1) Warfarin is an oral anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent clotting factors in the liver through competitive antagonism of vitamin K. 2) It has a delayed onset of action of 8-12 hours and reaches its peak effect in 2-5 days by gradually reducing the synthesis of clotting factors II, VII, IX, and X. 3) Warfarin is used long-term to prevent thromboembolic events associated with conditions like atrial fibrillation, mechanical heart valves, and deep vein thrombosis.

1. ANTICOAGULANTS
(ORAL )
Dr.Sourya Mohapatra
DEPT.OF PHARMACOLOGY
SCBMCH

2. CLASSIFICATION:
I. Used in vivo
A. Parenteral anticoagulants
( i) Indirect thrombin inhibitors:
1.Unfractionated Heparin(UFH)
2.Low molecular weight heparins : enoxaparin ,dalteparin ,reviparin ,nadroparin, ardeparin, parnaparin
3.Selective factorXa inhibitor: Fondaparinux,
4.Heparinoids: Danaparoid
(ii) Direct thrombin inhibitors: Lepirudin, Bivalirudin, Argatroban
B. Oral anticoagulants
(i) Coumarin derivatives: Warfarin sodium, Bishydroxycoumarin( dicumarol),, Acenocoumarol
(Nicoumalone), Ethylbiscoumacetate
(ii) Indandione derivative: Phenindione.
(iii) Direct factor Xa inhibitors: Rivaroxaban
(iv) Oral direct thrombin inhibitor: Dabigatran etexilate

3. WARFARIN SODIUM
HISTORY:
▪ The clinical use of the coumarin anticoagulants began with the discovery of an
anticoagulant substance formed in spoiled sweet clover silage, which caused
hemorrhagic disease in cattle(1924).
▪ A chemist at the University of Wisconsin identified the toxic agent as
bishydroxycoumarin.
▪ Dicumarol, a synthesized derivative, and its congeners, most notably warfarin
(Wisconsin Alumni Research Foundation, with “-arin” from coumarin added
were initially used as rodenticides.
▪ In the 1950s, warfarin (under the brand name Coumadin) was introduced as an
antithrombotic agent in humans.
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4. MECHANISM OF ACTION
▪ Coumarin anticoagulants acting in vivo inhibit the synthesis
of vit K dependent clotting factors in liver.
▪ Act as competitive antagonists of vit K and lower the plasma
levels of functional clotting factors in a dose-dependent
manner.
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5. Vit K CYCLE
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6. PHARMACOLOGICAL ACTIONS
▪ Its anticoagulant effect results from a balance between partially
inhibited synthesis and unaltered degradation of the 4 vitamin
K–dependent clotting factors.
▪ This inhibition of coagulation is dependent on degradation half-
lives of clotting factors in circulation e.g 6h(VII), 24h(IX),
40h(X), and 60h.
▪ There is 8- to 12-hour delay in onset of action of warfarin----
synthesis of clotting factors diminishes within 2–4 hours of
warfarin administration----- anticoagulant effect develops
gradually over the next 1–3 days . 6

7. ▪ Therapeutic effect----- synthesis of clotting factors is reduced by 40–50%.
▪ Protein C, protein S (both having anticoagulant property) and osteocalcin
contain glutamate residues that require vit. K dependent γ carboxylation
are also inhibited .
▪ Lab monitoring done by-------INR (patient prothrombin time/mean
of normal prothrombin time for lab).
▪ Mutational change of the gene for the responsible enzyme, vitamin
K epoxide reductase (VKORC1), can give rise to genetic resistance
to warfarin in humans and rodents. 7

8. PHARMACOKINETICS
▪ Given as a racemic mixture of S- and R-warfarin .S-Warfarin is
3- to 5-fold more potent than R-warfarin.
▪ Bioavailability of warfarin is nearly complete ------- Orally,
intravenously, or rectally.
▪ Food in the GI tract -----decrease the rate of absorption
▪ Plasma warfarin concentrations peak in 2–8 h.
▪ The t1/2 varies (25–60 h), but the duration of action of warfarin is
2–5 days.
METABOLISM: LIVER ( CYP2C9).
EXCRETION: URINE AND STOOL.
▪ It crosses placenta and is secreted in milk; 8

9. Clinical Use
1.Prevent the progression or recurrence of acute deep vein thrombosis or
pulmonary embolism following an initial course of heparin, LMWH, or
fondaparinux .
2.Effective in preventing stroke or systemic embolization in patients with atrial
fibrillation, mechanical heart valves, or ventricular assist devices.
3 For treatment of acute venous thromboembolism, heparin, LMWH, or
fondaparinux usually is continued for at least 5 days after warfarin therapy is
begun.
(Frequent INR measurements are indicated at the onset of therapy to ensure that a therapeutic effect is
obtained. Once a stable dose of warfarin has been identified, the INR can be monitored every 3 to 4
weeks).
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10. ADMINISTRATION & DOSAGE
▪ Treatment with warfarin should be initiated with standard doses of 5–10 mg.
▪ The initial adjustment of the prothrombin time takes about 1 week, which usually
results in a maintenance dosage of 5–7 mg/d.
▪ For most indications, an INR range of 2–3 is used.
▪ A lower initial dose should be given to patients with an increased risk of bleeding,
including the elderly.
▪ Inherited polymorphisms in 2CYP2C9 and VKORC1 have significant effect on
warfarin dosing.
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11. ADVERSEEFFECTS
▪ BLEEDING ---- most important problem causing ecchymosis ,epistaxis,
hematuria, bleeding in the g.i.t. Intracranial or other internal haemorrhages may even
be fatal.
Bleeding -----therapy is not properly monitored, or when INR exceeds 4, or interacting
drugs/contraindications are present.
Treatment of bleeding due to oral anticoagulants consists of:
• Withhold the anticoagulant.
• Give fresh blood transfusion and fresh frozen plasma.
• Give vit K1---- specific antidote (slow iv infusion) --- takes 6–24 hours for the clotting factors to be
resynthesized and released in blood.
▪ Others : Cutaneous necrosis , alopecia, urticaria, dermatitis, fever, nausea, diarrhea,
abdominal cramps, and anorexia 11

12. CONTRAINDICATIONS
▪ All contraindications to heparin apply to these drugs as well.
▪ PREGNANCY:
Early pregnancy increases birth defects, especially skeletal abnormalities. It
can produce foetal warfarin syndrome—hypoplasia of nose, eye socket, hand
bones, and growth retardation.
Later in pregnancy------ CNS defects, foetal haemorrhage, foetal death and
accentuates neonatal hypoprothrombinemia.
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13. OTHER ORAL ANTICOAGULANTS:
COUMARIN DERIVATIVE:
▪ Bishydroxycoumarin (Dicumarol) not preferred now.
DICOUMAROL 50 mg tab.
▪ Acenocoumarol (Nicoumalone) The t½ of acenocoumarol as such is 8
hours, but an active metabolite is produced so that overall t½ is about 24
hours. Acts more rapidly. ACITROM, 1, 2, 4 mg tabs.
▪ Ethyl biscoumacetate It has a rapid and brief action; occasionally used to
initiate therapy, but difficult to maintain.
INDANDIONE DERIVATIVE
Phenindione : part from risk of bleeding, it produces more serious organ
toxicity; should not be used. DINDEVAN 50 mg tab.
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14. DRUG INTERACTIONS
A.Enhanced anticoagulant action
1. Broad-spectrum antibiotics: inhibit gut flora and reduce vit K production.
2. Newer cephalosporins (ceftriaxone, cefoperazone) cause
hypoprothrombinaemia by the same mechanism as warfarin —additive action.
3. Aspirin: inhibits platelet aggregation and causes g.i. and also displace
warfarin from protein binding site.
4.Body factors: hepatic ds.
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15. 4. Long acting sulfonamides, indomethacin, phenytoin and probenecid:
displace warfarin from plasma protein binding.
5. Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol,
amiodarone and metronidazole: inhibit warfarin metabolism
6. Tolbutamide and phenytoin: inhibit warfarin metabolism and vice
versa.
7. Liquid paraffin (habitual use): reduces vit K absorption.
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16. B. Reduced anticoagulant action
1. Barbiturates (but not benzodiazepines), carbamazepine, rifampin and
griseofulvin induce the metabolism of oral anticoagulants.
2. Oral contraceptives: increase blood levels of clotting factors.
3.Body factors : heriditary resistance.
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17. DIRECT FACTOR Xa INHIBITORS
▪ orally active drugs ----inhibit free and clot-associated factor Xa---- reduced thrombin
generation----reduced fibrin formation and platelet aggregation.
▪ act rapidly without a lag time (as in case of warfarin.), and have short-lasting action.
Rivaroxaban
▪ Orally active direct inhibitor of activated factor Xa ---80%oral BA.
▪ Its anticoagulant action develops rapidly within 3–4 hours of ingestion and lasts for ~24
hours.
▪ Metabolism : Kidney and liver
▪ Excretion: urine(max), feces.
▪ Plasma t½ is 7–11 hours.
▪ No laboratory monitoring of PT or aPTT, and is recommended after surgery for
prophylaxis of venous thromboembolism following total knee/hip replacement.
▪ Available for prophylaxis and treatment of DVT.
▪ Equally effective as warfarin for preventing stroke in patients with atrial fibrillation.
Side effects: bleeding, nausea, hypotension, tachycardia and edema.
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18. Direct Oral Thrombin Inhibitor
Dabigatran
▪ Dabigatran etexilate is a synthetic prodrug with a molecular
weight of 628 Da.
Mechanism of Action.
▪ Dabigatran etexilate is rapidly converted to dabigatran by
plasma esterases.
▪ Competitively and reversibly blocks the active site of free
and clot-bound thrombin.
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20. ADME
▪ Oral bioavailability of about 6%,
▪ A peak onset of action in 2 h, and a plasma t1/2 of 12–14
h.
▪ Dabigatran is given twice a day in capsule form.
(Capsules should be swallowed whole )
▪ Excretion: 80%-----excreted unchanged by KIDNEYS.
▪ No lab monitoring required.
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21. Therapeutic Uses
I. Treatment of acute venous thromboembolism after at least 5
days of parenteral anticoagulation with heparin, LMWH, or
fondaparinux.
II. Secondary prevention of venous thromboembolism.
III. Licensed for stroke prevention in patients with non valvular atrial
fibrillation .
IV.In some countries, lower-dose regimens of once-daily dabigatran
are licensed for thromboprophylaxis after knee or hip
arthroplasty.
Dabigatran is contraindicated for stroke prevention in patients
with mechanical heart valves
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22. ADVERSE EFFECTS
1. Bleeding is the major side effect of dabigatran.
▪ In elderly patients with atrial fibrillation-------about 3.0%.
▪ Additional risks for bleeding with dabigatran include renal
impairment and concurrent use of antiplatelet agents or
nonsteroidal anti-inflammatory drugs.
Idarucizumab is a humanized monoclonal antibody Fab fragment
that binds to dabigatran and reverses the anticoagulant effect. The
recommended dose is 5 g given intravenously.
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