16. Anticoagulant

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ANTICOAGULANTS

By Dr Ayesha Afzal





INDIRECT THROMBIN INHIBITORS

Unfractionated Heparin

Low molecular weight Heparins

Enoxaparin

DalteparinFondaparinux

DIRECT THROMBIN INHIBITORS

Hirudin

LepirudinArgatroban

Dabigatran

CLASSIFICATION



VITAMIN K ANTAGONISTS

Coumarin Derivatives

Warfarin , Dicoumarol

Nicoumalone , AcenocumarolIndandione Derivatives

Phenindione, Diphenindione,Anisindione.

CALCIUM CHELATORSK- Oxalate

K- Citrate

Na –

CitrateEDTA (Etmylene Diamine Tetra

Acetic Acid)



HEPARIN - CHEMISTRY

Heparin consists of Heterogenous group of straight

chain anionic mucopolysaccharides of molecular

weights that average 15000. Commercial heparinconsists of polymers of two repeating sulphated

disaccharide units. These are D-glucosamine-L-

iduronic acid and D-glucosamine-D-glucuronic acid.



HISTORY

SOURCE

PHYSIOLOGICAL ACTIONS

MOA

Anticoagulant Effect

Lipolytic Effect

PHARMACOKINETICS

Route of administration Distribution

Metabolism





Heparin Dose is prescribed in Units

Unit of Heparin

The USP unit of Heparin is defined as the quantity

of Heparin that prevents 1.0 ml of citrated sheepplasma from clotting for 1 hour after the addition

of 0.2 ml of 1% Calcium chloride (CaCl2) solution.



Heparin

Standard Heparin or Unfractioned Heparin (UFH)

MW 5000-30000

Low MW Forms of Heparin preparations (2000-6000 MW)

Enoxaparin

Tinzaparin

Dalteparin

Fondaparinux



Control of Heparin Doses

Whole blood Clotting time to be maintained at 2-3 times the

control value.

OR

Activated Partial Thromboplastin Time (aPTT) maintaining

1.5 – 2.5 times control reading. (most commonly

employed)



Heparin Doses:- Treatment of Coronary / Thrombosis/

Thromboembolism 5000 – 10,000 Units I/V bolus then 1000 U/hr

10,000 U bolus, then 5000-10,000 U 4 hrly

Intermittently 1/V

Major Surgery for prevention of Thromboembolism

S/C dose 5000 units 2 hours before major

operation followed by 5000 units 8 hrly for

7 – 14 days.

Low dose (Minihep)

5000U S/C



THERAPEUTIC USES

1. To depress clotting during the first 36 - 48 hours of oral anticoagulant therapy for the treatment of venous thrombosis and pulmonary embolism or maybe employed as the sole anticoagulant for a longerperiod in pts who experience recurrent thrombo-embolism despite adequate oral anticoagulanttherapy e.g. Trousseau’s syndrome.

2. To prevent clotting during open heart surgery(cardiopulmonary bypass)

3. To prevent clotting during Haemodialysis.4. Acute myocardial infarction.



5. In combination with thrombolytics for

revascularization and in combination with

glycopotein IIb/IIIa inhibitors duringangioplasty and placement of coronary

stents

6. Drug of choice in pregnancy when ananticoagulant must be used.

7. Low- dosage Heparin used in preventing post

operative DVT (Deep Venous Thrombosis)and Pulmonary Embolism.



8. To Prevent Venous Thrombosis during

pregnancy and puerperium for 5-6

weeks after delivery.

9. Used intraperitoneally during Peritoneal

Dialysis.10. To clear intravascular cannulae.

11. DIC

12. To preserve blood in vitro.



ADVERSE EFFECTS

Overdose may cause bleeding.

A painful, blue-ting discoloration of the plantersurfaces and sides of toes.

Thrombocytopenia

Transient Alopecia

Diarrhoea

Allergic Reactions: Urticaria, Asthma andAnaphylactic shock.

Osteoporosis leading to spontaneousvertebral fractures.



Thrombosis in very high doses due to

depletion of antithrombin-III.Abnormalities in liver functions

Skin lesions at the site of SC injections



ANTIDOTE

Protamine sulphate obtained from Salmon sperm

Heparin1% solution given I / V.

For each Heparin (100U) 1 mg of Protamine

sulphate.

LMWH



CONTRAINDICATIONS

1. Hypersensitivity to the drug2. Haemophilia

3. Thrombocytopaenia

4. Purpura

5. Severe hypotension

6. Intracranial Haemorrhage

7. Infective endocarditis



8. Active TB

9. Ulcerative lesions of GIT

10. Threatened Abortion

11. Visceral Carcinoma

12. Advance Hepatic & Renal disease

13. Recent operation on Eye, Brain & Spinal

Cord

14. During Lumbar Puncture

ORAL ANTICOAGULANTS



ORAL ANTICOAGULANTS WARFARIN – Na

PHENINDIONE

CHEMISTRY



WARFARIN

PHARMACOKINETICS

Dose:

Initial dose: 5 – 10 mg

Maintenance dose: 5 – 7 mg daily.



MOA of Oral Anticoagulants





THERAPEUTIC USES OF WARFARIN

1. Acute MI.

2. DVT .

3. Pulmonary Embolism.

4. Cerebrovascular diseases.

5. Atrial Fibrillation.

6. Cardiac Surgery.



Control

I One stage Prothrombin Time

Ratio of the Prothrombin Time of patients IIIplasma to the Prothrombin Time of

control plasma being kept at 2.5 –

3.5II INR = PT pt

ISI

PT ref

INR is International Normalized Ratio

ISI is International Sensaty Index



ADVERSE EFFECTS

Bleeding

Skin rashes

Blood dyscrasias, Jaundice, Pyrexia, Nausea &Vomiting, Anorexia

Pregnancy-produce Fetal and Neonatal bleeding

Depression of Bone Formation

Cutaneous necrosis due to decreased synthesis of ProteinC Infarction of breast, Necrosis of fatty tissue,intestines and extremities

Alopecia



Phytonadione

Dose : 10 – 25 mg slow I/V.

Neonates 1mg slow I/V.

Severe cases of bleeding:-

Phytonadione IV+ Fresh Frozen

Plasma I/V.rVII

ANTIDOTE

INTERACTIONS



INTERACTIONS

Increased Sensitivity to Oral Anticoagulants

1. Displacement of anticoagulant from its bindingto 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 plateletfunction and prolong the bleeding time.



2. Inhibition of microsomal enzymes or competition forthem.

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, Cincophen

Thyroxine

4. Causation of Hepatic dysfunction

Anabolic steroids

5. Reduction of Vitamin K production by intestinalbacteria.

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.

DIFFERENCES BETWEEN HEPARIN & WARFARIN




HEPARIN

Chemistry

o Mucopolysaccharide

WARFARIN

o Coumarin Derivative Structure

Large polymer, acidc o Small lipid soluble molecule

Source

o Bovine Lungs

o Porcine int. Mucosa

o Semi-Synthetic

Site of action

o Blood

O Liver

Route of Adm:

o Parenteral (S/C, I/V) o Oral





HEPARIN

Onset of action:

o Quick (in seconds)

WARFARIN

o Slow (36

–

48 hrs)

Duration of Action

o Short (10 – 15 min)

Limited by half lives of factors being

affected

o Long (4-7 days)

Protein Bindingo Nil o Extensive

Monitoring aPPT for regular

heparin but not for LMM heparins

O PT

Metabolites

o Uroheparin OS.Warfarim-7 – Hydroxy warfarin,

o R.Warfarin- Warfarin alcohol

Half Life

40-90 Min

15-70 hrs

HEPARIN WARFARIN



HEPARIN

Pregnancy & Lactation

o Safely given

WARFARIN

o Contraindicated in Preg &

lactation

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.

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.

b. Vasodilator o Nil

c. Acts like Lipemic Plasma

clearing factor

o Nil

HEPARIN WARFARIN



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

WARFARIN

O MI

O D.V.T

o Pulmonary Embolismo CVA

o Atrial Fibrillation

o Cardiac surgery with artificial

valves implantation

Adverse Effects

o Bleeding

o Allergic reactions

o Diarrhea osteoporosis

o Alopecia

o Bleeding, Fetal bleeding

o Fetal bone formation depressed

o Protein C inhibition with issue necrosis

o Interaction with enzyme inhibitors and

inducers

Antidote for over dosage

(Protamine sulphate for regular heparin Vit K1 (phytonadione),

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16. Anticoagulant

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