ANTI-COAGULANTS : A BRIEF OUTLOOKPRESENTED BY:VISHNU.R.NAIRPHARM-D THIRD YEARNATIONAL COLLEGE OF PHARMACY (NCP), KERALA STATE SUBJECT : PHARMACOLOGY

INDEX: DEFINITION OF ANTICOAGULANTS CLASSIFICATION BLOOD CLOTTING FACTORS BRIEF OUTLOOK OF PARENTERAL ANTICOAGULANTS BRIEF OUTLOOK OF ORAL ANTICOAGULANTS BIBLIOGRAPHY

DEFINITION OF ANTICOAGULANTS : “ Drugs, that are used to reduce the COAGULABILITY (coagulating

capacity) of blood “……………………………..

Classification of anti-coagulants :IN – VIVO DRUGS :- PARENTERAL ANTICOAGULANTS:A. HEPARINS:1. High molecular weight Heparins :• Unfractionated heparin (UFH)2. Low molecular weight Heparins :• Enoxaparin• Dalteparin• Tinzaparin

CONTINUED………………………….• Reviparin• DanaparoidB. HEPARINOIDS:- Heparan sulphate- Hirudin- Lepirudin- Bivalirudin- Argatroban

CONTINUED……………………………..- ORAL ANTICOAGULANTS:1. COUMARIN DERIVATIVES:• Bishydroxycoumarin (Dicumarol)• Warfarin sodium• Acenocoumarol (Nicoumalone)• Ethyl biscoumacetate 2. INDANDIONE DERIVATIVES :* Phenindione

CONTINUED……………………………..IN – VITRO DRUGS:1. Heparin2. Sodium citrate (used in blood banks to store blood)3. Sodium oxalate (used as anticoagulant in laboratory)4. Sodium edetate (used as anticoagulant in laboratory)

………………….

Blood clotting factors : FACTOR I : FIBRINOGEN FACTOR II : PROTHROMBIN FACTOR III : TISSUE FACTOR / THROMBOPLASTIN FACTOR IV : CALCIUM FACTOR V : PROACCELERIN (LABILE FACTOR ) FACTOR VI : NOT AN INDEPENDENT FACTOR FACTOR VII : PROCONVERTIN (STABLE FACTOR) FACTOR VIII : ANTI-HEMOPHILIC FACTOR (GLOBULIN) ‘A’ FACTOR IX : ANTI-HEMOPHILIC FACTOR ‘B’ (CHRISTMAS FACTOR)

CONTINUED………………………………… FACTOR X : STUART- PROWER FACTOR FACTOR XI : PLASMA PROTHROMBIN ANTECEDENT FACTOR FACTOR XII : HAGEMANN FACTOR FACTOR XIII : FIBRIN- STABILIZING FACTOR (LAKI-LORAND

FACTOR)…………………………

PARENTERAL ANTICOAGULANTS : Here , we will discuss on HEPARIN and associated

HEPARINOIDS………………….

HEPARIN

1. GENERAL PROPERTIES : Discovered by McLean Howell and Holt named the word “HEPARIN” in 1918 Mainly occurs in MAST CELLS Richest source of MAST CELLS:1. Lungs2. Liver3. Intestinal mucosa• Commercial heparin is synthesized from :1. Porcine intestinal mucosa2. Bovine lungs

CONTINUED………………………………. HEPARIN : A mixture of STRAIGHT CHAIN (ANIONIC)

GLYCOSAMINOGLYCANS, with a wide range of molecular weights Strongly acidic, due to the presence of sulphate and carboxylic acid

groups………………………..

2. MECHANISM OF ACTION (M.O.A) OF HEPARINS :• At low doses, heparin shows 2 actions:a. Inactivates FACTOR Xab. Inhibits conversion of PROTHROMBIN to THROMBIN• At high doses, heparin shows 2 actions:a. Inactivates factors IX, X, XI, XII, and thrombinb. Inhibits conversion of FIBRINOGEN to FIBRIN• Drug inhibits activation of FACTOR VIII • Overall precisely:Drug binds to Antithrombin-III forms ‘Heparin- AT-III complex’ inactivates clotting factors Xa, IIa, IXa, XIIa, and XIIIa…….

PICTORICAL REPRESENTATION OF HEPARIN MOA:

3. COMPARISON BETWEEN LOW AND HIGH MOL. WT. HEPARINS:CRITERIA HMW HEPARINS LMW HEPARINSMolecular weight High (30,000 Daltons) Low (5,000 Daltons)Biotransformation Low High (90%)Half-life Shorter (dose- dependent) Longer (dose- independent)M.O.A Inactivates both factor IIa,

and XaInactivates Xa

Anti-coagulant effect More effective Less effectiveMonitoring By a PTT ( Activated

prothrombin time )Can be given once or twice daily without monitoring

ADRs High risk of thrombocytopenia, long term osteoporosis

Less chance of thrombocytopenia and long term osteoporosis

Excretion Cleared by reticuloendothelial system

Cleared unchanged by kidneys

Reversal By protamine Not fully reversed by protamine

Expense Not expensive Expensive

4. ADVANTAGES OF LMWH OVER HMWH :• Better s.c availability:- LMWH : 70-90%- HMWH : 20-30 %• Better and consistent half life• Since a PTT/ clotting times are not prolonged LMWH requires fewer lab

monitorings• Lower incidence of hemorrhagic complications• LMWH Decreased antiplatelet action decreased interference with

thrombosis…………………………….

5. PHARMACOKINETICS OF HEPARIN: HEPARIN Highly charged poorly crosses cell membranes thus

given parenterally For low dose : give s.c For high dose : give s.c and i.v Metabolism : by liver Half-life depends on dose given………………………….

6. PHARMACOLOGICAL ACTIONS OF HEPARIN :A. ANTICOAGULANT ACTIVITY:- Powerful and instantaneous acting anti-coagulant- Effective both in-vivo and in-vitro- Sudden stoppage of conventional- dose therapy causes rebound increase in

coagulability for few days

B. ANTI-PLATELET EFFECT:- In high doses, heparin has 2 effects :

i. Inhibits platelet aggregation

ii. Prolongs bleeding time

CONTINUED……………………………….3. IN LIPAEMIA CLEARING:- HEPARIN (low dose), when injected causes release of LIPOPROTEIN LIPASE from vessel wall and tissues Hydrolyzes triglycerides of chylomicra and VLDLs to Free Fatty Acids causes clearing of post-prandial lipaemic plasma (plasma looks clear)……………………………….

7. ADRs OF HEPARIN:a. Bleeding (most common)

b. Allergy

c. Anaphylaxis

d. Alopecia

e. Long term osteoporosis spontaneous susceptibility to fractures

f. Thrombocytopenia:- Once thrombocytopenia is determined stop heparin give DIRECT THROMBIN

INHIBITOR

- Do not give platelets platelets react with antibody already being produced by human increased chance of thrombosis………………

8. DRUG INTERACTIONS OF HEPARIN :A. HEPARIN + CORTICORELIN Increased toxicity of CORTICORELIN

increased risk of SEVERE HYPOTENSION

B. HEPARIN + MIFEPRISTONE Excessive post abortion bleeding

C. HEPARIN + ASPIRIN Both increase anticoagulation dangerous interaction

D. HEPARIN + FLUOROURACIL Both increase bleeding effects

E. HEPARIN + MIPOMERSEN Increased hepatic enzymes level…………………..

9. HEPARIN IN PREGNANCY : Drug does not cross placenta should be used instead of warfarin in pregnancy Warfarin crosses placenta causes changes in fetus to cause fetal warfarin

syndrome not good…………………..

10. CONTRAINDICATIONS OF HEPARIN : Documented hypersensitivity Bleeding disorders (hemophilia) Thrombocytopenia Intracranial hemorrhage GI ulcerations Threatened abortion Advanced renal/ hepatic disease……………………..

11. FOR HEPARIN TOXICITY : Give antidote as PROTAMINE SULPHATE Protamine combines with heparin forms stable complex devoid

of anticoagulant activity Also used to reverse hemorrhage if 1 mg of protamine is given / 100 U

of heparin……………………

12. USES OF HEPARIN :a. Treatment and prevention of DEEP VEIN THROMBOSIS (DVT) in:- Immobilized patients (bedridden)- Old people- Post-operative- Post-stroke patients- Leg fractures- Elective surgeryb. In IHD:- For unstable angina, Post MI- After angioplasty, CABG, Stent replacement For prophylaxis

CONTINUED…………………………………….c. In Rheumatic Heart Disease/ Atrial Fibrillation:- Decreases stroke due to embolid. In cerebrovascular diseases:- In cerebral emboli (to prevent recurrence)e. In vascular surgery, prosthetic heart valves, hemodialysis :- To prevent thromboembolismf. In Defibrination syndrome/ DIC:- To prevent malignancies / infections…………………

ASSOCIATED HEPARINOIDS

1. They are drugs, that bind to thrombin without additional binding proteins such as anti-thrombin

2. HIRUDIN and BIVALIRUDIN :- Bind at both catalytic and / active site of thrombin- Also bind at substrate recognition site3. ARGATROBAN :- Binds only at thrombin active site4. LEPIRUDIN :- Monitored by a PTT- Action independent of anti-thrombin

CONTINUED……………………………………..- Used in thrombosis related to heparin induced thrombocytopenia- No antidote available- ADR: Antibody formation against thrombin-Lepirudin complex5. BIVALIRUDIN :- Inhibits platelet activation- Used in percutaneous coronary angiography6. ARGATROBAN :- Used in heparin induced thrombocytopenia , with/ without thrombosis- Monitored by a PTT- Dose is reduced in liver disease………………………

Oral anticoagulants Here, we are focusing mainly on WARFARIN……………………….

1. M.O.A OF WARFARIN :- WARFARIN Interferes with hepatic synthesis of Vitamin K

dependent clotting factors ( II, VII, IX, and X) , as well as anticoagulant proteins ‘C’ and ‘S’

- Drug depletes functional Vit. K reserves Competitively inhibits subunit 1 of multi unit Vitamin K epoxide reductase complex 1 (VKOR 1 ) Reduces synthesis of active clotting factors ……………..

2. PHARMACOKINETICS OF WARFARIN :- Rapidly and completely absorbed after oral administration- 100% bioavailability- High plasma protein binding capacity : 99%- Crosses placenta TERATOGENIC- Drug appears in milk thus, infants are given Vitamin K- Shows hepatic clearance- Metabolism: By liver , via oxidation, glucuronidation- Take 12-16 hours before effect is observed………………..

3. ADRs OF WARFARIN :- BLEEDING:• Common ADR• Hematuria• GI bleeding• Internal hemorrhages- CUTANEOUS NECROSIS :• Due to decreased activity of Protein ‘C’- INFARCTION OF BREAST, FATTY TISSUES,INTESTINE and EXTREMITIES:• Decreased activity of Protein ‘C’ venous thrombosis occurs causes above

symptoms……………………………..

4. HYPO-ACTIVITY OF WARFARIN CAUSES…………..a. Affected pregnancy (due to increase in clotting factors)b. Nephrotic syndromec. Warfarin resistance (Genetic)…………………

5. HYPER-ACTIVITY OF WARFARIN CAUSES……………a. Malnutritionb. Debilityc. Affects newborns (due to Vitamin K deficiency)d. Liver diseasee. Chronic alcoholism (due to decrease in clotting factors)f. Hyperthyroidism (due to increased degradation of clotting factors)

………………………………

6. FOR WARFARIN TOXICITY…………………- Stop warfarin- Administer Vitamin K (Antidote)- The following can also be given :a. Fresh frozen plasmab. Prothrombin complex concentratesc. Recombinant factor VIIa……………………..

7. CONTRAINDICATIONS OF WARFARIN:- In pregnancy:a. Fetal protein in bone and blood affectedb. Birth defectsc. Abnormal bone formationd. Bone hyperplasiae. CNS defectsf. Fetal hemorrhageg. Fetal hypoprothrombinemiah. Fetal death- Other contraindications same as that of heparin………………

8. DRUG INTERACTIONS OF WARFARIN:A. PHARMACOKINETIC INTERACTIONS:i. Drugs, that inhibit warfarin metabolism:- Cimetidine- Imipramine- Co-trimoxazole- Chloramphenicol- Ciprofloxacin- Amiodarone- Metronidazole

CONTINUED………………………………..ii. Drugs, that increase warfarin metabolism:- Barbiturates- Rifampin iii. Drugs, that displace warfarin from binding sites on plasma albumin :- Chloral hydrate- NSAIDsiv. Drugs, that decrease GI absorption of warfarin:- Cholestyramine

CONTINUED………………………………….B. PHARMACODYNAMIC INTERACTIONS:- Shows synergistic effects with heparin and aspirin- Antibiotics +warfarin decreased bacterial flora decreased Vitamin

K synthesis increased warfarin effects……………….

9. USES OF WARFARIN :- Same as that of heparin and other anticoagulants- Monitoring is necessary, due to low therapeutic index- Prothrombin Time (PT) should be noted (Time taken for blood to clot)- Usually, patients on heparin are shifted to oral warfarin only after 3-5

days…………………………………..

10. GENERAL COMPARISON BETWEEN WARFARIN AND HEPARIN :CRITERIA HEPARIN WARFARINROUTE OF ADMINISTRATION

Parenteral Oral

POLARITY Polar charged molecule UnchargedONSET OF ACTION Rapid 12-16 hoursM.O.A Inactivates clotting factors

by AT- IIIInhibits gamma-carboxylation of glutamic acid residues of clotting factors

THERAPEUTIC INDEX Not low safe Low not safeMONITORING Via a PTT Via PTADRs Alopecia, osteoporosis,

thrombocytopenia…Cutaneous necrosis, breast and other fatty tissue infarction….

MANAGEMENT OF PATIENT

Start with heparin Switch over to warfarin in 3-5 days

ANTIDOTE Protamine sulphate Vitamin KCONTRAINDICATION IN PREGNANCY

No Yes

INTERACTIONS Not much significant Significant

BIBLIOGRAPHY :1. Nichols.W.L ; Bowie E.J.W ; Standardization of Prothrombin Time ;

Mayo Clinical Procedure 1993 ; 68 : 897-982. Lippincott’s Pharmacology Reviews3. Essentials of Medical Pharmacology by Dr. Tripathi. K. D4. The Pharmacological basis of Therapeutics by GOODMAN and

GILMANN5. www.emedicine.net6. www.healthline.com

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