Anticoagulants

Dr Naser

Case study

• A 25-year-old woman presents to the emergency department complaining of acute onset of shortness of breath & pleuritic pain. she noted that her left leg was swollen and red 2 days prior . Her only medication was oral contraceptives. Family history was significant for a history of "blood clots" in multiple members of the maternal side of her family. The left lower extremity demonstrates erythema and edema and is tender to touch.

Common Thrombo Embolic Disorders For Drug Intervention

• Post myocardial infarction• Prosthetic heart valves• Chronic atrial fibrillation • Acute deep vein thrombosis• Pulmonary embolism• Patients undergone orthopedic or

gynecological surgery & in bed ridden patients

Hemostasis

• Hemostasis:– Minimization or arrest of blood loss

• Haemostatic mechanisms– Vasoconstriction – Platelet plug formation – Blood coagulation (Formation of clot)

Factors involved in coagulation

Factor I: Fibrinogen Factor II : Prothrombin Factor III:Tissue factor/ tissue

thromboplastin Factor IV : calcium

Factor V: proaccelerin Factor VII: stable factor/

proconvertin Factor VIII: antihaemophilic

factor A

Factor IX: Christmas factor / Anti HB/ PTC

Factor X: Stuart –Prower factor

Factor XI: PTA

Factor XII: Hageman Factor

Factor XIII: Fibrin Stabilizing Factor

Extrinsic Pathway Intrinsic Pathway

Tissue Trauma

VII

VIIa

X

IXa

Prothrombinase

Prothrombin Thrombin

FibrinogenFibrin insoluble

Stabilized fibrin threads

Damaged endothelial cells/ contact with glass

XII

XIa XI

IX

XIIa

Xa XVIIIVIIIa

XIII

XIIIa

Ca2+

TF

Ca2+

PL

Ca2+VIIa

Ca2+

PL

Activation of platelets

PL (Used in cascade)

Ca2+ PLVa

Fibrinolytic system

• The process of dissolution of clot is called fibrinolysis

Plasminogen

t-PA Endothelial cells

Plasmin

Digests fibrin

Natural anticoagulant mechanisms

• Prostacyclin (PGI2)– Inhibits action of TXA2

• Antithrombin III:– blocks the action of factors II,IX,X,XI,XII

• Protein C:– Blocks the action of factors V &VIII– ↑ t-PA action

• Heparan sulphate :– Cofactor , enhances activity of antithrombin III

• Used in vivo – Parenteral

• Heparin, Low molecular weight heparins, heparinoids

– Oral• Coumarin derivatives• Indandione derivatives

• Used in vitro – Heparin – Calcium complexing agents

• Sodium citrate, sodium oxalate, sodium edetate

Classification of anticoagulants

Classification of anticoagulants(used in Vivo)

Parenteral :• Heparin • LMW heparins

– Enoxaparin, dalteparin, ardeparin, nadoparin, reviparin

• Heparinoids– Heparan sulfate,

danaparoid, lepirudin, ancrod

Oral anticoagulants:• Coumarin derivatives

– Warfarin, dicumarol, acenocoumarol, ethyl-biscoumacetate

• Indandione derivates– Phenindione

Heparin

• Discovered by Mc Lean in 1916 • Mixture of sulfated mucopolysaccharides

10,000 to 20000 MW • Strong electronegative compound• Strongest organic acid in body • Present in all tissues containing mast cells • Commercially prepared from beef lung and pig

intestinal mucosa

Mechanism of action

Antithrombin IIISlowly

Inactive Coagulation factors

+

Heparin accelerates Antithrombin III activity by 1000 foldEspecially against IIa & Xa

Fast Heparin AT-III complex

AT-IIIHeparin

•Heparin provides scaffolding for clotting factors & AT-III•Induces confirmational changes in AT-III to expose its interactive site

Other actions of heparin

• Antiplatelet – High doses inhibits platelet aggregation and

prolongs bleeding time • Lipaemia clearing

– Clears turbid postprandial lipaemic plasma by releasing lipoprotein lipase from vessel wall & tissues

Pharmacokinetics

• Orally not absorbed -Large molecules • Route – IV/SC• Does not cross BBB/ Placenta• Metabolised by Heparinase in Liver• Heparin sodium - 5ml vials 1000 & 5000 units/ml• t1/2 – 1 hr

Dosage

• 5000-10000 units I.V , 4-6 hrly or• IV bolus 5000 units followed by continuous 750-

1000 units/IV/hr• Deep SC 10000-20000 units every 8-12hrly • Low dose SC regimen 5000 units every 8-12hrly

to prevent post operative DVT• Dose controlled by APTT (1.5-2.5 times normal) Total Clotting time (2 times the normal)

HEPARIN – ADVERSE EFFECTS

1. Bleeding due to overdose2. Osteoporosis 3. Thrombocytopenia4. Hypersensitivity (Anaphylaxis)5. Transient alopecia

• Antidote – Protamine sulphate 50 mg in 5ml for IV

1mg IV for 100 units heparin

Contraindications

• Bleeding disorders • Heparin induced thrombocytopenia• Severe hypertension • Threatened abortion, piles • SABE • Occular , neurosurgery , lumbar puncture • Chronic alcoholics, cirrhosis• Aspirin other antiplatelet drugs use cautiously

Protamine sulfate

• Strongly basic LMW protein • Obtained from sperm of certain fish• 1 mg IV neutralizes 100 U of heparin• Needed infrequently to antagonize heparin

action rapidly • Can act as week anticoagulant in absence of

heparin • Rapid IV injection causes flushing and

breathing difficulty

Low Molecular Weight Heparins• M.Wt : 3000-7000• Selectively inhibit factor Xa ,No effect on IIa• Used for prophylaxis of Deep Vein Thrombosis

Pulmonary Embolism, Unstable angina• ENOXAPARIN: 20-40 mg S.C , O.D • REVIPARIN:13.8mg(0.25ml) S.C/OD for 5-10

days• NADROPORIN :0.3ml(3075 units)• TINZAPARIN :3500 units S.C every 24hr)

LOW MOLECULAR WEIGHT HEPARINS

• Higher S.C bioavailability• Longer duration of action • Do not routinely require aPTT monitoring • Lesser antiplatelet action• Less antigenic• Less hemorrhagic complications• Better patient compliance

HEPARINOIDS• Used In patients developing thrombocytopenia

with Heparin1. HEPARAN SULPHATE : less potent, better profile. 2. LEPIRUDIN : Recombinant preparation of Hirudin .

Inhibits Thrombin directly, it is indicated in patients with heparin induced thrombocytopenia.

3. ANCROD : enzyme from Malayan Pit Viper venom

Fibrinogen

Unstable fibrin(Taken up by RE cells)

Slow IV infusion 2units/kg over 6hrs for DVT

Oral Anticoagulants 1924 – Hemorrhagic disease in cattle due to feeding of spoiled sweet clover (contained bishydroxy coumarin)

Mechanism of action

Vitamin K reduced form Hydroquinone KH

Vitamin K oxidized form Epoxide KO

Descarboxy factors II,VII,IX,X

carboxylated factors II,VII,IX,X

NAD NADH

VitK reductase

Warfarin

Pharmacokinetics & dosage of oral Anticoagulants :

DRUG t½ (hr) DURATION OF ACTION(days)

DOSAGELOADING (mg)

DOSAGE MAINTENANCE(mg)

Bishydroxycoumarin

25-100 4-7 200 for 2 days

50-100

Warfarin sodium

36-48 3-6 10-15 2-10

Ethylbiscoumacetate

24 1-3 900 300-600

Acenocoumarol

18-24 2-3 8-12 2-4

Phenindione 5 1-3 200 50-100

• Most popular oral anticoagulant• Racemate • Absorbed orally, crosses placenta • 99% pl.protein bound• Partially conjugated with glucuronic acid• Available as 1,2.5 mg tablet • Can be given parenterally as it is water

soluble

Warfarin Sodium

• Dose Regulation Of Oral Anticoagulants : By Prothrombin time

• INR

• ADVERSE EFFECTS :1. Bleeding- antidote: Vit.K2. Teratogenic 3. Agranulocytosis 4. nephropathy 5. Hepatitis by phenindione6. orange urine

DRUG INTERACTIONS Oral anticoagulant effect

ed by• Broad spectrum

antibiotics • Phenylbutazone• Aspirin• Sulfonamides• Phenytoin

ed by

• Barbiturates• Rifampin• Oral contraceptives

Uses of anticoagulants

• Deep Vein Thrombosis & Pulmonary Embolism in bed ridden , old , post operative, leg fracture pts

• MI – for short period till pts become ambulatory• Unstable angina• Rheumatic Heart Disease , Atrial Fibrillation• CerebroVascular Diseases• Prosthetic heart valves• Hemodialysis • Disseminated Intravascular Coagulation

Comparison

HEPARIN • Mucopolysaccharide • Parenteral • Immediate onset • Duration of action 4-6 hrs• Activity invitro & in vivo • Blocks action of factor X & II

• Antagonist - protamine • Monitor aPTT

WARFARIN • Coumarin derivative • Oral • Delayed onset of action • 3-6 days • Only invivo • X synthesis of clotting

factors • Antagonist is Vit K • Monitor PT/INR