1.
Basic pharmacology of
the anticoagulant drugs
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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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11.
Contraindications
 HIT
 Hypersensitivity to the drug
 Active bleeding
 Hemophilia
 Severe hypertension
 Intracranial hemorrhage
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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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