Anti anaemia

Dr. Rika Yuliwulandari, PhD

Anti anemia

Fe --Hb production Anemia hipochromic microciticsd

Vit B12 (Cyanocobalamine), Folic acid

DNA synthesis
Ery production and maturation Anemia megaloblastic

Def B12: + Neurologic disorders

Fe

In the body
3.5 g ( complex structure with protein) 70% is essential/funcsional (66% in Hb, 3% in myoglobin, 0.5 % in citocrom oxidase, succinil dehydrogenase, xanthine oxidase, 0.1% in transferin 30% is non essential (25% in feritin and hemosiderin, 5% in parenchime) Fe Depot

Women: 200-400 mg Man: 1 g

Pharmacokinetic
Absorption: duodenum In mucosa: Ferro ----- into ferri (for erythropoiesis or depot as ferritin) Severe anemia, hypoxia: erythropoiesis increase 5x Absorption of fe increase in

Fe deficiency Decrease of Fe depot Increase erythropoiesis

Fe from food: 5-10%, esp from meat, egg and their products. Abs of Fe : Cobal, Inosin, Etimin, Vit C, Hcl, Suksinat Abs of Fe : Phosphat, Anticid (Ca Co3, MgCl2, Al(OH)3

Fe depot:
Iv: bind to Apo ferritin, depot in liver Po: depot in lien and bone marrow From erythrocyte ---- depot in lien and bone marrow

Excretion:
0.5-1 mg/day Through: skin epithelial cell, GI epithel, sweat, urine, feces, nail, cut hair Menstruation: 0.5-1 mg/day

Intake Fe depends on
Age, sex, Hb, Depot Fe Man 10 mg/day, women 12 mg/day (+5 mg in pregnancy and lactation)

Natural Fe resource:
5 mg/100 mg: Liver, Heart, Yeast, Nuts, dry fruits, 1-5 mg/100 mg: meat, fish, birds, green vegetables, beans 1 mg/100 mg: milk and its products, other vegetables

Se:

Po: intolerance
Stomach ache (7-20%), constipation (15%), diarrhea (5%), colic dose, take Fe after meal Feces black

Se

Im: local reaction (pain in inj site, brown colouring, local irritation) Sistemic reaction in 0.5-0.8 % cases, 10-20 min post inj.

Headeache, Myalgia, Hemolysis, Tachikardia, Flushing, Sweating, Nausea, vomitus, Bronchospasm, Hypotension, Collapse circular
Syncope, chills, fever, rash, urticaria, chest pain, myalgia, encephalopathy, shock, heart block

30 min-24hrs post inj

Acute intoxication (30 min several hrs)

Often in children: irritation, corrosion until necrosis of GI tr. Nausea, vomitus, diarrhea, hematemesis, black feces, shock, CVS collapse, pylorus stenosis, dead Tx: Vomitus, lavage if < 1hr, Milk, egg to bind Fe, Tx shock
dehydration, acidosis, Chellating agent: deferoxamin

Chronic intoxication:

Hemosiderosis
Anemia def . Fe:
Blood lost Multipara Growth period

Indication:

Posology:

Oral: Fero salt (sulfat, fumarat, glukonat, suksinat, glutamat, laktat)---- absorbsi similar, PK different
Fe salt in sitrat, tartrat, carbonat, pirofosfat, feri is difficult to absorb FeSo4.7H2O: 20% Fe, 3 dd I tab, 6 months Fe fumarat: 600-800 mg/day, divided dose

Parenteral: deep im, iv

Indication: if tolerant to oral, if not responsive to oral Iron dextran (imferon): 50 mg/5 ml, total dose 250 mg Fe/1 g Hb def.

Im: start with 50 mg ---- 100-250 mg/day Iv: max 25 mg/day ---- increase every 2-3 days untul 100 mg/day, slow injection within 20-50 mg/min

Anti Anemia Megaloblastic

Vit B12 and Folic Acid ----- for erythropoiesis Due to:

Low intake, malabsorbtion, increase uptake, increase blood destruction, increase excretion

B12 deficiency:
Hematopoiesis disturb, neurologic disorder, GI epithelial cell, general dibilitas Anemia perniciosa addison, parasite investation---esp. in adult

B12 in adult:
1 ug/day Excretion: 3-7 ug/day to gal bladder ---- reabsorb in gut

Source of B12
Animal: liver, ren, heart, scallop, egg yolk, milk, sea food Internal: B12 is produced in colon, bind to prot----but absorption in ileum --- not effective

Pharmacokinetic
Abs: good and fast for iv and im T max: 1 hr post im, -12 hrs po Abs decrease: chellating agent, sorbitol high dose

Transport of B12

Bind to protein
Beta glikoprotein Alfa glikoprotein (transkobalamin I) Inter alfa glikoprotein (transkobalamin II)

B12 level
Blood N: 200-9 pg/ml Depot: 1-10 mg (in liver)

Indication: Anemia pernicious Dose:

Severe anemia pernicious + neurologic disorder, liver: 100 ug B12, 1-5 mg Folic acid, im ---- 100 ug B12 im, 1-2 mg Folic acid po

Dose maintenance

100 ug pe 5-10 days ----- 100-200 ug/month until ery count 4.5 million/m3

Posology of B12
B12 sol: 10-1000 ug/ul Liver extract sol in water Depo B12 inj Not recommended: Inj hidroxocobalamin ---- form Anti body to transcobalamin II

SE: allergy to B12, usually inj of liver extractf

Folic Acid

Source:

Liver, Yeast, Fresh Green vegetable

Easily damage during cooking Function:

Synthesis purin and pirimidin Interconversion amino acid (serin-glisin, histidinglutamic acid, homosistein-methionin)

Daily need: 50 ug/day (increase in infection, anemia hemolytic, cancer)

Folat deficiency:

Disease complication
Ileum disease Alcoholism ---- food intake low Liver toxic due to alcohol Anemia hemolytic

Drugs
Methotrexate Trimetoprim

Symptom: hematopoisis megaloblastic, glositis, diarrhea, low body weight Pharmacokinetic

Abs good in 1/3 prox of Gitr Excretion: ren in metabolic

Posology
Inj: 5 mg/ml solution In multivitamin tab and anti anemia ta

Indication:

Prev and tx folat deficiency 0.5-1 mg/day, po , 10 days ----- 0.1-0.5 mg/day

Dose:

Anticoagulant, Fibrinolytic and Antiplatelet

Usage

Tx thromboembolism
Heart failure Diabetes Mellitus Vein varicosis Arterial damage ---- Trauma, smoking, op, immobilization, pregnancy, drug with estrogen ---- Anti coagulant, Anti thrombosis, Thrombolytic

Tx of bleeding
---- Hemostatic

Homeostasis
Primary Hemostasis

Within seconds 1. Vasospasm:

contract to stop bleeding Vasoconstriction of the blood vessel by Prostacyclin (PI2), Thromboxane A2 (TXA2) and serotonin (5-HT). Slows down the bleeding.

2. Platelet Plug:

Platelet adhesion Role of thrombin, adenosine diphosphate (ADP), PI2, TXA2, 5-HT and prostaglandins.

Secondary Hemostasis

Takes several minutes. Stabilizes the soft clot and maintains vasoconstriction. 3. Fibrin Clot:

Conversion of prothrombin to thrombin. Thrombin stimulates the conversion of fibrinogen (Blood protein) to polymerized fibrin (mesh).

4. Dissolution of the clot by fibrinolysis:

degradation of clot after tissue repair

The hemostatic process is a protective mechanism to prevent blood loss from the circulatory system.

Blood Coagulation:
Intrinsic Pathway

Blood comes in contact with the subendothelial surface or negatively charged surface resulting from an injury to the blood vessel. The Hageman factor (factor XII) binds to the subendothelial surface. It is then cleaved to XIIa. XIIa activates XI to form XIa. XIa activates IX to form IXa which then activates factor X to Xa.

Extrinsic Pathway

Tissue factor (factor III) is located on the membrane of most cells. Once activated, it converts VII to its active form, VIIa. A complex of VIIa+III+calcium+a phospholipid converts factor X to its active form, Xa.

Common Pathway

Factor Xa is the convergence point for both the intrinsic and extrinsic pathways. Factor Xa converts prothrombin to active thrombin. Thrombin is required for the conversion of soluble fibrinogen to insoluble fibrin protein. The fibrin meshwork is then stabilized by active factor XIIIa.

EMBOLISM

THROMBOSIS T
H R

A thrombus is a blood clot in an intact blood vessel. It forms under normal physiological and pathological conditions. When a thrombus dislodges, it becomes an embolus.

ANTI COAGULANT

Purpose

To prevent blood coagulation

Thrombus Emboli In vitro blood coagulation

3 groups:
Parenteral anticoagulant (Heparin) Oral anticoagulant Chelating anti coagulant

Anticoagulants Parental (Heparin)

Heparin endogen
Produced by mast cell May have a role in immunologic reaction

D D

Heparin Sodium, Heparin Calcium

Anticoagulants (Parental) cont.

Enoxaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 20009000 g/mol) Factor IIa is thrombin aPTT is not used

Heparin Sodium, Heparin Calcium:

5000-30,000 g/mol.

Clinical Use:

Prevention and treatment of embolism (i.e., post-op or following myocardial infarction), deep vein thrombosis, pulmonary embolism. Initial management of unstable angina or acute myocardial infarction. Pregnancy, in case anticoagulant is needed

MOA:

Increases the activity of antithrombin III Inactivates thrombin and F Xa High doses will inhibit platelet aggregation.

Pharmacokinetics:

Administration: oral is not absorbed i.v. and s.c.. Immediate onset (30-60 mins); Hepatic elimination and excretion, some excreted unchanged in urine. Dosage is determined by the activated partial thromboplastin time (aPPT; 1.5-2 times is normal). IM tidak dianjurkan Not found in placenta and breast milk

Side effects:

Hemorrhage. Allergic reaction

Gi bleeding Hematuria

Long term

Chill, febrile, urticaria, anaphylactic syock Myalgia, osteoporosis Alopecia Trombositopenia in 25% of px Necrosis in injection site

Contraindications:

existing bleeding condition or bleeding tendency.

Drug Interactions:

During and post op Px with high dose of ethanol, alcoholic, hypersensitive to heparing Risk of bleeding is increased by salicylates protamine sulfate (positive charge binds heparin). 1 mg protamine --- 80-100 usp heparin

Hemophilia, increase capillary permeability, abortus imminens, endocarditis, intra cranial bleeding etc

In case of overdose:

Monitoring:
Right dose Accurate laboratory test

Whole blood clotting time PTT: partial tromboplastin time aPTT: activated partial thromboplastine time

Normal: 40 sec aPTT 60-80 sec

Posology:
Pe: sol 1000-40.000 u/ml Depo: 20.000 40.000 u/ml

Dose:
Iv: 5000 unit ----- 5000-10.000 u/4-6j depend on BW and response Infus: Heparin 20.000-40.000 u in 1l D5%/NaCl 0.9% for 24 hrs Deep sc

For prophylaxis of thromboemboli 5000 u 2hrs pre op ---- 5000 u /12hrs

Anticoagulants (Oral)

Coumarins: dicumarol and warfarin; warfarin is structurally related to vitamin K.

Clinical Use: Treatment of embolism, deep vein thrombosis or atrial

fibrillation, patients with prosthetic valves (at risk for thrombosis). production of active vitamin K.

MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the

Active form

Coumarins: dicumarol and warfarin; warfarin is structurally related to vitamin K.

Pharmacokinetics: Route of administration: p.o.; 100% absorbed; 99%
bound to plasma proteins; slow onset of activity; Hepatic elimination and excreted in the urine. Dicumarol is incompletely absorbed from the gut. - Wardaron* po, im, iv

Side effects: Hemorrhage in 2-4%. Contraindications: Patients with Hemophilia. Drug Interactions:

Drugs that inhibit CytoP450 Enzymes will increase levels, ie cimetidine, Macrolide antibiotics, antifungal agents. Drugs that induce CytoP450 enzymes will decrease levels, ie rifampin and Barbiturates.

In case of overdose: Vitamin K (phytonadione)

Sensitive to oral anticoagulant: - Cachexia, new born baby, liver failure Decrease response to oral anticoagulant: - renal insufficiency, febrile, scorbut

Calcium binder anticoagulant

Natrium sitrat
Na sitrat + Calcium: Often for transfusion

Oxalat acid
For anticoagulant in vitro Toxic

Natrium edetat

Bind calcium komplek calcium natrium edetat

THROMBOLYTIC

Dissolve thrombus Indication

Acute Myocard infark Vein thrombosis Pulmonal emboli Arterial thrombo emboli Iv cathether Valve replacement

Streptokinase, urokinase, aktiator plasminogen, rt-PA (recombinant hujan tissue-type plasminogen activator) Very expensive, tight monitoring

These agents are enzymes or large proteins that dissolve clots, ie., an existing thrombus in pts with myocardial infarction, thrombotic stroke or pulmonary embolism.

Fibrinolytic Drugs: (Thrombolytics)

Urokinase; enzyme obtained from urine

MOA: Directly activates plasminogen; isolated from human kidney, therefore less chance of evoking an allergic reaction. Dose: loading 1000-4500 iu/kg iv --- infus 4400 iu/kg/hr

Streptokinase: protein obtained from streptocci; anistreplase (a preformed complex of streptokinase and plasminogen)

MOA: Combines with plasminogen to form an active complex that converts plasminogen to plasmin to dissolve the fibrin. Dose: iv for IMA 1.5 million unit, infus for 1 hr Acut vein thrombosis, lung emboli, acut arterial thrombosis: loading dose 250.000 iu inful 30 min ---- 100.000 iu/hr (24 hrs for lung emboli, 24-72 hrs for arterial thrombosis, 72 hrs for deep vein thrombosis)

Thrombolytics

Pharmacokinetics: Parental administration, i,.v. Side effects: hemorrhage, hypersensitivity reactions and reperfusion arrythmias.

Contraindications: Bleeding disorders; recent surgery; severe hypertension.

Drug Interactions: Increases risk of bleeding with dicumarol, warfarn, heparin, aspirin, ticlopidine, abciximab. In case of overdose: Aminocaproic acid inhibits fibrinolysis by competitively blocking plasminogen activation.

ANTITHROMBOTIC

Antiplatelet drugs:
Aspirin, sulfinpirazon, dipiridamol, dextran Epoprostenol (prostasiklin, PGI2I), ticlopidin

Antiplatelet Agents

GP: glycoprotein vWF: von Willebrands factor

Antiplatelet Agents

Aspirin

Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina.
MOA: Irreversible cyclooxygenase inhibitor and inhibits the formation of thromboxane A2. Pharmacokinetics: Oral administration Side effects: Bleeding; gastrointestinal irritation, hypersensitivity reactions and thrombocypenia. Contraindications: Bleeding disorders, hypersensitivity and Reyes syndrome. Drug Interactions: Increased hypoglycemic effects of sulfonylureas, inhibits uricosuric effect of probenecid. In case of overdose: Forced Alkaline Diuresis Recommended dose: 325 mg/day

Antiplatelet Agents

Dipyridamole

Clinical Use: Prosthetic valves; may be used as an adjunct with aspirin therapy. MOA: Lowers platelet calcium and increases the formation of cAMP (weak antiplatelet drug) , coronary vasodilator. Pharmacokinetics: Oral administration Side effects: GI distress, headache, dizziad4eness and rash. Contraindications: Hypersensitivity to this drug Drug Interactions: Increases risk of bradycardia with Beta adrenergic receptor antagonists.

Antiplatelet Agents
Clopidogrel

(Plavix)

Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. MOA: Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen. Pharmacokinetics: Oral administration; eliminated in urine and feces. Side effects: Bleeding, neutropenia and thrombocytopenia.

Antiplatelet Agents

Ticlopidine (Ticlid )

Clinical Use: Patients intolerant to aspirin; prevents thrombotic stroke. MOA: Inhibits ADP-induced expression of platelet glycoprotein receptors and reduces fibrinogen binding and platelet aggregation. Effects on platelet function are irreversible. Pharmacokinetics: Oral administration; eliminated in the urine and feces Side effects: Bleeding; mild to moderate neutropenia, increased cholesterol and triglyeride levels. Contraindications: Bleeding disorders, severe liver disease Drug Interactions: Inhibits cytoP450 drug metabolizing enzymes.

Antiplatelet Agents

Abciximab

Clinical Use: Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin.
MOA: Binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen. Pharmacokinetics: Parental administration, i.v. Side effects: Bleeding, thrombocytopenia, hypotension and bradycardia. Contraindications: Aneurysm, bleeding, recent surgery, stroke Drug Interactions: Unknown

HEMOSTATIC AGENTS

To stop bleeding

Local hemostatic
Absorbable hemostatic: spons gelatin, oksisel, human fibrin foam Astringent: ferry cloride, argenti nitrate, tanic acid Coagulant: Russels viper venom Vasoconstrictor: epinephrin, norepinephrin

Sistemic hemostatic
Antihemolytic factor (F VIII) Cryoprecipitated antihemophylic factor Desmopressin, tranexamid acid, Aminocaproic acid, Complex factor IX

For Hemophili, von Willebrand disease

Aminocaprioic acid, Tranexamic acid, Antihemophilic factor, Antiinhibitor coagulants, Factor IX complex and Desmopressin

Clinical Use: Decrease bleeding which may be due to hereditary deficiencies, surgery, or thrombolytic overdose.