IC3 Pharmacology of Antiplatelets, Anticoagulants, Fibrinolytics + Flashcards

Question

Why is LMWH favoured over heparins?

Answer 1

1. Longer half-life 2. higher bioavailability 3. Not associated with HIT

Answer 2

ADVERSE EFFECTS: - **Bleeding** (in 1-5 % of patients treated with IV heparin) o Anticoagulant effect disappears within hours of discontinuation (due to short t1/2) o Reversal agent: **Protamine sulfate IV infusion** to reverse effects of heparin  5-kDa **cationic polypeptide** derived from salmon sperm  Highly **basic** peptide stably binds negatively charged heparin and neutralizes anticoagulant properties of heparin  **Incomplete reversal for LMWHs ** - **Increased risk of epidural or spinal haematoma** and paralysis in patients receiving epidural or spinal anaesthesia or spinal puncture - **Heparin-induced thrombocytopenia** (low platelet count) o Binds to **platelet factor 4 (PF4)** on activated platelet surface o **IgG antibody** against the heparin-PF4 complex o Lower risk with LMWHs PREGNANCY: - Unlike warfarin, heparin and LMWH do not cross the placenta, and have not been associated with fetal malformations. - **Preferred in pregnancy than warfarin** CONTRAINDICATIONS & CAUTIONS: - Contraindicated in patients with: o Hypersensitive to heparins or pork products (cross reactivity) o Active major bleeding o Thrombocytopenia or antiplatelet antibodies - Caution in: o Elderly patients o Risk of bleeding(hematoma), including patients with prosthetic heart valves, major surgery, regional or lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis or pericardial effusion, renal insufficiency (for LMWHs) DRUG-DRUG, DRUG-HERB & DRUG-FOOD INTERACTIONS: - ↑risk of bleeding: anitplatelets, anticoagulants, fibrinolytics, NSAIDs, SSRIs - ↑risk of bleeding: with various herbs/foods, including chamomile, fenugreek, garlic, ginger, ginkgo, ginseng.

Answer 3

Endogenous thrombolysis: - tPA activates conversion of plasminogen to plasmin - enzyme that mediates fibrinolysis - depolymerizing and breaking down the meshwork - allows RBC and platelets trapped in clot to be slowly released back into bloodstream

Answer 4

Fibrinolytics: - Risk/Danger: broken down too quickly, clot can break up too fast in clumps rather than by gradual release ofRBC and platelets trapped in the clot, risk of circulating and causing embolism - **Thus, only use when pre-existing clots are causing an imminent death / irreversible damage e.g. thrombotic stroke, pulmonary embolism** - Other conditions e.g. DVT, allow endogenous tPA to degrade the clot and treat them with ACG aggressively to prevent the growth of the clot

Answer 5

Recombinant variants of t-PA are produced by recombinant DNA technology. - Recombinant tissue plasminogen activator (r-tPA) drugs end in -teplase e.g., alteplase o Differ from native t-PA by having **longer plasma half-lives** that allow convenient intravenous dosing o An advantage of –teplases over urokinase and streptokinase is that the **–teplases bind preferentially to clot-associated plasminogen**, activating plasmin at the clot

Answer 6

Alteplase ADVERSE EFFECTS: - Haemorrhage/bleeding - Ventricular arrhythmias, hypotension, oedema (can be monitored and managed) - Cholesterol embolization, venous thromboembolism (due to embolism) - Hypersensitivity and anaphylaxis (rare but severe) Anti-fibrinolytic agents (antidotes) such as **tranexamic acid** and **aminocaproic acid:** - **Compete for the lysine binding sites on plasminogen** and plasmin --> thus blocking their interaction with fibrin. - Used to reverse states of excessive fibrinolysis. CONTRAINDICATIONS & CAUTIONS: - Contraindicated in patients with active bleeding, prior intracranial haemorrhage, or recent (within the last 3 months) intracranial or intraspinal surgery, serious head injury, or stroke. - Caution in patients with major surgery within 10 days, risk of bleeding (e.g., peptic ulcer), cerebrovascular disease, mitral stenosis, atrial fibrillation, acute pericarditis or subacute bacterial endocarditis DRUG-DRUG INTERACTIONS: - ↑risk of bleeding – antiplatelets (especially **dipyridamole** and **aspirin**), and anticoagulants (especially **warfarin** and **heparin**). - ↓ alteplase level – **Nitroglycerin**

Answer 7

Drug-induced Haematological Disorders 1. Aplastic Anaemia a. Drugs that induce – chemotherapies, chloramphenicol, CBZ, phenytoin b. Treatment – immunosuppressants, GM-CSF, G-CSF, IL-14 (withdraw, transfusion of erythrocytes and platelets, HSCT) 2. Immune Thrombocytopenia a. Drugs that induce – heparin, CBZ, phenytoin, sulphonamides, GP IIb/IIIa inhibitors (eptifibatide) b. Treatment – immunosuppressants (withdraw, platelet transfusion) 3. Agranulocytosis / Neutropenia a. Drugs that induce – clozapine, thioamides (anti-hyperthyroidism), B-lactam b. Treatment – GM-CSF, G-CSF (withdraw) 4. Immune Haemolytic Anaemia a. Drugs that induce – methyldopa, quinidine, penicillins, cephalosporins, streptomycin, cisplatin, oxaliplatin, b-lactamase inhibitor b. Treatment – steroids, immunoglobulins, rituximab (withdraw, RBC transfusion, hemodialysis for acute renal failure)

Answer 8

Haematological Drugs for Supportive Care (Leukaemia, Myelodysplastic syndromes, lymphoma) 1. Anaemia a. Nutrients: i. Iron – Ferrous sulphate, Fe sucrose ii. Vit B12 – hydroxocobalamin iii. Folic acid b. Erythropoiesis-stimulating agents (ESA) i. Darbepoietin alfa, epoietin alfa 2. Neutropenia a. Recombinant G-CSF – filgrastim, pegfilgrastim (PEG covalently linked to G-CSF) b. Recombinant GM-CSF – sargramostim 3. Thrombocytopenia a. Recombinant IL-11 – Oprelvekin b. Fc fusion protein thrombopoietin receptor agonist – romiplostim c. Oral non-peptide thrombopoietin receptor agonist – eltrombopag

Answer 9

Nutrient Deficient: Microcytic anaemia – Fe deficiency --> inhibits Hg synthesis Megaloblastic anaemia – VitB12 / Folic acid deficiency --> inhibit DNA synthesis

Answer 10

Iron - **Oral** ferrous (Fe3+) salts e.g., **ferrous sulphate** - **Parenteral** e.g., **iron sucrose** - Minimal elimination in faeces, bile, urine and sweat --> therefore careful dosing required to avoid toxicity - Adverse Effects / Toxicity: o Acute: Necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhoea followed by shock, lethargy, dyspnea, metabolic acidosis, coma and death. o Chronic: **Haemochromatosis** with iron deposited in heart, liver, pancreas and other organs → organ failure, death. o Reversal Agents: **Parenteral deferoxamine** or **oral deferasirox iron chelators** to treat overdose

Answer 11

Vitamin B12 (cyanocobalamin) - Parenteral **(IM or SC)** e.g., **hydroxocobalamin** - Hydroxocobalamin precursor preferred to cyanocobalamin as --> **protein binding so retained longer** in circulation - Oral **not** usually effective as deficiencies are usually caused by **gastrointestinal malabsorption --> reduce F** - Excretion via bile and urine - Excess stored in liver (normally 3 years supply stored) - Elimination half-life: 26-31 hours (IV) - Adverse Effects / Toxicity: o May cause **photosensitivity**, avoid direct exposure to sunlight o **Injection site pain** o **Hypertension**, hot flushing, arrhythmias secondary to hypokalaemia, gastrointestinal disturbances, dizziness, tremor, headache, paraesthesia, chromaturia, acneiform and bullous eruptions, rash and itching. - Drug Interaction: **PPIs may reduce oral absorption (but there’s already malabsorption)**

Answer 12

Folic Acid - Absorption: Rapidly absorbed. - Bioavailability: Approx **100% (for supplement)**; Peak plasma concentration: 1 hour. - Metabolism: Metabolised in liver and plasma; converted to **active metabolite, 5 methyltetrahydrofolate (5MTHF); undergoes enterohepatic circulation.** - Excretion: Via urine. - Contraindications: Untreated cobalamin deficiency (including untreated pernicious anaemia or other causes e.g. lifelong vegetarians), malignant disease - Special Precautions: o Folate-dependent tumours, haemolytic anaemia, alcoholism. o Women with pre-existing diabetes, obesity, family history of neural tube defects, or previous pregnancy affected by neural tube defect. o **Not appropriate for monotherapy** in pernicious, aplastic, or normocytic anaemias when anaemia is present with **vitamin B12 deficiency.** o Children. Pregnancy and lactation. - Adverse Reactions: GI disorders --> **Bitter or bad taste, nausea**, abdominal distension, flatulence - Immune system disorders: Rarely, allergic reactions (e.g. rash, pruritus, erythema, urticaria, dyspnoea, shock); allergic sensitization. - Metabolism and nutrition disorders: Rarely, anorexia. - Drug Interaction: o May reduce the plasma concentrations of anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine, valproic acid) o Enhances the efficacy of lithium o May decrease the therapeutic effect of methotrexate chemotherapy o Increased elimination with aspirin o Reduced absorption with sulfasalazine and triamterene o Chloramphenicol and sulfamethoxazole + trimethoprim may interfere with folate metabolism

Answer 13

Drugs for Anaemias – Erythropoiesis-Stimulating Agents (ESAs) Darbepoetin alfa, Epoetin alfa administered **parenterally** - Mechanism of Clinical Action: Biosynthetic forms of erythropoietin - Stimulate division and differentiation of erythroid (RBC lineage) progenitor cells - Reticulocytes (immature RBC) are released from the bone marrow and mature into erythrocytes thereby regulating erythropoiesis - Absorption: o IM: Slow; o SC: Slow and incomplete. o **IV: Rapid** - Distribution: Concentrated in the liver, kidneys and bone marrow - Metabolism: Limited degradation occurs - Excretion: Mainly in faeces with small amounts in urine o Half-life (IV) **Epoetin alfa: 4-13 hr;** **Darbepoetin alfa: 20-25 hr (longer t1/2)** o **Conjugation with polyethylene glycol** (e.g., Methoxy polyethylene glycol-epoetin beta) prolongs half-life allowing **2 wks or 1 month** dosing interval. - Contraindications: o **Uncontrolled hypertension**, hypersensitivity (rare) - Special Precautions o **Hypertension; history of seizures**; ischaemic vascular disease o Hepatic impairment, renal impairment, sickle cell anaemia o Pregnancy, lactation, children. - Adverse Reactions o **Hypertension**, oedema; increased platelet count, **thrombosis**, stroke; hyperkalaemia; seizures; myalgia, arthralgia, limb pain; gastrointestinal effects including nausea and vomiting o Epoetin alfa: **Pruritus** o Darbepoetin alfa: **Dyspnoea, cough, bronchitis**

Answer 14

Drugs for Neutropenia – Myeloid Growth Factors - Granulocyte colony-stimulating factor (G-CSF) o Recombinant human G-CSF e.g. **filgrastim** o Filgrastim covalently conjugated with polyethylene glycol to extend half-live e.g., **pegfilgrastim** o Can be combined with hematopoietic stem cell mobiliser, plerixafor - Granulocyte-macrophage colony-stimulating factor (GM-CSF) o Recombinant human GM-CSFe.g., **sargramostim** - Mechanism of Clinical Action: o Stimulate myeloid progenitor cells o G-CSF  Stimulates **proliferation and differentiation** of progenitors committed to **neutrophil lineage** and  Additional **activates phagocytic activity of mature neutrophils** and prolongs their survival in circulation o GM-CSF broader spectrum effects than G-CSF additionally o Stimulates **proliferation and differentiation** of early and late **granulocytic, erythroid and megakaryocyte progenitors** - Adverse Effects o G-CSF (e.g., filgrastim and pegfilgrastim) more frequently used than GM-CSF (e.g., sargramostim) as better tolerated o G-CSF causes **bone pain**, reversible when drug discontinued o GM-CSF causes **fever, malaise, arthralgias, myalgias** o Potentially Fatal:  Severe sickle cell crisis, capillary leak syndrome, respiratory failure or acute respiratory distress syndrome (ARDS)  Rarely, splenic rupture - Special Precautions o Patient with pre-malignant or malignant myeloid condition, acute myeloid leukaemia; sickle-cell trait or disease, recent history of pneumonia or lung infiltrates, osteoporotic bone disease **o Not indicated for use in chronic myeloid leukaemia or myelodysplastic syndrome**

Answer 15

Drugs for Thrombocytopenias - Megakaryocyte growth factors - Mechanisms of clinical action o Recombinant interleukin-11 (IL-11) e.g., **oprelvekin** o Fc-peptide fusion thrombopoietin receptor agonist e.g., **romiplostim** o Orally active nonpeptide thrombopoietin receptor agonist e.g., **eltrombopag** - Adverse Effects o **Thromboembolic events** o Oprelvekin: fluid retention, peripheral edema, dyspnea on exertion - Special Precautions o With / history of **cerebrovascular disease** o RF for **thromboembolism** (e.g., advanced age, prolonged periods of immobilisation, malignancies, surgery/trauma, bleeding, obesity, smoking, contraceptives and hormone replacement therapy) o **Eltrombopag: higher dose required for non-Asian ancestr**y (e.g., not Chinese, Koreans, Japanese, Taiwanese, Thai) o **Oprelvekin: chronic HF** or at risk of developing HF; and susceptibility to develop fluid retention

IC3 Pharmacology of Antiplatelets, Anticoagulants, Fibrinolytics + Flashcards

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