Drugs for Venous Thromboembolism Flashcards
Formation of prothrombin (factor II)
a. Decarboxy prothromin is biologically inactive unless it is 1).
b. The reaction requires carbon dioxide,
molecular oxygen, and 2). It is catalyzed by 3)
c. In the process of carboxylation
vitamin K is oxidized to its corresponding epoxide
1) carboxylated
2) reduced vitamin K
3) γ-glutamyl carboxylase;
Formation of prothrombin (factor II) Reduced vitamin K is regenerated from the epoxide by the enzyme 1). 2) are biologically activated by the same mechanism.
1) vitamin K epoxide reductase;
2) coagulation factor II
(prothromin), factors VII, IX,
and X and the anticoagulant
proteins C and S
Results from clot formation in the venous circulation; manifested as deep vein thrombosis (DVT) or pulmonary embolism
Venous thromboembolism
A number of factors increase the risk of developing VTE including1).
1) age,
history of VTE, venous stasis, vascular injury, and drug therapy
Once formed a venous thrombus may:
a. remain asymptomatic
b. spontaneously lyse
c. obstruct the venous circulation
d. propagate into more proximal veins
e. embolize
f. act in any combination of these
Xa and IIa inhibitors
heparin and low-molecular weight heparin aka Enoxaparin
Unfractionated heparin
derived from 1) or porcine intestinal mucosa
1) bovine lung
Unfractionated heparin
made up of repetitive units of 1) and 2)
1) D-glycosamine
2) uronic acid
heparin and LMWH (and fondaparinux) have no 1) Instead, they bind to 2) and
accelerate the rate at which it inhibits various coagulation proteases
(e.g., thrombin and Xa).
1) intrinsic
anticoagulant activity.
2) antithrombin
Heparin:
1) on the heparin molecule binds 2) provoking a conformational change;
the 3) is 100x-1000x more potent as an anticoagulant compared to antithrombin alone
1) Pentasaccharide
2) antithrombin
3) heparin-antithrombin
complex
how does Heparin inactivate thrombin (factor IIa)?
-the unfractionated heparin molecule contains enough 1) (>18) to form a 2) bridging 3)
inactivating thrombin
1) saccharides
2) ternary complex
3) antithrombin and thrombin
how does Heparin inactivate Factor Xa?
-inactivation of factor Xa does not require the bridging between 1); it requires only the binding of antithrombin to the pentasaccharide
1) antithrombin and thrombin
Heparin inactivates Factor IIa (thrombin) and Xa; compare?
To inactivate Thrombin, forms a ternary complex to bridge antithrombin and thrombin;
To inactivate Factor Xa–> antithrombin ginds to the pentasaccharide
Heparin
anti-Xa to anti-IIa ratio is 1)
LMWH (enoxaparin) anti-Xa to anti-IIa ratio is 2)
1) 1:1
2) 4:1
heparin uncouples from 1) after it has produced its effect
and quickly recouples with another 1)
1) antithrombin
the heparin-antithrombin complex is too large to inactivate Xa and thrombin within 1)
heparin prevents 2) of a formed thrombus allowing the patient’s own thrombolytic system to degrade the clot
1) a formed clot
2) growth and propagation
The mechanism is the same as for heparin but it is less effective in inhibiting thrombin
Enoxaparin (LMWH)
why are LMWH such as Enoxaparin have decreased activity against Thrombin (factor IIa) compared to Heparin
the low-molecular-weight heparins (enoxaparin) have a shorter
chain length which limits their activity against thrombin
Heparin eliminated by two mechanisms:
(a) 1)enzymatically inactivate heparin
molecules - the process is zero order (saturable)
(b) heparin is also eliminated 2)(first order) but this process is slower
1) heparinases and desulfatases
2) renally
heparin is administered 1) for prophylaxis;
2) is preferred for acute treatment (bolus dose followed by continuous infusion)
1) subcutaneously in abdominal fat
2) intravenous route
the1) is used to assess anticoagulation with heparin; it is determined before administration and 6 hours later or after a dose
change
1) aPTT
because the anticoagulant effect is more predictable, routine
laboratory monitoring is usually not necessary; when it is,
measurement of anti-factor Xa is used
Enoxaparin
bioavailability and anticoagulant response after subcutaneous
administration is better than with heparin and is the route of
administration
Enoxaparin
it is eliminated renally so half-life may be prolonged in patients with
renal impairment
Enoxaparin
when bleeding occurs, heparin should be discontinued immediately and
1) administered; it forms a 2) with heparin with loss of anticoagulant activity
1) protamine
2) stable salt
major bleeding with 1) less than with heparin but when it occurs protamine can be used;
however, Protamine does not bind as well to 1) as well as Heparin b/c of the shorter chains.
1) enoxaparin; LMWH
Compare Protamine efficacy in Heparin vs. LMWH bleeding
More effective in reversing bleeding caused by Heparin than LMWH
Heparin-induced thrombocytopenia –>more commonly seen with heparin (LMWH do not bind 1) to the same degree as heparin)
1) platelets
and PF-4
because of cross-reactivity with heparin antibodies, 1) should not be use in patients diagnosed or have a history of HIT
1) LMWH (enoxaparin)
Xa inhibitors: ID (1) consists only of the pentasaccharide (2) causes a permanent conformational change in antithrombin (3) it is not destroyed but released to interact with other antithrombin molecules (4) it has no direct effect on thrombin
Fondaparinux
it has no direct effect on thrombin
Fondaparinux
It is rapidly and completely absorbed (100% bioavailabilty) after subcutaneous administration
(2) eliminated renally and thus should not be used in patients with
severe renal impairment
Fondaparinux
Direct Factor Xa inhibitor not requiring antithrombin
Rivaroxaban
Inducer of P-gp will 1) concentration of Rivaroxaban;
inhibitors will 2).
Inducers of 3) will DEC. the concentration of Rivaroxaban;
1) DEC
2) INC
3) CYP3A4
Contraindication:
Anti-platelet drug (aspirin, clopidogrel) can increase the risk of bleeding
Rivaroxaban
Clinical use Rivaroxaban: Thromboprophylaxis in patients undergoing 1) Treatment and secondary prevention of 2)
1) hip or
knee replacement surgery
2) VTE (DVT or
pulmonary embolism)
Direct thrombin inhibitors:
Able to inhibit 1)
thrombin
1) circulating and clotbound
Direct thrombin inhibitors: c.1) is the most potent since it binds to both the active site and a second site on the thrombin molecule d. 2) bind only to the active site of thrombin
1) Lepirudin
2) Argatroban and dabigatran
1) is rapidly absorbed from the gastrointestinal
tract and converted by 2) to dabigatran, which is the
active form
1) Dabigatran etexilate
2) serine esterases
used in patients with HIT to prevent further
thromboembolic complications
Lepirudin and argatroban
Primary and secondary prevention of thromboembolism in patients with nonvalvular atrial fibrillation
Dabigatran
Dabigatran clinical use:
Primary and secondary prevention of thromboembolism in patients with nonvalvular atrial fibrillation
The drug inhibits vitamin K epoxide reductase which is the enzyme that
regenerates reduced vitamin K. its action occurs in the liver
warfarin
Warfarin has no effect on the activity on the clotting factors 1). Therefore the onset of warfarin activity depends upon
the rate of metabolism of the performed factors
1) that are
already formed
There is a delay of several days between the drug administration and the
peak anticoagulant effect
warfarin
Skin necrosis (Lesions are characterized by widespread thrombosis of
the microvasculature and can spread rapidly, sometimes becoming
necrotic and requiring debridement or amputation.)
warfarin
Fetal toxicity: it includes abortion, fetal bleeding and a characteristic
pattern of malformations called 1)
1) fetal warfarin syndrome
Absorption of warfarin in pt. taking cholestyramine
Reduced absorption b.c Warfarin binds to cholestyramine in the GIT;
Drug interactions associated with decreased effect of Warfarin:
1) Cholestyramine
2) Increased metabolic clearance of drug secondary to ____
induction of hepatic enzymes (e.g., barbiturates);
Effect on warfarin
Ingestion of large amounts of vitamin K-rich foods or supplements
Decreases effect of Warfarin
Drugs that INC. bioavailability of Warfarin and can cause hemorrhage:
1) drugs that inhibit P450 such as a);
2) Elimination of b)
3) Hormone replacement therapy for hypothyroid pts
a) Cimetidine;
b) intestinal flora by antibiotics
Hormone replacement therapy for hypothyroid pts; effect on Warfarin
INC. effect of warfarin
Hypothyroid patients catabolize coagulation factors 1)
than euthyroid patients. When thyroid function is normalized, anticoagulant effects can2) due to increased rate of catabolism of coagulation factors
1) more slowly
2) increase
Contraindicated in pregnancy
WARFARIN
Contraindicated in any disease that increases risk of hemorrhage
Warfarin
-Prevention and treatment of VTE
-In patients with a) and a presumed cardiac source of
embolism, warfarin is the antithrombotic agent of first choice for primary
and secondary prevention of b)
a) atrial fibrillation
b) ischemic stroke
Genetic variations in the 1) (responsible for metabolizing
warfarin) and vitamin K epoxide reductase (VKOR) have been shown to correlate with warfarin dose requirements
1) CYP2C9 isozyme
Routine monitoring of the 1) is used to
assess anticoagulation in Warfarin use; the goal range is determined by the therapeutic
indication; usually a target of 2) with an acceptable range of 3)
1) INR (International Normalized Ratio)
2) 2.5
3) 2.0-3.0.
Bleeding or high INR in WARFARIN
(1) administered orally or intravenously can be used to lower
the INR rapidly
-In cases of serious or life-threatening bleeding, 1) should be administered with 2)
1) Vitamin K
2) fresh-frozen plasma, clotting factor concentrates,
or recombinant factor VIII.
Treatment of acute venous thromboembolism (DVT or PE):
Initiate therapy with rapid-acting injectable anticoagulant such as 1)
Begin 2) concurrently with rapid-acting injectable
anticoagulant therapy;
1) (heparin, enoxaparin, fondaparinux)
2) warfarin therapy
1) is indicated for treatment of DVT but it does not have the long-term history for use in DVT as the injectable agents have
1) Rivaroxaban
Treatment of acute venous thromboembolism
Rapid acting injectable anticoagulant and warfarin concurrent therapy should overlap for 1) and until the INR is
at least 5 days;
2) INR is greater than or equal to 2.0
Treatment of acute venous thromboembolism:
The warfarin dose should be periodically adjusted to maintain an INR
between 1)
c. The minimum duration of warfarin therapy for an acute first episode of
VTE is 3 months
1) 2.0 and 3.0.
Advantage and disad. of Rivaroxaban over Warfarin
It does not need to be monitored;
however unlike warfarin it is NOT reversible
How to treat VTE in pregnant person;
Low-molecular weight heparins (e.g., enoxaparin);
1) can be used in
pregnant patients with severe allergic reactions to heparin (e.g., HIT).
1) Fondaparinux and parenteral direct thrombin inhibitors
- Pathophysiology of HIT:
a. Heparin binds 1) (released from activated platelets) forming a negatively charged polysaccharide molecule that is highly antigenic
b. 2) antibody production is stimulated and 2) complexes with heparin-PF4
c. The 3) complexes bind to Fc receptor on platelets leading to further activation of platelets and release of PF4
d. PF4 and heparin-like molecules bind to the surface of endothelial cells resulting in antibody-induced endothelial cell damage and the release of tissue factor
1) PF4
2) IgG
3) IgG-heparin-PF4
Heparin Induced Thrombocytpenia:
Net result: increased risk of thrombotic events secondary to 1)
1) platelet activation, endothelial damage, and thrombin generation
HIT:
Thrombotic complications
(1) VTE is most common including DVT and pulmonary embolism; a) is less common
(2) Skin lesions, venous limb gangrene and anaphylactic-type reactions after intravenous heparin are atypical manifestations
a) arterial thrombosis
Goal of therapy is to reduce the risk of thrombosis
HIT:
HIT: drug of choice
Direct thrombin inhibitors (argatroban or lepirudin) are the drugs of
choice in patients with or without thrombosis
HIT:
Patients without thrombosis receive therapy until the platelet count normalizes;
Patients with thrombosis should receive therapy with 1) and transition to 2) after platelet counts recover. 2)
therapy is then maintained for at least 6 months
1) direct thrombin inhibitors
2) warfarin
