recent drugs in haematinics 2014 pharmacology

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Dr.vishnu priya NMCH 1

description

its a update of recent drugs( haematinics)2014 explains anemia,treatment,newer drugs

Transcript of recent drugs in haematinics 2014 pharmacology

Page 1: recent drugs  in haematinics 2014 pharmacology

Dr.vishnu priya NMCH

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DEFINITION

These are substances required in blood formation are used as adjuvants in treatment of anemia

• Iron• vitamin B12• Folic acid• Growth factors

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Anemia• Decrease in circulating RBC mass ,the criteria in

which Hb <12g/dl in women and <14g/dl in men

ETIOLOGY

A complex interaction of socio-economic conditions,

nutritional deficiencies and co-existing disease (malaria, HIV) are key contributors to anemia in developing nations.

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CLASSIFICATION OF ANEMIA

According to morphology• Hypochromic microcytic anemia• Macrocytic anaemia/megaloblastic anemia• Normochromic normocytic anemia

According to underlying mechanism :• Blood loss (acute/chronic)• Decreased RBC production• Increased RBC destruction (haemolysis)

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Adult Reference Ranges for Red Cells

source:Robbins and Cotran pathologic basis of diseases,8edtn

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IRON DEFECIENCY ANEMIA HISTORY:• 1713 iron was shown to be present in blood• 19th century Blaud developed Blaud’s pill consists of ferrous

sulfate and potassium carbonate for anemia.

IRON DEFICIENCY ANEMIA• Iron defeciency is most Common and seen in developing and

developed countries as well.

• particularly in toddlers, adolescent girls, and women of childbearing age

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CAUSES OF IRON DEFICIENCY ANAEMIA

Dietary lack, impaired absorption, increased requirement, or (most importantly) chronic blood loss.

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IRON LOSS

• Each Hb molecule has 33% iron for loss of 100ml of blood there will be loss of 50mg of elemental iron

Normal iron requirement

Adult male – 0.5-1mg• Adult female (mensurating) - 1-2mg• Infants - 60µg/kg• Children - 25µg/kg• Pregnancy -3-5mg

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Requirement and availability of iron

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Iron deficiency anemia cont…

• IRON DISTRIBUTION

Iron content in mg

Male Female

Haemoglobin – 2500 1700

Myoglobin/enzymes – 500 300

Transferrin iron – 3 3

Iron stores - 600-1000 0-300

Total body iron in adult is 2.5-5g, more in men than women

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Iron metabolism

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Transport of iron

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TREATMENT OF IRON DEFICIENCY ANEMIA

Indication:

only clinical indication of iron in iron deficiency anemia with MCV < 80 fL and MCHC < 30%lab parameter:

Low SI < 30 mcg/dL with increased TIBC,

% saturation (SI/TIBC) of < 10%;

low serum ferritin level (< 20 mcg/L)

PREPARATIONS:• Oral• parentral

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ORAL IRON PREPARATIONS

• Ferrous sulphate(32% iron): cheap, metallic taste is present 200mg tab

• Ferrous gluconate (12% iron) 300mg,400mg/15ml elixer• Ferrous fumarate (33% iron) 200mg tab• Colloidal ferric hydroxide (50% iron) 50mg/ml drops• Carbonyl iron highly pure fine powder prepared by

decomposition of iron pentacarbonyl ,toxic compound

• Ferrous salts are cheap, high iron content, better absorbed than ferric salts

• All have same degree of gastric tolerance

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• For full haematopoietic effect –• adult total dose of 200mg of elemental iron given daily in 2 or 3

divided doses in empty stomach.• Child- 3-5mg/kg in 3 divided doses

prophylaxis:• 30mg elemental iron/day is sufficient

Other preparations :• Ferrous succinate (35%iron)• Iron choline citrate• Iron calcium complex(5% iron)• Ferric ammonium citrate (20% iron)• Ferrous aminoate (10% iron)

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Oral iron preparation cont..

• Ferric glycerophosphate• Ferric hydroxy polymaltose

These are better absorbed or less side effects but has lower iron content and expensive

• Iron solutions given in some patients with gastric disease or prior gastric surgery

• The reticulocyte count should begin to increase within 4–7 days after initiation of therapy and peak at 1–11/2 weeks.

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Adverse drug reactions of oral therapy

Constipation due to astringent effect is common than diarrhoea Epigastric pain Heartburn Nausea Vomiting, bloating, Teeth staining Metallic taste, Start with low dose then increase the dose higher

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Parentral preparations

Indications : Oral iron not tolerated, Failure to absorb oral iron Non compliance Severe deficiency – chronic bleeding Along with erythropoietin oral iron may not be absorbed at sufficient

rate to meet demands

For replinishment of iron stores this formula is been used

Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)

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Organic preparations• Iron dextran & iron sorbitol - citric acid (i.m)• Ferrous sucrose & ferric carboxymaltose

Iron dextran: i.v/i.m• Colloidal preparation of ferric oxyhydroxide complexed with

polymerized dextran

• High molecular weight >6000,dark brown viscous liquid

• 50mg of elemental iron is present in one ml

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IRON DEXTRAN I.M cont…..

On i.m:• 30% binds locally with muscles taken up by macrophages

• Since its antigenic anaphylactic reactions more common

• Given deep in gluteal region using Z track technique

• Dose:

2ml daily or alternative days or 5ml each side on same day (local pain lasting weeks may occur at higher days)

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On i.v administration:• After test dose injected I.V over 5-10mins, 2ml injected/day

10mins • Alternatively total calculated dose is diluted in 500ml of

glucose/saline solution infused i.v over 6-8hrs under constant observation

• If any complaints of giddiness, paresthesia, chest tightness present should be terminated

To avoid risk of hypersensitivity 0.25-0.5ml inj i.v over to ½-1hr reactions perform sensitivity test with small test dose before i.v/i.m

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ADVERSE DRUG REACTIONS

Local:

Pain at inj site, pigmentation, sterile abscess- old deblitated pts

Systemic:

Fever, headache, joint pain, flushing, palpitation, chest pain, dyspnoea, lymph node enlargement

Rare:

Anaphylactoid reaction vascular collapse and death

IRON SORBITOL CITRIC ACID COMPLEX:• Low mol wt, by i.m route does not bind locally in muscular tissues

directly available for haemopoiesis

• Cannot be used by i.v route, binds with transferrin may saturate it

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• 30% iron unbound is excreted in urine imparting black colour to urine due to formation of iron sulphide

Adverse drug reaction

Ventricular tachycardia, A-V block, other irregularities, hypotension, flushing is higher.

It is contraindicated in patient with kidney disease

Dose:75mg i.m max 100mg daily or alternative days

FERROUS SUCROSE:Newer formulation high molecular weight complex of iron hydroxide with sucrose that on i.v is taken by RE cells

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Safer

Dose:• 100mg iv taking 5mins once daily to once weekly till total

calculated dose is administered• Hypersensitivity lower

FERRIC CARBOXYMALTOSE

Latest drug ,ferric hydroxide core is stabilized by carbohydrate shell

Macromolecule taken by RE Cells primarily in bone marrow, liver and spleen

Dose:100mg i.v injection or upto 1000mg is diluted with 100ml saline infused i.v takin 15min or more,repeated after week

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Adverse drug reactions

Mild:• Headache, nausea, abdominal pain.• Pain at injection site, rash, anaphylaxis rare• Hypotension, flushing, chest pain infrequent• Not recommended for children <14yrs

Iron poisoning

In Infants and children 10-20 tab or equivalent liquid preparation cause serious toxicity

Manifestations are:

Vomiting,Abdominalpain,Haematemisis,diarrhoea,lethargy,cyanosis,dehydration,acidosis,convulsion,shock,cardiovascular collapse and death

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• Haemorrhage and inflammation of gut will be present• Hepatic necrosis and brain damage present.

Treatment of poisoning

Supportive measuresfluid and electrolyte balance

vitals monitoring

Diazepam i.v – convulsions

Prevent absorption from gut: • induce vomiting & gastric lavage with sodium bicarbonate solution• Egg yolk and milk orally it causes complex of iron

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Treatment of poisoning cont…

Bind and remove iron already absorbed:Desferrioxamine :• iron chelator is D.O.C• Obtained from streptomyces pilosus potent and specific• Readily binds ferric iron to form ferrioxamine• Well tolerated • rapid iv causes hypotension, tachycardia, anaphylactoid reaction &

urticaria,

Dose: I.M 0.5-1g (50mg/kg) repeatedly 4-12hrs required or

I.V in case of shock 10-15mg/kg/hr, max 75mg/kg in a day till serum iron falls below 300µg/dl

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contraindication for treatment :• Severe renal disease• Pregnant women• Available in lyophilized powder 500mg ,i.v,i.m.

Hemochromatosis:• Desferrioxamine useful in prevention and treatment of iron

overload in chronic anemia in thalassemia major with multiple transfusions,

• given continuous infusion 2g for 12hrs OD,but phlebectomy is treatment of choice

• Deferiprone, Deferasirox are alternative choice who cannot tolerate the above drug

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ADJUVANTS TO IRON THERAPYVitamin c, cobalt, copper, zinc & manganese

Vitamin B12(extrinsic factor)History• 1820 Combe and Addison described megaloblastic anemia• 1860- Austin flint described in certain patient with treatment

failure with iron found it was related with atrophy of gastric mucosal cells.

• 1926- Minot and murphy received noble prize demonstrated correction of pernicious anemia by feeding liver

• 1929-Castle extrinsic factor in diet and intrinsic factor in parietal cells both important of hematopoietic effect

• Vitamin B12 isolated in 1948• Dorothy Hodgkin determined structure of vitamin B12 received

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Structure of vitamin B12:Porphyrin like rings with cobalt in centre with various organic groups attached by covalent bond.

Congeners:

Cyanocobalamin and Hydroxycobalamin (therapeutically used)

Methylcobalamin and deoxyadenosylcobalamin

Source and requirements:

Synthesized by normal gut flora in human beings

Diet source : non vegetarian food,legimunous plants,milk and milk products

Requirement:2-3µg in normal adults

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Pharmacokinetics:• Vit B12 (diet) + protein → acidic environment + intrisic factor of

castle (glycoprotein)

Extrinsic factor

+ receptors (gastric mucosal cells)

Intrinsic factor

Absorbed (carrier mediated active transport)• If high dose consumed transported by ß globulin to various tissues

excess transported to liver for storage.• Undergoes enterohepatic circulation affected in presence of

malabsorption worsens if deficiency present • Storage: total amount stored in body 3-5g lasts for 3-5yrs

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Functions:Methylation Occurs simultaneously using homocysteine methionine methyltransferase

1.Methyltetrahydrofolate Tetrahydrofolate

(methyl donar) cobalamin

Homocysteine

Methionine

In this reaction inactive methyl FH4 is converted to active FH4 at same time homocysteine converted to methionine,

in case of deficiency it prevents activation of methyl FH4 called ‘methylfolate trap’.

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• Isomerization of methylmalonyl-CoA to succinyl-CoA

  Deficiency of B12

Causes:• Deficiency in diet,• Intrinsic factor of castle,• Transcobalamin II genetic deficiency,• Diseases,• worm infestation with D.latum,• Drug induced

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Treatment-pernicious Anaemia

Oral B12

Parentral B12

Dosage:

1)Initially 100 microg -1000 microg IM(daily or alternate days for 1-2 weeks to replenish the body store)

2)Maintenance therapy:

Without neurological manifestation –

100 microg – 1000microg ,once a month for lifetime

With neurological manifestation-

once a week or once every 2 weeks for 6 months, followed by once a month lifelong

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In Megaloblastic anemia

Dose:

parentral (IM/SC) -100 to 1000 microgram of cyanocobalamin is given

FOLIC ACID

History: • Wills identified crude liver extract that correct macrocytic

anemia and is called wills factor later as folic acid. • 1941 Mitchell named Folic acid

Requirement: 100 micro gram(Normal Adult)

500 – 600 microgram( Pregnancy, Lactation)

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Pharmacokinetics of folic acid:• Absorption primarily – proximal jejunum• conjugates hydrolyse dietary pteroylmonoglutamic by

conjugases • Folic acid reduced by dihydrofolate reductase to THFA• Methylated to 5-MeTHFA THFA→ folate

polyglutamate Methionine synthase

• Rest 5-20mg stored in liver undergoes enterohepatic circulation

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Functions of folic acid

THFA Folate cofactors

Synthesis of purine and pyrimidine

Deficiency folic acid:

Diet lack, malabsorption syndrome, excessive demands in

Pregnancy & anemia, liver disease & renal dialysis, drug

induced, megaloblastic anemia and teratogenic effects

Doses:• Daily requirement of folic acid 50µg • Pregnancy & lactation :↑200-300µg/day• Therapeutic doses :1-5mg/day• Folinic acid - prevention or in treatment of toxicity from

Methotrexate

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• Folic acid - treat folate deficiency by phenytoin or phenobarbitone

• Prophylactically given during pregnancy, lactation or using oral contraceptive

• Given along with vitB12 treat megaloblastic anemia

HEMATOPOIETIC GROWTH FACTORS• Maintains balance between proliferation and differentiation of

various blood cells• Known as cytokine growth factor glycoproteins responds to

any stimulation anemia & hypoxia• Regulates host defense system to inflammation.• These are erythropoietin, CSF, IL-11

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Hematopoietic Growth factors

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ERYTHROPOIESIS STIMULATING AGENTS

Important regulator of the proliferation CFU-E and their progeny.

• During states of hypoxia, the prolyl hydroxylase is inactive, accumulates of HIF-1 activates erythropoietin expression, stimulates rapid expansion of erythroid progenitors.

ERYTHROPOIETIN• Encoded by a single copy gene on human chromosome 7 that is

expressed primarily in peri-tubular interstitial cells of the kidney.

• Binds to a receptor on the surface of committed erythroid progenitors in the marrow

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EPOETIN ALFA:• Produced using recombinant DNA technology EPOETIN ALFA

using mammalian cell lines • Used to identify in athlete “blood doping”.• Kidney disease, bone marrow damage, iron deficiency leads to

improper secretion in case of anemia or hypoxia• inflammatory cytokines also ↓ secretion –infection and

inflammation

Pharmacokinetics:• Comes in single-use vials having 2000-40,000 units/mL i.v/s.c• On iv it clears from plasma with t1/2 of 4-8 hours

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DarbopoietinGenetically modified, four amino acids have been mutated with carbohydrate side chains thus increases the action drug to 24-26 hours in body.• Stimulates erythrocyte proliferation and differentiation causes

release of reticulocytes

USES: EPOETIN ALPHA: Anemia of chronic renal failure –• Before starting therapy plasma ferritin >400µg/l should be

present.• Gradual ↑ in 2-4mths hematocrit levels >36% is not

recommended ,hematocrit >40% causes myocardial infarction and death.

Dose: 80-120 units/kg given subcutaneously, thrice a week.

Maintenance dose :10-300u/kg (average 75u/kg)

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• Drug resistance due to occult blood loss, folic acid deficiency, inadequate dialysis, aluminum toxicity, and osteitis fibrosa cystica secondary to hyperparathyroidism

HIV-infected patients: on zidovudine therapy

Dose :100-300 units/kg, given s.c three times a week

Cancer-Related Anemias: multiple myeloma

Dose: 150 units/kg three times a week or 450-600 units/kg once a week, can reduce the transfusion requirement in cancer patients undergoing chemotherapy

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Surgery:

Perioperatively orthopedic and cardiac procedures treat anemia and reduce the need for erythrocyte transfusion

Dose:150-300 units/kg OD for the 10 days before surgery,on the day of surgery, and for 4 days after surgery

Other Uses

Orphan drug status from the FDA for the treatment of the anemia of prematurity, HIV infection, and myelodysplasia.

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• Darbopoietin alfa

uses• approved in anemia associated with chronic kidney disease and

is under review for several other indications• tested in cancer patients undergoing chemotherapy and in

preliminary studies

Dose:• 0.45 g/kg intravenously or subcutaneously once weekly, with

dose adjustments depending on the response• Iron & folic acid supplements given were increased demand is

present during therapy

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Adverse drug reactions of Epoetin and Darbopoietin

• Flu like symptoms• Mild hypertension,• Encephalopathy with headache,• Disorientation, • Convulsions• Thrombosis during hemodialysis

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Myeloid Growth Factors

• Glycoproteins stimulate the proliferation and differentiation of one or more myeloid cell lines.

• Enhance the function of mature granulocytes and monocytes

• By Recombinant technology: G-CSFs GM-CSFs cytokines, stimulates (CFU-GEMM) enhance cell

production, neutrophil, monocyte & eosinophil

IL-11,CSF-1 SCF & Thrombopoietin been produced.

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G-CSF: • Used in treatment & prevention of neutropenia• stimulates proliferation and differentiation of neutrophil

progenitor cells,• activates phagocytic activity of mature neutrophil

FILGASTRIM:• Recombinant human G-CSF is produced in E.coli,

nonglycosylated glycoprotein

LENOGRASTIM –

similar to Filgastrim but glycosylated, given 5µg/kg/day s.c/i.v

started within 24-72h after cytotoxic chemotherapy completion continued till neutrophil count reaches >10,000cells/µl

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PEGFILGASTRIM: S.C given• Pegylation increases molecular size so plasma t1/2 ↑ 10-12

times• Longer acting given Once per chemotherapy cycle till

chemotherapy lasts, shortens period of neutropenia• mobilize haematopoietic stem cells increases their

concentration in peripheral blood • Used in autologous haematopoietic stem cell transplant

Dose:• 6mg s.c OD single dose during each cycle of cytotoxic

chemotherapy

• Side effects: fever, bone pain, myalgia, rashes & GI effects49

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GMCSF: Stimulates development of progenitor cells & multipotent

haematopoietic growth factor By acting along with IL2 & 3 causes Proliferation and

differentiation of T cells

SARGRAMOSTIM: Recombinant human GM-CSF produced in yeast cell similar

to endogenous GMCSF Used in neutropenia due to cytotoxic drugs, lymphoma,

leukaemia, Hodgkin disease & bone marrow transplantation, intermittent cancer chemotherapy & AIDS

doses of 125-500 g/m2 per day. Plasma levels of GM-CSF rise rapidly after subcutaneous injection and then decline with a t1/2 of 2-3 hours.

given intravenously, infusions should be maintained over 3-6 hours.

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In clinical trials

MOLGRAMOSTIM(bacterially derived, REGRAMOSTIM(Mammalian derived

Adverse effects of GM-CSF: Fever, skin rash, muscle pain and lethargy, pain and redness at injection site, flushing, fall in Bp, tachycardia, breathlessness, nausea & vomiting

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MEGAKARYOCYTE GROWTH FACTORSUsed in treatment of thrombocytopenia due to cancer chemotherapy& bone marrow transplantation

IL-11:

Endogenous megakaryocyte growth factor

Its Cytokine, produced by fibroblasts and bone marrow stromal cells

THROMBOPOIETIN:

Glycoprotein produced by hepatocytes, bone marrow stromal cells and other organs, level is ↓ cases of thrombocytopenia & cirrhosis of liver

↑platelets and neutrophils

OPRELVEKIN:• Recombinant form IL-11 produced by expression of ecoli• t1/2:7-8hr 52

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Function:

Stimulates growth of myeloid and lymphoid cells.

Dose:

50µg/kg/day S.C until 2-3 weeks or Until platelet count reaches >50000 cells/µ L

6-24h after completion of cancer chemotherapy

Uses• Thrombocytopenia, secondary prevention of thrombocytopenia

following cancer chemotherapy• IL11 reduces platelet transfusion in cancer chemotherapy for

non myeloid cancers

Adverse effects:• Dizziness, headache, fatigue, anemia, dyspnoea & hypokalemia.

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Recombinant thrombopoietin:Two types :

Recombinant human megakaryocyte growth and development factor(rHuMGDF):

Pegylated covalently ↑ plasma t1/2 so the duration of action

Recombinant human thrombopoietin (rHuTPO):

Polypeptide with full length

Trials shows reduction in platelet transfusion & duration of severe thrombocytopenia in patient receiving cancer chemotherapy.

Results were not encouraging in leukaemia patients54

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Newer drugs for ITP

ROMIPLOSTIM:Peptibodies,

Non immunogenic,

t1/2- 3to4days,

S.C route is used

ELTROMBOPAG:

Orally effective agonist at thrombopoietin receptor,

restricted use due to toxicity.

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REFERENCES

• Principles of pharmacology – HL Sharma & KK Sharma.

• Pharmacology – Rang & Dale 5th Edition. • Text book of pharmacology – K. D. Tripathi.7th

Edition.• Basics & clinical pharmacology – Katzung 11th edition.• Pharmacology & Pharmacotherapeutics - Satoskar-

21st edition.• Pharmacological basis of Therapeutics – Goodman &

Gilman 12th Edition.

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