SEMINAR ON ANTI-COAGULANTS AND INRBY: VISHNU.R.NAIR3rd year PHARM. DKERALA UNIVERSITY OF HEALTH SCIENCES(KUHS)KERALA STATE.

ANTICOAGULANTS…………………

A. DEFINITION: “ Drugs, used to reduce coagulability (coagulating capacity) of blood”

B. CLASSIFICATION:1. IN-VIVO DRUGS:i. Parenteral anti-coagulants:

** Heparins:

- High molecular weight heparins (UNFRACTIONATED HEPARINS)

- Low molecular weight heparins :

a. Enoxaparin

b. Dalteparin

c. Tinzaparin

d. Reviparin

e. Danaparoid

** Heparinoids:

- Heparan sulphate - Lepirudin

- Hirudin - Bivalirudin - Argatroban

CONTINUED…………………….ii. Oral anticoagulants:

a. Coumarin derivatives:

- Bishydroxycoumarin ( Dicumarol)

- Warfarin sodium

- Acenocoumarol

- Ethyl biscoumacetate

b. Indandione derivatives:

- Phenindione

CONTINUED……………………….2. IN- VITRO DRUGS:- Heparin

- Sodium citrate ( used in blood banks to store blood)

- Sodium oxalate (used as anticoagulant in laboratory)

- Sodium edetate (same function as that of sodium citrate )

C. PARENTERAL ANTICOAGULANTS:HEPARIN

1. HISTORY OF HEPARIN:• Discovered by McLean

• Howell and Holt coined the word “HEPARIN” in 1918

• Mainly occurs in mast cells

• Richest source of mast cells:

a. Lungs

b. Liver

c. Intestinal mucosa

. Commercial heparin is synthesized from :

- Porcine intestinal mucosa

- Bovine lungs

. Heparin : A mixture of straight chain (anionic) glycosaminoglycan, with a wide range of molecular weights

. Strongly acidic, due to the presence of sulphate and carboxylic acid groups…………

2. PHARMACOKINETICS:- Heparin highly charged poorly crosses cell membranes thus

given parenterally

- Low dose : given s.c

- High dose : given s.c and i.v

- Metabolism : by liver

- Half life depends on dose given

3. MECHANISM OF ACTION (MOA) OF HEPARIN:

CONTINUED………….• 1. AT LOW DOSES:

- Drug inactivates factor Xa and inhibits conversion of prothrombin to thrombin

2. AT HIGH DOSES:- Drug inactivates factors IX, X, XI, and XII, thrombin

- Drug inhibits conversion of fibrinogen to fibrin

3. Drug inhibits activation of Factor VIII

4. Overall:

Drug binds to Antithrombin (AT)- III Forms heparin-AT III complex inactivates clotting factors Xa, II a, Ix a, XIII a, and XII a.

4.COMPARISON BETWEEN HIGH MOL. WT AND LMWH:CRITERIA HIGH MOL.WT

HEPARINSLOW MOL. WT HEPARINS

Molecular weight High (30, 000 Daltons)

Low (5,000 Daltons)

Biotransformation low High (90%)Half life Short (Dose

dependent)Longer (Dose independent)

MOA Inactivates both factor II a and X a

Inactivates X a

Anticoagulant effect More effective Less effectiveMonitoring By aPTT Doesn’t usually

need monitoringExcretion Cleared by

reticuloendothelial system

Cleared unchanged by kidneys

Expense Not expensive Expensive Reversal By protamine Not fully reversed by

protamine

5. ADVANTAGES OF LMWH OVER HMWH:a. Better s.c availability:

- For LMWH : 70-90%

- For HMWH : 20-30%

b. Better and consistent half life

c. Since Aptt / clotting times are not prolonged LMWH requires fewer lab monitorings

d. Lower incidence of hemorrhagic complications

e. LMWH decreased antiplatelet action reduced interference with thrombosis…………….

6. USES OF HEPARIN:A. Treatment and prevention of DEEP VEIN THROMBOSIS in:

- Elderly patients

- Immobilized people

- Post-operative patients

- Post-stroke patients

- Leg fractures

B. In IHD:

- Unstable angina

- Post-MI

- After angioplasty, CABG, Stent replacement for prophylaxis

C. In rheumatic heart disease/ Atrial Fibrillation:

- To reduce risk of stroke due to emboli

CONTINUED………………………..E. In vascular surgery, prosthetic heart valves, hemodialysis:

- To prevent thromboembolism

F. In Defibrination syndrome or DIC (Disseminated intravascular coagulation):

- To prevent malignancies or infections…

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

b. Allergy

c. Alopecia

d. Anaphylaxis

e. Long term osteoporosis spontaneous fractures

f. Thrombocytopenia:

- Once thrombocytopenia is detected stop heparin given direct thrombin inhibitor

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

8. HEPARIN IN PREGNANCY:- If 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……………….

9. CONTRAINDICATIONS:• Hypersensitivity

• Bleeding disorders ( Hemophilia)

• Thrombocytopenia

• Intracranial hemorrhage

• GI ulcerations

• Threatened abortion

• Advanced renal/ hepatic disease………………….

10. 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 per 100 U of heparin………………..

DIRECT THROMBIN INHIBITORS (HEPARINOIDS):1. Drugs bind to thrombin without additional binding proteins such as anti- thrombin

2. HIRUDIN and BIVARUDIN:

- Bind at both catalytic and active site of thrombin

- Also bind at substrate recognition site

3. ARGATROBAN : binds only at thrombin active site

4. LEPIRUDIN :

- Monitored by Aptt

- Action independent of anti-thrombin

- Used in thrombosis related to heparin induced thrombocytopenia

- No antidote

- ADR: Antibody formation against thrombin- Lepirudin complex

CONTINUED……………………5. BIVALIRUDIN:

- Inhibits platelet activation

- Used in percutaneous coronary angiography

6. ARGATROBAN:

- Used in heparin induced thrombocytopenia, with / without thrombosis

- Monitored by Aptt

- Dose reduced in liver disease

7. DABIGATRAN : Direct thrombin inhibitor

8. APIXABAN , RIVAROXABAN : Factor X a inhibitors

9. DABIGATRAN ETEXILATE : Orally available pro-drug of DABIGATRAN………………………….

D. ORAL ANTICOAGULANTS:WARFARIN

1. PHARMACOKINETICS:- 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 Vit. K

- Slow hepatic clearance

- Metabolism : by liver, via OXIDATION and GLUCURONIDATION

- Take 12-16 hours before effect is observed……………..

2. M.O.A OF WARFARIN:- Drug 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………………………

3. USES OF WARFARIN:- Same as that of heparin and other anticoagulants

- Monitoring necessary, since it a low therapeutic index drug

- Prothrombin time (PT) should be noted (Time taken for blood to clot)

- Usually patients on heparin are shifted to oral warfarin after 3-5 days……………………..

4. ADRs OF WARFARIN:i. BLEEDING:

- Common ADR

- Hematuria

- GI bleeding

- Internal hemorrhages

ii. CUTANEOUS NECROSIS:

- Due to decreased activity of Protein C

iii. INFARCTION OF BREAST, FATTY TISSUES, INTESTINE AND EXTREMITIES:

- Decreased activity of Protein C Causes venous thrombosis causes above symptoms………….

5. FOR WARFARIN TOXICITY :- Stop warfarin

- Administer Vitamin K (antidote)

- The following can also be given:

a. Fresh frozen plasma

b. Prothrombin complex concentrates

c. Recombinant factor VII a

6. CONTRAINDICATIONS:A. PREGNANCY:

- Fetal protein in bone and blood affected

- Birth defects

- Abnormal bone formation

- Bone hyperplasia

- CNS defects

- Fetal hemorrhage

- Fetal hypoprothrombinemia

- Fetal death

B. Other contraindications same as that of heparin…………..

7. WARFARIN DRUG INTERACTIONS:A. PHARMACOKINETIC DRUG INTERACTIONS:

i. Drugs, that inhibit warfarin metabolism:

- Cimetidine

- Imipramine

- Cotrimoxazole

- Chloramphenicol

- Ciprofloxacin

- Metronidazole

- Amiodarone

ii. Drugs, that increase warfarin metabolism:

- Barbiturates -Rifampin

iii. Drugs, that displace warfarin from binding sites on plasma albumin: Chloral hydrate, NSAIDs

iv. Drugs that decrease GI absorption of warfarin : Cholestyramine

CONTINUED………………….B. PHARMACODYNAMIC DRUG INTERACTIONS:

- Shows synergistic effect with heparin and aspirin

- Antibiotics + warfarin decreased bacterial flora decreased Vitamin K synthesis increased warfarin effect………………

8. HYPER-ACTIVITY OF WARFARIN:• Causes:

1. Due to decreased Vit. K:

- Malnutrition

- Debility

- Affects newborns

2. Due to decreased clotting factors:

- Liver disease

3. Due to increased degradation of clotting factors:

- Hyperthyroidism…………………..

9. HYPO-ACTIVITY OF WARFARIN:• Affects in pregnancy (due to increase in clotting factors)

• Nephrotic syndrome

• Warfarin resistance (genetic)…………………………

GENERAL COMPARISON BETWEEN WARFARIN AND HEPARIN:CRITERIA HEPARIN WARFARINRoute of administration

Parenteral Oral

Polarity Polar charged molecule

Uncharged

Onset of action Rapid 12-16 hoursM.O.A Accelerates

inactivation of clotting factors by AT- III

Depletes vitamin K reserves and inhibits synthesis of clotting factors

Therapeutic index Not low safe Low not safeMonitoring aPTT PTADRs Alopecia,

osteoporosis, thrombocytopenia etc.

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 KContraindicated in pregnancy, interactions

No , not significant Yes, significant

Inr- international normalized ratio…………………………

1. GENERAL PROPERTIES:- “Standardization method, that attempts to decrease or reduce

differences between thromboplastin reagents, through a calibration process, in which all commercial thromboplastins are compared with an International Reference Preparation (IRP), maintained by WHO”

- Should only be used for patients on stable anticoagulant therapy……………

2. FORMULA FOR INR:• INR = (PT of patient / PT normal) * ISI

• Terms used:

- PT patient: prothrombin time of patient (measured, in seconds)

- PT normal: Laboratory’s mean value for normal patients (in seconds)

- PT normal depends on 3 Vitamin K dependent clotting factors : II, VII, IX

- ISI: International Sensitivity Index………………….

3. DESIRED INR VALUE:- Desired INR value depends on the reason why you need anti-

coagulants

- 3 most common reasons for warfarin use, along with their target INR values, include:

a. For ATRIAL FIBRILLATION: 2.0-3.0

b. For VENOUS THROMBOEMBOLISM: 2.0-3.0

c. For PROSTHETIC HEART VALVES: 2.0-3.5…………………………..

REFERENCE:• Nichols. W.L, Bowie E.J.W, Standardization of prothrombin time

, Mayo Clinical Procedure 1993; 68: 897-98• Lippincott’s Pharmacology reviews• Essentials of Medical Pharmacology by Dr. K.D.Tripathi• The pharmacological basis of therapeutics by GOODMAN and

GILMANN• www.emedicine.net

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