anticoagulants & fibrinolytic therapy
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Anticoagulants & Fibrinolytic Therapy.pptTRANSCRIPT
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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