Oral Anticoagulant Drugs l Spoiled sweet clover caused
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Oral Anticoagulant Drugs l Spoiled sweet clover caused hemorrhage in cattle(1930 s). l Substance identified as bishydroxycoumarin. l Initially used as rodenticides, still very effective, more than strychnine. l Warfarin was introduced as an antithrombotic agent in the 1950 s. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 1
Oral Anticoagulant Drugs l Warfarin: l Is one of the most commonly prescribed drugs, usually underprescribed. l 100% bioavailability, peaks after one hour. l 99% bound to plasma proteins, leading to small volume of distribution and long half life(36 hr). Does not cross BBB, but crosses the placenta. l Hydroxylated in the liver. l Present in two enantiomorphs. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 2
Oral Anticoagulant Drugs Mechanism of Action: Act in the liver, not in the circulation. Structure is similar to vitamin K. l Block the Ɣ-carboxylation which is a final synthetic step that transforms a common precursor into various factors: prothrombin, VII, IX, and X as well as the endogenous anticoagulant proteins C and S. l This blockade results in incomplete coagulation factor molecules that are biologically inactive. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 3
Oral Anticoagulant Drugs Mechanism of Action: The protein carboxylation reaction is coupled to the oxidation of vitamin K. l The vitamin must then be reduced to reactivate it. l Therefore, warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 4
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Warfarin Onset of Action: l Action starts after about 48 hrs after elimination of the factors in the circulation. l Effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K dependent clotting factors. l Time to maximal effect depends on factor degradation half-lives in the circulation. VII=6, IX=24, X= 40 and II=60. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 7
Warfarin l Administration and Dosage: l Treatment is initiated with small doses of 5 -10 mg, not large loading doses. l Warfarin resistance seen in cancer patients. l Response monitored by Prothrombin Time. l International Normalized Ratio (INR)= l Patient Dec-21 PT/ Mean of normal PT for the lab. Munir Gharaibeh, MD, Ph. D, MHPE 8
Warfarin Toxicity: l Bleeding. l Teratogenicity. l Cutaneous necrosis, infarction of breast, fatty tissues, intestine and extremities. This is due to inhibition of Protein C and S, especially in patients genetically deficient in them. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 9
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Warfarin l Reversal of Action: l Vitamin K. l Fresh-frozen plasma. l Prothrombin complex concentrates. l Recombinant factor VII. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 11
Fibrinolytic Agnets l These drugs rapidly lyse thrombi by catalyzing the formation of the serine protease Plasmin from its precursor zymogen, Plasminogen. l They create a generalized lytic state. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 12
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Fibrinolytic Agents Streptokinase: synthesized by Streptococcus. l Binds with the proactivator plasminogen in plasma to activate it. l Not fibrin - specific Bleeding. l Highly antigenic : l Protein l Allergic reactions l Can be inactivated. l Early Dec-21 administration is important. Munir Gharaibeh, MD, Ph. D, MHPE 14
Fibrinolytic Agents Urokinase: l Is a human enzyme synthesized by the kidneys. l Directly converts plasminogen into Plasmin. l Not antigenic. l Expensive. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 15
Fibrinolytic Agents Anistreplase (Anisoylated Plasminogen. Streptokinase Activator Complex, ASPAC): l Deacylated at fibrin surface Active complex released. l More active and selective. l Long t½ Action 6 h Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 16
Fibrinolytic Agnets l l l l l Tissue-type Plasminogen Activators (t-PA): Ateplase Reteplase. Tenecteplase Synthesized by the endothelial cells, also recombinant. Bind to fibrin and activate plasminogen at the fibrin surface. Action less affected by age of thrombus. Specific action within the thrombus, avoids systemic activation. Short action t½ = 8 min. Given by infusion over 1 -3 hours. Very Expensive. Should add Aspirin. Munir Gharaibeh, MD, Ph. D, MHPE 17 Dec-21
Fibrinolytic Agnets Indications: l Pulmonary embolism with hemodynamic instability. l Deep venous thrombosis. l Ascending thrombophlebitis. l Acute myocardial infarction. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 18
Antiplatelet Drugs Platelet Regulators: l Agents generated outside platelets and interact with membrane receptors: Catecholamines, collagen, thrombin, and prostacyclin. l Agents generated inside and interact with membrane receptors: ADP, PGD 2, PGE 2 and serotonin. l Agents generated within and interact within platelets: TXA 2, c. AMP, c. GMP and calcium. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 19
Platelet adhesion and aggregation l GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (v. WF), causing platelets to adhere to the subendothelium of a damaged blood vessel. l P 2 Y 1 and P 2 Y 12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 20
Platelet adhesion and aggregation l PAR 1 and PAR 4 are protease-activated receptors that respond to thrombin (IIa). l Thromboxane A 2 (Tx. A 2) is the major product of COX-1 involved in platelet activation. l Prostaglandin I 2(prostacyclin, PGI 2), synthesized by endothelial cells, inhibits platelet activation Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 21
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Sites of action of antiplatelet drugs. Aspirin inhibits thromboxane A 2(Tx. A 2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced Tx. A 2 release attenuates platelet activation and recruitment to the site of vascular injury. l Ticlopidine, clopidogrel, and prasugrel irreversibly block P 2 Y 12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P 2 Y 12. l Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 23
Sites of action of antiplatelet drugs. l l Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (v. WF) from binding to activated glycoprotein (GP) IIb/IIIa. SCH 530348 and E 5555 inhibit thrombinmediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 24
Antiplatelet Drugs l Aspirin l = Acetyl Salicylic Acid Irreversible acetylation of COX in platelets. Platelets do not have DNA or RNA, so permanent inhibition of platelets’ COX (half-life 7 -10 days). Endothelium can synthesize new COX, so PGI 2 production is not affected. l Dec-21 Dose: 80 325 mg. Munir Gharaibeh, MD, Ph. D, MHPE 25
Antiplatelet Drugs l Clopidogrel (Plavix). l Ticlopidine (Ticlid). l Irreversibly block ADP receptors on platelets. l Useful in TIAs, completed stroke, unstable angina and after placement of coronary stents. l Useful for patients who cannot tolerate aspirin. l Can cause leukopenia, GI irritation and skin rash. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 26
Antiplatelet Drugs l Abciximab. l C 7 E 3 monoclonal antibody of glycoprotein IIb/IIIa receptor complex. l Eptifibatide. l Synthetic peptide. l Tirofiban. l All inhibit the platelet glycoprotein IIb/IIIa complex, which works as a receptor mainly for fibrinogen and vitronectin as well as for fibronectin and von Willebrand factor. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 27
Antiplatelet Drugs Dipyridamole Cilostazole Vasodilator. Inhibit adenosine uptake and phosphodiesterase enzyme c AMP in platelets and elsewhere. l Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 28
Antiplatelet Drugs Dazoxiben: Inhibits TX synthetase enzyme. Sulotroban: Inhibits TXA 2 receptor. Anagrelide: Reduces platelet production by decreasing megakaryocyte maturation. Lipid Lowering Agents Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 29
Hemostatic Agents l Whole Blood l Fresh Frozen Plasma. l Plasma fractions. l Vitamin K. Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 30
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Plasmin Inhibitors l 2 Antiplasmin l Physiological. l Aprotinin: l Bovine parotid gland. l Aminocaproic Acid l Tranexamic Acid Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 32
Hemostatic Agents l Absorbable Gelatin Foam l Absorbable Gelatin Film l Oxidized Cellulose l Thrombin Dec-21 Munir Gharaibeh, MD, Ph. D, MHPE 33
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