PHARMACOLOGY

IMMUNOPHARMACOLOGY
Dra.Manalang
Nov 21, 2012

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CASES IN THE BOOK AGENTS USED IN ANEMIAS; HEMATOPOIETIC GROWTH FACTORS A 65-year-old woman with a long-standing history of poorly controlled type 2 diabetes mellitus presents with increasing numbness and paresthesias in her extremities, generalized weakness, a sore tongue, and gastrointestinal discomfort. Physical examination reveals a frail-looking, pale woman with diminished vibration sensation, diminished spinal reflexes, and a positive Babinski sign. Examination of her oral cavity reveals Hunter's glossitis, in which the tongue appears deep red in color and abnormally smooth and shiny due to atrophy of the lingual papillae. Laboratory testing reveals a macrocytic anemia based on a hematocrit of 30% (normal for women, 3748%), a hemoglobin concentration of 9.4 g/dL (normal for elderly women, 11.713.8 g/dL), an erythrocyte mean cell volume (MCV) of 113 fL (normal, 8499 fL), an erythrocyte mean cell hemoglobin concentration (MCHC) of 34% (normal, 31 36%), and a low reticulocyte count. Further laboratory testing reveals a normal serum folate concentration and a serum vitamin B12 (cobalamin) concentration of 98 pg/mL (normal, 2501100 pg/mL). Results of a Schilling test indicate a diagnosis of pernicious anemia. Once megaloblastic anemia was identified, why was it important to measure serum concentrations of both folic acid and cobalamin? Should this patient be treated with oral or parenteral vitamin B12? DRUGS USED IN DISORDERS OF COAGULATION A 25-year-old 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. Ultrasound reveals a deep vein thrombosis in the left lower extremity; chest computed tomography scan confirms the presence of pulmonary emboli. What are the likely risk factors in this womanhereditary, acquired, or both? What therapy is indicated acutely? What are the long-term therapy options? How long should she be treated? Should this individual use oral contraceptives? ANTI-COAGULANTS A. Antiplatelet Drugs 1.Aspirin 2.Glycoprotein IIb/IIIa Inhibitors 3.ADP Inhibitors (Clopidogrel) 4.PDE/Adenosine Uptake Inhibitors B. Anticoagulants 1.Indirect Thrombin Inhibitors a. High Molecular Weight (HMW) b.Unfractionated Heparin (UFH) c. Low Molecular Weight Heparin (LMW) Ardeparin Dalteparin Danaparoid Enoxaparin Tinzaparin Fondaparinux 2.Direct Thrombin Inhibitors 1.Parenteral: Hirudin Lepirudin Dada.Guia.Macy.Roch.Gine.Angel

Bivalirudin Argatroban 2.Oral: Ximelgatran Dabigatran 3.Warfarin & the Coumarin anticoagulants C. Thrombolytics/Fibrinolytics 1.t-PA Derivatives a. Alteplase b.Reteplase c. tenecteplase 2.Streptokinase a. Urokinase b.Anistreplase DRUGS THAT FACILITATE CLOTTING 1. Vitamin K 2. Replacement Clotting Factors 3. Antiplasmin Drugs 4. Sclerosing Agents 5. Anti-hemorrhagic 6. Fibrinolytic inhibitors 7. Serine protease inhibitors BLOOD PRODUCTS 1.Whole blood 2.Packed RBCs 3.Plasma 4.Platelets 5.Cryoprecipitate ANEMIA 1.Anti-anemia a. Iron b.Vit B12 c. Folic acid 2.Hematopoietic growth factors a. Erythropoietin b.Myeloid growth factor c. Megakaryocyte growth factor ANTICLOTTING DRUGS ANTI- PLATELETS Platelet aggregation is the initial step in the normal repair system for blood vessels. Drugs that interfere with this process are termed anti-platelet drugs. Indicated for arterial thrombosis Prevent stenosis, angioplasty, acute coronary syndrome, unstable angina MECHANISM OF ACTION INHIBITS CYCLOOXYGENASE (COX) a. ASPIRIN Interferes with the synthesis of eicosanoids Irreversibly inhibit COX by acetylation Prevents 1st infarcts and further infarcts ONLY effective platelet aggregation inhibitor in NSAIDs class Eliminates platelets ability to produce and release TXA2 ADR: Aspirin, NSAIDS GI tract, CNS (transient ischemic attack, stroke) b. IBUPROFEN Reversibly inhibit without acetylation INHIBITORS OF PHOSPHODIESTERASE a. DIPYRIDAMOLE Dual MOA: o Inc intracellular conc of cAMP o Inc cellular uptake of adenosine

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 For intermittent claudication ADR: headache and palpitation b.PENTOXIFYLLINE Inhibits phosphodiesterase and reduces platelet aggregation Decreases circulating fibrinogen Improves RBC flexibility Decrease risk of thromboembolism (improves overall viscosity of blood) c. CILOSTAZOL New drug same with dipyridamole For those with prosthetic heart valves INHIBITS ADP (ADENOSINE 5 PHOSPHATE BINDING) a. CLOPIDOGREL & TICLOPIDINE Both irreversibly inhibit binding of ADP to its receptor in platelets Prevents platelet-platelet aggregation Prevents platelet-fibrinogen binding ANTAGONIST OF GLYCOPROTEIN IIB/IIIA RECEPTOR GCD COMPLEX (RECEPTOR OF PLATELETS) Glycoprotein IIb/IIIa complex serves as a receptor on platelets for fibrinogen , vitronectin, fibronectin & vWF Used for non-Q wave, AMI Prevent stenosis after coronary angioplasty a. ABCIXIMAB o Monoclonal antibody against GP IIb/IIIa complex b. TIROFIBAN & EPTIFIBATIDE o Occupy GP receptor to prevent aggregation of platelet; reversible occupant; no platelet aggregation INDICATIONS General use: Prevent arterial thrombus formation Aspirin dec incidence of 1st infarct Prevent transient ischemic attacks (TIA), stroke Prevent infarcts in px who have 1 or more infarcts Dipyridamole peripheral arterial dse, intermittent claudication Pentoxifylline intermittent claudication Cilostazol peripheral arterial dse, intermittent claudication, prosthetic heart valve surgery Clopidogrel & Eclopidine reduce risk of MI, stroke, TIA, vascular death in px who cannot tolerate aspirin Ticlopidine for pts who cannot tolerate aspirin (e.g. those with GIT bleeding disorders). prevent death by clotting (vascular death) Abciximab prevent restenosis after coronary angioplasty Tirofiban acute coronary syndrome, unstable angina ADVERSE DRUG REACTIONS Aspirin and NSAIDs GIT and CNS effect Ticlopidine severe bleeding, neutropenia, idiopathic thrombocytopenic purpura Abciximab, Eptifibatide bleeding, thrombocytopenia Dipyridamole + Cilostazol HA + palpitations ANTICOAGULANTS INDIRECT THROMBIN INHIBITORS HIGH MOLECULAR WEIGHT HEPARIN MW 5000-3000 Desired level occurs immediately on entry into blood Highly charged at pH of the stomach Peak is 30-60 mins, half life = 60-90 mins Neutralized by Protamine Sulfate Not given via IM due to risk of hematoma formation

Cleared from blood at constant rate by reticuloendothelial system = time required to reduce plasma concentration Excreted in urine HEPARIN Heterogenous mixture of sulfated, highly polar mucopolysaccharides Antithrombin- natural anticoagulant; waiting for heparin to bind it MECHANISM OF ACTION Accelerates binding of antithrombin III to clotting factors, thrombin & factor Xa Suppresses the rate of aldosterone secretion Increases concentration of free thyroxine Marked inhibition of coagulation thru factor Xa and thrombin INDICATIONS Deep Venous Thrombosis (pre-operative & postoperative) Pulmonary embolism Acute myocardial infarction >40 yrs. old for thoraco-abdominal surgery DOC for pregnancy, Orthopedic surgery Not used for brain, spinal cord, or eye surgery Tubing used for dialysis and blood containers are washed with heparin ADVERSE DRUG REACTIONS: Increased bleeding o Excessive blockade of fibrin formation o Interference with normal hemostasis o Treatment of ADRs: Control of dosage Hemorrhagic stroke Transient Thrombocytopenia Heparin-induced platelet aggregation Formation of heparin-dependent antiplatelet antibodies Osteoporosis Prolonged heparin therapy Allergy: chills, fever, urticaria Other allergic reaction: Rhinitis asthma anaphylaxis Transient Alopecia CONTRAINDICATIONS: Neurosurgery Recent major surgery Active TB Recent head trauma Bacterial endocarditis UNFRACTIONATED HEPARIN MW: 5000 to 30,00 Desired level of anticoagulation occurs immediately on entry into the blood Highly charged at pH of the stomach Neutralized by protamine Given at 35 - 100 units /kg IV or SQ at slow, continuous absorption over 8 - 12 hours Not by IM due to hematoma formation Cleared by reticuloendothelial system To reduce plasma concentration of heparin by 50% depends on concentration of drug originally in blood Elimination half life of 1, 2.5, and 5 hours at doses of 100, 400 or 800 units /kg respectively Excreted in urine LOW MOLECULAR WEIGHT HEPARIN Given by SQ Greater bioavailability Longer duration of action than regular heparin Anticoagulant effect persist for about 24 hours Given OD or BID Eliminated in urine Exert little effect on thrombin

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DANAPAROID SODIUM A depolymerized mixture of heparin sulfate, dermatan sulfate & chondroitin sulfate Given IV or SC ENOXAPARIN Formed by depolymerizing HMW heparin MW: 2000-6000 92% bioavailability t longer half life 4.5 hr. More anti-Factor Xa activity Effective for DVT after hip replacement 30 mg BID x 710 days SQ ARDEPARIN, DALTEPARIN Both given by SC, onset of 20-60 min Peak 3-5 hr, duration 12 hrs High protein binding ADR: hematoma formation, not given orally, 24 hrs anticoagulant effect FONDAPARINUX A small synthetic drug with key pentasaccharide ADR: increased bleeding, excessive blockade of fibrin formation, interference with normal hemostasis CI: bacterial endocarditis, active TB, neurosurgery or other recent major surgeries DIRECT THROMBIN INHIBITORS Directly binds to the active site of thrombin A. Parenteral: Hirudin Lepirudin Bivalirudin Argatroban B. Oral: Ximelgatran Dabigatran LEPIRUDIN Recombinant form of leech protein Hirudin Synthesized in the kidney Bind to thrombin and thrombin substrate MOA: Inhibit platelet activation Alternative to heparin induced thrombocytopenia ROA: Parenteral. Monitored by aPTT DONT give to patients with renal insufficiency accumulates in RF, no antidote Prolonged infusion induced- formation of antibodies BIVALIRUDIN Modified form of hirudin Bivalent inhibitor of thrombin. Administered IV, w/ rapid onset and offset of action MOA: o Binds simultaneously w/ lepirudin to active site of thrombin o Inhibits soluble thrombin and thrombin enmeshed w/in developing clots o Inhibit platelet activation USE: Combined w/ aspirin to prevent percutaneous coronary angioplasty Tx for external hemorrhoids ARGATROBAN Small molecule given parenterally Synthesized in the liver. Accumulate in liver disease. Binds alone to thrombin Used in px with heparin induced thrombocytopenia (HIT) w/ or w/out thrombosis and coronary angioplasty in px with HIT Similar to lepirudin for its use Short half life so given by continuous IV infusion

COUMARIN (WARFARIN) Best oral anticoagulant Vit. K antagonist; Epoxide reductase prevents formation of Vit L from Vit K Impairs factors II, VII, IX, X. Effective only in vivo. Administered as sodium salt, 100% bioavailability Half life = 36 hrs with 8-12 hrs delay INDICATIONS: Prophylactic treatment of venous thrombosis Pulmonary embolism Chronic anticoagulant MI of 2-6 months (maintenance treatment) PHARMACOKINETICS: Small lipid-soluble Well absorbed orally, peak in 1 hr 99% bound to albumin Metabolized in liver; Excreted in urine and feces Cross placental barrier Needs PT monitoring ADVERSE DRUG REACTIONS: Major bleeding Frequent in women menopause Warfarin necrosis Painful erythamatous patch of the skin 3-10 days after treatment Purple toe syndrome (nangingitim parang talong) 38 days after tx (indication to stop drug) Cholesterol emboli from atheromatous plaques Bone defects in fetus (microencephaly) Subdural/intracerebral hematoma on >50% px CI: o Pregnant woman cross the placental barrier readily but does not pass thru milk o Not for >50y/o px Antidote: FFP, rapid reversal o Vit. K1 (phytonadione) - IV, slow infusion DRUG INTERACTIONS: Increases response to oral anticoagulants o Aspirin (ASA) o Ketoconazole o Disulfiram o Phenylbutazone o Metronidazole o Cimetidine o Clofibrate o Erythromycin o Trimethoprim-methoxazole Decreases response to anticoagulant o Barbiturates o Rifampicin o Gluthetimide o Vit. K o Cholestyramine o OCP o Phenobarbital Warfarin increases action of phenytoin and tolbutamide THROMBOLYTIC/FIBRINOLYTIC DRUGS GENERAL MOA: dissolve thrombi after they form FIRST GENERATION STREPTOKINASE Prototype MOA: Combines with plasminogen to form activator complexes that then convert plasminogen to plasmin Immediate action; Peak: 30-60 min; t1/2: 23 min Duration: 4-12 hrs Cleared in the circulation by Antibodies Does NOT cross placenta Safe for pregnant women UROKINASE Isolated from human urine MOA: directly activate plasminogen Immediate onset - peaking by the end of the infusion Crosses the placental membrane; passes in breast milk Duration: 12 hrs; t1/2: < 20 mins Liver metabolism

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SECOND GENERATION ALTEPLASE (tPA) Tissue plasminogen activator (tPA) Produced by recombinant DNA technology, is fibrin specific. MOA: converts trapped plasminogen to plasmin Less effect on circulating plasminogen DOC for patients: o Who have previously received streptokinase o Who have been given APSAC o Who have been treated for streptococcal infection w/in the previous year Alternate for streptokinase Rapidly absorbed IV; Immediate onset of action Cross placental barrier, present in breast milk Biotransformation occurs in the liver & with small amounts eliminated in the urine. Inactivation is caused by binding to plasma activators Peak: 5-10 mins; Duration: 2.5 -3 hrs ANISTREPLASE Anysolated plasminogen streptokinase activator complex (Apsac) Active complex of streptokinase & plasminogen Clot specific drug Works well on systemic plasminogen conversion blocked temporarily by an anisoyl group Immediate onset of action; peak: 45 mins Cross placenta & passes in breast milk Biotransformed in plasma Inactivation due to binding w/ plasmin activators t1/2: 70 -120 mins; duration 4-6hrs THIRD GENERATION RETEPLASE Recombinant protein derived from tPA Lowers affinity to fibrin but better clot penetration t1/2: 13 -16 min; biotransformed in liver Eliminated in urine Safety & efficacy in children not yet established TENECPLASE Newest recombinant thrombolytic drug MOA: catalyzes conversion of plasminogen to plasmin Fibrin specific protein Distributes in a volume approximating the plasma volume Cleared primarily by the liver; elimination half-life of about 2 hours INDICATION Treat acute MI, pulmonary embolism, Deep Venous Throbosis, arterial occlusion restore patency to occluded vessel in central venous catheters (Urokinase) best for chest pain consistent w/ MI for at least 30mins but no longer than 6hrs Ischemic CVA (alteplase) Restore patency to occluded AV cannula (streptokinase) ADVERSE DRUG REACTION Bleeding IN 8-16% of patients more common in women Hemorrhagic CVA in 0.5-1% of Px Drug-induced hypotension (streptokinase, anistreplase) Reperfusion arrhythmia N/V Hypersensitivity reaction

CONTRAINDICATIONS ABSOLUTE CI: Px who are at high risk for complications Those whom the risks outweigh the benefits that they would receive Patient with surgery or organ biopsy within 10 days of administration Arteriovenous malformations Serious GI bleeding w/in 3 mos Uncontrolled HPN Active bleeding or hemorrhagic bleeding disorder History of cerebrovascular bleeding Intracranial neoplasm Aneurysm RELATIVE CI: 75 y/o Acute pericarditis CVA; CRF Diabetic hemorrhagic retinopathy Hemorrhagic ophthalmic condition HPN Liver dysfunction Mitral stenosis w/ atrial fibrillation Septic thromboplebitis SB Endocarditis Drug Alteplase Anistreplase Reteplase Streptokinase Tenecteplase
Route

Onset Immediate Immediate Immediate Immediate Immediate

Peak 5-10 min 45 min 5-10 min 3060 min UA

Durat ion

t1/2 5 min 70-120 min 13-16 min 23 min 90-130 min

IV IV IV IV IV

2.5-3 hrs 4-6 hrs UA 4-12 hrs UA

GOALS OF THERAPY Opening the occluded artery as soon as possible Maintaining patency after blood flow is reestablished Preventing ischemia-related arrhythmia Minimizing the loss of tissues DRUGS THAT FACILITATE CLOTTING Drugs used in bleeding disorders Causes of inadequate blood clotting: o Vit K deficiency o Errors of clotting factors synthesis o Thrombocytopenia VITAMIN K Fat soluble vitamin Common in newborns and older individuals Treated with oral or parenteral Vit K supplements (phytonadione) Commonly given in newborn and older hemorrhagic disease of the newborn Supplements phytonadione (K1) cabbage, cauliflower, broccoli, tomato Menadione (K2) REPLACEMENT CLOTTING FACTORS Agents used to treat hemophilia o Fresh plasma o Purified human blood clotting factors especially factor VIII and factor IX These products are expensive and carry a risk of infection and immunologic reaction

but

infrequent

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ANTIPLASMIN AGENTS For management of acute bleeding episodes Aminocaproic acid and tranexamic acid are agents that inhibit fibrinolysis Systemic hemostatic For management of acute bleeding episodes in hemophiliacs; Prophylaxis for intracranial aneurysm SCLEROSING DRUGS Sclerosis (hardening of the veins) MOA: traumatize the endothelial lining of distended veins cause thrombosis w/in vessels Cause thrombosis within the vessel Ethanolamine oleate Hypertonic saline (18-30%) Morrhuate sodium USES: Superficial varicose veins of lower extremities (aesthetics) Condyloma acuminate (wart) removal Hemorrhoids; Obscure hernia rings Adjunct rather than tx for varicosities Endoscopic sclerosing therapy for acute and chronic esophageal varices Injected into varicose veins goes to circulation portal vein Cleared via portal circulation Morrhuate Na esoph varices with varicose veins ADVERSE REACTIONS: Burning or cramping at the injection site Sloughing of tissue occurs if the drug is allowed to extravasate. Urticaria Tissue sloughing and necrosis and anaphylaxis. Pleural effusion or infiltrate Esophageal perforation, ulceration, and strictures Severe necrosis of the esophagus Local reactions include esophagitis, tearing of the esophagus, and sloughing of the mucosa CONTRAINDICATIONS: Superficial thrombophlebitis Valvular or deep vein incompetency Large superficial veins that communicate freely with deep vein Varicosities caused by abdominal & pelvic tumors Uncontrolled DM ANTI-HEMORRHAGIC OCTREOTIDE MOA: Unknown May involve suppression of vasoactive GI hormone & Vasoconstriction w/in splenic circulation USES: Control bleeding assoc w/ esophageal improve w/in 5 days Acromegaly GI endocrine tumor SQ or IV; Long duration of action Renal elimination varices

SERINE PROTEASE INHIBITOR APROTININ direct inhibitor of plasmin BLOOD PRODUCTS WHOLE BLOOD 45% cells o Erythrocytes, Leucocytes, & Platelets 55% plasma 90% water, 10% solutes Solutes are made up of: o Crystalloids ions, glucose o Colloids proteins of all types (ex. Albumin, etc) MOA: Provides recipient with oxygen via O2 carrying capacity of RBC Intravascular volume expander Source of protein, with oncotic properties and stable coagulation factors 1 unit of whole blood contains 500mL blood, 275ml is plasma, 62 ml is anticoagulant 3% Hct raised with every 1 unit of whole blood INDICATIONS: Gross bleeding, Symptomatic anemia, Hypovolemic shock (Loss of 25-30% or more circulating blood volume) Significant blood loss, Exchange transfusion WBC <7 days old Number of units or volume of transfusion depends on patients condition ADMINISTRATION: Infuse at 5ml/min during the 1st 15 mins. of reaction Remainder should be infused as quickly as necessary Source of viable platelets, WBCs or labile coagulation Factors V and VII broken down after 24 hrs of collection request blood that is <24hrs esp. for new born Computed at 20ml/kg ADR: o Febrile nonhemolytic reaction, o Facial flushing, o Chills and fever, o Headache, o Red urine, o Hypothermia, o Circulatory overload (dyspnea), o Hypocalcemia o Hyperkalemia o Coagulopathy

PACKED RBC Minus the plasma from 1 unit of whole blood or RBC concentrate (20-30% plasma) Donor must be ABO compatible with the recipient 1 unit = 300ml blood with Hct of 65% to 80% Shelf life of 1 unit = 42 days Decreases viscosity 1 unit should be infused for 2-3 hours Given at 9-10 ml/kg for 2-3 hrs when blood loss is <25% of blood volume INDICATIONS : Not hypovolemic, With heart failure, Older adults, debilitated px, Has had multiple transfusions (i.e those with leukemia, aplastic anemia), Those who cannot tolerate rapid shift volume, Those with Paroxysmal Nocturnal hemoglobinuria, pale looking with significant bleeding 9-10ml/kg For those with Hemoglobin of 7 give pack RBC ADR: Reduced risk of febrile non-hemolytic reaction and circulatory overload

ADVERSE REACTIONS: Arrhythmia, hyperglycemia, pancreatitis, lower limb edema, bradycardia, diarrhea, facial flushing Long term therapy: GI pain, alopecia, dizziness, edema CI: arrhythmia, hypoglycemia, pancreatitis FIBRINOLYTIC INHIBITORS AMINOCAPROIC ACID TRANEXAMIC ACID Dada.Guia.Macy.Roch.Gine.Angel

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PLASMA Clear portion of blood separated from cells with anticoagulant added 3 types: o Fresh plasma o Liquid plasma o Fresh frozen plasma 1 unit = 180 of anticoagulated plasma PLASMA AND LIQUID PLASMA Clear portion of blood separated from cells w/ anticoagulant added Contain stable coagulation factors (fibrinogen & factor IX) 1 unit contains 180 & 300 ml of anticoagulated plasma FRESH FROZEN PLASMA Separated from a fresh unit of whole blood (<6 hrs old) and frozen 91% water, 7% protein, 2% carbs If frozen within 6 hrs of collection o Stored without loss labile and non-labile coagulation factors Fresh = less than 6 hrs old after collection from fresh unit of whole blood Without loss of labile and non-labile coagulation factors 1 unit = 2-4 mg of fibrinogen and causes a raised plasma fibrinogen level, about 10mg/ml Crossmatching is not needed Must be compatible with donors cell 10-15 ml/kg based on PT monitoring and with prolonged PT(2x the control) MOA Provide fibrinogen and factor IX, no need for cross match Plasma must be compatible with recipients blood INDICATION ITP Impending shock Bleeding requiring labile plasma coagulation factors and blood volume Pediatric clot deficiency 1-2 ml/min, Stable clotting factor deficiency, Not volume expander or nutrition source PLATELETS Give platelet concentrate at 1 unit/ 7 kg if: o < 50,000 in a patient with significant bleeding o < 20,000 in a patient without bleeding 1 unit has 2-4 mg of fibrinogen Disadvantage: Platelets are very fragile, immediate transfusion is needed CRYOPRECIPITATE Give 1unit/5kg if with prolonged PTT o >50 secs if there is no reference value (N=2340secs) o >10 secs more than upper limit or normal o >20 secs more than the control with DIC Labile and non-labile coagulation factors 1 unit contains 2-4 mg of fibrinogen & causes a raise of plasma fibrinogen level about 10 mg/ml Computed 10-15 ml /kg based on PT monitoring w/ prolonged PT (2x the control) ANEMIA Treatment is through replacement of what is missing Erythrocyte defects due to deficiency in Vit B12, Folate and Iron Very common but preventable Alternative tx: recombinant hematopoietic substance (factors) stimulate red cell production FACTORS: Erythrocyte comprised of Iron, B12, folic acid Granulocyte Platelet (megakaryocyte growth factor) ANTI ANEMIA IRON Majority is found in hemoglobin Essential metallic component of heme A fraction is bound to transferrin; Stored as ferritin When absent microcytic & hypochromic anemia eg. Pregnant women, hookworm parasitic infections

DISTRIBUTION: 70% Hgb in RBC 10-20% hemosiderin 10% myoglobulin <1% cytochrome PHARMACODYNAMICS: Regulation of body iron content Absorbed as ferrous (Fe2+) ion in the intestines Two forms of Iron (oral and parenteral) ORAL IRON FERROUS SULFATE: 20% elemental iron DOC for iron deficiency anemia Cheaper, easy absorption FERROUS FUMARATE 33% elemental iron In multivitamin-mineral complex FERROUS CHOLINE FIBRATE/GLUCONATE: 12% elemental iron Intake: 20mg/day, <5% absorbed Use: IDA, rapid growth, pregnancy ADR: Nausea, heartburn, diarrhea, constipation, toxicity, shock, necrotizing gastroenteritis; hemochromatosis iron overload due to genetics, blood transfusions, excess liver and pancreas storage CI: gastritis, malabsorption syndrome Take with vit C increase absorption Never take with aluminum salts (antacids) DEFEROXAMINE: Antidote for iron toxicity or hemochromatosis; a potent iron chelating compound (acute toxicity) (Katzung): Activated charcoal does not bind iron ineffective INTERMITENT PHLEBOTOMY: Used in chronic iron overload in the absence of anemia (katzung) Deferasirox oral iron chelator for treatment of iron overload PARENTERAL IRON Given to those who cannot tolerate orally administered iron pain upon oral intake, gastrectomy, IBD For patients with malabsorption syndrome IRON DEXTRAN: Complex of ferric hydroxide and low molecular weight dextran IV route preferred Need to perform a test dose during the first 5 mins of infusion 50mg Fe/ml ADR: If given IM, there is local discomfort, brownish discoloration, malignant skin disease (after 6 mos of injection), lymphadenopathy, anaphylaxis(rare but can be fatal), headache, fever, urticaria, bronchospasm

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PHARMACOKINETICS: Regulation of body iron content occur Intestinal absorption Efficient excretion of iron Absorbed as the ferrous ion Oxidized in the mucosal cell to ferric form Lost from the body with sweat, saliva and exfoliated skin VITAMIN B12 Cobalamin Porphyrin ring with central cobalt atom attached to a nucleotide Cofactor in the transfer of 1 carbon unit in DNA synthesis; Essential for cell growth maintenance of normal myelin Cannot be synthesized by multicelled organisms synthesized by bacteria from meat products Absorbed from gastrointestinal tract Stored in the liver Deficiency in VitB12 megaloblastic anemia o Dec THF dec dTMP affect normal DNA synthesis Histological appearance: macrocytic RBCs 2 essential reactions where B12 is involved: 1. Conversion: methylmalonyl-CoA succinyl CoA Homocysteine methionine 2. Linked to folic acid metabolism synthesis if dTMP 2 forms of Vitamin B12: 1. Cyanocobalamin deep orange solution 2. Hydroxocobalamin May be administered deep IM, SQ Uses: pernicious anemia, megaloblastic anemia demyelination and cell death (antidote for cyanide poisoning) ADR: Rare INDICATIONS: Used for treatment of pernicious anemia Given with Orlistat (Xenical) in px who are trying to lose wt during the first few wks, afterwards fenfluramine is used FOLIC ACID Absorbed at the proximal 3rd of the SI (proximal jejunum) w/ small amount stored in the body required for normal DNA synthesis Converted to (THF) tetrahyrofolate Precursor of coenzymes + tetrahydrofolic acid Prototype: Pteroylglutamic acid Transported to tissues maintained by food intake & heterohepatic cycle Deficiency in folic acid neural tube defects such as spina bifida & meningocele Excreted in urine Must be taken with anticonvulsant drugs ADR: No recognized toxicity INDICATIONS: Leucovorin for cancer tx Oral Folic acid both: IM, IV, SQ to circumvent action of dihydrofolate HEMATOPOEITIC GROWTH FACTORS Bone Marrow Colony Stimulating Factor ERYTHROPOEITIN Glycoprotein hormone produced by kidney; appears on surface of platelet Stimulates proliferation of immature erythroid progenitor cells Primary regulator of erythropoeisis stimulates the proliferation of immature erythroid progenitor cells 165-amino acid glycoprotein

INDICATIONS: Treatment of anemia of renal failure, chemo in Ca, HIV, bone marrow transplantation, avoid chronic anemia, anemia in AIDS, accelerates replacement of RBC removed by phlebotomy Elevates RBC by combination with specific receptors of erythroid progenitor Not affected by dialysis IV or SQ only, not given orally because it is broken down in the GIT Not intended for Px with severe anemia needing immediate correction IV: t1/2=5-13 hrs, not affected by dialysis ADR: Hypertension Seizures (1st 90 days of treatment) EPOEITIN ALPHA Given 1 wk (min) or up to 3 mos (max); injectible but manufactured by vial preparation DARBOPOEITIN ALPHA Glycosylated form of epoeitin with longer t1/2, injectible form of epoeitin alpha MYELOID GROWTH FACTOR For WBC deficiency FILGRASTIM Synthetic G-CSF, granulocyte colony stimulating factor Affects neutrophil only, stimulates its production More selective than sargramostin Has no effect on other granulocytes ADR: Bone pain Splenomegaly Abnormal uric acid concentrations SARGRAMOSTIM GM-CSF (granulocyte-macrophage colony stimulating factor) - synthetic Affects neutrophils, monocytes and macrophages Increase WBC in 2-3 days Reduces infection following bone marrow transplantation Given IV or SQ When there is bone marrow suppression, it increases granulocyte within 7-14 days INDICATIONS: Short term treatment of patients with primary bone marrow deficiency status or dysfunction as in cancer chemo Patients with aplastic anemia ADR: Fever Arthralgia Capillary damage Edema Fluid accumulation (pleural and pericardial effusions) MEGAKARYOCYTE GROWTH FACTOR OPRELVEKIN AND INTERLEUKIN 11 Increases number of peripheral platelets prior to episode of thrombocytopenia; reduces the need for platelet transfusion reduces the need for platelet transfusions stimulates the growth of primitive megakaryocyte progenitors IL-11 primitive megakaryocyte stimulator for post ca chemo ADR: Fatigue Headache Dizziness Fluid retention

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