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, reversible 6. Allergy.

Treatment of of Heparin toxicity:

Stop the drug.

Specific antidote:

Protamin sulphate:

Mechanism: it is highly basic protein carry electropositive 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-anticoagulated, 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. Alopacia 4. 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 anticoagulant 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, embolism. post-operative thrombosis & pulmonary

Prevention thrombosis:

&

ttt

of

coronary

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. 2. 3. 4. Ocular thrombosis (urokinase). Thrombosed arteriovenous shunts (streptokinase). Life-threatening venous thrombosis. 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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