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ANEMIA I. IRON Site of absorption: DUODENUM AND PROXIMAL JEJUNUM...

ANEMIA I. IRON Site of absorption: DUODENUM AND PROXIMAL JEJUNUM IRON DEFICIENCY ANEMIA TREATMENTS 1. ORAL IRON THERAPY IRON FORMS DOSAGE DURATION SIDE EFFECTS Ferrous salts (e.g., ferrous 200–400 mg of elemental iron daily Continue therapy for 3–6 months nausea, abdominal discomfort, sulfate, ferrous gluconate, ferrous is recommended, with lower doses if after correcting the cause of iron constipation, fumarate) side loss to diarrhea, and black stools effects occur. replenish iron stores. Lowering the dose or taking iron with food can help manage these effects. 2. PARENTERAL IRON THERAPY Iron Dextran Sodium Ferric Gluconate and Iron-Sucrose Ferric Carboxymaltose and Ferumoxytol Complex Can be given intramuscularly or intravenously, Alternative options with fewer Newer preparations with specific with intravenous administration being preferred. severe reactions. considerations, such as ferumoxytol Adverse effects include headache, fever, potentially interfering with MRI studies. The nausea, and rarely, anaphylaxis. A test dose FDA has issued warnings about severe is recommended to check for allergic reactions with ferumoxytol. hypersensitivity. TABORA | 1  DAILY/ DIETARY % ABSORBED # ABSORBED DOSAGE STORAGE REQUIRED INTAKE AMOUNT IRON 10-15 mg 5-10% 0.5-1 mg daily 200-400 mg B12 5-30 mcg 1-5 mcg 3000-5000 mcg 2 mcg (daily (total body pool) requirement) B9 500-700 mcg 1 mg (daily oral 5-20 mg (American diet) dose) TABORA | 2  HEMATOPOIETIC GROWTH FACTORS I. ERYTHROPOIETIN GENERAL INFO ADMINISTRATION SCHEDULE HALF-LIFE Recombinant Human Erythropoietin recombinant form produced in a Typically given three times a week 4–13 hours in patients with chronic (rHuEPO) mammalian cell expression system renal failure administered intravenously measured in international units (IU) and is not cleared by dialysis Darbepoietin Alfa erythropoietin with additional Administered weekly Two-fold to three-fold longer glycosylation half-life than epoetin alfa Methoxy Polyethylene isoform of erythropoietin attached Given every 2 weeks or once a long Glycol–Epoetin Beta to a long polyethylene glycol month. polymer Erythropoietin-Stimulating Agents (ESAs) TREATMENT TIMELINE DOSAGE AND TARGET LEVELS ADVERSE EFFECTS After ESA treatment, reticulocyte counts increase ESA dosages are adjusted to maintain COMMON SERIOUS in about 10 days, and hematocrit and hemoglobin hemoglobin levels between 10–12 g/dL, ensuring levels rise within 2–6 weeks. the patient’s safety. Hypertension and Cardiovascular events, thrombotic Thromboembolic complications events, Stroke, and Mortality (hemoglobin >11 g/dL.) TABORA | 3  II. MYELOID GROWTH FACTORS 1. Recombinant Human G-CSF (rHuG-CSF; Filgrastim) GENERAL INFO HALF-LIFE OTHER FORMS TREATMENT/ CLINICAL ADVERSE EFFECTS GUIDELINES Produced in bacterial 2–7 hours after intravenous Pegfilgrastim (long-acting): Accelerates neutrophil Common Side Effect: Bone expression systems or subcutaneous A conjugation product of recovery, reduces the pain, typically resolving after administration filgrastim and polyethylene duration of neutropenia, and discontinuation of the drug. Non-glycosylated peptide glycol. typically increases the nadir with 175 amino acids, 18 neutrophil count Rare Complication: Splenic kDa molecular weight. Longer serum half-life allows rupture, a serious risk during for single injection per Reserve G-CSF for PBSC mobilization. Tbo-filgrastim: Similar to chemotherapy cycle. High-risk patients based on filgrastim with minor age, history, and disease. More frequently used due to differences but equivalent Lenograstim better tolerance and fewer activity. A glycosylated form of Patients on dose-intensive severe side effects. recombinant G-CSF, widely chemotherapy (>20% risk of used in Europe febrile neutropenia). Those with previous febrile neutropenia or unlikely to survive such an episode. Pegfilgrastim: An alternative to G-CSF, offering once-per-cycle administration. approved for AML treatment, aiding neutrophil recovery and reducing infection and hospitalization G-CSF (5 mcg/kg daily) starts 24–72 hours post-chemotherapy, continuing until neutrophil TABORA | 4  counts exceed 10,000 cells/μL. 2. Recombinant Human GM-CSF (rHuGM-CSF; Sargramostim) GENERAL INFO HALF-LIFE OTHER FORMS TREATMENT/ CLINICAL ADVERSE EFFECTS GUIDELINES Produced in yeast 2–7 hours after intravenous - approved for AML treatment, Severe Side Effects at expression systems. or subcutaneous aiding neutrophil recovery Higher Doses: Fever, Partially glycosylated administration and reducing infection and malaise, arthralgias (joint peptide with 127 amino hospitalization pain), and myalgias (muscle acids pain). Exists in three molecular Reduces neutropenia species with weights: duration like G-CSF but is Capillary Leak Syndrome: 15,500, 15,800, and 19,500 less effective in reducing Can lead to peripheral kDa. febrile neutropenia due to edema and pleural or potential fever induction. pericardial effusions. GM-CSF (250 mcg/m² daily) starts 24–72 hours post-chemotherapy, continuing until neutrophil counts exceed 10,000 cells/μL. III. THROMBOPOIETIN RECEPTOR AGONISTS 1. Romiplostim A thrombopoietin agonist peptide linked to antibody fragments to extend its half-life. Used for chronic immune thrombocytopenia in patients unresponsive to other treatments. Peak platelet count responses in ~2 weeks. HALF-LIFE VARIATION 3–4 days after subcutaneous administration Half-life is longer in patients with thrombocytopenia and shorter in those with normal platelet counts 2. Eltrombopag For chronic immune thrombocytopenia in patients with inadequate responses to other therapies. TABORA | 5  For thrombocytopenia in hepatitis C patients to enable interferon therapy. TYPE PHARMACOKINETICS Oral nonpeptide thrombopoietin agonist. Peak levels achieved following oral administration. ROMIPLOSTIM AND ELTROMBOPAG Effective for chronic immune thrombocytopenia unresponsive to steroids, immunoglobulins, or splenectomy. Dosage is adjusted to maintain platelet counts above 50,000 cells/μL. COAGULATION HEPARIN TABORA | 6  MOA ADMINISTRATION AND ADVERSE EFFECTS AND REVERSAL MONITORING CONTRAINDICATIONS Heparin A mixture of sulfated Bleeding: Protamine Sulfate: Used to mucopolysaccharides that The most common adverse neutralize the anticoagulant bind to antithrombin, effect, especially in elderly effect of heparin. However, accelerating its ability to women and patients with its effectiveness is limited inhibit clotting factors by renal failure. Long-term for LMW heparins and does 1000-fold. heparin use can lead to not reverse fondaparinux. osteoporosis and hair loss. Excessive protamine should Unfractionated Heparin Binds to antithrombin, Requires close monitoring of be avoided as it can also accelerating its inhibition of activated partial Heparin-Induced have anticoagulant effects. thrombin, factor Xa, and thromboplastin time (aPTT) Thrombocytopenia (HIT): other clotting factors by or anti-Xa levels. Occurs more frequently with 1000-fold UFH than with LMWH. Low Molecular Weight Shorter-chain fractions Dosing is weight-based, with Management includes Heparin mainly inhibit factor Xa with predictable discontinuing heparin and less impact on thrombin. pharmacokinetics; generally starting a direct thrombin does not require routine inhibitor, like argatroban. monitoring unless in cases of renal insufficiency, Heparin is contraindicated in obesity, or pregnancy. patients with HIT, hypersensitivity, active bleeding, or those Fondaparinux A synthetic molecule that Has a long half-life, allowing undergoing certain surgeries specifically binds to for once-daily dosing and is or procedures (e.g., brain antithrombin and inactivates effective in preventing and surgery, lumbar puncture). factor Xa efficiently. treating venous thromboembolism. A synthetic pentasaccharide that selectively inhibits factor Xa by binding to antithrombin. Does not inhibit thrombin Daily subcutaneous dose Long half-life allows for once-daily dosing and does TABORA | 7  not cross-react with antibodies causing heparin-induced thrombocytopenia (HIT). COUMARIN ANTICOAGULANTS: WARFARIN PHARMACOKINETICS MOA DOSING AND MONITORING ADVERSE EFFECTS REVERSAL Administered orally with nearly Warfarin blocks the enzyme Warfarin therapy is guided by Bleeding Reversal strategies include 100% bioavailability. vitamin K epoxide reductase the international normalized vitamin K, fresh-frozen plasma (VKORC1), reducing the ratio (INR), with a typical target Warfarin-induced skin necrosis (FFP), prothrombin complex Highly protein-bound, mainly to regeneration of active vitamin range of 2-3 for most concentrates (PCCs), and albumin, with a long half-life of K and thereby diminishing the indications. Teratogenicity recombinant factor VIIa around 36 hours. synthesis of active clotting (rFVIIa), depending on the factors. Genetic variations in VKORC1 When the INR is too high, there severity of bleeding. S-warfarin is more potent than and CYP2C9 can influence is increased risk of R-warfarin, contributing to its Onset of action is delayed (8-12 dosing requirements. hemorrhage. When the INR is The most specific antidote for complex drug interactions hours) due to the time required too low, there is increased risk warfarin toxicity is vitamin K. for depletion of preexisting for thrombosis Vitamin K works by inhibiting active clotting factors VKOR, the enzyme responsible for reducing vitamin K. Vitamin K takes several hours to reverse the effects of warfarin ORAL DIRECT FACTOR Xa INHIBITORS CLINICAL USE INFO ORAL BIOAVAILABILITY HALF-LIFE Rivaroxaban Approved for preventing Extensively protein-bound, high oral bioavailability when 5-9 hours embolic stroke in metabolized by the taken with food nonvalvular atrial fibrillation, cytochrome P450 system preventing venous and excreted in both urine thromboembolism (VTE) and feces. post-hip or knee surgery, and treating VTE. Apixaban Approved for stroke Metabolized by cytochrome 50% 12 hours prevention in nonvalvular P450 and excreted in urine atrial fibrillation, prevention and feces. of VTE post-hip or knee TABORA | 8  surgery, and treatment and Similar to rivaroxaban, drug long-term prevention of VTE. effect is enhanced by CYP3A4 and P-glycoprotein inhibitors. Edoxaban Approved for stroke Primarily excreted 62% 10-14 hours prevention in nonvalvular unchanged in the urine and atrial fibrillation and VTE does not require dose treatment post-heparin or adjustment with LMWH therapy. P-glycoprotein inhibitors. DIRECT THROMBIN INHIBITORS PARENTERAL Bivalirudin parenteral bivalent thrombin inhibitor with rapid onset and offset, FDA-approved for use during percutaneous coronary angioplasty. It also inhibits platelet activation and has a short half-life, with clearance split between renal and metabolic pathways. Argatroban a small-molecule thrombin inhibitor used in HIT patients with or without thrombosis and in coronary angioplasty. It is administered intravenously, with liver metabolism dictating its clearance. Elevated INR levels during its use can complicate the transition to warfarin, requiring specialized dosing guidelines. ORAL Dabigatran etexilate mesylate Indications include reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment and prevention of venous thromboembolism (VTE), and prophylaxis following hip or knee replacement surgery. REVERSAL: ○ Idarucizumab is a monoclonal antibody fragment used to reverse the anticoagulant effects of dabigatran, particularly in emergencies or life-threatening bleeding situations. It acts quickly, with a recommended dose of 5 g intravenously, and is primarily excreted by the kidneys. FIBRINOLYTIC DRUGS TABORA | 9  INFO INDICATION MONITORING REVERSAL Streptokinase A protein produced by Pulmonary Embolism No specific monitoring is While not commonly used, streptococci that forms a required for most fibrinolytic, idarucizumab is an example complex with plasminogen, Severe Deep Venous but bleeding risks must be of a specific antidote for converting it to plasmin. Thrombosis managed carefully. dabigatran, but general antidotes for fibrinolytic are Urokinase A human enzyme that Ascending Thrombophlebitis limited ( directly converts plasminogen to plasmin. Peripheral Vascular Disease Acute Myocardial Infarction Tissue Plasminogen Endogenously activate (AMI) Activators (t-PAs) plasminogen bound to fibrin, focusing fibrinolysis on the clot rather than systemically. ACUTE MYOCARDIAL INFARCTION ACUTE ISCHEMIC STROKE Streptokinase and urokinase can be used, but alteplase, reteplase, and Alteplase is approved for use within 3 hours of symptom onset. tenecteplase are more commonly preferred due to their specific benefits. Streptokinase is contraindicated for ischemic stroke due to increased bleeding risk at doses of 1.5 million units PLATELET INHIBITORY DRUGS INDICATIONS DOSAGE AND MONITORING ADVERSE EFFECTS/ CAUTION/ RESTRICTION CONTRAINDICATIONS Aspirin Irreversible inhibition of cyclooxygenase (COX) enzyme through acetylation. This inhibition reduces the synthesis of thromboxane A2, Ticlopidine Prevention of stroke in Regular white blood cell Common: Nausea, Should be reserved for patients with a history of count monitoring is dyspepsia, diarrhea (up to patients intolerant to or who transient ischemic attack necessary during the first 3 20%). have failed aspirin therapy (TIA) or thrombotic stroke. months. Serious: Hemorrhage (5%), Used with aspirin for 250 mg orally twice daily. leukopenia (1%), and risk of coronary stent thrombosis thrombotic prevention thrombocytopenic purpura. TABORA | 10 Clopidogrel Approved for unstable NSTEMI: 300 mg loading Fewer than ticlopidine, rare Drugs like omeprazole that angina, NSTEMI, STEMI, dose, followed by 75 mg neutropenia; thrombotic impair CYP2C19 should be recent myocardial infarction, daily. thrombocytopenic purpura used carefully stroke, and peripheral reported. arterial disease. STEMI: 75 mg daily, in combination with aspirin. Recent events: 75 mg daily. Prasugrel Similar to clopidogrel, used 60 mg loading dose, CI: history of TIA or stroke for acute coronary followed by 10 mg daily in due to bleeding risk. syndromes. combination with aspirin. NEWER AGENTS Ticagrelor Cangrelor An oral ADP inhibitor approved for acute A parenteral P2Y12 inhibitor approved for IV coronary syndromes in combination with use in coronary interventions in patients without previous ADP P2Y12 aspirin. inhibitor therapy GP IIb/ IIIa ANTAGONISTS INDICATIONS Abciximab Used in patients with acute coronary syndromes to inhibit platelet aggregation Eptifibatide Tirofiban ADDITIONAL ANTIPLATELET-DIRECTED DRUGS FUNCTION USE COMBINATION TABORA | 11  Dipyridamole Acts as a vasodilator and inhibits Primarily used in combination with A combination formulation of platelet function by: aspirin to prevent cerebrovascular dipyridamole with 25 mg of aspirin is ischemia available for secondary prophylaxis of - Inhibiting adenosine uptake. cerebrovascular disease. Can be combined with warfarin for - Inhibiting cGMP primary prophylaxis of thromboemboli phosphodiesterase activity to in patients with prosthetic heart valves. reduce cAMP degradation. Cilostazol A phosphodiesterase inhibitor that Mainly prescribed for the treatment of promotes vasodilation and inhibits intermittent claudication, a condition platelet aggregation. characterized by leg pain due to inadequate blood flow. VITAMIN K FORM SOURCE ADMINISTRATION RECO USE Vitamin K1 (PHytonadioine) Found in leafy green vegetables and Intravenous Administration: This Newborns : Vitamin K1 is available in both oral and parenteral should be done slowly to avoid administered to all newborns to forms. adverse effects such as dyspnea, prevent hemorrhagic disease of chest pain, and even death. vitamin K deficiency, particularly in Vitamin K2 (Menaquinone) Found in human tissues and premature infants synthesized by intestinal bacteria Oral Administration: Preferred due to better bioavailability compared to Vitamin K3 (Menadione) : The water subcutaneous routes. - soluble salt should not be used therapeutically, as it is ineffective for treating warfarin overdose. FACTOR TREATMENTS FACTOR CONCENTRATES Concentrated Plasma Fractions Plasma-derived, heat- or detergent-treated concentrates. Recombinant Protein Preparations Standard treatments for hemophilia to prevent and treat bleeding. Lyophilized Factor VIII Concentrates Prepared from large pools of plasma. Risk of viral disease transmission (hepatitis B and C, HIV) is minimized through pasteurization and solvent/detergent extraction, but prion transmission risk remains. TABORA | 12  Recombinant Clotting Factor Preparations Recommended whenever possible for factor replacement due to lower risk of disease transmission. Intermediate Purity Factor VIII Concentrates Contain significant amounts of von Willebrand factor. Humate-P: An FDA-approved factor VIII concentrate for treating bleeding associated with von Willebrand disease Recombinant von Willebrand Factor Vonicog alfa: Approved for treatment and control of bleeding in adults with von Willebrand disease Recombinant Factor VIIa INDICATION Treatment of inherited or acquired hemophilia A or B with inhibitors. Treatment of bleeding associated with invasive procedures in congenital or acquired hemophilia. Treatment of factor VII deficiency. In the European Union, it is also approved for treating Glanzmann’s thrombasthenia MOA Factor VIIa activates the clotting pathway by: ○ Activating factor IX and factor X in association with tissue factor. LONGER-ACTING FACTOR PREPARATIONS Eloctate A factor VIII-Fc domain conjugate that prolongs the half-life of factor VIII, allowing for dosing twice a week. Idelvion A factor IX-albumin conjugate with a prolonged half-life of 100 hours (compared to the native factor IX half-life of 16 hours), FDA-approved for prophylaxis and treatment in hemophilia B, allowing for once-weekly dosing. ADDITIONAL Fresh Frozen Plasma Used for factor deficiencies when no recombinant form is available. Four-Factor Plasma Replacement Preparation 4F PCC (Kcentra): Contains vitamin K-dependent factors II, VII, IX, and X; used for rapid reversal of warfarin in bleeding patients FIBRINOLYTIC INHIBITORS Aminocaproic Acid (EACA) MOA: Competitively inhibits plasminogen activation, reducing fibrinolysis. Pharmacokinetics: ○ Rapidly absorbed orally. ○ Cleared from the body by the kidneys. Clinical Uses: ○ Adjunctive Therapy: In hemophilia. ○ Bleeding Management: From fibrinolytic therapy. TABORA | 13  Prophylaxis for rebleeding from intracranial aneurysms. Tranexamic Acid Classification: Analog of aminocaproic acid with similar properties. Administration: ○ Oral: 15 mg/kg loading dose followed by 30 mg/kg every 6 hours. TABORA | 14