2. Learning objectives
To discuss the mechanisms of action of anticoagulants
To describe the side effects of heparin
To discuss the clinical management of heparin toxicity
To list the common adverse effects of warfarin
To discuss the drug interactions of warfarin
To describe the clinical management of warfarin toxicity
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3. Introduction
The ideal anticoagulant drug would prevent pathologic
thrombosis but allow a normal response to vascular injury
and limit bleeding
This could be accomplished by preservation of the TF-VIIa
initiation phase of the clotting mechanism
Practically , such a drug does not exist;
All anticoagulants have an increased bleeding risk
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4. Indirect thrombin inhibitors
Antithrombotic effect is exerted by their interaction with a
separate protein, antithrombin
Unfractionated heparin (UFH)
lowmolecular-weight heparin (LMWH)
Fondaparinux
Bind to antithrombin and enhance inhibition of clotting factor
proteases
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5. Heparin
Chemistry & Mechanism of Action
A heterogeneous mixture of sulfated mucopolysaccharides
Its biologic activity is dependent upon the endogenous
anticoagulant antithrombin
Antithrombin inhibits clotting factor proteases, especially thrombin
(IIa), IXa, and Xa, by forming stable complexes with them
In the absence of heparin, these reactions are slow; in the
presence of heparin, they are accelerated 1000-fold
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6. Cont..
The active heparin molecules bind tightly to
antithrombin and cause a conformational change in
this inhibitor
The conformational change of antithrombin exposes
its active site for more rapid interaction with the
proteases (the activated clotting factors)
Heparin functions as a cofactor for the antithrombin-
protease reaction without being consumed
Once the antithrombin-protease complex is formed,
heparin is released intact for renewed binding to more
antithrombin
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7. Cont..
High-molecular-weight (HMW), also known as UFH
HMW : fractions of heparin with high affinity for antithrombin
low-molecular-weight (LMW) fractions of heparin have less effect on
thrombin than the HMW species
LMW heparins such as enoxaparin, dalteparin, and tinzaparin
LMWHS are effective in several thromboembolic conditions
LMW heparins—in comparison with UFH
equal efficacy
increased bioavailability from the subcutaneous site of injection
less frequent dosing requirements (once or twice daily is sufficient)
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8. Toxicity
A. Bleeding and miscellaneous effects
The major adverse effect of heparin is bleeding
Elderly women and patients with renal failure are more prone to
hemorrhage
Heparin is of animal origin and should be used cautiously in
patients with allergy
Increased loss of hair and reversible alopecia have been
reported
Long-term heparin therapy is associated with osteoporosis and
spontaneous fractures
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9. B. Heparin-induced thrombocytopenia
(HIT) is a systemic hypercoagulable state that occurs in 1–
4% of individuals treated with UFH for a minimum of 7 days
Surgical patients are at greatest risk
The risk of HIT may be higher in individuals treated with
UFH of bovine origin and is lower in those treated with
LMWH
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10. Reversal of heparin action
If bleeding occurs, administration of a specific antagonist such as
protamine sulfate is indicated
Protamine is a highly basic, positively charged peptide that combines
with negatively charged heparin as an ion pair to form a stable complex
devoid of anticoagulant activity
For every 100 units of heparin remaining in the patient, 1 mg of
protamine sulfate is given intravenously
the rate of infusion should not exceed 50 mg in any 10-minute period
Excess protamine must be avoided; it also has an anticoagulant effect
Neutralization of LMW heparin by protamine is incomplete
1 mg of protamine sulfate may be used to partially neutralize 1 mg of
enoxaparin
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12. Direct thrombin inhibitors
Exert their anticoagulant effect by directly binding to
the active site of thrombin
Thereby inhibiting thrombin’s downstream effects
Hirudin and bivalirudin are bivalent DTIs in that they
bind at both the catalytic or active site of thrombin as
well as at a substrate recognition site
Argatroban and melagatran are small molecules that
bind only at the thrombin active site
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13. Cont.…
Hirudin
A specific, irreversible thrombin inhibitor
Now available in recombinant form as lepirudin
it must be administered parenterally
Lepirudin is approved by the FDA for use in patients with thrombosis
related to heparin-induced thrombocytopenia
Lepirudin is excreted by the kidney and should be used with great
caution in patients with renal insufficiency
No antidote exists
Up to 40% of patients who receive long-term infusions develop an
antibody directed against the thrombin-lepirudin complex
These antigen-antibody complexes are not cleared by the kidney and
may result in an enhanced anticoagulant effect
Some patients re-exposed to the drug have developed life-threatening
anaphylactic reactions
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14. Bivalirudin
Another bivalent inhibitor of thrombin
Is administered intravenously
With a rapid onset and offset of action
The drug has a short half-life with clearance that is
20% renal and the remainder metabolic
Also inhibits platelet activation and has been FDA-
approved for use in percutaneous coronary angioplasty
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15. Oral direct factor XA inhibitors
Rivaroxaban and apixaban
Inhibit factor Xa, in the final common pathway of clotting
Approved in advanced stages of development and along with
oral thrombin inhibitors
Given as fixed doses and do not require monitoring
They have a rapid onset of action and shorter half-lives than
warfarin
Half-life may be prolonged in elderly patients or those with renal
impairment
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16. Oral direct thrombin inhibitors
Advantages of oral direct thrombin inhibitors
o Predictable pharmacokinetics and bioavailability, which
allow for fixed dosing and predictable anticoagulant
response
o Make routine coagulation monitoring unnecessary
Dabigatran etexilate mesylate is the first oral direct
thrombin inhibitor approved by the FDA
Dabigatran was approved in 2010 to reduce risk of
stroke and systemic embolism with atrial fibrillation
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17. Warfarin
Pharmacokinetics
In the 1950s warfarin (under the brand name Coumadin)
was introduced as an antithrombotic agent in humans
Warfarin is generally administered as the sodium salt
has 100% bioavailability
Over 99% of racemic warfarin is bound to plasma albumin,
Small volume of distribution (the albumin space)
Long half-life in plasma (36 hours)
The lack of urinary excretion of unchanged drug
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18. A racemic mixture composed of equal amounts of
two enantiomorphs
The levorotatory S-warfarin is four times more
potent than the dextrorotatory R-warfarin
Stereoselective nature of several drug interactions
involving warfarin
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19. Mechanism of action
Coumarin anticoagulants block the γ-carboxylation of several
glutamate residues in prothrombin and factors VII, IX, and X as well
as the endogenous anticoagulant proteins C and S
The blockade results in incomplete coagulation factor molecules that
are biologically inactive
The protein carboxylation reaction is coupled to the oxidation of
vitamin K. The vitamin must then be reduced to reactivate it
Warfarin prevents reductive metabolism of the inactive vitamin K
epoxide back to its active hydroquinone form
Mutational change of vitamin K epoxide reductase, can give rise to
genetic resistance to warfarin
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20. Toxicity
warfarin should never be administered during pregnancy
Crosses the placenta readily and can cause a hemorrhagic
disorder in the fetus
The drug can cause a serious birth defect characterized by
abnormal bone formation
Cutaneous necrosis with reduced activity of protein C
sometimes occurs during the first weeks of therapy
The pathologic lesion associated with the hemorrhagic infarction
is venous thrombosis, suggesting that it is caused by warfarin-
induced depression of protein C synthesis
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21. Drug interactions
Interactions can be broadly divided
pharmacokinetic
pharmacodynamic
Pharmacokinetic mechanisms
enzyme induction,
enzyme inhibition,
reduced plasma protein binding
Pharmacodynamic mechanisms
synergism
competitive antagonism
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22. Cont..
The most dangerous of these interactions are the pharmacokinetic
interactions with the mostly obsolete pyrazolones phenylbutazone and
sulfinpyrazone
These drugs not only augment the hypoprothrombinemia but also inhibit
platelet function and may induce peptic ulcer disease
The mechanisms for their hypoprothrombinemic interaction are a
stereoselective inhibition of oxidative metabolic transformation of S-warfarin
and displacement of albumin- bound warfarin, increasing the free fraction
Metronidazole, fluconazole, and trimethoprim-sulfamethoxazole also
stereoselectively inhibit the metabolic transformation of S -warfarin
Amiodarone, disulfiram, and cimetidine inhibit metabolism of both
enantiomorphs of warfarin
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23. Aspirin, hepatic disease, and hyperthyroidism
augment warfarin’s effect
The third-generation cephalosporins eliminate the
bacteria in the intestinal tract that produce vitamin K
and, like warfarin, also directly inhibit vitamin K
epoxide reductase
Barbiturates and rifampin cause a marked decrease of
the anticoagulant effect
Cholestyramine reduces its absorption and
bioavailability
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24. Pharmacodynamic reductions of anticoagulant effect occur
o with vitamin K (increased synthesis of clotting factors)
o the diuretics chlorthalidone and spironolactone (clotting factor
concentration)
o hypothyroidism (decreased turnover rate of clotting factors)
Drugs with no significant effect on anticoagulant therapy include
o Ethanol
o Phenothiazines
o Benzodiazepines
o Acetaminophen
o Opioids
o indomethacin
o most antibiotics
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25. Reversal of warfarin action
Excessive anticoagulant effect and bleeding can be reversed by
stopping the drug and administering oral or parenteral vitamin K 1
(phytonadione), fresh-frozen plasma, prothrombin complex concentrates
such as Bebulin and Proplex T, and recombinant factor VIIa (rFVIIa)
Excess of anticoagulant effect without bleeding may require no more
than cessation of the drug
Important to note that due to the long half-life of warfarin, a single dose
of vitamin K or rFVIIa may not be sufficient
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