Drugs Affecting the Blood Ass.Prof. Naza M. Ali

1. Drugs Affecting the Blood Ass.Prof. Naza M. Ali 9 Oct 2018

2. References • Lippincott’s IIIustrated Reviews / Pharmacology 6th Edition • Katzung and Trevor’s Pharmacology / Examination & Board Review • Bertram G. Katzung Basic and Clinical Pharmacology

3. Lecture Outlines: • Introduction • Platelets Response to Vascular Injury • Drugs that Inhibit Platelet Aggregations • Blood Coagulation • Types of anticoagulant • Vitamin K Antagonists • Thrombolytic Agents • Drugs Used to Treat Bleeding

4. Hemostasis: Is a complex process which causes the bleeding process to stop. • Bleeding disorders: is a failure of hemostasis. These disorders include: • Hemophilia • Vitamin K deficiency

5. Thrombosis: mean the formation of an unwanted clot within blood vessel. Thrombotic disorders include: Acute MI DVT Pulmonary embolism Acute ischemic Stroke. Embolus: An intravascular clot that floats in the blood, a detached thrombus becomes an embolus.

6. Types of thrombi: I. An arterial thrombus • is composed of so-called white thrombus • consisting mainly of platelets in a fibrin mesh. • It is usually associated with atherosclerosis & can interrupt blood flow, • causing ischaemia or infarction of tissue downstream. • Theactivation of platelets is an essential process for arterial thrombosis

7. II. Venous thrombus • is composed of ‘red thrombus’ • consists of a small white head and a large jelly-like red tail, similar in composition to a blood clot, which streams away in the flow. • Fibrin deposit in very small blood vessel or capillaries • is triggered by blood stasis or inappropriate activation of the coagulation cascade The Risk Factors in Venous Thrombosis: • Inherited disorders B. Acquired disease

8. Platelets Response to Vascular Injury • Resting Platelet • Platelet Adhesion • Platelet Activation • Platelet Aggregation • Formation of Clot • Fibrinolysis

9. Resting platelets: Platelets act as vascular sentries, monitoring the integrity of the endothelium. Chemical mediators synthesized by endothelial cells and act as inhibitors of platelet aggregation are: • Prostacyclin (PGI2) acts by binding to platelet membrane receptors that are coupled to the synthesis of cAMP. • Nitric oxide

10. Roles of thrombin, thromboxanes & collagen: • The platelet membrane also contains receptors that can bind thrombin, thromboxanes, and exposed collagen. • Normal vessel, circulating levels of thrombin& thromboxane are low, the intact endothelium covers the collagen in sub-endothelial layers.

11. The corresponding platelet receptors are unoccupied and remain inactive; as a result, platelet activation and aggregation are not initiate. • When occupied, each of these receptor types triggers a series of reactions leading to the release into the circulation of intracellular granules by the platelets and stimulates platelet aggregation.

14. B. Platelet Adhesion • When the endothelium is injured, platelets adhere to and cover the exposed collagen of the sub-endothelium. • This triggers a complex series of chemical reactions, resulting in platelet activation

15. C. Platelet Activation • Plateletson the surface of the adhering platelets are activated by the collagen of the underlying connective tissue. • This causes morpholgic changes in the platelets • The release of platelet granules containing chemical mediators: ADP, Thromboxane A2, Serotonin, PAF, Thrombin.

16. These signaling molecules bind to receptors in the outer membrane of resting platelets circulating nearby. • These receptors function as sensors that are activated by the signals sent from the adhering platelets. • The previously dormant platelets become activated & start to aggregate actions mediated by several messenger systems that result in elevated levels of Ca2+ and a decreased concentration of cAMP within the platelet.

18. D. Platelet Aggregation • Theincrease in cytosolic Ca2+ accompanying activation is due to a release of sequestered stores in platelet. This leads to 1) release of platelet granules containing mediators, ADP and serotonin that activate other platelets; 2) activation of thromboxane A2 synthesis 3) activation of the glycoprotein (GP) IIb/IIIa receptors that bind fibrinogen and, regulate platelet-platelet interaction and thrombus formation.

20. Fibrinogen is a soluble glycoprotein that simultaneously binds to GP IIb/IIIa receptors on two separated platelets, resulting in platelets cross-linking and platelets aggregation. • This leads to avalanche of platelet aggregation

23. E. Formation of a clot • Local stimulation of the coagulation cascade by tissue factors released from the injured tissue and by mediators on the surface of platelets results in the formation of thrombin (Factor IIa). • Thrombin a serine protease catalyzes the hydrolysis of fibrinogen to fibrin, which is incorporated into the plug. • Subsequent cross-linking of the fibrin strands stabilizes the clot and forms a hemostatic platelet-fibrin plug

24. F. Fibrinolysis • During plug formation, the fibrinolytic pathway is locally activated. • Plasminogen is enzymatically processed to plasmin (fibrinolysin) by plasminogen activators in the tissue. • Plasmin limits the growth of the clot and dissolves the fibrin network as wounds heal.

26. Platelet Aggregation Inhibitors: Decrease the formation or the action of chemical signals that promot platelet aggregation. Mechanism of Platelate Aggregation Inhibitors: • by inhibition COX-1 • or block GP IIb/IIIa • or block ADP receptors

27. Drugs that Inhibit Platelet Aggregations: 1. Aspirin 2. Ticlopidine , Clopidogrel, Prasugrel 3. Abciximab 4. Eptifibatide , Tirofiban 5. Dipyridamole 6. Cilostazol

28. 1. Aspirin TXA2 is a potent stimulator of platelete aggregation

29. Aspirin inhibits TXA2 synthesis from A.A in platelets • by irreversible acetylation of a serine • The inhibitory effect is rapid • The resulting of inhibition of platelate aggregation last for the life of the anucleate platelete 7-10 days.

30. 2. Ticlopidine , Clopidogrel Prasugrel • They are irreversibly inhibit the binding of ADP to its receptors on platelets • Inhibit the activation of the GP IIb/IIIa receptors • The maximum effect is achieved in 3-5 days

31. 3. Abciximab / IV • is reversibly inhibits the binding of fibrinogen to the platelet GP IIb/IIIa, so aggregation does not occur. Adverse effect: is bleeding Abciximab is expensive, limiting its use

32. 4. Eptifibatide and tirofiban / IV • Same mechanism of abciximab • Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa • Tirofiban is not a peptide, but it blocks the same site as eptifibatide. • The major adverse effect of both drugs is bleeding.

33. 5. Dipyridamole • A coronary vasodilator • It is usually given in combination with aspirin or warfarin (it is ineffective when used alone). • Increases intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased thromboxane A2 synthesis. • It may potentiate the effect of prostacyclin to antagonize platelet stickiness and, decrease platelet adhesion to thrombogenic surfaces.

34. 6. Cilostazol • Oral antiplatelet agent that also has vasodilating activity. • FDA approved used to reduce the symptom of intermittent claudication • Non-FDA approved include treatment of Buerger disease, vascular sclerosis complication diabetic mellitus and improvement symptoms in patients chronic cerebral ischemia.

35. Blood Coagulation The coagulation process consists: • Extrinsic system initiated by activation of Factor VII by tissue factor, or thromboplastin. • Intrinsic system by the activation of clotting Factor XII, following its contact in vitro with glass or highly charged surfaces.

37. Anticoagulants:reduce the formation of fibrin clots. Types of anticoagulant I. Indirect thrombin inhibitors: Heparin and LMWHs Fondaparinux II. Direct thrombin inhibitors: A. Oral / Dabigartan B. Parenteral / Lepirudin, Bivalirudin , Argatroban III. Coumarin anticoagulants: Warfarin

38. Indirect thrombin inhibitors Heparin and LMWHs • Heparin is a large sulfated polysaccharide polymer obtained from animal sources. • Each batch contains molecules of varying size, with an average molecular weight of 15,000-20,000. • Heparin is highly acidic and can be neutralized by basic molecules (protamine). • Heparin must be parenterally …………. • LMWHs of 2000-6000 example Enoxaparine Dalteparin Tinzaparin

41. Mechanism of Action • Unfractionated heparin binds to endogenous antithrombin ƖƖƖ (AT ƖƖƖ). • Heparin – AT ƖƖƖ complex combines with & irreversibly inactivates thrombin and factor xa. • In the absence of heparin, antithrombin III interact very slowly with thrombin and factor Xa. • Heparin molecules bind antithrombin III inducing a conformational change that accelerates its rate of action 1000-fold than in its absence.

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44. Therapeutic uses of heparin and LMWHs • Acute DVT, • Pulmonary embolism • is used prophylactically to prevent postoperative venous thrombosis in patients undergoing elective surgery. • In the acute phase of MI • Coronary artery rethrombosis. • In dialysis machines to prevent thromobosis. • For treating pregnant women.

45. Heparin advantage is speed onset of action. • LMWHs, like enoxaparin injected s.c. • Effect of heparin within minutes of IV or (1-2 hr sc sc) While LMWHs occurs about 4 hours after s.c • Heparin is administered by IV in a bolus, followed by lower dosed or continuous infusion of heparin for 7-10 days, titrating the dose so that the aPTT is 1.5 to 2.5 fold that of normal control. • Heparin & LMWHs do not cross the placental barrier.

46. Adverse effects: • Bleeding complications, • hypersensitivity reactions, • thrombosis, • thrombocytopenia condition, in which circulating blood contains an abnormally small number of platelets, called heparin-induced thrombocytopenia (HIT). Contraindications: • hypersensitive to it, have bleeding disorders, alcoholics, surgery of the brain, eye, or spinal cord.

47. Fondaparinux / Inhibit factor Xa • Class of pentasaccharide anticoagulants. • Selectively inhibits only Factor Xa, • by selectively binding to antithrombin III • Can be used in patients with HIT

48. II. Direct thrombin inhibitors: • Oral / Dabigatran etexilate • Is a prodrug which is direct thrombin inhibitors • Used for prevention of stroke and systemic embolism in patients with atrial fibrillation. • It is first oral anticoagulant after warfarin and dose not require routine monitoring INR. • Dabigatran may be an alternative to enoxaparin for thromboprophylaxis in orthopaedic surgery.

49. B) Other parenteral anticoagulants 1. Lepirudin A highly specific, direct thrombin antagonist • Bivalirudin 3. Argatroban • Both Lepirudin and Argatroban are used as alternative in patients with heparin induced thrombocytopenia.

50. Vitamin K Antagonists