1. بسم الله الرحمن الرحيم

2. Pharmacology of pulmonary embolism

3. Pulmonary embolism results from entry of blood clots, fat, tumor cells, air, amniotic fluid, or foreign material into the venous system.
Clots from the lower extremities, pelvic veins, or less commonly the right side of the heart are usually responsible.
Venous stasis or hypercoagulability is often contributory in such cases.
The symptoms and signs of pulmonary embolism are generally characterized by low diagnostic specificity.

4. Pharmacologic treatment of pulmonary embolism
Anticoagulants
Fibrinolytics

5. Anticoagulants
Parenteral anticoagulants
Oral anticoagulants

6. Heparin
Heparine is a heterogeneous mixture of sulfated mucopolysaccharides, with high molecular weight; it is highly acidic with electronegative charges.
It combines with the protease inhibitor antithrombin (natural anticoagulant). Antithrombin inhibits clotting factors (Πa, IXa and Xa) by forming equimolar stable complexes with them.
In the absence of heparin these reactions are slow, in the presence of heparin; they are accelerated fold.

7. Pharmacokinetics of heparin
It has immediate onset of action after IV injection and short duration (4 – 6 hours). 80% is metabolized in the liver by heparinase enzyme, and 20 % are excreted unchanged by the kidney.
It does not cross the placenta & it is not secreted in milk so, it can be used during pregnancy or lactation.
Initial bolus injection of 80 – 100 units/kg, followed by continuous infusion of 15 – 22 units/kg/hour is required to maintain the aPTT st 2 – 2.5 times control.

8. Contraindications of heparin therapy
Hypersensitive to the drug.
Patients with active bleeding.
Hemophilia.
Significant thrombocytopenia.
Purpura.
Severe hypertension.
intracranial hemorrhage.
Infective endocarditis, active tuberculosis.
Ulcerative lesions of the gastrointestinal tract.
Threatened abortion.

9. Complications of heparin therapy
Hematoma (if injected intramuscularly).
Hair loss osteoporosis (if given for long periods).
Thrombocytopenia.

10. Heparin induced thrombocytopenia (HIT)
This thrombocytopenia may be early (seen in 25% of patients) due to heparin – induced aggregation that is postulated to be benign and transient in character.
The late form of thrombocytopenia (5% of patients) is an antibody mediated and associated with paradoxical thrombosis.
In such cases the heparin induced antibody is directed against the heparin – platelet factor 4 complex.
These complexes bind to receptors on adjacent platelets causing aggregation and thromboembolism.

11. The following factors should be considered in all patients receiving heparin:
platelet counts should be done performed frequently; thrombocytopenia should be considered heparin induced; any new thrombus can be the result of heparin; and thromboembolic disorders thought to be heparin – induced should be treated by discontinuance of heparin and administration of an alternative drug.

12. Excessive anticoagulant action of heparin is treated by discontinuance of the drug.
If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in the patient I mg of protamine sulfate should be administrated intravenously.
The rate of infusion should not exceed 50 mg in any 10-minutes period. Excess protamine should be avoided, it also has anticoagulant activity.

13. Low – Molecular – Weight Heparins (LMWHs)
They are fractions of the standard heparin with low molecular weight. The mode of action is by increasing the activity of antithrombin against factor Xa.
They have equal efficacy (to heparin), increased bioavailability from the subcutaneous site of injection, and less frequent dosing requirements (once or twice daily).
Prophylactic LMWH is given subcutaneously in a dose of 30 mg twice daily or 40 mg once daily. Full dose enoxaparin therapy is 1 mg/kg subcutaneously every 12 hours.
The use of LMW heparins is discouraged or contraindicated in patients with renal insufficiency.
LMW heparins do not require monitoring (no effect on aPTT).

14. Oral anticoagulants (Warfarin)
Warfarin inhibits the effective synthesis of biologically active forms of the vitamin K-dependent clotting factors: II, VII, IX and X, as well as the regulatory factors protein C, protein S .
The precursors of these factors require carboxylation of their glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces.
This carboxylation is linked to oxidation of vitamin K to form vitamin K epoxide, which is in turn recycled back to the reduced form by the enzyme vitamin K epoxide reductase (VKOR).

15. Warfarin inhibits epoxide reductase (specifically the VKORC1 subunit), thereby diminishing available vitamin K stores and inhibiting production of functioning coagulation factors.
As the body stores of previously-produced factors degrade (over several days), the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation.
They are well absorbed orally with over than 95% is bound to plasma albumin, so they have small volume of distribution, long plasma half life(36 hours) , lack of urinary excretion of unchanged drug.

16. Treatment with warfarin should be initiated with standard doses of 5 – 10 mg/day.
The initial adjustment of the prothrombin time takes about one week, which usually results in a maintenance dose of 5 – 7 mg/day.
The therapeutic range for oral anticoagulant therapy is defined in terms of an international normalized ratio (INR) which should be in the range of 2.5 – 3.5.

17. Warfarin crosses the placenta readily and can cause a hemorrhagic disease in the fetus or serious abnormal bone defects. Thus warfarin should not be used during pregnancy (first trimester).
Cutaneous necrosis with reduced activity of protein C sometimes occurs during the first weeks of therapy.

18. Drug interactions of warfarin
Oral anticoagulants often interact with other drugs and with disease states. The most serious interactions with warfarins are those that increase the anticoagulant effect and the risk of bleeding.
These interactions may be pharmacodynamic or pharmacokinetic.

19. pharmacokinetic interactions
Antiplatelet analgesic antipyretics ( Aspirin , phenylbutazone, sulphinpyrazone) inhibition of oxidative metabolism of warfarin.
Metronidazole, Amiodarone, disulfiram, and cimetidine also inhibit metabolism of warfarin.
Third generation cephalosporins eliminate intestinal bacteria that produce vitamin k and, like warfarin, also directly inhibit vitamin k epoxide reductase.
Heparin directly prolongs the prothrombin time by inhibiting the activity of several clotting factors.
Barbiturates and rifampicin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes.
Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability.

20. Pharmacodynamic interactions
Reductions of anticoagulant effect occur with vitamin k (increased synthesis of clotting factors).
diuretics chlorthalidone and spironolactone (clotting factor concentration).
hereditary resistance (mutation of vitamin k reactivation cycle molecules).
hypothyroidism (decreased turnover rate of clotting factors).

21. Excessive anticoagulant effect and bleeding from wayfaring can be reversed by stopping the drug and administrating vitamin k1(phytonadione) , fresh frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa.

22. Fibrinolytics (Thrombolytics)
These drugs cause lyses of thrombi by catalyzing the formation of the serine protease plasmin from its precursor plasminogen.
Plasmin causes degradation of fibrin as well as fibrinogen, factors Va and VIIIa, so if excess plasmin circulates in plasma, bleeding may occur.
Streptokinase is a protein synthesized by streptococci that combines with the proactivator plasminogen.
This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin.
Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin.

23. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within.
Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PA). These activators preferentially activate plasminogen that is bound to fibrin, which confines fibrinolysis to the formed thrombus and avoids systemic activation.

24. Alteplase is a human t-PA synthesized by recombinant DNA technology.
Tenecteplase is a mutant form of t-PA that has a longer half life, and it can be given as an intravenous bolus, it is slightly more fibrin – specific than other t-Pas.

25. The best treatment for pulmonary embolism is prevention especially for high risk patients. Minidose heparin (5000 IU/12 hours) subcutaneously preoperatively or immediately postoperatively decreases the incidence of venous thrombosis.
Systemic anticoagulation prevents the formation of new blood clots or the extension of existing clots.
Heparin therapy is begun with the goal of achieving an aPTT of 1.5 – 2.5 times normal. LMWH is as effective and is given subcutaneously at a fixed dose (based on body weight) without laboratory monitoring, it more expensive than unfractionated heparin but more cost – effective

26. All patients should start warfarin therapy concurrent with starting heparin therapy and the two should overlap for 4 – 5 days.
The INR should be within the therapeutic range on two consecutive measurements at least 24 hours apart before the heparin is stopped.
Warfarin should be continued for 3 – 12 months.
Thrombolytic therapy with tissue plasminogen activators or streptokinase is indicated for patients with massive pulmonary embolism or circulatory collapse.
Recent surgery and active bleeding are contraindications to anticoagulation and thrombolytic therapy.