Oral anticoagulants

Warfarin is a vitamin K antagonist. It antagonizes the cofactor functions of vitamin K.

Firstly, it was used as rodenticide.

Mechanism of action:

Factors like II, VII, IX, and X and certain natural anticoagulants such as protein C require vitamin K as cofactor for their synthesis.

These factors undergo vitamin K dependent posttranslational modification resulting in the carboxylation of glutamic acid residue which is converted into γ-carboxyglutamic acid residue by vitamin K dependent carboxylase. This residue gets bind to calcium ions, which is important for interaction between coagulation factors and platelet membranes.

The reduced form of vitamin K cofactor (active hydroquinone form) is changed into vitamin K epoxide during reaction. Vitamin K cofactor is regenerated by vitamin K epoxide reductase.

Warfarin inhibits this enzyme leading to inactive coagulation factors due to lack of γ-carboxyglutamyl chain.

Therapeutic Uses:

It is used for prophylaxis therapy of pulmonary embolism and venous thrombosis.

Pharmacokinetics:
It is readily absorbed by oral ingestion. 99% bind to plasma albumin leading to stoppage of its movement to CSF, breast milk and urine. Its onset of action is 8-12 hours.

It can cross placenta.

It is metabolized by cytochrome P450 system and its half life is variable ranging from 40-60 hours. Elimination is done through urine and feces after conjugation with glucuronic acid.

Dosage:
It is given in the dose of 2-5 mg for one week daily.

Adverse effects:
It may cause hemorrhage. In this case, dose must be adjusted. It can be controlled by intravenous administration of vitamin K. Plasma concentrates of the blood factors may be employed in severe cases. It may also cause rashes, diarrhea and alopecia.

Drug Interactions:
Food may delay its absorption.

Drugs having higher attraction for albumin binding sites such as sulfonamides can displace warfarin leading to short duration of increased activity.

Contraindications:
It is contraindicated in pregnancy as it is teratogenic and can lead to abortion.

Antidote:
Vitamin-K

Danaparoid

It is a complex of sulfates of heparin, dermatan and chondroitin. It acts through antithrombin III. It is anti-factor Xa and to a lesser extent it is also inhibitor of thrombin.


Extraction:
It is obtained from porcine mucosa.

Administration and elimination:
It is administered subcutaneously and is eliminated through kidneys.

Therapeutic uses:
Prophylactically, it is used in deep vein thrombosis in hip replacement surgery.

It is effective in Type-II, heparin induced thrombocytopenia.

Adverse effects:
Allergic reactions such as anaphylaxis or asthma may develop. Hemorrhage may occur.

Excess danaparoid can be displaced by plasmapheresis.

Lepirudin

It is a polypeptide and highly specific direct thrombin antagonist whereas it shows no effect on antithrombin-III.


Production:
It is synthesized by recombinant DNA technology in yeast cells.

Mechanism of action:
One molecule of lepirudin gets bind to one molecule of thrombin causing stoppage of thrombogenic effect of thrombin.

Administration:
It is administered intravenously.

Pharmacokinetics:
It undergoes hydrolysis in the body. Its half life is 1 hour. Drug and its metabolites are excreted in the urine.

Therapeutic uses:
It is used effectively in the treatment of thrombocytopenia induced by heparin.

It is also used for other thromboembolic disorders and also causes stoppage of further thromboembolic complications.

Adverse effects:
It may cause bleeding. The drug forms complex with antibody in the body and anticoagulant effect may be elevated, than required, by the slower rate of excretion of the drug-antibody complex from the body.

It may also cause certain allergic reactions of the skin and air passages.

Heparin

Introduction:

Presence in the body:

It is present in the body in the form of histamine-macromolecule complex in the mast cells. (Its functional role in the body is not much clear.)

Extraction of heparin:
It is obtained on commercial scale from

1. Porcine intestine
2. Bovine lung

Properties of heparin:
1. Unfractionated heparin is a mixture of straight chain anionic glycosaminoglycans with wide range of molecular weight.
2. Due to the presence of sulfate group and carboxylic acid groups it is strongly acidic.

Enoxaparin is a low molecular weight (LMWH) heparin. LMWH are prepared by either chemical or enzymatic depolymerization of unfractionated heparin.

Mechanism of action:
It causes a decreased formation of fibrin by changing the activity of plasma protease inhibitor antithrombin III.

Where as enoxaparin binds to anti-thrombin and affects more on Factor Xa as compared to thrombin (Factor IIa).

Therapeutic Uses:
Heparin is used mostly in postoperative venous thrombosis and various other thrombotic diseases such as pulmonary embolism and myocardial infarction.

It is also used in extracorporeal devices such as dialysis machine to prevent thrombosis.

Note: Heparin and enoxaparin are drugs of choice in venous thromboembolism in pregnancy as they do not cross placenta.

Administration:
Heparin is administered IV or deep subcutaneously. And enoxaparin is administered subcutaneously.

Pharmacokinetics:
Heparin has rapid onset of action and this action is finished rapidly after the stoppage of treatment with heparin.

Anticoagulant effect of heparin takes place within minutes after IV injection and 1-2 hours after subcutaneous injection. Anticoagulant effect of LMWH takes about 4 hours to take place after subcutaneous injection.

When heparin gets bind to plasma proteins the activity is neutralized.

Although heparin remains in the general circulation but when taken up by monocyte or macrophage system, it undergoes depolymerization and desulfation leading to inactive products.

The drug and its metabolites are excreted through urine.

Half life of LMWH is approximately 4 hours which is nearly double than that of larger species. Renal insufficiency may prolong its half life.

Dosage:
It is given prophylactically in the dose of 5000 units subcutaneously, two or three times in a day.

For diseases which have already been developed, initially 5000-10,000 units will be given intravenously followed by continuous infusion of 900 units per hour.

Adverse effects:
Enoxaparin causes less thromboembolic problems than heparin.

Some of the adverse effects common to them are:

1. Hemorrhage

2. Hypersensitivity reactions such as fever, chills, urticaria and anaphylactic shock.

3. Chronic administration can decrease antithrombin III activity leading to thrombosis.

4. Transient alopecia can also occur.

5. Heparin induced thrombocytopenia (platelet count can decrease up to 50%), which is of two types:

Type-I: which is mild and is for 1st 5 days

Type-II: Which is IgG mediated and is very serious and is with in 5-14 days

Antidote:
Protamine sulfate

Classification of anti-coagulants

These drugs prevent the clotting of the blood.


Oral Anti-coagulants:
Warfarin Na, Phenprocoumon, Dicumarol (Bishydroxycoumarin), Diphenadione, Phenindione, Acenocoumarol, Coumetarol

Thrombin inhibitors:
Heparin, Hirudin, Enoxaparin, Hirugen, Lepirudin, Danaparoid

Fibrinolytic (Thrombolytic) drugs:
Streptokinase (Plasminokinase), Anistreplase, Urokinase, Tissue plasminogen activator, Staphylokinase

Anti-thrombotic drugs:
Aspirin, Dipyridamole, Ticlopidine, Sulfinpyrazone, Clopidogrel, Abciximab, Eptifibatide, Tirofiban

Extra-vascular anti-coagulants:
Fluorides, Citrates, Oxalates

Natural anti-coagulants present in the body

These are of the following types:

1. Those that causes inhibition of fibrin (Fibrin Inhibitors)
These are basically inhibitors of protease. They causes the inhibition of coagulation proteins as they move from the site of vessel injury.

2. Those that causes lysis of fibrin (Fibrinolytics)
These are basically tissue plasminogen activators.

Hemostasis

It refers to the spontaneous arrest of the flow of blood from a vessel which is damaged.
Hemostatic response:
Vasospasm:
Vessels become spasmodic suddenly after the vessel is damaged.

Formation of platelet plug:
After the endothelium is damaged the platelets get stick to collagen as well as to each other resulting in the formation of platelet plug.

Several factors are released by platelets such as ADP, TXA2, and serotonin which results in further aggregation of platelets as well as vasoconstriction.

Next in the process, aggregated plug of platelets make it possible for the platelet factor 3 availability leading to the sequence of coagulation process further to take place.

Fibrin reinforcement of platelet plug:
A series of reactions are activated after the stimulation of coagulation system. Coagulation system works through two interrelated processes – Intrinsic and extrinsic processes.

Extrinsic pathway:
Extrinsic denotes something that comes from outside. Extrinsic pathway denotes a series of reactions which is activated by tissue factor that comes from outside of blood.

It activates Factor VII by a tissue factor i.e. thromboplastin

Intrinsic Pathway:
Intrinsic denotes something which is found in body part. In the intrinsic pathway proteins for the activation of the process of blood coagulation are present in the blood.
Intrinsic process activates Factor XII.
Both of these processes mainly activate the formation of thrombin.
And in the final result fibrin molecules are released which are helpful for giving firmness to the platelet plug.