Anticoagulants & Antiplatelet Drugs (PDF)

2024/09/17 Anticlotting agents: Intro and Anticoagulating Drugs L1 Dr Sarentha Chetty BPharm, MSc, PhD Objectives Pathophysiology of clots Classification anticlotting drugs Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions ...

2024/09/17 Anticlotting agents: Intro and Anticoagulating Drugs L1 Dr Sarentha Chetty BPharm, MSc, PhD Objectives Pathophysiology of clots Classification anticlotting drugs Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/09/17 Blood Clots Clot - important physiological process Prevent excessive bleeding Body naturally dissolves the clot once the injury is healed Clots - inside of vessels when there is no injury/clots do not dissolve naturally – DANGEROUS Clots can occur in veins or arteries Disorders in coagulation Hemostasis: finely tuned process of maintaining blood fluidity, repairing vascular injury, limiting blood loss whilst preventing tissue occlusion Platelet defects e.g. von Willebrand disease: Bleed from surfaces (gingiva, skin, heavy menses) on injury Defects in the clotting mechanism e.g. haemophilia: Bleed into deep tissues (joints, muscle, retroperitonium) – unpredictable Platelet rich thrombi (white thrombi) – high flow rate – arteries Venous clots (red thrombi) – more fibrin rich & trapped RBCs  2024/09/17 Disorders in coagulation Thrombus - unwanted clot in a blood vessel. Blood flow is sluggish accumulation of activated clotting factors Deep vein thrombosis (DVT) - major vein of leg/arms, pelvis or other large veins Part of a thrombus breaks off can travel to the heart or lungs -lodge and prevent adequate blood flow Pulmonary embolism (PE) -lungs How DVT Can Lead to Pulmonary Embolism: https://www.hematology.org/education/patients/blood-clots Atrial fibrillation (AF): Problems in atrial contraction  risk blood stasis Promotes the formation of a thrombus –could detach causes a MI or travel to the brain were it can cause cerebral embolism (stroke).  2024/09/17 The Clotting cascade Blood coagulation cascade Coagulation – transformation of soluble fibrinogen to insoluble fibrin Tissue factor (TF) main initiator binds to factor VIIa begins the cascade Antithrombin (AT) – endogenous anticoagulant Protein C and Protein S – attenuates the blood clotting cascade  2024/09/17 Anticlotting Drugs - Uses Treatment and prevention: oMyocardial infarction oIschaemic stroke in patients with AF oDVT Anticoagulant and thrombolytic drugs: Effective in treatment of venous and arterial thrombosis Antiplatelet drugs: Useful only for treatment of arterial disease.  2024/09/17 Anticoagulants Inhibit the formation of fibrin clots. Three major types: Heparin and related products Direct thrombin and factor X inhibitors Coumarin derivatives Heparin Large sulfated polysaccharide polymer Naturally occurring Molecules of varying size of between 5,000 – 20,000 Unfractionated Highly acidic IV or SC Risk of hematoma associated with IM  2024/09/17 Heparin - Mechanism and effects Unfractionated heparin (UFH) - indirect thrombin inhibitor. Binds to antithrombin III (ATIII) Heparin–ATIII complex irreversibly inactivates thrombin & several other factors, particularly factor Xa. Heparin acts on preformed blood components - immediate anticoagulation Anticoagulation effects monitored - activated partial thromboplastin time (aPTT) Low molecular Weight Fractions Heparin Dalteparin, enoxaparin, nadroparin: MW 2000 – 6000 Better bioavailability and longer durations of action than UFH Once or twice a day S/C Fondaparinux: Active pentasaccharide chemically related to LMW heparin Selective inhibitor of factor Xa with no effect on thrombin Administered S/C once daily.  2024/09/17 LMW Heparins Enoxaparin, dalteparin, and tinzaparin and fondaparinux binds ATIII. Also inhibits factor Xa LMW heparin–ATIII and fondaparinux–ATIII complexes -more selective action because no effect on thrombin. Heparin - Clinical use Rapid effect Common uses : DVT, pulmonary embolism, acute myocardial infarction. Combined with thrombolytics for revascularization Combined with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents. Does not cross the placental barrier – safe in pregnancy. LMW heparins & fondaparinux - similar clinical applications to heparin  2024/09/17 Heparin - Toxicity & Reversal Bleeding May result hemorrhagic stroke Antidote for UFH is Protamine sulphate Protamine partially reverses effects of LMW heparins, no effect on fondaparinux UFH causes moderate transient thrombocytopenia Heparin-induced thrombocytopenia (HIT) - Severe thrombocytopenia and thrombosis in those who produce an antibody that binds to a complex of heparin and platelet factor 4 LMW heparins and fondaparinux - less likely to cause HIT Prolonged use UFH - associated with osteoporosis Direct Thrombin Inhibitors Based on proteins made by Hirudo medicinalis Desirudin and bivalirudin are modified forms of hirudin Both are not yet available in SA. Argatroban (not available in SA) is a small molecule with a short half-life. Dabigatran is the only orally active direct thrombin inhibitor.  2024/09/17 Direct Thrombin Inhibitors – Clinical Uses MOA: Binds to the active site of thrombin and to thrombin substrates. The action of these drugs is monitored with the aPTT lab test Dabigatran: Prevention of stroke and systemic embolism in non-valvular AF Prophylaxis of venous thromboembolism (VTE) following hip or knee replacement surgery and Reduction of the risk of recurrent VTE Advantages of oral direct thrombin inhibitors Predictable pharmacokinetics - fixed dosing Predictable immediate anticoagulant response that makes routine monitoring or overlap with other anticoagulants unnecessary.  2024/09/17 Toxicity & Reversal Bleeding CI: Concomitant administration with heparins/warfarins/thrombolytic agents, GP IIb/IIIa inhibitors, clopidogrel, ticlopidine Drug Interactions Itraconazole, tacrolimus, ketoconazole - level of dabigatran by P- glycoprotein (MDR1) efflux transporter Idarucizumab (Praxbind®)is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. Direct Oral Factor Xa inhibitors Rivaroxaban, apixaban (available in SA), and edoxaban (not available in SA) Rapid onset of action and shorter half-lives than warfarin. Fixed oral doses and do not require monitoring. Undergo cytochrome P450-dependent and cytochrome P450- independent elimination. MOA: Bind directly to and inhibit both free factor Xa and factor Xa bound in the clotting complex.  2024/09/17 Direct Oral Factor Xa inhibitors- Clinical use Rivaroxaban Prevention and treatment of VTE following hip or knee surgery Prevention of stroke in patients with AF, without valvular heart disease. Apixaban - Prevention of embolic stroke in patients with non-valvular AF Toxicity & Reversal Can cause bleeding. Reversal agent is andexanet alfa (AndexXa). This is a coagulation factor Xa [recombinant], inactivated-zhzo. Warfarin and Other Coumarin Anticoagulants Small, lipid-soluble molecules Oral Readily absorbed Highly bound to plasma proteins (>99%) Metabolised by cytochrome P450 enzymes  2024/09/17 Warfarin inhibits vitamin K epoxide reductase (VKOR) VCOR converts vitamin K epoxide Mechanism and effects to reduced Vitamin K Vitamin K dependent factors - thrombin and factors II, VII, IX, and X Clotting factors have half-lives of 8–60h. Anticoagulant effect - only after the elimination of the normal preformed factors (4-5 days). Mostbauer, Halyna & Nishkumay, Olga & Rokyta, Oksana & Vavryniuk, Valeriia. (2022). Warfarin resistance: possibilities to solve this problem. A case report. The Journal of international medical research. 50. 3000605221103959. 10.1177/03000605221103959.  2024/09/17 Warfarin – long half life (40hrs) Take up to 5 days for the prothrombin to return to normal after stopping warfarin Reversed with phytomendione (vitamin K), but requires the synthesis of new clotting factors, slow action (6–24 h) Rapid reversal – transfuse with fresh or frozen plasma that contains normal clotting factors. Monitored by the prothrombin time (PT) test Warfarin – Clinical Use Prevention and control of thromboembolism ↓thromboembolism - AF & prosthetic heart valves Toxicity Bleeding Contraindicated: Pregnancy - bone defects, hemorrhage in the developing fetus, CNS effects Recent stroke, intracerebral bleeding, aneurysms Narrow therapeutic window Monitor INR (International normalized Ratio)  2024/09/17 Warfarin – Drug Interactions Metabolized in the liver to inactive 7-hydroxywarfarin. Cytochrome P450-inducing drugs (carbamazepine, phenytoin, rifampin, barbiturates) warfarin’s clearance and ↓ the anticoagulant effect Cytochrome P450 inhibitors (amiodarone, SSRIs, cimetidine) ↓ warfarin’s clearance and  the anticoagulant effect. Genetic variability in cytochrome P450 2C9 and VKOR affect responses to warfarin: Over/under anticoagulation – dependent on metabolizing status (slow or ultra-rapid) Individualized warfarin therapy Task 1 Have a look in the current SAMF? 1. Identify the drugs that have drug-drug interactions with warfarin Group them into P450 inducers and inhibitors 2. Are there any other types of drug-drug interactions? 3. What common foods have interactions with warfarin? 4. What complementary medicines can enhance the effect of warfarin?  2024/09/17 Cautions & Adverse effects CAUTIONS:  risk of bleeding – chronic hepatic disease or severe renal disease Geriatrics -  risk of bleeding over 65 yr Paediatrics – more susceptible to anticoagulant effects – because of Vitamin K deficiency ADVERSE EFFECTS: Haemorrhage - due to warfarin toxicity Warfarin induced skin necrosis (Breasts, buttocks & thighs) Purple-toe syndrome: Rare – painful, purple lesions on the toes and sides of the feet Direct Oral Anticoagulants (DOACs) vs Warfarin DOACs (dabigatran, rivaroxaban) - similar antithrombotic efficacy Lower bleeding tendencies - compared to warfarin. No need for monitoring Fewer drug interactions in comparison to warfarin. Short half-life of the newer anticoagulants means that if the patient is non- compliant - could quickly lead to loss of anticoagulant effect and risk of thromboembolism. Convenient once or twice daily oral dosing Fewer documented drug and dietary interactions  2024/09/17 Drugs that affect Coagulation Michael J. Neal, Pharmacology at a Glance, References Medical Pharmacology at a Glance (Michael J. Neal) Chapter 34: Drugs Used in Coagulation Disorders, Katzung & Trevor's Pharmacology: Examination & Board Review, Basic and Clinical Pharmacology (Katzung), 12e, Accessed at: https://0-accessmedicine- mhmedical-com.innopac.wits.ac.za/Book.aspx?bookid=2465 SAMF  2024/09/17 Anticoagulants, fibrinolytic agents and antiplatelet agents L2 Dr Sarentha Chetty BPharm, MSc, PhD THROMBOLYTIC AGENTS Endogenous tissue plasminogen activator (t-PA) alteplase, tenecteplase, and reteplase I/V Mechanism of Action Plasmin is an endogenous fibrinolytic enzyme. Thrombolytic enzymes catalyze- conversion of inactive precursor (plasminogen) to plasmin.  2024/09/17 Tissue plasminogen activator (t-PA) t-PA - converts plasminogen to plasmin Little activity unless it is bound to fibrin, theoretically increases selectivity for plasminogen that is bound to fibrin (in a clot) and there is less likelihood of widespread production of plasmin and spontaneous bleeding. At the pharmacologic doses of t-PA used in thrombolytic therapy, clot specificity is lost. Alteplase is recombinant human plasminogen activator. Reteplase is a mutated form of human t-PA with similar effects but a slightly faster onset of action and longer duration of action. Tenecteplase is another mutated form of t-PA with a longer half-life.  2024/09/17 Streptokinase & Urokinase Streptokinase is obtained from bacterial cultures. Streptokinase forms a complex with endogenous plasminogen The plasminogen then undergoes a conformational change that allows it to convert free plasminogen into plasmin. Unlike t-PA, streptokinase lacks selectivity for fibrin-bound plasminogen Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Clinical Use - Fibrinolytics Alternative to percutaneous coronary angioplasty in the emergency treatment of coronary artery thrombosis Under ideal conditions (i.e. treatment within 6 h) If tPa used within 3 h of the first symptom in patients with ischemic stroke - better clinical outcomes. Cerebral hemorrhage must be positively ruled out before use Thrombolytic agents also used in severe pulmonary embolism  2024/09/17 Toxicity Bleeding Cerebral hemorrhage is the most serious Streptokinase: Is a bacterial protein Can induce the production of antibodies that induce severe allergic reactions on subsequent therapy Patients who have had streptococcal infections may have preformed antibodies to the drug. The recombinant forms of t-PA don’t have the same problem but is more expensive than streptokinase and not much more effective. Antiplasmin drugs Aminocaproic acid and tranexamic acid inhibit plasmin formation.  2024/09/17 ANTIPLATELET DRUGS Video Link https://www.msdmanuals.com/home/multimedia/video/antiplatelet -drugs Anticoagulants - not as useful in preventing arterial thrombosis. In the arteries - faster blood flow, thrombi consist mainly of platelets with little fibrin. Antiplatelet drugs reduce platelet aggregation  2024/09/17 Classification and Prototypes Antiplatelet drugs: aspirin glycoprotein IIb/IIIa receptor inhibitors (abciximab, tirofiban, and eptifibatide) antagonists of ADP receptors (clopidogrel, prasugrel, ticagrelor, ticlopidine), inhibitors of phosphodiesterase 3 (dipyramidole) Aspirin Mechanism of Action Prevents TXA2 synthesis by blocking cyclooxygenase (COX I) Irreversible COXI & COX II inhibitor, but more selective for COX I Thromboxane A2 (TXA2) - potent stimulator of platelet aggregation. The endothelial cells of the vascular wall make prostaglandin (PGI2) which may be a physiological antagonist to TXA2.  2024/09/17 PGI2 activates adenyl cyclase cAMP which ↓ intracellular Ca2+ and inhibits platelet aggregation. When Aspirin blocks COX 2 in the platelets. Platelets are unable to synthesize new COX, but vascular endothelial cells can. Low dose of aspirin (75 -300mg) can provide selective inhibition of TXA2 over PGI2 Aspirin’s antiplatelet action lasts for several days until new platelets are formed Glycoprotein IIb/IIIa receptor Antagonists Platelet glycoprotein IIb/IIIa receptor - a cell surface protein involved in platelet cross-linking. Abciximab is a monoclonal antibody that reversibly inhibits the binding of fibrin and other ligands to the Glycoprotein IIb/IIIa receptor inhibitors Eptifibatide and tirofiban also reversibly block the glycoprotein IIb/IIIa receptor.  2024/09/17 Antagonists of ADP receptors: Clopidogrel, prasugrel, and ticlopidine Prodrugs - converted in the liver to active metabolites that irreversibly inhibit the platelet ADP receptor and thereby prevent ADP-mediated platelet aggregation Ticagrelor - Selective & reversible P2Y12ADP antaganist Inhibitors of phosphodiesterase 3 Dipyridamole and cilostazol have a dual mechanism of action. Inhibits phosphodiesterase enzymes which cAMP, which inhibits platelets activation and inhibits cyclic guanosine monophosphate (cGMP) which is a vasodilator Also inhibits the uptake of adenosine by endothelial cells and erythrocytes and thereby  the plasma concentration of adenosine. Adenosine by acting on the platelet adenosine A2 receptors  platelet cAMP.  2024/09/17 Clinical Use Aspirin is used to prevent MI in persons who have had a myocardial infarction. Used to prevent transient ischemic attacks (TIAs), ischemic stroke, and other thrombotic events. Glycoprotein IIb/IIIa inhibitors : Prevent restenosis after coronary angioplasty Used for short periods in acute coronary syndromes (eg, unstable angina and non-Q-wave acute myocardial infarction) Clinical Use Clopidogrel and ticlopidine Effective in preventing TIAs and ischemic strokes, especially in patients who cannot tolerate aspirin. Clopidogrel with aspirin - routinely used for 6–12 months to prevent thrombosis in patients after placement of a coronary artery stent. Dipyridamole with warfarin in the prevention of thrombosis in those with cardiac valve replacement and has been used in combination with aspirin for secondary prevention of ischemic stroke. Cilostazol is used to treat intermittent claudication, a manifestation of peripheral arterial disease.  2024/09/17 Clinical Use Ticagrelor with aspirin – prevent thrombosis in acute coronary syndrome Toxicity Aspirin - GIT and CNS effects All antiplatelet drugs significantly enhance the effects of other anticlotting agents. Major toxicities of glycoprotein IIb/IIIa receptor-blocking drugs are bleeding and with chronic use - thrombocytopenia. Ticlopidine is used rarely - causes bleeding in 5% of patients, severe neutropenia in about 1%, and very rarely thrombotic thrombocytopenic purpura (T T P). Clopidogrel is less hematotoxic.  2024/09/17 Most common adverse effects of dipyridamole and cilostazol - headaches and palpitations. Cilostazol is contraindicated in patients with congestive heart failure because of evidence of reduced survival Other antithrombotic agents - Anagrelide ↓platelet production and at higher does – platelet aggregation MOA - unclear In vitro – Inhibits cAMP phosphodiesterase, ADP, collagen induced platelet aggregation Indicated - essential thrombocytopenia Caution: Positive inotropic and chronotropic effects and may prolong QT interval – caution in cardiac disease ADR: anaemia, diarrhoea, dizziness, fatigue Less common: arrhythmias, CCF, confusion, depression, oedema , HT, thrombocytopenia  2024/09/17 Summary Pharmacology - ANTICOAGULANTS & ANTIPLATELET DRUGS (MADE EASY) https://www.youtube.com/watch?v=eZBtQ0rDnG4 CASE STUDY A 25-yearold woman presents to the emergency department complaining of acute onset of shortness of breath and pleuritic pain. She had been in her usual state of health until 2 days prior when she noted that her left leg was swollen and red. Her only medication was oral contraceptives. Family history was significant for a history of “blood clots” in multiple members of the maternal side of her family. Physical examination demonstrates an anxious woman with stable vital signs. The left lower extremity demonstrates erythema and edema and is tender to touch. Oxygen saturation by fingertip pulse oximeter while breathing room air is 87% (normal >90%). Ultrasound reveals a deep vein thrombosis in the left lower extremity; chest computed tomography scan confirms the presence of pulmonary emboli. Laboratory blood tests indicate elevated D-dimer levels.  2024/09/17 What therapy is indicated acutely? What are the long-term therapy options? How long should she be treated? Should this individual use oral contraceptives? References Medical Pharmacology at a Glance (Michael J. Neal) Chapter 34: Drugs Used in Coagulation Disorders, Katzung & Trevor's SAMF  2024/09/26 Drugs used in Bleeding disorders Dr Sarentha Chetty BPharm, MSc, PhD Objectives Introduction Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/09/26 VITAMIN K Co-factor for prothrombin and factors VII, IX, and X Fat soluble vitamin found primarily in leafy green vegetables Obtain from diet and it is synthesized by bacteria in the human intestine Two natural forms exist: vitamins K1 and K2 Vitamin K1 (phytomenadione) obtained from food Vitamin K2 (menaquinone) is synthesized by intestinal bacteria. Vitamin K1 - oral and parenteral forms Onset of action ± 6 hours and is complete by 24 hours. I/V Vitamin K1 – must be slow As rapid infusion can produce dyspnea, chest, back pain, even death Vitamin K1 - currently administered to all newborns to prevent the hemorrhagic disease of Vitamin K deficiency, especially common in premature infants.  2024/09/26 Vitamin K deficiency frequently occurs in ICUs because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy, and uremia In severe hepatic failure → diminished protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K Tx of depression of prothrombin activity e.g. excess warfarin or vitamin K deficiency Plasma coagulation deficiencies Deficiencies in plasma coagulation factors can cause bleeding Spontaneous bleeding occurs when factor activity is less than 5–10% of normal  2024/09/26 Haemophilia Rare inherited disease in which causes the blood to clot less, which results in an increased risk of bleeding or bruising. Deficiency or dysfunction of certain clotting factors Factor VIII (classic hemophilia, or hemophilia A) Factor IX (Christmas disease, or hemophilia B) “Inhibitors” in hemophilia are IgG alloantibodies to exogenous clotting factor VIII (FVIII) or factor IX (FIX) Inhibitors are more frequently with severe disease than in those with moderate or mild haemophilia More commonly in patients with hemophilia A than in those with hemophilia B  2024/09/26 Haemophilia Treatment Concentrated plasma fractions and recombinant protein preparations Lyophilized factor VIII concentrates are prepared from large pools of plasma Transmission e.g. hepatitis B and C and HIV ↓ or eliminated by pasteurization and by extraction of plasma with solvents and detergents. Does not remove other potential causes of transmissible diseases e.g. prions. Recombinant clotting factor preparations – therefore recommended Von Willebrand Disease Bleeding disorder in which blood does not clot properly Symptoms: nosebleeds, easy bruising, heavy menstruation, longer than normal bleeding after injury, surgery, dental work, childbirth Low levels of von Willebrand factor Von Willebrand factor in the blood functions as a carrier for factor VIII to maintain its levels and help in platelet adhesion and binding after a vascular injury.  2024/09/26 Desmopressin acetate Desmopressin acetate: synthetic analog of vasopressin ↑ the factor VIII activity Patients with mild hemophilia A or von Willebrand disease Prep for minor surgery e.g. tooth extraction High-dose intranasal desmopressin - efficacious and well tolerated by patients Blood coagulation Factors  2024/09/26 Fresh human plasma Fresh frozen plasma or lyophilized equivalent (Bioplasma) Sources for all coagulation factors Preferable for bleeding associated with multiple clotting factor deficiencies Emergency use –massive bleeding Life-threatening bleeding due to overcoagulation with warfarin Used for factor deficiencies for which no recombinant form of the protein is available Recombinant activated factor VII (NovoSeven) MOA: Binding of factor VIIa to exposed tissue factor This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin.  2024/09/26 Used to treat: Coagulopathy associated with liver disease and major blood loss in trauma and surgery Congenital haemophilia In patients with acquired haemophilia Haemophilia patients with inhibitors to factor VIII and IX for life- threatening bleeds or surgical interventions Cryoprecipitate Plasma protein fraction obtained from whole blood Used to treat deficiencies or qualitative abnormalities of fibrinogen e.g. disseminated intravascular coagulation and liver disease Source of fibrinogen, factor VIII, von Willabrand factor, factor XIII, fibronectin Indications: Treatment or prophylaxis of bleeding in significant hypofibrinogenaemia Factor XIII deficiency Emergency treatment of bleeding – haemophilia A if factor VIII is not available  2024/09/26 Cryoprecipitate is not treated to ↓ the risk of viral exposure Rh negative women with potential for childbearing should receive only Rh negative cryoprecipitate because of possible contamination of the product with Rh positive blood cells. Factor VIII Endogenous glycoprotein factor VIII available as a pooled lyophilized (freeze-dried) virus–inactivated antihaemophilia factor concentrate Indications: Treatment and prophylaxis of haemorrhage in haemophillia A and von Willebrand disease (with factor VIII deficiency)  2024/09/26 Factor VIII inhibitor bypassing activity (FEIBA) Contains an inti-inhibitor-coagulant complex Prepared from pooled human plasma Indications: o Treatment and prophylaxis of haemorrhage in Haemophilia A with actor VIII inhibitor Haemophillia B with IX inhibitor Factor IX Complex /Prothrombin Complex Contains vitamin K–dependent factors II, VII, IX, and X Used for rapid reversal of warfarin overdose in bleeding patients Treatment and prophylaxis of haemorrhage in hereditary or acquired disorders of coagulation with factor IX deficiency e.g. haemophilia  2024/09/26 Human Fibrinogen (factor I) Treatment of haemorrhage in congenital or acquired hypofibrinogenaemia Other haemostatics Romiplostin and Elthrombopag: Thrombopoetin receptor agonists Indications: Chronic thrombocytopaenia in patients refractory to corticosteroids, immunoglobulins or who have had a splenectomy  2024/09/26 Emicizumab Bi-specific monoclonal antibody to factor IXa and factor X It bridges factor Ixa and X thereby restoring the function of the missing factor VIII in Haemophilia A Prophylaxis of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Aminocaproic acid (EACA), which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis Competitively inhibits plasminogen Tranexamic acid is an analog of aminocaproic acid and has the same properties.  2024/10/02 Anaemia L1 Dr Sarentha Chetty BPharm, MSc, PhD Objectives Introduction Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/10/02 Introduction Hematopoiesis – bone marrow Requires essential nutrients— iron, vitamin B12, and folic acid Hematopoietic growth factors, proteins - regulate the proliferation and differentiation of hematopoietic cells Anaemia, a deficiency in oxygen carrying erythrocytes Due to deficiency of : Iron Vitamin B12 Folic acid Sickle Cell Anaemia Genetic cause Inherited disease Hemolytic anemia →↑ erythrocyte destruction Homozygous for the aberrant β-hemoglobin S (HbS) allele or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC) or β-thalassemia. Increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria.  2024/10/02 Majority of patients - anemia is not the primary presenting problem Anemia is generally well compensated even though: Chronically low hematocrit (20–30%) Low serum hemoglobin level (7–10 g/dL) Elevated reticulocyte count. Healthy red blood cells are flexible In sickle cell disease, the hemoglobin is abnormal, causing the red blood cells to be rigid and shaped like a "C" or sickle Abnormal erythrocytes aggregate in the microvasculature Causes veno-occlusive damage, block blood flow, causing pain and infections ancer.osu.edu/for-patients-and-caregivers/learn-about-cancers-and-treatments/cancers-conditions-and-treatment/benign-blood-diseases/sickle-cell-anemia  2024/10/02 Musculoskeletal system → extremely severe bone and joint pain Cerebral vascular system → ischemic stroke Damage to the spleen ↑risk of infection, particularly by Streptococcus pneumoniae Pulmonary system, ↑ risk of infection ↑ in embolism and pulmonary HT Supportive treatment: analgesics, antibiotics, pneumococcal vaccination, and blood transfusions Treatment Hydroxyurea (hydroxycarbamide) ↓ venoocclusive events. MOA: Acts to ↑ the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS Adverse effects: Hematopoietic depression, gastrointestinal effects, and teratogenicity  Voxelotor approved - binds HbS and reduces sickling by increasing its affinity for oxygen  2024/10/02 AGENTS USED IN ANEMIAS Haemoglobin Haemoglobin (Hb) consists of iron-porphyrin heme ring and globin chains Hb reversibly binds oxygen and delivers it from the lungs to other tissues  2024/10/02 Iron Deficiency Anaemia Most common cause of chronic anemia Symptoms: pallor, fatigue, dizziness, exertional dyspnea Chronic anemia— tachycardia, ↑cardiac output, vasodilation—can worsen underlying CVD Inadequate iron → small erythrocytes with insufficient hemoglobin →microcytic hypochromic anemia Hypochromic, microcytic anemia, low erythrocyte mean cell volume (MCV) and mean cell hemoglobin concentration Food Sources of Iron Meat - efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed without first having to be dissociated into elemental iron Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption Non-heme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferric reductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells Ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues – therefore serum ferritin level can be used to estimate total body iron stores.  2024/10/02 A. Indications for the Use of Iron Treatment or prevention of iron deficiency anemia Iron deficiency commonly seen in populations with ↑ iron requirements Infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis Inadequate iron absorption also can cause iron deficiency Gastrectomy, severe small bowel disease that results in generalized malabsorption. Most common cause of iron deficiency in adults is blood loss. Menstruating women lose about 30 mg of iron with each menstrual period In men and postmenopausal women, the most common site of blood loss is GIT Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding. Fe deficiency in Children: Can lead to behavioral disturbances and can impair development May not be fully reversible Can lead to an increased risk of lead toxicity secondary to pica and an increased absorption of heavy metals  2024/10/02 B. Treatment Oral or parenteral iron preparations Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin For these patients, parenteral iron administration is preferred Oral iron therapy Ferrous iron (Fe2+) is most efficiently absorbed Ferrous sulfate, ferrous gluconate, and ferrous fumarate Different iron salts provide different amounts of elemental iron Treatment with oral iron should be continued for 3–6 months after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores. Vitamin C (ascorbic acid) increases absorption of iron Ascorbic acid forms a chelate with ferric (Fe3+) iron in the low pH of the stomach, this remains soluble in the alkaline environment of the duodenum Also enhances iron absorption due to its ability to reduce ferric to ferrous iron due to its anti-oxidant property  2024/10/02 Adverse effects Common: nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea. Usually dose-related, overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals, without dairy Some patients have less severe gastrointestinal adverse effects with one iron salt than another Patients taking oral iron commonly develop black stools Drug Interactions: Fe salts reduce the absorption of levothyroxine, tetracyclines Antacids, tea, calcium reduces iron absorption  2024/10/02 2. Parenteral iron therapy Reserved for patients who are: Unable to tolerate or absorb oral iron Patients with extensive chronic anemia who can’t be maintained with oral iron alone Advanced chronic renal disease requiring hemodialysis Various post-gastrectomy conditions and previous small bowel resection Inflammatory bowel disease involving the proximal small bowel Malabsorption syndromes Parenteral administration causes dose-dependent toxicity, Severely limits the dose that can be administered When ferric iron is formulated as a colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate, bioactive iron is released slowly from the stable colloid particles Traditional parenteral irons: iron dextran, sodium ferric gluconate complex, and iron sucrose Iron dextran Stable complex of ferric oxyhydroxide and dextran polymers IM/ IV infusion IV – eliminates local pain and tissue staining that often occur with I/M  2024/10/02 Adverse effects: Headache, lightheadedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, rarely, anaphylaxis and death. Small test dose of iron dextran - check for hypersensitivity before full doses Risk of anaphylaxis mainly with high molecular formulations Alternate preps: Sodium ferric gluconate, iron sucrose, Ferric carboxymaltose, Ferumoxytol For patients chronically on parenteral iron Important to monitor iron storage levels to avoid serious toxicity associated with iron overload Oral iron therapy has a regulatory mechanism provided by the intestinal uptake system But parenteral administration— bypasses this regulatory system—can deliver more iron than can be safely stored Iron stores - estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron binding capacity (TIBC).  2024/10/02 Clinical Toxicity A. Acute Iron Toxicity Young children who accidentally ingest iron tablets As few as 10 tablets of any of the commonly available oral iron preparations can be lethal in young children Oral iron should be stored in childproof containers, out of reach of children Children poisoned with oral iron →necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death Requires urgent Tx Whole bowel irrigation to flush out unabsorbed pills. Deferoxamine/desferrioxamine: I/V iron-chelating compound to bind iron and promote excretion in urine and faeces. Activated charcoal, a highly effective adsorbent for most toxins, but does not bind iron and is ineffective Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided.  2024/10/02 B. Chronic Iron Toxicity Also known as hemochromatosis Results when excess iron is deposited in the heart, liver, pancreas, and other organs Can lead to organ failure and death Most commonly occurs in patients with inherited hemochromatosis Disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, individuals with β-thalassemia) Chronic iron overload in the absence of anemia - treated phlebotomy Iron chelation therapy using parenteral deferoxamine VITAMIN B12 Vitamin B12 (cobalamin) is a cofactor for several essential biochemical reactions in humans Deficiency →megaloblastic anemia Symptoms: gastrointestinal symptoms and neurologic abnormalities Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin and other cobalamins found in food sources are converted to the active forms. Chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products  2024/10/02 Vitamin B12 is absorbed after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa Vitamin B12 deficiency in humans: Most often from malabsorption of vitamin B12 due either to lack of intrinsic factor or To loss or malfunction of the absorptive mechanism in the distal ileum Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. Citation: Chapter 33 Agents Used in Cytopenias; Hematopoietic Growth Factors, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281752393 Accessed: June 18, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved  2024/10/02 1. Methyl Transfer: Methylcobalamin is an intermediate in the transfer of a methyl group from N-5-methyltetrahydrofolate to homocysteine, forming methionine Without vitamin B12, conversion of N5-methyltetrahydrofolate to tetrahydrofolate, the precursor of folate cofactors, cannot occur. Depletion of tetrahydrofolate prevents synthesis of adequate deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells Enzymatic reactions that use vitamin B12. See text. Citation: Chapter 33 Agents Used in Cytopenias; Hematopoietic Growth Factors, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281752393 Accessed: June 18, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved The accumulation of folate as N-5-methyltetrahydrofolate and depletion of tetrahydrofolate cofactors in vitamin B12 deficiency have been referred to as the “methylfolate trap.” Explains why megaloblastic anemia of vitamin B12 deficiency can be partially corrected by ingestion of large amounts of folic acid Folic acid can be reduced to dihydrofolate by the enzyme dihydrofolate reductase and thereby serve as a source of the tetrahydrofolate required for synthesis of the purines and dTMP required for DNA synthesis.  2024/10/02 Enzymatic reactions that use folates. Section 1 shows the vitamin B12-dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the “folate trap” in vitamin B12 deficiency. Section 2 shows the deoxythymidine monophosphate (dTMP) cycle. Section 3 shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool. Double arrows indicate pathways with more than one intermediate step. dUMP, deoxyuridine monophosphate. Citation: Chapter 33 Agents Used in Cytopenias; Hematopoietic Growth Factors, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281752393 Accessed: June 18, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Vitamin B12 deficiency → accumulation of homocysteine due to reduced formation of methylcobalamin ↑serum homocysteine - used to help establish a diagnosis of vitamin B12 deficiency Elevated serum homocysteine ↑risk of atherosclerotic cardiovascular disease RCTs have not shown a definitive reduction in cardiovascular events (myocardial infarction, stroke) in patients receiving vitamin B12 supplementation that lowers serum homocysteine.  2024/10/02 The second reaction that requires vitamin B12 is isomerization of methylmalonylCoA to succinylCoA by the enzyme methylmalonylCoA mutase In vitamin B12 deficiency, this conversion cannot take place MethylmalonylCoA, as well as methylmalonic acid accumulate The accumulation of methylmalonic acid (MMA) can disrupt normal glucose and glutamic acid metabolism ↑in serum and urine concentrations of methylmalonic acid can be used to support a diagnosis of vitamin B12 deficiency New evidence suggests that disruption of the methionine synthesis pathway cause of neurologic problems Administration of folic acid where there is vitamin B12 deficiency will largely correct the anemia caused by the vitamin B12 deficiency but will not prevent neurologic manifestations  2024/10/02 Clinical Pharmacology Vitamin B12 - to treat or prevent deficiency Clinical manifestation: Megaloblastic, macrocytic anemia often with associated mild or moderate leukopenia or thrombocytopenia (or both) Neurologic syndrome associated with vitamin B12 deficiency usually begins with paresthesias in peripheral nerves and weakness that progresses to spasticity, ataxia, and other central nervous system dysfunctions Correction of Vitamin B12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms Schilling test measures absorption and urinary excretion of radioactively labeled vitamin B12 and can define the mechanism of vitamin B12 malabsorption Most common causes of vitamin B12 deficiency: pernicious anemia, partial or total gastrectomy, conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, small bowel resection Strict vegans eating a diet free of meat and dairy products may become B12 deficient.  2024/10/02 Pernicious anemia →defective secretion of intrinsic factor by the gastric mucosal cells Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid) Frequently have autoantibodies to intrinsic factor Almost all cases of Vitamin B12 deficiency are caused by malabsorption of the vitamin; therefore needs parenteral vitamin B12 injections For patients with potentially reversible diseases, the underlying disease should be treated after initial treatment with parenteral vitamin B12. Most patients, however, do not have curable deficiency syndromes and require lifelong treatment with vitamin B12. Vitamin B12 for parenteral injection -available as cyanocobalamin or hydroxocobalamin Hydroxocobalamin - preferred because it is more highly protein bound therefore remains longer in the circulation Initial therapy: 100–1000 mcg of vitamin B12 intramuscularly daily or every other day for 1–2 weeks to replenish body stores. Maintenance therapy consists of 100–1000 mcg intramuscularly once a month for life If neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for 6 months before switching to monthly injections.  2024/10/02 FOLIC ACID Reduced forms of folic acid -required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency In patients with megaloblastic anemia, folate status is assessed with assays for serum folate or for red blood cell folate. Folic acid deficiency - often caused by inadequate dietary intake of folates. Patients with alcohol dependence and patients with liver disease → poor diet and diminished hepatic storage of folates Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid deficient Maternal folic acid deficiency → fetal neural tube defects Patients with malabsorption syndromes also frequently develop folic acid deficiency. Renal dialysis - risk of folic acid deficiency because folates are removed from the plasma during the dialysis procedure Folic acid deficiency can be caused by drugs: Methotrexate, trimethoprim and pyrimethamine Inhibit dihydrofolate reductase which may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia  2024/10/02 Dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption/dietary inadequacy Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients Pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis. HEMATOPOIETIC GROWTH FACTORS Regulate the proliferation and differentiation of hematopoietic progenitor cells in bone marrow Produced by recombinant DNA technology Clinical use: Erythropoietin stimulation agent (epoetin alfa and epoetin beta) Granulocyte colony stimulating factor (GCSF) Granulocyte macrophage colony stimulating factor (GMCSF) Interleukin 11 (IL11) Thrombopoietin receptor agonists (romiplostim and eltrombopag)  2024/10/02 ERYTHROPOIETIN stimulating agents (ESA) Recombinant human erythropoietin (epoetin alfa, epoetin beta) Administered three times a week Darbepoetin alfa - modified form of erythropoietin Has a 2-3 x longer half-life than epoetin alfa Administered weekly. Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is produced primarily in the kidney In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene Results in correction of the anemia In patients with renal disease, erythropoietin levels are usually low because the kidneys cannot produce the growth factor Require treatment with exogenous erythropoietin  2024/10/02 Clinical Pharmacology (ESAs) Used in patients with anemia secondary to chronic kidney disease An increase in reticulocyte count is usually observed in about 10 days and an increase in hematocrit and hemoglobin levels in 2–6 weeks. Dosages of ESAs are adjusted to maintain a target hemoglobin up to, but not exceeding, 10–12 g/dL. To support the increased erythropoiesis, patients with chronic kidney disease require oral or parenteral iron supplementation Folate supplementation may also be necessary Erythropoietin is also used to reduce the need for RBC transfusion in patients undergoing myelosuppressive cancer chemotherapy who have a hemoglobin level < 10 g/dL, and for selected patients with low risk myelodysplastic syndromes and anemia requiring RBC transfusion  2024/10/02 Blood Doping Eythropoeitin commonly used illegally by endurance athletes to enhance performance. Other methods such as autologous transfusion of red cells or use of androgens also have been used to increase hemoglobin “Blood doping” constitutes a serious health risk to athletes, Considered a form of cheating, and is universally banned and routinely tested for in athletic events. Toxicity Most common adverse effects of erythropoietin are HT and thrombotic complications ESAs ↑risk of serious cardiovascular events, thromboembolic events, stroke, and mortality in clinical studies when hemoglobin levels > 11 g/dL ESAs should be used conservatively in cancer patients (eg, when hemoglobin levels are