A Presentation on-

ANTICOAGULANTS

Prepared & Presented By-KULDIP DEKA : Roll No: 19 : B. Pharm 4th

year

A Blood Clot Consists of platelets

meshed into fibrin A web-like accumulation

of strands with RBCs There are two major

facets of the clotting mechanism – the platelets, and the thrombin system

Platelets

Tiny cellular elements, made in the bone marrow, that travel in the bloodstream waiting for a bleeding problem to develop

When bleeding occurs, chemical reactions change the surface of the platelet to make it activated and become “sticky”

These activated platelets begin adhering to the wall of the blood vessel at the site of bleeding

Thrombin System

Calcium ions must be present for the thrombin system to begin

The thrombin system consists of several blood proteins that activate when bleeding occurs

The activated clotting proteins engage in a chemical reactions that finally produce a substance called fibrin

Fibrin strands stick to the exposed vessel wall, clumping together and forming a web-like complex of strands

Red blood cells become caught up in the web, causing a clot

Anticoagulants –

Drugs that help prevent the clotting (coagulation) of blood

Coagulation will occur instantaneously once a blood vessel has been severed

Blood begins to solidify to prevent excessive blood loss and to prevent invasive substances from entering the bloodstream

Classification of Anticoagulant-i)Used in vivo- A) Parenteral anticoagulants- i) Indirect thrombin inhibitors:

Heparin, Low molecular weight heparins, Fondaparinux, Danaparoid

ii) Direct thrombin inhibators: Lepirudin, Bivalirudin, Argatroban

B) Oral anticoagulants- i) Coumarin derivatives:

Bishydroxycoumarin, Warfarin sod,Acenocoumarol

ii) Indandione derivatives: Phenindione

iii) Direct factor Xa inhibators: Rivaroxaban

iv) Oral direct thrombin inhibator: Dabigatran etexilate

II) Used In vitro

A) HeparineB) Calcium complexing agents: E.g. – Sodium citrate

In vivo Parenteral anticoagulants-

Heparin Heparin is a naturally-occurring anticoagulant

produced by basophils and mast cells to prevent formation and extension of blood clots

Chemicaly Heparin is a non-uniform mixture contains polymer of 2 sulfated units having m.w 10,000 to 20,000

Heparin permits the body's natural clot lysis mechanisms, i.e. fibrinolysis, to work normally to break down previously formed clots

As the thrombokinase is released, it neutralizes the action of heparin to allow clotting to occur

Pharmacological action: Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro. It activate indirectly the plasma anti thrombin III and form Heparin-AT III complex and binds to clotting factors. Anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin mediated conversion of fibrinogen to fibrin. High dose of heparin inhibits platelets aggregation and prolonged bleeding time.

Pharmacokinetics: Heparin is a large, highly ionized molecule therefore not for orally absorbed. Injected i.v. it acts instantneously but in s.c. injection efeect develops after approx. 60 min. Doesn't cross BBB or placenta. Metabolites in liver and excreted in urine.Adverse effects: -Bleeding due to overdose - Thrombocytopenia is another common problem - Osteoporosis may develop on long term use of high dose. - In rare Hypersensitivity reactions are occurs.

Low molecular weight heparins(LMWH) Low molecular weight heparins (LMWHs) are obtained from heparin via chemical or enzymatical degradation. This procedure results in some heparin chains cleaving at the site where thrombin binds. Thus, LMWHs have a reduced capacity to inhibit thrombin, but the anti-factor Xa activity remains intact as this factor does not need the thrombin binding site. Pharmacokinetics- -Better s.c. bioavailibility 70-90% - Longer and more consistent monoexponential t ½ : 4-6 hrs. - Risk of osteoporosis after long time use is less than Heparin.

In vivo Parenteral anticoagulants- Directly thrombin inhibitors: They are recently developed anticoagulants bind directly to thrombin and inactivate it without combine with and activate AT III. Lepirudin: This recombinant preparation of hirudin binds to the catalytic and substrate recognition site of thrombin and inhibit directly. Injected i.v. in patients who are at risk of heparin induced thrombocytopenia. In prolong uses anaphylaxis may occurs. Its action cant be reversed by any antidote.Bivalirudin: Smaller peptide prepared synthetically which has actions and uses similar to lepirudin.

B)Oral anticoagulants:Warfarin sodium is an oral medication It is a synthetic derivative of coumarin, found naturally in many plants -- it decreases blood coagulation by interfering with vitamin K metabolism It stops the blood from clotting within the blood vessels and is used to stop existing clots from getting bigger and to stop parts of clots breaking off and forming emboli The most common side effects of warfarin are bleeding and bruising . Treatment is monitored by regular blood testing using the International Normalized Ratio (INR), which is a measure of how much longer it takes the blood to clot when oral anticoagulant drug is used.

Oral direct thrombin inhibitor:

Dabigatran etexilate: It is a prodrug which after oral administration is rapidly hydrolyzed to dabigatran a direct thrombin inhibitor which reversely blocks the catalytic site of thrombin and produces a rapid anticoagulant action.

An 'ideal anticoagulant' approved by US FDA.

Dabigatran and apixaban are approved to reduce the risk of stroke and thrombosis in patients. • Oral bioavialability is low and effect is consistent.• Plasma t ½ is 12-14 hrs. and duration of action is 24 hrs.

Clinical Use Of Anticoagulants: 1) Deep vein thrombosis(DVT) and pulmonary embolism(PE) 2) Unstable angina 3) Myocardial infarction(MI) 4) Cerbrovascular disease 5) Rheumatic heart disease 6) Vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, haemodialysis. 7) Defibrination syndrome.

Contraindications:In case of-a. Bleeding disorders, history of heparin

induced thrombocytopenia.b. Severe hypertension, piles, g.i.

ulcersc. Subacute bacterial endocarditis,

tuberculosis.d. Ocular and neurosurgery, lumbar

puncture.e. Chronic alcoholics, cirrhosis, renal

failuref. Aspirin and other antiplatelet drugs

should be used very cautiously during heparin therapy.

Major Side effects :A possible side effect of anticoagulants

is excessive bleeding (haemorrhage), because these medicines increase the time it takes for blood clots to form.*Signs of excessive bleeding can include:

Passing blood in urineSevere bruisingProlonged nosebleeds (lasting longer than 10

minutes)Bleeding gumsVomiting blood or coughing up bloodSudden severe back painDifficulty breathing or chest painIn women, heavy or increased bleeding from vagina

Possible other side effects include:Diarrhoea or constipation,feeling and being sick,Indigestion,Dizziness ,headaches,Rashes,itchy skin,hair loss,jaundice  etc.

ReferencesBook : Essentials of MEDICAL PHARMACOLOGY By- KD Tripathy:7th edition:Pubilshed by Jaypee Brothers Medical Publishers(p) Ltd: Section No 10:Internet : http://science.j rank.org/pages/419/Anticoagulants-How-works.htmlhttp://asheducationbook.hematologylibrary.org/cgi/reprint/2006/1/450http://www.medic8.com/healthguide/articles/warfarin.html