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ANTICOAGULANTS
(ORAL )
Dr.Sourya Mohapatra
DEPT.OF PHARMACOLOGY
SCBMCH
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
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.
3
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.
4
Vit K CYCLE
5
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
▪ 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
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
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).
9
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.
10
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
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.
12
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.
13
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.
14
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.
15
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.
16
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.
17
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.
18
19
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.
20
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
21
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.
22
23

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Oral anticoagulants

  • 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. 3
  • 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. 4
  • 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). 9
  • 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. 10
  • 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. 12
  • 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. 13
  • 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. 14
  • 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. 15
  • 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. 16
  • 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. 17
  • 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. 18
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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. 20
  • 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 21
  • 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. 22
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