Blood Disorders Drugs PDF

Blood Disorders Drugs 1  Topics  Drugs affecting blood clot formation o Platelet aggregation inhibitors o Anticoagulants (injectable and oral) o Thrombolytics/Fibrinolytics  Treatment of anemia 2 ...

Blood Disorders Drugs 1  Topics  Drugs affecting blood clot formation o Platelet aggregation inhibitors o Anticoagulants (injectable and oral) o Thrombolytics/Fibrinolytics  Treatment of anemia 2  Hemostasis  Hemostasis: Stop of blood loss from a damaged blood vessel.  Balance between too much clotting vs. insufficient clotting  Unwanted blood clots vs. hemorrhage or bleeding  Thrombosis: formation of thrombus or blood clot  Thrombus vs. Embolus  Thrombus: A clot that adheres to a vessel wall  Embolus: An intravascular clot that floats in the blood = A detached thrombus 3  Hemostasis Too much clotting – Thrombotic disorders such as acute myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), and acute ischemic stroke  TTT: antiplatelets, anticoagulants and fibrinolytics Insufficient clotting – Bleeding disorders such as hemophilia  TTT: transfusion of recombinant factor VIII / vitamin K deficiency  TTT: vitamin K supplementation. 4 Advanced Pharmacology  Hemostasis Hemostasis mechanism is divided into 5 stages: 1. Constriction of the blood vessel (vasospasm) 2. Formation of a temporary “platelet plug" 3. Activation of the coagulation cascade 4. Formation of the final clot 5. Clot lysis (fibrinolysis) Also described as primary hemostasis (platelet plug), secondary hemostasis(coagulation cascade) and tertiary hemostasis (fibrinolysis) 5 Advanced Pharmacology  Clot formation Blood vessel injury  Endothelial damage Exposure of sub-endothelial collagen & Von Willebrand factor (vWF) (role?) + Release of inflammatory mediators Vascular spasm (by endothelin from damaged endothelial cells) Platelets (Adhesion  Activation (disc shape to dendritic shape)  Aggregation) – Release of ADP, Thromboxane A2 TXA2, serotonin, APF Formation of  Transient plug 6  Clot formation Clotting factors coagulation cascade (intrinsic/extrinsic pathways) Formation of thrombin & activation of fibrinogen & formation of fibrin  Blood clot (thrombus) – Thrombosis? Injury healing  Blood clot lysis – Fibrinolysis: Plasminogen, antithrombin III (ATIII) Protein C, Protein S 7 Blood Clot Formation 8 9 Advanced Pharmacology  Blood Clot Formation Platelet Tissue aggregations Damage King, M. (2010). Blood Coagulation: Hemostasis. Themedicalbiochemistrypage.org. Retrieved 27 August 2010, from http://themedicalbiochemistrypage.org/blood-coagulation.php 10  Clot Formation Shier, D., Butler, J., & Lewis, R. (2009). Hole's essentials of human anatomy & physiology (10th ed., p. 330). New York, NY: McGraw-Hill Education. 11  Drugs Affecting Clot Formation & Lysis Antiplatelet Agents & Anticoagulants (Blood Thinners) Thrombolytics/Fibrinolytics 12  Drugs Affecting Clot Formation Blood Thinners & Fibrinolytics Platelet aggregation inhibitor o Acetylsalicylic Acid = ASA (Aspirin®) o P2Y12 (ADP) receptor blockers: clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta®) and ticlopidine (Ticlid®) o GP IIb/IIIa Receptor blockers: abciximab (ReoPro®), eptifibatide (Integrillin®), and tirofiban (Agristat®) o Dipyridamole Anticoagulants o Injectable: Heparin (unfractionated heparin / fractionated =LMWH) o Oral: Warfarin (Coumadin®), dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Lixiana®) Fibrinolytic drugs Alteplase (Activase rt-PA®), reteplase (Retavase®), tenecteplase (TNKase) and streptokinase (Streptase®) 13 Platelet Aggregation Inhibitors (Antiplatelets) 14  Acetylsalicylic Acid (ASA) Mechanism: Inhibits TXA2 by inhibiting COX-1 enzyme irreversible inhibition of aggregation (what is the life span of platelet?) Uses: Blood thinner in CV conditions. During acute MI (↓ mortality), prevention of 1ry and 2ry MI and stroke, unstable angina, prevent VTE after hip surgery Dose: 81 – 325mg/day. Higher doses ↑ ADR Patients with coronary artery disease, including those who have had a heart attack, stent, or CABG, are treated with aspirin for their whole lives. Aspirin® Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 15  Acetylsalicylic Acid (ASA) Who should not take ASA? Allergy, active bleeding, 3rd trimester of pregnancy, history of ASA/NSAID- induced asthma, children with febrile viral infection, and kidney/liver impairment Stop before surgery?? Rapid reversal?? Adverse Reactions Upset stomach Bleeding Tinnitus, vertigo, hearing loss Reye syndrome May worsen asthma in certain patients Aspirin® Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 16  Acetylsalicylic Acid (ASA) Drug Interactions Drugs inhibiting clot formation, excess alcohol, NSAIDs, steroids, SSRI: ↑ effect and risk of bleeding ASA ↑ effect of hypoglycemic agent, valproic acid and digoxin ASA ↓effect of uricosuric agents and antihypertensive drugs Aspirin® Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 17  Acetylsalicylic Acid (ASA) Drugs in Canada Aspirin® / generics ASA 25mg + Dipyridamole 200mg (Aggrenox®) Dipyridamole: vasodilator + inhibits aggregation (by decreasing thromboxane A2 synthesis) Combination for TIA and stroke, NOT heart Dispense in original container Dipyridamole: may cause headache & dizziness Aspirin® Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 18 P2Y12 (ADP) Receptor Blockers 19  P2Y12 (ADP) Receptor Blockers Mechanism: Block the binding of ADP to (P2Y12) receptors on resting platelets  prevent activation of GP IIb/IIIa on platelets that is required for platelets to bind to fibrinogen and to each other  irreversible (except ticagrelor) inhibition of platelet aggregation Clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta®) and ticlopidine (Ticlid®) Indications: 2ry prevention of MI and stroke (Prasugrel is contraindicated in patients with history of TIA or stroke) In combination with Aspirin to prevent blood clot after stent placement. Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 20 P2Y12 (ADP) Receptor Blockers In combination with Aspirin to prevent blood clot after stent placement Image from: https://centralgaheart.com/need-know-heart-stent/ 21  P2Y12 (ADP) Receptor Blockers Effect is similar to ASA but slightly safer All are prodrugs EXCEPT ticagrelor Require oral loading doses for quicker effect +/- food EXCEPT ticlopidine Adverse Reactions: o Bleeding (especially GI)  No antidote o Ticlopidine: diarrhea, ↑ TG  Ticlopidine: reserved for patients who are intolerant to other therapies due to life-threatening hematologic adverse reactions Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 22  P2Y12 (ADP) Receptor Blockers Drug interactions: o ↑ effect of other clot inhibitors o PPI + clopidogrel ?? o Prasugrel has no important interactions Clopidogrel is a prodrug that is activated via metabolism by CYP 2C19 o omeprazole and esomeprazole inhibit CYP 2C19 Poor metabolizers are recommended to use other antiplatelet agents (prasugrel or ticagrelor) Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 23  Aspirin + P2Y12 inhibitors (DAPT) Many heart attack and stroke patients — and people seeking to avoid these events, are treated with two types of antiplatelet agents to prevent blood clotting: Aspirin and a P2Y12 inhibitor. This is called dual antiplatelet therapy (DAPT) Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 24  GP IIb/IIIa Receptor Blockers Mechanism: Block GP IIb/IIIa receptors  prevent adherence of platelets to fibrin (potent platelet aggregation inhibitors) Drugs in Canada: - Eptifibatide (Integrillin®) - Tirofiban (Agrestat®) - Abciximab (Reopro®) – D/C’ed 2018 due to longer reversal in 1-2 days Given IV along with heparin and aspirin, as an adjunct to PCI for the prevention of cardiac ischemic complications. Eptifibatide and tirofiban effect is reversed within 2-4 hr o Tirofiban is available in 250 mL bag for IV infusion, and Eptifibatide is available in IV vials Side effects: Bleeding (esp. when used with anticoagulants) Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 25 pigmy rattlesnake venom (eptifibatide) pigmy rattlesnake venom (eptifibatide) 26 Injectable Anticoagulants 27  Heparin (UFH) & LMWH Mechanism: Heparin increases the effect of antithrombin III at least a thousand-fold  Antithrombin III is polypeptide synthesized in liver & circulates in plasma. Inhibits activated thrombin, Xa, and IIa) Onset: 1 – 2 hours Dose is IU/Kg, administered IV/SC Variable (30 – 70%) and unpredictable response Monitoring:  aPTT Activated Partial Thromboplastin Time Test Unfractionated Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. Low Molecular Weight Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 28  LMWH LMWH in Canada: dalteparin (Fragmin®), enoxaparin (Lovenox®), nadroparin (Fraxiparine®), and tinzaparin (Innohep®) 29  Heparin (UFH) & LMWH Uses: o UFH and LMWH in treatment and prevention of DVT (e.g., prophylaxis in patients undergoing hip replacement) o Heparin is used to prevent clotting during dialysis and maintain IV line open  UFH and LMWH Anticoagulants of choice during pregnancy. Why? Image from: https://www.centerforvein.com/the-danger-of-dvts-deep- vein-thrombosis/ Unfractionated Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. Low Molecular Weight Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 30  Heparin (UFH) & LMWH Contraindication: HIT, bleeding, recent surgery Adverse reactions: Bleeding, bruising, thrombocytopenia, osteoporosis. Antidote: Protamine sulfate Unfractionated Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. Low Molecular Weight Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 31  Heparin (UFH) & LMWH How LMWH Compare to UFH? Pros? o Longer t½ o SC is preferred (self-injection) o Predictable response = Less monitoring (saving lab costs and nursing time) so useful for both inpatient & outpatient o Less drug-drug interaction Cons: o Elimination by kidney only o Poorly reversible Unfractionated Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. Low Molecular Weight Heparin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 32  Other Parenteral Anticoagulants Fondaparinux (Arixtra®) – factor Xa inhibitor Lepirudin (Refludan®) – thrombin inhibitor (from leech) Argatroban – thrombin inhibitor 33 Oral Anticoagulants 34 Oral Anticoagulants 35 Warfarin 36  Warfarin Prothrombin precursor Prothrombin Carboxylase enzyme Active Vitamin K Inactive Vitamin K Recycling 37  Warfarin (Vitamin K Antagonist) Mechanism: inhibiting vitamin K epoxide reductase (VKOR)  Blocks the recycling of vitamin K  inhibit Factors II, VII, IX, and X  Prevent clot, stop expansion, and ↓ breaking off Indications: o Prevention and treatment of VTE (DVT and PE) o Prevent stroke in patients with A.Fib o Post MI to reduce recurrence and death Monitoring with INR is required  Why? Warfarin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 38  Warfarin Onset 24 hours and peak is 3 – 4 days  Why? Monitoring: INR (target 2–3 for most patients) is required when start/↑/↓ or DDI Antidote: Vitamin K (PO/IV) - Rapid reversal? Dose is individualized (wide range) Should be taken the same time every day. Sukhum, D. (2009). Anticoagulation Clinic Guidelines, complete. Pradub-sukhum.com. Retrieved 6 September 2016, from http://pradub-sukhum.com/Anticoagulation/Anticoagulation%20Guidelines/Anticoagulation%20Guidelines%203,%20Complete.htm 39  Warfarin Factors affecting warfarin therapy: Comorbidities Genetics Aging Diet Social history Environment Drug-Drug interactions (metabolism and plasma protein binding) Warfarin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 40  Warfarin Health Canada recommends a daily intake of 90 – 120 mcg of vitamin K. The total amount of vitamin K you have from day to day may be higher or lower than the recommended amount. It is okay to eat food with different levels of vitamin K, but because vitamin K can interfere with blood-thinning effects of warfarin, it is important to eat the same amount from day to day (i.e., Do not eat a lot one day and none the next  Maintain a consistent amount of vitamin K in your diet) 41 https://www2.gov.bc.ca/assets/gov/health/about-bc-s-health-care-system/bc-guidelines/warfarin_management_food_guide.pdf  Warfarin Adverse Reactions Bleeding (urine, stool, bruising, gum, nose, superficial injury, ulcer, tumor, lesions) Nausea, vomiting, and diarrhea Tissue necrosis e.g., Purple toe Source of image: http://www.medscape.com/viewarticle/455759_2. Accessed Aug/2011 Warfarin Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 42  New Oral Anticoagulants Direct Thrombin inhibitor: o Dabigatran (Pradaxa®) – thrombin inhibitor Antidote: Idarucizumab (Praxbind®) Direct factor Xa inhibitors o Rivaroxaban (Xarelto®) – Xa inhibitor o Apixaban (Eliquis®) – Xa inhibitor o Edoxaban (Lixiana®) – Xa inhibitor No antidote Uses: Similar to warfarin Adverse Reactions: bleeding 43  New Oral Anticoagulants How the New OAC Compare to Warfarin? What is good? Rapid onset (peak in 3 – 4 h), fixed daily dose, no monitoring, and less interaction with drugs and food What is NOT good? Cost, not for impaired kidney function, limited data, NO antidote (EXCEPT dabigatran) Kosar L, Hewitt M, Jensen B, Kosar L, Downey S, Regier L. Oral Antithrombic Agents. In: Rxfiles: Drug Comparison Charts. 10th ed. Saskatoon: Saskatchewan Health Authority; 2018: 18 44  New Oral Anticoagulants Dabigatran antidote : Praxbind® (Idarucizumab) Immediately binds to 99% of dabigatran and lasts for 12 hours Dose: 2 vials of 2.5g each (total dose = 5 g) used as two consecutive IV infusions over 5-10 minutes for EACH vial or bolus dose. Storage: o Unopened vial to be stored in the fridge. o Opened vial can be kept at room temp and should be used within 1 hour. Praxbind Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 45 Fibrinolytic Drugs 46  Fibrinolytic Agents Drugs in Canada Activase® (alteplase) rTPA – localized effect Retavase® (reteplase) Streptase® (streptokinase) – from bacterial source/ may cause other problems. TNKase® (tenecteplase) 47  Fibrinolytic Agents Mechanism: stimulate the conversion of plasminogen to plasmin which cleaves the fibrin threads  lysis of the thrombi  restore blood flow to vital organs; heart (in case of MI) and brain (in case of stroke). To be used ASAP to reduce complications and death. Door to needle is 30 minutes (MI) and 60 minutes (stroke). Contraindications: patients with bleeding, pregnancy, severe HTN, and on anticoagulants. 48 Drugs used for treatment of anemia 49  Anemia Definition: ↓ in hemoglobin (Hgb) or RBCs reduces oxygen carrying capacity of blood. Estimated to occur in 2.5 billion around the world. It’s the most common single nutritional deficiency Types Iron deficiency anemia (microcytic, hypochromic) Vit. B12/ folic acid (macrocytic, normochromic) Anemia of chronic disease 50  Types of Anemia Aplastic Anemia and MDS Awareness Week: Let's Fight Against Anemia. (2015). Consumerhealthdigest.com. Retrieved 6 September 2016, from https://www.consumerhealthdigest.com/health- awareness/aplastic-anemia-and-mds-awareness-week.html 51  Types of Anemia Image From: http://www.irondisorders.org/tests-to-determine-iron-levels/ 52  Types of Anemia Iron Deficiency Anemia Type: Microcytic, hypochromic anemia Causes o Increased requirements (pregnancy, lactation, and infancy) o Decreased intake (poor nutrition) o Decreased absorption (enteritis, gastrectomy, drug interactions) o Blood loss: menstruation (0.5-1mg/day) , PU, cancer, surgery Symptoms: Pallor, weakness, fatigue, dizziness, dyspnea, chest pain, light headedness, increased heart rate, decreased exercise tolerance. 53  Types of Anemia Megaloblastic Anemia Type: Macrocytic, hypochromic anemia Symptoms: Ataxia, fatigue, glossitis, loss of fine & vibratory touch, neurologic changes, pallor. Causes of vitamin B12 deficiency o Inadequate intake (extremely rare) o Decreased absorption (deficiency of intrinsic factor = pernicious anemia) o Inadequate utilization (transcobalamin II deficiency) http://www.coldbacon.com/mdtruth/pics/glossitis2.jpg 54  Types of Anemia Megaloblastic Anemia Causes of folic acid deficiency o Nutritional (elderly, alcoholics, poverty, chronically ill or demented) o Decreased absorption (CD, extensive small bowel resection) o Increased utilization (ex. pregnancy) o Altered metabolism (Drugs: OC, triamterene, Sulfasalazine, SMX, trimethoprim) 55  Types of Anemia Anemia of chronic diseases Anemia characterized by decreased response of bone marrow to erythropoietin. Causes of anemia of chronic diseases o Chronic infection (ex. Deep abscess, osteomyelitis) o Malignancy o Chronic diseases (CHF, IBD, liver, and renal diseases) 56  Iron Deficiency Anemia Treatment of IDA Oral Iron Injectable Iron 57  Iron Deficiency Anemia Oral Iron replacement therapy Preferred Several salts are available Difference? o Fumarate (33%), Sulfate (20%), gluconate (11%), polysaccharide iron complex (FeraMax® 150mg elemental iron), and heme iron (Proferrin® 11mg) Fe. Fumarate and sulfate are available in Liquid formulations. Heme iron: higher bioavailability, sharper increase in the serum iron, less side effects and absorption is not affected by administration with food. Oral Iron Preparations Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 58 60 61  Iron Deficiency Anemia Oral Iron replacement therapy Only 20% of the dose is absorbed in patients with IDA Maximal absorption in the duodenum and proximal jejunum. Delayed release? Absorption enhancer? 10% No evidence that one preparation is superior to others Oral Iron Preparations Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 62  Iron Deficiency Anemia Oral Iron replacement therapy Recommendations Used for prevention and treatment Dosage Elemental Iron Daily = 200mg of elemental iron/day When to Start and what is the Duration? Empty stomach Vs With meals Immediate release Vs Controlled release Oral Iron Preparations Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 63  Iron Deficiency Anemia Oral Iron replacement therapy Drug Interactions Antacids Bisphosphonates (risedronate, alendronate, etidronate), tetracycline (tetracycline, minocycline, doxycycline), quinolones antibiotics (Cipro, Nor, levo, mox-floxacin), levothyroxin, phenytoin, L-Dopa and methyldopa) Cholestyramine Vitamin E Oral Iron Preparations Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 64  Iron Deficiency Anemia Oral Iron replacement therapy Adverse reactions Gastric side effects (5 – 20% , nausea, epigastric pain, constipation, abdominal cramps and diarrhoea. Dose dependant) – Start low and go slow. Dark stool. Metallic taste. Teeth stain (what preparation/ how to avoid?) Image from: https://www.researchgate.net/figure/Dark-brown-extrinsic- staining-due-to-iron-containing-medicament_fig1_264393077 Oral Iron Preparations Monograph. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2014. 65  Iron Deficiency Anemia Injectable Iron Replacement Therapy When to be used? Failure to respond to oral iron. Intolerance to oral therapy Required antacids therapy. Significant iron loss in patient refusing transfusion. Drugs in Canada Iron dextran (Infufer®) Sodium ferric gluconate (Ferrlecit®) Iron sucrose (Venofer®) 66  Iron Deficiency Anemia Injectable Iron Replacement Therapy Side effects Anaphylactic reaction After 24 – 48 hours: Fever, chills, headache, myalgia, and urticaria. 67  Iron Deficiency Anemia Treatment Failure Continuous bleeding Inadequate therapy Poor compliance Malabsorption Associated diseases Concomitant deficiencies Incorrect diagnosis 68 Treatment of Megaloblastic Anemia B12 Cyanocobolamine and hydroxycobolamine IM is most effective because of pernicious anemia High oral dose is also effective. Folic acid Should be given only for confirmed folate deficiency. Used during pregnancy to prevent neural tube defects. Dose is 1 – 5 mg daily 69  Anemia of Chronic Diseases Erythropoietin Analogues Drugs in Canada: Eprex® (epoetin alpha) – given 3x/wk and Aransep® (darbepoetin alpha) – given weekly/ biweekly/ monthly. Erythropoietin analogues are beneficial in anemia associated with chronic diseases such as: o Chronic renal failure o HIV infected patient o Chronic hepatitis C patients o Patients receiving chemotherapy Iron, B12 and folic acid supplement is required. 70  Anemia of Chronic Diseases Colony stimulating factors for patients with low neutrophils (mostly cancer patients) o Stemgen® (ancestim) o Neupogen® (filgrastim) o Neulasta® (pegfilgrastim) Neupogen® (filgrastim) o 300 mcg/mL and 600 mcg/mL (SC or IV Only) o Hematopoietic Agent. Granulocyte Colony Stimulating Factor: G-CSF regulates the production of neutrophils within the bone marrow 71