ANTICOAGULANTS

DEFINITION
 Tissue factor pathway inhibitor: Effect on
factor Xa
 CLASSIFICATION
 Parenteral Anticoagulants
 Indirect Thrombin Inhibitors:

a. Heparins:
 High Molecular Weight:
o Unfractionated Heparin (UFH)
 Low Molecular Weight:
o Enoxaparin
o Dalteparin
o Danaproid

b. Synthetic Pentasaccharide
o Fondaparinux
 Direct Thrombin Inhibitors
o Hirudin
o Lepirudin
o Bivalirudin
o Argatroban

B. Oral Anticoagulants
 Coumarins
o Warfarin
o Dicumarol
 Indanediones
o Phenindione

 Oral Direct Thrombin Inhibitors

o Ximelagatran
o Dabigatran
 Oral Direct Factor Xa Inhibitors:
o Rivaroxaban
o Apixaban
Heparin
Standard Heparin or Unfractioned Heparin (UFH)

MW 5000-30000
Low MW Forms of Heparin preparations (2000-6000 MW)
Enoxaparin
Nadroparin
Dalteparin
 Sources of Heparin

 Pharmacokinetics
 Route of Administration
 Metabolism
 Excretion
MECHANISM OF ACTION
THERAPEUTIC USES

 Venous Thrombosis
 Pulmonary embolism
 Open Heart Surgery
 Hemodialysis
 MI
 During Angioplasty and placement of coronary stents
 Drug of choice in pregnancy
 Low Dose Heparin: Prophylaxis of postop DVT,emb
 To clear intravascular cannulae
 In vitro preservation of blood
 DIC
CONTROL OF HEPARIN DOSAGE

Activated Partial Thromboplastin Time

ADVERSE EFFECTS

 Bleeding, Thrombosis in very high dose

 Heparin Induced Thrombocytopenia
 Allergic Rxns
 Alopecia
 Osteoporosis, Skin Necrosis
 Abnormal LFTs
 Local Rxns at the Site of Injection
 Heparin Resistance

Antidote
Protamine Sulphate
CONTRAINDICATIONS

 Hypersensitivity
 Active Bleeding
 Thrombocytopenia
 Severe Hypertension
 Active Infections
 Hepatic, Renal Insufficiency
 Oral Direct Thrombin Inhibitors
 Dabigatran
 Uses

 Advantages
 Pharmacokinetics

Mechanism of Action
THERAPEUTIC USES

 DVT
 Pulmonary Embolism
 Acute MI
 Atrial Fibrillation
 Cardiac Surgery
Dose Monitoring
 PT
 INR = (PTpatient / PTcontrol) ISI
Adverse Effects

 Bleeding

 Skin rashes

 Blood dyscrasias

 Pregnancy-produce Foetal and Neonatal bleeding

 Depression of Bone Formation

 Cutaneous necrosis: dec activity of proteins C & S

 Phenindione causes red colour of urine  misleading

to haematuria
 INTERACTIONS
Increased Sensitivity to Oral Anticoagulants
1. Displacement of anticoagulant from its binding to
plasma protein.
Phenylbutazone and numerous NSAIDs Sulphonamides,
Co-trimoxazole
Oral anti-diabetic agents
Ethacrynic acid
Mefenamic acid
Nalidixic acid
Aspirin and numerous non-steroidal anti-
inflammatory agents may also interfere with platelet
function and prolong the bleeding time.
2. Inhibition of microsomal enzymes or competition for
them.
Alcohol
Disulfiram
Chloramphenicol
3. Depression of the formation of factors II, VII, IX and X
(i.e. vitamin K-dependent factors) in the liver.
Quinine, Quinidine
Thyroxine
4. Causation of Hepatic dysfunction
Anabolic steroids
5. Reduction of Vitamin K production by intestinal
bacteria.
Tetracyclines
6. Reduction of vitamin K absorption.
Liquid paraffin
7. Uncertain
Cimetidine causes increased sensitivity to
warfarin
Clofibrate probably causes reduced platelet
function and a more rapid turnover of the
vitamin-K-dependent clotting factors.
8. Renal damage.
9. Acute illness, weight loss or decreased intake of
vitamin K.
Decreased Sensitivity to Oral Anticoagulants

1. Genetic Variation.
Hereditary resistance may be a dominant trait.
2. Induction of hepatic microsomal enzymes by a number of drugs
Barbiturantes
Phenytoin
Dichloralphenazone
Ethchlorvynol
Glutethimide
Halperidol
Griseofulvin
Mercaptopurine
Rifampicin
It is belived that Nitrazepam, Diazepam and Flurazepam do
not have this effect.
3. Reduction of Antithrombin III level and a possible rise in
the levels of factor VII, IX or X.
Oral Contraceptives
Oestrogens
4. Increased excretion in the faeces.
Cholestyramine
Stopping the administration of a drug that
increases sensitivity will, of course, lead to a decrease in
sensitivity to anticoagulants.
 Pathological/ Physiological Factors Affecting
Warfarin Actions:
 Increased Warfarin Action:
 Malnutrition
 Liver Diseases
 Hyperthyroidism
 Newborns

 Decreased Warfarin Action:

 Pregnancy
 Genetic
DIFFERENCES BETWEEN HEPARIN & WARFARIN
HEPARIN WARFARIN
· Chemistry
o Mucopolysaccharide o Coumarin Derivative
· Structure
Large polymer, acidic o Small lipid soluble molecule
· Source
o Bovine Lungs o Semi-Synthetic
o Porcine int. Mucosa
· Site of action
o Blood O Liver
· Route of Adm:
o Parenteral (S/C, I/V) o Oral
DIFFERENCES BETWEEN HEPARIN & WARFARIN
HEPARIN WARFARIN
· Onset of action:
o Quick (in seconds) o Slow (36 – 48 hrs)

· Duration of Action Limited by half lives of

affected
factors being

o Short (10 – 15 min) o Long (4-7 days)

· Protein Binding
o Nil o Extensive

· Monitoring aPPT for regular O PT

heparin but not for LMM heparins
· Metabolites
OS.Warfarim-7–Hydroxy warfarin,
o Uroheparin
o R.Warfarin- Warfarin alcohol
Half Life 15-70 hrs
40-90 Min
HEPARIN
· Pregnancy & Lactation
o Safely given
· MOA
a. Acts by activating
Antithrombin III, forming a
complex with
Antithrombin III & activated
factors IXa, XIa, Xa, XIIa, XIIIa ,
accelerating the activity of
Antithrombin III to inactivate the
above factors & thrombin.
b. Acts like Lipemic Plasma
clearing factor
WARFARIN
o Contraindicated in Preg &
lactation
o Inhibits Vit – K dependent
synthesis of factor II, VII, IX
and X in the liver by inhibiting
gamma-carboxylation of glutamate
resides in the above mentioned
factors, by inhibiting the enzyme vit
K Epoxide reductase.
o Nil
HEPARIN
Therapeutics Uses
o Open Heart surgery,
o Perimtoneal dialysis,
o Haemodialysis, D.V.T and
Pulmonary Embolism
o Acute M I
o Pregnancy, Puerperium
o DIC
Adverse Effects
o Bleeding
o Allergic reactions
o Diarrhea osteoporosis
o Alopecia
Antidote for over dosage
(Protamine sulphate for regular
heparin
WARFARIN
O MI
O D.V.T
o Pulmonary Embolism
o CVA
o Atrial Fibrillation
o Cardiac surgery with artificial
valves implantation
o Bleeding, Fetal bleeding
o Fetal bone formation depressed
o Protein C inhibition with issue necrosis
o Interaction with enzyme inhibitors and
inducers
Vit K (phytomenadione), FFP