxis in patients with knee or hip replacement)
Importance of free thrombin vs. fibrin-bound thrombin
Thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by antithrombin.
Fibrin-bound thrombin can locally activate platelets and trigger coagulation thereby causing thrombus growth
Monitoring of dabigatran and rivaroxaban
None. little effect on PT or INR
Thrombolytic drugs
Aminocaproic acid
Tissue plasminogen activator (t-PA)
Alteplase
Mechanism for fibrinolysis
Plasminogen converted to plasmin by cleavage of single peptide bond Arg560-Val561). Generates a towo chain disulfide linked molecule exposing the kringles. N terminus/heavy chain has 5 disulfide bonded loops to bind lysine residues in polymerized fibrin. C terminus/light chain, contains the active catalytic site
t-PA (endogenous) and Alteplase (exogenous) cleaves the ARG-VAL bond to form plasmin from plasminogen
Plasmin is fibrin-specific due to alpha2-antiplasmin
Alteplase
t-PA recombinant
Activates bound plasminogen several hundred fold more rapidly than free plasminogen
Very short half life, requires IV
Limits systemic lytic state only at low phys concentrations.
SE: Hemorrhage
Therapeutic Uses:
Acute MI (STEMI)
Treatment of pulmonary embolism/DVT
Stroke within first 3 hours
Aminocaproic acid
Inhibitor of Fibrinolysis
A lysine analog that binds to lysine binding sites on plasminogen and plasmin blocking binding of plasma to fibrin
Reverse states assoc with excessive fibrinolysis
Concentration in urine can be 100x that in plasma; useful for treating urinary tract bleeding
Antiplatelet drugs
Aspirin
Dipyridamole
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Abciximab, Eptifibatide
Important platelet receptors
GlycoProtein receptor proteins (integrins) binding collagen, vWF causing platelets to adhere to subendothelium: GPIb, GPIa/IIa,
GPIIb/GPIIIa: glycoprotein receptor binding fibrinogen
PAR1/PAR4: protease activated receptors; thrombin (IIa) binds to these receptors
P2Y/P2Y12: purinergic receptors for ADP
Activation of PAR1/PAR4 or P2Y1/P2Y12 receptors: stimulates COX and GPIIb/IIIa: fibriongeon binding results in cross linking of adjacent platelets
COX mediated production of TXA2/PGI2
Aspirin
Low dose aspirin. Irreversible inhibitor of COX-1 in platelets, inhibit platelet production of TXA2 preserves PGI2
SE: GI irritation/bleeding
low dose aspirin could haeve potentially adverse effects assoc with aspirin/nsaids like hypersensitivity
Therapeutic uses:
MI prophylaxis
alone or in comb with thrombolytics in acute MI
Acute phase of ischemic stroke
Stroke prophylaxis
Unstable angina/acute coronary syndrome (unexpected chest pain at rest)
Preeclampsia prophylaxis- remains controversial
Dipyridamole
A vasodilator and inhibitor of platelet aggregation
Main mechanism: Inhibition of phosphodiesterase (PDE3 and PDE5), increasing cAMP in platelet, inhibits platelet aggregation
SE: headache/GI upset
Therapeutic use:
Primary prophylaxis of thromboemboli in patients with prosthetic heart valves, given in combination with warfarin
In combination with aspirin for secondary prevention of MI or TIA
