Understanding Warfarin: Mechanism, Dosage & Toxicity in Oral Anticoagulant Therapy

1. Edited slides #4 • Anything written in purple (italic) was mentioned by Dr. Munir • Anything in a box wasn’t mentioned by the doctor but might be helpful for memorizing • Anything underlined is important • Do not memorize doses

2. Oral Anticoagulant Drugs • Spoiled sweet clover caused hemorrhage in cattle(1930s). • Substance identified as bishydroxycoumarin. • Initially used as rodenticides “مدام بيقتل البقرة الكبيرة، أكيد بيقتل الفارة الصغيرة” still very effective, more than strychnine. Stychnine is a very toxic compound, however, it wasn’t effective for rodents because they usually send a volunteer which dies immediately. • Warfarin was introduced as an antithrombotic agent in the 1950s. Munir Gharaibeh, MD, PhD, MHPE

3. Warfarin looks like vitamin K (Vitamin K analogue) so it’s a competitive inhibitor of vitamin K. Vitamin K is imp for the synthesis of clotting factors (2,7,9,10) Munir Gharaibeh, MD, PhD, MHPE

4. Warfarin: • Is one of the most commonly prescribed drugs“not alone, also Xarelto is widely used/ anti-coagulants have wide applications” usually underprescribed “prescribed less than needed; doctors are afraid when prescribing oral anti-coagulants”. • 100% bioavailability, peaks after one hour“activity doesn’t correlate to serum level but occurs much later after absorption” Munir Gharaibeh, MD, PhD, MHPE

5. Warfarin: • 99% bound to plasma proteins “Plasma’s volume is 4L” , leading to small volume of distribution and long half life(36hr) “because it’s bound so it cannot go out of the intravascular compartment”. -Warfarin is dangerous because it’s 99% bound  drug-drug interactions • Does not cross BBB, but crosses the placenta. • Hydroxylated in the liver “the 1% that is unbound” • Present in two enantiomorphs“act in the liver”. Munir Gharaibeh, MD, PhD, MHPE

6. Mechanism of Action: • Act in the liver, not in the circulation. • Structure is similar to vitamin K “again competitive inhibitors”. • Block the γ-carboxylation which is a final synthetic step that transforms a common precursor into various factors: prothrombin (II), VII, IX, and Xas well as the endogenous anticoagulant proteins C and S. • This blockade results in incomplete coagulation factor molecules that are biologically inactive. Vitamin K dependent clotting factors: 2+7 = 9 , 10 * Note: factor 10 is always inhibited by whatever pre-mentioned drugs. Munir Gharaibeh, MD, PhD, MHPE

7. Mechanism of Action: • The protein carboxylation reaction is coupled to the oxidation of vitamin K “see next slide”. • The vitamin must then be reduced to reactivate it. • Therefore, warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form. Munir Gharaibeh, MD, PhD, MHPE

8. Carboxylation of prothrombin Blocks the rxn: no reactivation of Vit.K Reduced Vit.K Oxidized Vit.K Munir Gharaibeh, MD, PhD, MHPE

9. Onset of Action: • Time to maximal effect depends on factor degradation half-lives in the circulation. VII=6, IX=24, X= 40 and II=60 hrs. “so you have to wait until almost all of these factors are degraded. As a result, warfarin has a delayed onset of action” • Action starts after about 48 hrs“average”, i.e. after elimination of most of the factors in the circulation. So, do not increase the dose. “Be careful! If you increase the dose toxicity will appear later on So what do we do? Shall we wait for 48 hs? We actually give the patient heparin + oral anti-coagulant and we stop heparin after 48 hours. OR we prescribe Rivaroxaban (xarelto) or LMWH. Warfarin comes after these 2 but in certain conditions doctors prefer Warfarin” Munir Gharaibeh, MD, PhD, MHPE

10. Onset of Action: • Effect results from a balance between: (1) partially inhibited synthesis And (2) unaltered degradation of the four vitamin K dependent clotting factors. Munir Gharaibeh, MD, PhD, MHPE

11. Administration and Dosage: • Treatment is initiated with small doses of 5-10 mg, not large loading doses. • Warfarin resistance seen in cancer patients. • Response monitored by Prothrombin Time (PT). “remember that we use PTT to monitor heparin” • International Normalized Ratio (INR)= Patient PT/ Mean of normal PT for the lab. Munir Gharaibeh, MD, PhD, MHPE

12. Toxicity: • Bleeding as in heparin because it’s an extension of the pharmacological effect • Teratogenicity. It crosses the placental barrier So if a woman was taking an oral anti-coagulant then wanted to get pregnant, she has to stop them and we give her LMWH instead” • Cutaneous necrosis, infarction of breast, fatty tissues, intestine and extremities. This is due to inhibition of Protein C and S “physiological anti-coagulants so their inhibition causes thrombosis + infarction”, especially in patients genetically deficient in them. Munir Gharaibeh, MD, PhD, MHPE

13. So the problems with oral anti-coagulants: 1- Teratogenicity 2- delayed onset of action 3- protein bound  serious drug-drug interactions; anything competes in its binding to plasma protein will double its free amount. Munir Gharaibeh, MD, PhD, MHPE

14. Never think about memorizing them! Remember: Doc. Malik spent the introductory course giving Warfarin as an example on drug-drug interactions, especially those which are displaced from their binding proteins by other drugs. Munir Gharaibeh, MD, PhD, MHPE

15. Reversal of Action of Warfarin: • Vitamin K. • Fresh-frozen plasma. • Prothrombin complex concentrates. • Recombinant factor VII. Munir Gharaibeh, MD, PhD, MHPE

16. “ so far we have discussed drugs which can be used in thromboembolic disease & those used in preventing coagulation. However, those cannot lyse the already formed clots! So we will talk about another group of drugs “Fibrinolytic Agents” which can lyse those clots.” Munir Gharaibeh, MD, PhD, MHPE

17. These are the drugs that we’re going to talk about Munir Gharaibeh, MD, PhD, MHPE

18. Fibrinolytic Agents • These drugs rapidly lyse thrombi by catalyzing the formation of the serine protease Plasmin from its precursor zymogen, Plasminogen. (plasmin is an anti-platelet factor which dissolves already formed clots) • They create a generalized lytic state. • Aspirin (an anti-platelets drug) will be still required. Fibrinolytic drugs are important for recanalization of arterioles/ venules, however, aspirin is still required because recanalization is a gradual process and platelets will try to stop it. Munir Gharaibeh, MD, PhD, MHPE

19. Munir Gharaibeh, MD, PhD, MHPE

20. Fibrinolytic Agents “the idea of fibrinolytic drugs came from an enzyme (streptokinase) which was synthesized by streptococcus” Streptokinase: • Protein synthesized by Streptococcus. This enzyme is used by this microorganism to let it invade the body. • Binds with the proactivatorplasminogen in plasma to activate it. • Not fibrin - specific  Bleeding. • Works on a proximal part of the coagulation process.. Munir Gharaibeh, MD, PhD, MHPE

21. Streptokinase • Highly antigenic : “because it’s produced by a microorganism” • Can cause allergic reactions “if the patient was exposed to styptococcus, antigen-antibody rxn may take place  rash” • Can result in inactivation of the drug. • Early administration is important. *early after the incidence of thrombosis. In acute myocardial infarction, for example, it should be introduced during the first 6 hours *it’s rarely used because we have newer agents. Sometimes e use it because it’s cheap Munir Gharaibeh, MD, PhD, MHPE

22. Fibrinolytic Agents Urokinase: “the second fibrinolytic drug” • Is a human enzyme synthesized by the kidneys. • Directly converts plasminogen into plasmin. Not antigenic “ ’cause it’s obtained from a human source” • Expensive. Munir Gharaibeh, MD, PhD, MHPE

23. Fibrinolytic Agents Anistreplase (Anisoylated Plasminogen Streptokinase Activator Complex,ASPAC): “the structure of streptokinase was modified to produce a new fibrinolytic drug” • Deacylated at fibrin surface  Active complex released. “so this will produce a selective action of fibrin; our propose is to dissolve fibrin/ thrombin.” • More active and selective. “Selective means it is restricted to the site of thrombosis” • Long action, t½  6h Munir Gharaibeh, MD, PhD, MHPE

24. Fibrinolytic Agnets Ateplase Reteplase. Tenecteplase “these drugs represent the newest category of fibrinolytic agents” Munir Gharaibeh, MD, PhD, MHPE

25. Tissue-type Plasminogen Activators (t-PA): • Synthesized by the endothelial cells, also recombinant. • Bind to fibrin and activate plasminogen at the fibrin surface.“site of action is very well localized” • Action less affected by age of thrombus. “unlike streptokinase” • Specific action within the thrombus, avoids systemic activation. (unlike streptokinase which causes systemic activating of plasmin) • Short action t½ = 8 min “so it has to be given by cont. infusion”. • Given by infusion over 1-3 hours. “its action starts immediately” • Very Expensive. “but it’s a lifesaving agent and very effective if the patient was successfully transferred to the hospital” Munir Gharaibeh, MD, PhD, MHPE

26. FibrinolyticAgnets Indications: • Pulmonary embolism with hemodynamic instability. • Deep venous thrombosis. • Ascending thrombophlebitis. • Acute myocardial infarction. • These agents give best results in myocardial infarction. • Usually the patient is astonished by the treatment & the price :’) • His relatives may suspect the procedures done for him due to the very high price, although these agents + cardiac stents have prevented sever complications like chronic heart failure. Munir Gharaibeh, MD, PhD, MHPE

27. Antiplatelet Drugs • platelets try to close the endothelial injury by vasoconstrictors (TxA2) released from the endothelium. • platelet factors make channels, which are important for fibrinolysis, but the can be blocked easily by the platelets! So we have to prevent platelets activity in order to achieve fibrinolysis. Munir Gharaibeh, MD, PhD, MHPE

28. Other antiplatelet drugs: أنا دزيت سولو Anagelide Dazoxiban Sulotroban Munir Gharaibeh, MD, PhD, MHPE

29. Antiplatelet Drugs Types of Platelet Regulators: • Agents generated outside platelets which interact with membrane receptors: (Catecholamines“released by the sympathetic NS + adrenal grand during stress”, collagen, thrombin, and prostacyclin). • Agents generated inside and interact with membrane receptors: ADP“or adenosine”, PGD2, PGE2 and serotonin“5-hydroxytryptamine”. These agents are generated inside the platelets but when the platelets are destroyed they are released to affect other platelets. • Agents generated within and interact within platelets: TXA2, cAMP, cGMP and calcium. Munir Gharaibeh, MD, PhD, MHPE

30. Platelet adhesion and aggregation • GPIa/IIa and GPIbare platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. • P2Y1 and P2Y12 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. deficiency in protein GPIIb/IIIa is the cause of Glanzmann's thrombasthenia, which is a common bleeding disorder in Jordan (more than hemophilia) Munir Gharaibeh, MD, PhD, MHPE

31. Platelet adhesion and aggregation • PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa). • Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. • Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation Munir Gharaibeh, MD, PhD, MHPE

32. Thrmoboxane A2 + Prostacyclin work against each other • So If we give aspirin (for example) in small doses  it affects the platelets not prostacyclin Munir Gharaibeh, MD, PhD, MHPE

33. Munir Gharaibeh, MD, PhD, MHPE

34. Sites of action of antiplatelet drugs. • Aspirin inhibits thromboxane A2(TXA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activation and recruitment to the site of vascular injury. “ this is the intended activity  inhibits platelets’ thromboxane-A2 production, rather than affecting prostacyclin” • Ticlopidine, clopidogrel, and prasugrelirreversibly block P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelorare reversible inhibitors of P2Y12. Irreversible: Taklo bi grill? Ticlopidine, colpidogrel, prasugrel Reversible: Gerlor Cangrelor, ticagrelor Munir Gharaibeh, MD, PhD, MHPE

35. Sites of action of antiplatelet drugs. • Abciximab, eptifibatide, and tirofibaninhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) from binding to activated glycoprotein (GP) IIb/IIIa. • SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets. These 2 drugs are still under clinical trials, so their name is like a code understood only by the team working on it. Abciximab, eptifibatide, and tirofiban فيــهبـالمدرسةABC Munir Gharaibeh, MD, PhD, MHPE

36. Antiplatelet Drugs • Aspirin “trade name” = Acetyl Salicylic Acid “chemical name” • No generic name! • Causes irreversible acetylation of COX in platelets. • In small amounts it stays in the plasma affecting platelets only. Platelets do not have DNA or RNA, so aspirin causes permanent inhibition of platelets’ COX (half-life 7-10 days)Aspirin irreversibly affects old platelets only, which means that newly formed platelets aren’t affected . Munir Gharaibeh, MD, PhD, MHPE

37. Aspirin Endothelium can synthesize new COX, so PGI2 production is not affected. Again: in small doses! • Dose: 80  325 mg. Aspirin originally was given in higher doses as an antipyretic/ analgesic. Nowadays it’s used in smaller doses (baby aspirin for adults 80-81 mg) to prevent platelets aggregation +activation. 325 mg = 1 grain (grain was used for dosing in the 19th century, and 81mg is exactly the ¼ of a grain. Munir Gharaibeh, MD, PhD, MHPE

38. AntiplateletDrugs Remember: irreversible Taklo bi grill? Ticlopidine, colpidogrel, prasugrel • Clopidogrel (Plavix). • Ticlopidine (Ticlid). • Irreversibly block ADP receptors on platelets. • Useful in TIAs, completed stroke, unstable angina and after placement of coronary stents (mesh-شبكة). • Stents can be blocked easily by platelets, so antiplatelet drugs should be taken! • Useful for patients who cannot tolerate aspirin “stomach pain/ gastric ulcer”. • Can cause leukopenia, GI irritation “but not like aspirin”and skin rash. • Note: TIAs are transient ischemic attacks caused by minor/ incomplete strokes. If they happen in cerebral arteries they cause momentary blockade leading to momentary loss of consciousness; maybe he will have some neurological problems which are transient. Munir Gharaibeh, MD, PhD, MHPE

39. Remember: Abciximab, eptifibatide, and tirofiban فيــهبـالمدرسةABC Antiplatelet Drugs «هدول أدوية بنقدر نمشي عنهم عالسريع» د.منير • Abciximab. • C7E3 monoclonal antibody of the glycoprotein IIb/IIIa receptor complex. • Eptifibatide. • Synthetic peptide. • Tirofiban. • 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. Munir Gharaibeh, MD, PhD, MHPE

40. Taj mall Cilostazole Dipyridamole Antiplatelet Drugs Dipyridamole Cilostazole • Work by inhibiting adenosine uptake and phosphodiesterase enzyme c AMP in platelets and elsewhere. • Also work as vasodilators. Dipyridamole is not a new drug  an old one which was introduced as a replacement of Aspirin. It worked as a vasodilator in the treatment of Angina but later on it was found that the vasodilation is not produced in the ischemic part but in the other healthy (non-ischemic parts). This is due to the fact that vasodilation in the ischemic part has achieved its maximal level as a result of the active metabolism and chemicals released there.Also, this drug will cause a shift to the blood from ischemic areas “the most in need” to non ischemic ones so it’s useless to give vasodilators! However, it’s useful in cerebral ischemia ‘cause vasodilation there depends only on CO2 levels in the tissue. MunirGharaibeh, MD, PhD, MHPE

41. أنا دزيت سولو Anagelide Dazoxiban Sulotroban Antiplatelet Drugs *each enzyme is targeted by a certain drug. Dazoxiben: Inhibits TX synthetase enzyme. Sulotroban: Inhibits TXA2 receptor. Anagrelide: Reduces platelet production by decreasing megakaryocyte maturation. Lipid Lowering Agents: Do not react through platelets but they decrease lipid content in the plasma reducing adhesiveness of the platelets & other cells. This inhibits blood clotting. No need to have hyperlipidemia (دهنيات) to prescribe this drug. Some diabetic patients take it also. Munir Gharaibeh, MD, PhD, MHPE

42. Hemostatic agents: • Whole blood • Fresh frozen plasma • Plasma fractions • Viatmin K • Absorable gelatin foam • Absorabls gelatin film • Oxidized cellulose • thrombin • Plasmin inhibitors • Apo Amin rode a train • + Antiplasmin (من اسمه) • Aprotinin: • Aminocaproic Acid • Tranexamic Acid Munir Gharaibeh, MD, PhD, MHPE

43. Hemostatic Agents Those drugs work in the opposite direction; they’re not anti-coagulants neither fibrinolytic agents, but they work to enhance clot formation  to ↓ bleeding tendency (in injury/ surgery/ hemophilia/ purpura..). Even if you don’t know the diagnosis and our patient is in a shock, you have to give him whole blood. If you know he has a deficiency in clotting factors, you give him fresh frozen plasma. If you know which specific factor is defective you give him plasma fractions or that deficient factor (8/9/ prothrombin). Finally, we give vitamin K as a hemostatic agent. Remember that vitamin K is the antidote of oral anticoagulants. Munir Gharaibeh, MD, PhD, MHPE

44. Hemostatic Agents • Whole Blood • Fresh Frozen Plasma . • Plasma fractions. • Vitamin K. Munir Gharaibeh, MD, PhD, MHPE

45. * Blood donation for hemophilia patients has highly contributed to the spread of AIDS. Munir Gharaibeh, MD, PhD, MHPE

46. Hemostatic Agents • Absorbable Gelatin Foam: Used in surgeries. However, if you have bleeding from a blood vessel, the standard treatment is to tie that blood vessel. So don’t put the foam and expect that bleeding would stop! • Absorbable Gelatin Film • Oxidized Cellulose • Thrombin Munir Gharaibeh, MD, PhD, MHPE

47. Plasmin Inhibitors “Plasmin is responsible for clot resorption, so if we inhibit plasmin there would be no clot resorption.” • 2 Antiplasmin Physiological. • Aprotinin: Bovine parotid gland. • Aminocaproic Acid • Tranexamic Acid These agents inhibit bleeding in patients with bleeding tendency. Apo Amin rode a train + Antiplasmin (من اسمه) Aprotinin: Aminocaproic Acid Tranexamic Acid Munir Gharaibeh, MD, PhD, MHPE