ANTI COAGULANTS

Dr. Maria Khurshid

 Agents used for
controlling blood
fluidity/Hemostasis

Anticoagulant Anti platelets fibrinolytics

MOA OF ANTICOAGULANTS
1. By ↓ action of coagulation factors

2. By interfering synthesis
AN T IC O A G U L A N T S
DRUGS CLASSIFICATION
• Parenteral
• Direct
Thrombin inhibitor– argatroban, hirudin
• Indirect---UnFractionated Heparin, LMW, Fondaparinux
- Oral
• Direct
1. Thrombin inhibitor— dibagatric
2. Factor Xa inhibitor --rivaroxaban
• Indirect--- Vitamin K antagonist
HEPARIN & ITS DERIVATIVES (indirect parenteral)

• Heparin, LMWHs, and fondaparinux have no intrinsic

anticoagulant activity.

• Bind to antithrombin lll and accelerate the rate at which it

inhibits various coagulation proteases; unique
pentasaccharide sequence is needed for high-affinity
binding to antithrombin
• Antithrombin III is synthesized in liver and circulates in
plasma.

• Heparin & its derivatives activate Antithrombin III

inhibit factors Xa and to lesser extent activated thrombin

• Binding of these drugs catalytic action of ATIII 1000

times
18 or more saccharide units (molecular weight > 5400)= bridge thrombin & AT
HEPARIN & ITS DERIVATIVES
Pharmacokinetics:
• It is not orally-active so given by SC or IV.

• These drugs don’t cross BBB, blood placental barriersafe in

pregnancy

• Heparin metabolized by-- heparinase in liver & excreted in

urine

• Half life is longer in cirrhotic & kidney failure patients

HEPARIN & ITS DERIVATIVES

Clinical use:
1. Deep vein thrombosis
2. Pulmonary embolism
3. Prevention of thrombus in arterial and cardiac surgery’
ADVERSE EFFECT
1. Bleeding
2. Heparin induced thrombocytopenia– aggregation of
platelets
3. Alopecia
4. Osteoporosis
• High doses of heparin can interfere with platelet
aggregation and prolong the bleeding time. In contrast,
LMWH and fondaparinux have little effect on platelets

• Close monitoring of the activated partial thromboplastin

time (aPTT or PTT) is necessary in patients receiving
UFH.
CONTRAINDICATION
1. Bleeding disorder
2. Hemophilia
3. Hypersenstivity to drug
4. Severe hypertension
5. Ulcerative lesion in gut
6. Intracranial hemorhage
7. Threatened abortion
REVERSAL OF HEPARIN ACTION
1. Discontinuance of drug
2. If bleeding occurs, protamine sulfate is indicated
3. LMWH neutralization by protamine is incomplete.
4. Protamine donot reverse fondaparinux.
WARFARIN & OTHER COUMARINS

• Mechanism of action:
- Coagulation factors II, VII, IX, and X and proteins C and S
biologically inactive.

- 9–13 of the amino-terminal Glu residues are γ-carboxylated to

form the Ca2+-binding Gla domain.

- This carboxylation reaction uses reduced vitamin K and is

catalyzed by γ-glutamyl carboxylase.

- - Carboxylation is coupled to the oxidation of vitamin K to its

corresponding epoxide form.
Reduced vitamin K must be regenerated from the epoxide
form for sustained carboxylation and synthesis of functional
proteins.
The enzyme that catalyzes this reaction, VKOR is inhibited
by therapeutic doses of warfarin.
Warfarin (Pharmacokinetics)

• bioavailability nearly complete i.e almost 100%

• Food in GI tract can interfere in absorption
• Is mainly metabolized by cyp2C9
• Excreted in urine & stool
• Half life 25-60h
• Duration of action is 2-5 days
II, VII,IX,X (inactive) active
CLINICAL USE
1. Prevent progression or recurrence of acute deep vein
thrombosis or pulmonary embolism following heparin
therapy
2. Prevention of stroke, systemic embolization in pts. with
atrial fibrillation, mechanical heart valves
Monitoring
• PT should be increased  represent a reduction of
prothrombin activity decreased upto 25%

• If activity is less than 20%, warfarin dosage should be

decreased.

• The therapeutic range for oral anticoagulant therapy is

defined in terms of international normalized ratio (INR).

• Target range is 2-3. if it is below this range, risk of clotting

is there and if it higher range risk of bleeding.
ADVERSE EFFECT
1. Bleeding
2. Birth defects
3. Cutaneous necrosis
Drug interactions
Reversal of warfarin action
• Stop the drug
• Oral and parenteral vitamin K
• Fresh frozen plasma
• Prothrombin complex concentrate
• Recombinant factor VIIa

• Rapid reversal in severe bleeding by administration of

prothrombin complex or rFVIIa coupled with iv vitamin K.
ORAL DIRECT FACTOR Xa INHIBITOR
• Rivaroxaban, apixaban, edoxaban, betrixaban
• Need no monitoring

• MOA: inhibit factor Xa in the final common pathway of

clotting.
• Rapid onset of action
• Shorter half lives than warfarin
 Rivaroxaban Apixaban Edoxaban

bioavailability High oral 50% 62%

bioavailability

Half life 5-9hours 12 hours 10-14hours

Excretion 1/3rd excreted Urine/faeces urine

unchanged in
urine
Remainder
excreted in
urine/faeces

Substrate for cyp P Yes Yes No

450 & P glycoprotein
Clinical use
• Used in prevention of
1. embolic stroke in patients with non-valvular atrial
fibrillation
2. Venous thromboembolism following hip or knee surgery
Reversal of anti Xa drug action
• Andexanet alfa binds with factor X molecule to reverse
life threatening bleeding in patients treated with rivaroxa-
or apixaban.
Oral thrombin inhibitor
• DABIGATRAN:

Dabigatran etexilate mesylate, a prodrug converted to

diabagatran.
Oral bioavailability 3-7%
Substrate for  P-glycoprotein
Half life  12-17hours
Renal impairment results in prolonged drug clearance.
• Use in prevention of stroke and systemic embolism in
nonvalvular atrial fibrillation

• Dosage is 150mg twice daily in CrCl >30ml/min

• Dosage 75mg twice daily if CrCl is 15-30ml/min

Reversal of antithrombin drug effect
• Idarucizumab is a humanized monoclonal antibody Fab
fragment that binds to dabigatran and reverses the
anticoagulant effect.
PARENTERAL THROMBIN INHIBITOR
• lepirudin, bivalirudin, argatroban

• Hirudin a specific irreversible thrombin inhibitor form leech

saliva available in recombinant form as lepirudin
• Lepirudin is administered IV and monitored by aPTT.
• Excreted by kidney

• Bivalirudin, bivalent thrombin inhibitor, is administered IV,

with rapid onset of action. Short half life with 20%
clearance from kidney and other metabolic
• Argatroban:
• small thrombin inhibitor used in patients with
HIT with or without thrombosis & coronary angioplasty in
aptients with HIT
• Has short half life
• Given IV infusion
• Monitored by aPTT
THANKYOU