Anti-coagulants & Fibrinolytics

Mohamad-Hesham Daba

Anticoagulants

• Parenteral:

• Heparin. • Direct thrombin inhibitor.

• Oral Anticoagulants:

• Warfarin.

HEPARIN Pharmacokinetics:

• Sulfate polysaccharide. • Carry electro-negative charge.• Not effective orally as it is precipitated by HCl.• Not given I. M → produce muscle Haematoma.

SO it is given by S.C or I.V.• Not cross the placenta → safe in pregnancy.• Not excreted in milk → safe during lactation.• Metabolized in liver by Heparinase enzyme.• T1/2= 60-90 min.

Mech. of action:

• ↑ activity of anti-thrombin III (heparin cofactor) → ↑ inactivation of several clotting factors especially activated factor X (Xa), II (IIa), IXa, XIa, XIIa & XIIIa

N.B. Inactivation of factor (Xa) is important as:• Xa is involved in intrinsic & extrinsic system.• Need smaller dose of heparin than inactivation of

coagulation at thrombin stage (Ila).

Dosage:

• Prevention of thrombosis: 5000 unites S.C/8-12 hrs.• ttt of established thrombosis: 5000 - 10.000 unites I.V then 5000 unites

S.C/8hrs to maintain coagulation time & activated partial thromboplastin time (APTT) at 2-3 times of its normal value (Control of Therapy).

Side effects:

1. Bleeding. 2. Haematoma if given I. M.3. Transient reversible thrombocytopenia.4. Osteoprosis : spontaneous fracture of

long bone if used for long time.5. Alopacia:Transient, reversible6. Allergy.

Treatment of of Heparin toxicity:

• Stop the drug.

• Specific antidote: Protamin sulphate:• Mechanism: it is highly basic protein carry electro-

positive charge & combine e heparin (-ve charge) → stable complex.

• Dose: 1 mg protamine for every 100 units heparin. (N.B.Avoid excess protamine: as it has also anti-coagulant effect)

• Fresh blood transfusion.

Low molecular weight heparin (LMWH)• Definition: are fragments of UFH of a MW less

than 8000 daltons. • Classification:

• Enoxparin.• Dalteparin.• Tenzaparin.

Differences between :

Oral anti-coagulants: Warfarin

• Pharmacokinetics:• Absorption : Well absorbed from the GIT.• Distribution: Highly bound to the plasma

proteins (>90%). Cross the placenta & excreted in milk (contraindicated in pregnancy & lactation).

• Metabolism : in the liver. • Excretion: by the kidney.

Mech. of action:• Warfarin competes e

vit. K for vit. K epoxide reductase enzyme → ↓ formation of reduced vit. K (active form) → ↓ formation of vit. K dependent coagulation factors in the liver (II, VII, IX & X).

Dosage

• Initial dose: → small daily doses of 2-15 mg.

• Monitoring of therapy is controlled by: prothrombin time & INR which should be kept at 2 - 4 times of their normal value.

• INR: is the ratio of prothrombin time in the patient to that in a normal, un-anti-coagulated, person.

Side effects:

1.Bleeding: • is the main adverse effect,e.g.haematuria,melena

etc. • Hemorrhage may be life-threatening

• Treatment: • Fresh frozen plasma • Vit. K1 (phytomenadione): 5 - 40 mg slowly I.V or • Vitamin-K dependent clotting factors concentrate.

2. Allergy.3. Alopacia4. Cross placenta: → hemorrhagic

disorders in the fetus & abnormal bone formation (teratogenicity and abortion).

6. Sudden withdrawal: may lead to thrombotic episodes.

Drug interactions:

• The most serious is: to ↑ its anti-coagulant effect and risk of bleeding.• The most dangerous is:

pharmacokinetic interactions.

Drugs ↑ their anti-coagulant activity (↑↑their anticoagulant effects):

1. ↓ vit. K production: by Gut flora e.g. oral antibiotic as Tetracyclines.

2. ↓ vit. K absorption: from GIT e.g. prolonged use of liquid paraffin.

3. Competition e plasma protein binding → ↑ free level of warfarin → ↑ effect e.g. Aspirin

4. ↓ their hepatic metabolism : e.g. Cimetidine, Chloramphenicol

Drugs ↓ their anticoagulant activity:

1. ↓ Their absorption i.e. adsorpants e.g. Aluminum hydroxide & Cholestyramine.

2. ↑ Their hepatic metabolism e.g. Phenobarbitone, Phenytion, Rifampin

3. ↑ Formation of vit. K dependent clotting factors in the liver e.g. oral contraceptives & vit. K.

Indication of Anticoagulant Therapy

• Prevention & ttt of venous thrombosis e.g. D.V.T, post-operative thrombosis & pulmonary embolism.

• Prevention & ttt of coronary thrombosis:To avoid i extension of i thrombus & recurrence of i thrombosis.

• Acute arterial embolism:Start by heparin (which is also VD → opening of collateral circulation) & warfarin then after 3 days warfarin is given only.

DRUGS THAT PROMOTE FIBRINOLYSIS(FIBRINOLYTICS)A. NON-FIBRIN SELECTIVE• They are not well absorbed by fibrin thrombi. • They convert plasminogen to plasmin in the circulation

• e.g. Streptokinase and Urokinase B. FIBRIN SELECTIVE• They bind strongly to fibrin• They are selective for thrombi• e.g. Recombinant pro-urokinase and Recombinant

tissue plasminogen activator (rt-PA)

Uses of Fibrinolytic Drugs

1 .Coronary artery thrombolysis: Reduction in mortality: The earlier thrombolysis is begun, the better, and reduction in mortality may approach 50% when treatment is commenced within the first hour.

2 .Non- Coronary thrombolysis:e.g.1. Ocular thrombosis (urokinase).2. Thrombosed arteriovenous shunts (streptokinase).3. Life-threatening venous thrombosis. 4. Massive pulmonary embolism with shock (to avoid

embolectomy).

Adverse Effects• Bleeding :Activation of circulating

plasminogen leads to elevated levels of plasmin, which may precipitate bleeding by dissolving homeostatic plugs.

• Multiple microemboli from disintegration of pre-existing thrombus

• Cardiac dysrhythmias result from reperfusion of ischaemic tissue.

• Allergy : especially with Streptokinase. It is antigenic

•

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