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

30 min-24hrs post inj Syncope, chills, fever, rash, urticaria, chest pain,

myalgia, encephalopathy, shock, heart block

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

Indication: Anemia def . Fe:

Blood lost Multipara Growth period

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, histidin-glutamic 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

Dose: 0.5-1 mg/day, po , 10 days ----- 0.1-0.5

mg/day

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 THR

THROMBOSIS

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; 2000-9000 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.

Gi bleeding Hematuria

Allergic reaction Chill, febrile, urticaria, anaphylactic syock

Long term Myalgia, osteoporosis Alopecia Trombositopenia in 25% of px Necrosis in injection site

Contraindications: existing bleeding condition or bleeding tendency.

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

During and post op Px with high dose of ethanol, alcoholic, hypersensitive to

heparing Drug Interactions:

Risk of bleeding is increased by salicylates In case of overdose:

protamine sulfate (positive charge binds heparin). 1 mg protamine --- 80-100 usp heparin

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).

MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the production of active vitamin K.

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: glycoproteinvWF: von Willebrand’s 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 Reye’s 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.