Drugs affecting the Blood ahmed alekidi.pptx

this lecture by the doctor ahmed alekidi explaining what are the drugs that act on blood and affecting blood

1. Pharmacology Dr. Ahmed Al-Akydy MD, MSc, PhD د. أحمد العكيدي Department of Pharmacology & Clinical Pharmacology علم الأدوية

2. Drugs affecting the Blood

3. Blood must remain fluid within the vasculature Clot quickly when exposed blood vessels to injury INTRODUCTION Factors which promote blood fluidity Negative charge and smooth surface of vascular endothelium Endothelial- derived substances: Prostacyclin ( PGI 2 ) → inhibits platelet aggregation and secretion Heparan sulfate, stimulate antithrombin Tissue plasminogen activator (t-PA) Thrombomodulin that binds thrombin Endogenous anticoagulants: Antithrombin III (AT III) A glycosylated, polypeptide, synthesized in the liver Inhibits activated clotting factors of the intrinsic and common pathways (IIa, IXa, Xa, XIa, and XIIa).

4. Protein C and protein S Proteolysis of the Va and VIIIa →↓ activation of II and X 4) Fibrinolytic system: Plasminogen Plasmin t- PA 5) Tissue factor pathway inhibitor (TFPI) → inhibits TF- VIIa complex

5. Hemostasis : c essation of blood loss from a damaged blood vessel Achieved by several mechanisms: Vascular constriction Primary hemostasis 2) Formation of a platelet plug (3) Formation of a fibrin clot --------- Secondary hemostasis (4) Growth of fibrous tissue into the blood clot to close the hole in the vessel permanently Hemostasis

6. Coagulant and Anticoagulant factors More than 50 important substances cause or affect blood coagulation: Substances promote coagulation, called procoagulants Substances inhibit coagulation, called anticoagulants Physiological balance between these two groups is occur , where, the anticoagulants normally predominate, so that the blood does not coagulate When a vessel is ruptured, procoagulants activated and override the anticoagulants, and then a clot does develop

7. Has a central role in hemostasis and has many functions In clotting Cleaves small peptides from fibrinogen → fibrin clot Activates many upstream clotting factors ( V, VIII, XI) → more thrombin generation Activates factor XIII, that cross-links the fibrin polymer and stabilizes the clot A potent platelet activator In anticoagulant effects: Activate protein C pathway, which attenuates the clotting response by inactivate Va and VIIIa Thrombin: Receptors found on the platelet membrane Receptors for prostacyclin ( PGI 2 )- that is secreted from vascular endothelium Receptors for collagen (GPIa / IIa) Receptors for von Willebrand factor (vWF ) [GPIb] Receptors for fibrinogen (GPIIb / IIIa) PAR1 and PAR4 are protease-activated receptors that respond to thrombin ( IIa) Purinergic receptors ( P 2 Y 1 & P 2 Y 12 ) for ADP (adenosine diphosphate )

8. (GPIa/ IIa) for collagen [GPIb] for von Willebrand factor (vWF) (GPIIb/ IIIa) for fibrinogen Purinergic receptors ( P 2 Y 1 & P 2 Y 12 ) for ADP [TP] for TXA 2 [IP] for prostacyclin ( PGI 2 ) [5-HT] for serotonin [PAR1& PAR4],protease-activated receptors for thrombin

9. In intact blood vessels: Binds of PGI 2 to its platelet membrane receptors →↑ cAMP → ↓intracellular Ca 2+ → stabilizes inactive GPIIb/ IIIa receptors → inhibits platelet activation and release of platelet aggregation agents Remaining of GPIa/ IIa and GPIb inactive not cause platelets activation and aggregation In damaged blood vessel: ↓ PGI 2 →↓ cAMP → platelet aggregation Platelets adhere to the exposed collagen of the subendothelium → activate GPIa/ IIa and GPIb receptors → morphologic changes in the platelets (activation) → release of platelets granules containing chemical mediators Formation of a platelet plug

10. Such as ADP - inducer of platelet aggregation Thromboxane A 2 ( TXA 2 ) - stimulates platelet aggregation and vasoconstriction 5-HT - a platelet activator and potent vasoconstrictor PAF Thrombin These mediators bind to receptors in outer membrane of resting platelets circulating nearby →↓cAMP →↑ Ca 2+ → Release ADP and 5-HT Activation of TXA 2 synthesis Activation of GPIIb/ IIIa receptors that bind fibrinogen which cross-links adjacent platelets → aggregation and formation of a platelet plug

11. Formation of a platelet plug

12. Simultaneously, the coagulation system cascade is activated → thrombin generation → fibrin clot (stabilizes the platelet plug) Formation of a clot Fibrinolysis A process where fibrin is digested by plasmin Plasminogen → plasmin by t-PA Plasmin (nonspecific protease) → digests fibrin clots and other plasma proteins (dissolve both pathological thrombi and fibrin deposits at sites of vascular injury → hemorrhage) Note : Knowledge of the hemostatic mechanism → diagnosis of bleeding disorders: Defects in primary hemostasis (platelet function defects, von Willebrand disease) → bleed from mucosal sites (such as, gingiva), skin, heavy menses with injury Defects in secondary hemostasis (hemophilia A) → bleed into deep tissues (joints, muscle, retroperitoneum), with no apparent inciting event, and bleeding may recur unpredictably

13. Formation of a fibrin clot

14. Fibrinolysis

15. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury TF VIIa VII X Prothrombin Thrombin Fibrinogen Fibrin monomer Fibrin polymer XIII Intrinsic pathway Extrinsic pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants Clotting Cascade

16. Thrombin Activated partial thromboplastin time (aPTT ) Prothrombin time (PT) Intrinsic pathway Extrinsic pathway Common pathway Thrombin time (TT) Surface activating agent (Ellagic acid, kaolin) Phospholipid Thromboplastin Tissue factor Phospholipid Fibrin clot Laboratory evaluation of coagulation pathway Time required for recalcified plasma to clot after addition of Time required for the recalcified plasma to clot after addition of

17. PT: Normal values: 12 -14 sec Prolonged: ↓Clotting factors (I, II, V, VII, IX, X) Used to Diagnosis hemorrhagic disorders due to: Vit K deficiency Liver diseases Monitoring therapy by oral anticoagulant drugs (warfarin) Note : Because of considerable variation in the performance of the PT, results typically are normalized to an international standard and reported as the International Normalized Ratio “INR” aPTT: Normal values: 26 - 33 sec Prolonged: ↓Clotting factors (I, II, V, VIII,IX, X, XI) Used to monitoring therapy by heparin TT: Normal values: 10 -15 sec Prolonged: fibrinogen deficiency Congenital Acquired due to: Depletion of fibrinogen in disseminated intravascular coagulation (DIC) After treatment by fibrinolytic drugs

18. There are 3 important dysfunctions of blood: Thrombosis : formation of an unwanted clot within a blood vessel [eg. MI, deep-vein thrombosis(DVT), pulmonary embolism) - treated with anticoagulants and fibrinolytics Bleeding disorders : failure of hemostasis (eg. Hemophilia-treated by coagulant factor VIII , vitamin K deficiency -treated by dietary or supplements of vitamin K) Anemia : caused by nutritional deficiencies (Iron- deficiency anemia)- treated by either dietary or pharmaceutical supplementation Dysfunctions of blood

19. Thrombus: A clot that adheres to a vessel wall Embolus: An intravascular clot that floats in the blood Detached thrombus → embolus Thrombus and embolus → occlude blood vessels and deprive tissues of oxygen and nutrients Arterial thrombosis : Most occurs in medium- sized vessels and consists of platelet-rich thrombi (called white thrombi) Venous thrombosis: Tend to be more fibrin-rich, contain large numbers of trapped red blood cells (called red thrombi) Thrombus vs Embolus

20. Antiplatelet drugs Antiplatelet agents- such as , aspirin Anticoagulant agents: Parenteral anticoagulants – such as, heparin and its derivatives Oral anticoagulants- such as, coumarin Fibrinolytic (thrombolytic) agents-such as, alteplase Agents that control blood fluidity Also called platelet aggregation inhibitors ↓ Platelet aggregation by discrete mechanisms Include: Aspirin Ticlopidine Clopidogrel Abciximab Tirofiban Eptifibatide Dipyridamole Cilostazol

21. In platelets, the major COX product is TXA 2 Aspirin inhibits the synthesis of TXA 2 by irreversible acetylation of Ser residue near the active site of platelet COX-1 This action lasts for the life of the platelet (7–10 days) → repeated doses of aspirin → cumulative effect on platelet function Doses that maximally effective as an antithrombotic [50–320 mg/day) are much lower than those required for other actions Higher doses → inhibit PGI 2 production → abolish protective effect of aspirin Also higher doses → ↑ toxicity, esp. bleeding Other NSAIDs (reversible inhibitors of COX-1) not appear antithrombotic efficacy, but may interfere with low-dose aspirin regimens → antagonize the platelet inhibition Uses: Prophylactic of transient cerebral ischemia, ↓ recurrent MI, ↓mortality in pre-and post- MI Used in combination with other anticlotting (heparin, clopidogrel ) Aspirin

22. Side effects: Bleeding, gastrointestinal irritation, ↓ platelets , allergy , Reye's syndrome Contraindication: Bleeding disorders (hemorrhagic stroke, GI tract bleeding, blood loss during surgery interventions), a llergy Thienopyridine derivatives Include: Clopidogrel ( Plavix*) & Ticlopidine ( Ticlid*) Mechanism of action: Irreversibly blocking the ADP receptor on platelets [purinergic receptors ( P 2 Y 1 & P 2 Y 12 ] → inhibit activation of GPIIb/ IIIa receptors →↓platelet aggregation Pharmacokinetics: Both prodrugs with a slow onset of action Extensively bound to plasma protein Hepatic metabolism by CYP450 → active metabolites Drugs and their metabolites excreted by both renal and feces Drug interactions: Inhibit CYP450 → interfere with metabolism of other drugs (phenytoin, tolbutamide, warfarin, fluvastatin, and tamoxifen)

23. Therapeutic use: Although ticlopidine and clopidogrel are similar in structure and mechanism of action, their therapeutic uses are different Prevent cerebrovascular events in secondary prevention of stroke ↓Cardiac events in patients with unstable angina With aspirin in patients undergoing coronary stent implantation to ↓incidence of stent thrombosis Reserved for patients who are intolerant or allergic to aspirin Adverse effects: The most common Dyspepsia, nausea, vomiting, and diarrhea (up to 20%) Life-threatening blood dyscrasias Hemorrhage ( 5%) Leukopenia (1%), severe neutropenia (<1500/mL), Fatal agranulocytosis → regular monitoring of WBC during the first 3 months of treatment Rare cases Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome Aplastic anemia Administered : Orally Dose: 250 mg twice/day Inhibition of platelet aggregation persists for a few days after the drug is stopped Ticlopidine

24. Therapeutic use: ↓Rate of stroke, MI Prevention of atherosclerotic events following recent MI, stroke, or established peripheral arterial disease Prophylactic of thrombotic events in acute coronary syndrome (ACS)- unstable angina or non-Q-wave MI. With aspirin after angioplasty with or without coronary stent (should be continued for at least 1 year) Preferred agent than ticlopidine in ischemic heart disease (IHD) events Adverse effects: Fewer than ticlopidine Neutropenia(rare) TTP Administered: Orally Dose: Loading dose: 300 mg Maintenance dose: 75 mg/d The duration of the antiplatelet effect is 7-10 days Clopidogrel

25. Dipyridamole (Persantine ® ) Mechanism of action: Inhibits platelet function by : Inhibiting cyclic nucleotide PDEs → ↑ cAMP Blockade of uptake of adenosine, which acts at A 2 receptors on the surface of platelet → stimulate platelet AC → ↑ cAMP Cilostazol A newer PDEs inhibitor Promotes vasodilation and inhibition of platelet aggregation Uses: Primarily to treat intermittent claudication Therapeutic use: Has little or no beneficial effect In prophylactic therapy to angina pectoris (coronary vasodilator) Combination with warfarin, inhibits embolization from prosthetic heart valves Combination with aspirin to prevent cerebrovascular ischemia

26. Platelet cAMP ATP Adenosine Adenosine A 2 Receptor Adenylate cyclase Dipyridamole (Persantine) 5-Amp PDEs Dipyridamole Cilostazol Dipyridamole

27. The dimeric Glycoprotein (GP) is a receptor for fibrinogen, collagen and vWF → anchor platelets to foreign surfaces and to each other → platelet aggregation Activated by platelet agonists (thrombin, collagen, or TXA 2 ) → platelet aggregation Inhibition of binding to this receptor → blocks platelet aggregation Lacking this receptor → bleeding disorder called Glanzmann's thrombasthenia Include: Monoclonal antibodies: Abciximab (Reopro ® ) Peptide antagonists: Eptifibatide (Integilin ® ) Non-peptide antagonists: Tirofiban (Aggrastat ® ) Glycoprotein IIb/IIIa inhibitors

28. Abciximab Eptifibatide Tirofiban

29. Abciximab (Reopro ® ) The Fab fragment of a humanized monoclonal antibody directed against the IIb /IIIa receptor Also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells Uses: Combination with aspirin and heparin to percutaneous coronary intervention and in ACS (preventing restenosis, recurrent MI, and death) Administered : IV Adverse Effects: Bleeding (the major side effect) especially if it is used with anticoagulants or if the patient has a clinical hemorrhagic condition Thrombocytopenia (<50,000 platelets/mL) in ~2% Limiting use in some setting (expensive) The antiplatelet effect persisting for 24-48 hrs Platelet function gradually returns to normal (after cessation infusion)

30. Eptifibatide (Integilin) : A cyclic peptide Tirofiban (Aggrastat ): A nonpeptide small-molecule Both inhibit the fibrinogen binding site on IIb/IIIa receptor Not block the vibronectin receptor Duration of action: short and platelet aggregation is restored within 6 –12 hrs after cessation of infusion Given in conjunction with aspirin and heparin Therapeutic use: To ↓ incidence thrombotic complications associated with ACS and for angioplastic coronary interventions Administered : IV Adverse Effects: Bleeding(the major side effect) Thrombocytopenia(0.5–1%) Excretion: Eptifibatide and its metabolites are excreted by the kidney Tirofiban is excreted unchanged by the kidney