drug treatment of anemia

7/28/2019 Drug Treatment of Anemia

1/36

Drug Treatment of Anemia

DR. B.K. Mishra

DEPTT. OFPHARMACOLOGY,H.I.D.S.G-NOIDA


2/36

Drug Treatment of Anemia

Synopsis

Rational use of haematinic drugs is essential to thecorrection of anemia in its various forms. Theemergence of haemopoietic growth factors as drugsthat stimulate erythroid or myeloid cell lines hasopened the way to successful management of other

forms of hematological disease Iron:- therapy, acute overdose

Vitamin B12

Folic acid

Haemopoietic growth factors Sickle cell anemia

Polycthaemia rubra vera

Aplastic anaemia


3/36

The haemopoietic system

Main components are

Blood

Bone marrow

Lymph nodes

Thymus

With the spleen, liver and kidney as important accessoryorgans.

Blood consist of formed elements

Plasma

Important site of formation of RBC in adult is bone

marrow where as spleen acts as their graveyard. Liver stores vitamin B12 and kidney manufactures

erythropoietin


4/36

Anemia Defined as reduce concentration of hemoglobin

in the blood and is characterized by decrease inthe oxygen carrying capacity of the blood

Depending upon the indices of red cell size,hemoglobin content and microscopicalexamination of stained blood smear, it is

classified as Hypochromic micro-cytic anemia (small red cells

with low hemoglobin caused by iron deficiency). Macro-cytic anemia (large cells, few in number)

Normo-chromic normo-cytic anemia (fewernormal sized red cell, each with a normalhemoglobin content).

Mixed pictures.


5/36

Anemia can also be classified according to their etiology as

i). Anemia due to dietary deficiency or malabsorption of factorsessential for normal blood formation e.g. iron, folic acid vitamin B12vitamin C. and pyridoxine.

ii). Anemia due to blood loss e.g. menorrhagia, G.I. loss andhookworm infestation.

iii). Anemia due to excessive blood destruction e.g. thalassemia,sickle cell anemia auto immune haemolytic anemia.

iv). Anemia due to aplasia or hypo- plasia of the bone marrow e.g.anticancer drugs, chloramphenical.

v). anemia due to deficiencies of erythropoietin e.g. chronic renaldisease.

vi). Anemia of unceratain origin e.g. infection, rheumatoid arthritis,liver disease.

Note:-

The use of haematinic agent is often only an adjunct to treatmentof the underlying cause of the anemia.

Sometimes, we have to stop an offending drugs.


6/36

Haematinic agents:-

These are the agents required in the formation

of blood, and are used for treatment of anemia. Iron:-

Its deficiency is most common cause of chronicanemia. Its deficiency leads to

Pallor

Fatigue

Dizziness

Excertional dyspnoea Other generalized symptoms of tissue hypoxia

Blood Picture:- Micro-cytic hypochromicanemia.


7/36

Iron kinetics:-

Absorption takes place predominantly in the duodenumand proximal jejunum where the acid environment

enhances its solubility. Most iron in food is present as ferric hydroxide, ferric

protein complexes or haeme protein complex.

Ferrous iron is more readily absorbed than ferric.

Simultaneous ingestion of a reducing agent (as ascorbicacid) increases the amount of the ferrous form.

Food reduces iron absorption due to inhibition byphytates, tannates phosphates.

The body of 70 kg man contains 4g of iron , 65% ofwhich circulates in the blood as haemoglobin

Menstrual loss of iron is about 30mg/period;menstruating women may therefore be in negative ironbalance.


8/36

The distribution of iron in the body of a

healthy 70 kg Male

300bone marrow

48spleen

410LiverFerritin and hemosiderin

8Plasma and extra cellular

fluidTransferrin

25Liver and other tissuesEnzymes (Cytochromes,

catalase)

400MusclesMyoglobin

2600ErythrocytesHaemoglobin

Iron content (mg)TissueProtein


9/36

The normal daily requirement for iron is

approximately 5mg for men and 15mg for

growing children and for menstruating

woman and ten fold for pregnant lady

Iron is available in a wide variety of food

but especially abundant in meat.

Iron in other foods are present as non-

heme iron and must be reduced to ferrous

iron (F2+) before it can be absorbed byintestinal mucosal cells.


10/36


11/36

Transport:-

Transported in the plasma bound to transferrin, a globulin that specifically binds two molecules of ferrous

iron . Hence iron store depletion and iron deficiency anemia

are associated with an increased concentration ofserumtransferrin.

Storage:- In addition to the storage of iron in intestinal mucosal

cells, iron is also stored, primarily as ferritin, inmacrophages in the liver ,spleen and bone and inparenchymal liver cells.

Ferritin is detectable in serum; since the ferritin presentin serum is in equilibrium with storage ferritin in reticuloendothelial tissues. The serum ferritin level can beused to estimate total body iron stores


12/36

Elimination.:-

No mechanism for excretion of iron Small amount are lost in the feces by

exfoliation of intestinal mucosal cell, and

trace amounts are excreted in bile, urineand sweat .

Total loss account for no more than 1 mg

of iron per day.


13/36

Factors affecting iron absorption:- Type of iron In man, food iron must be reduced to ferrous form before it is

absorbed Reducing agents present in the diet:- example ascorbic acid,

succinate ,they convert ferric to ferrous forms, and helps ironabsorption.

A diet poor in phosphorus ehances iron absorption Antacids such as calcium carbonate, aluminum hydroxide,

magnesium hydroxide reduce iron absorption Other drugs:- like tetracycline, levodopa, fluroquinolones interferewith iron absorption.

Administration of iron along with or after food reduces its absorption In conditions like chronic pancreatitis and liver cirrhosis, iron

absorption is increased.

Pica :- iron deficiency can promote appetite for bizarre foods if clayis consumed (geophagia), there occurs chelation of iron in gut ,worsening the iron deficiency.


14/36

Indications for the use of iron:-

Indicated for treatment or prevention of

iron deficiency anemia seen in premature

infants.

Child during rapid growth period

Pregnant and lactating women

Patient with chronic kidney disease.

Inadequate iron absorption. Blood loss Menstruation

G.I. Tract


15/36

Iron therapy:- The goal is to repair the haemoglobin deficit and replenish

storage iron Iron deficiency anemia is treated with oral or parenteral

iron preparations. Oral iron preparation:-

Enormous variety of official and proprietary ironpreparations are available. Ferrous sulphate is more effective. A small dose is given at first and increase after a few days Objective is to give 100-200mg of elemental iron/day

(3mg/kg in a child) Iron given on a full stomach and causes less gastro

intestinal upset.,if daily dose does not exceed 180mgelemental iron


16/36

Commonly used preparation; give in divided dosesinclude

Ferrous sulphate tab, 200-400mg/day (Providing

67-195mg/d of elemental iron) Ferrous gluconate tabs, 300-1200mg daily (providing

35-140mg /day of elemental iron) Ferrous fumerate tab 200-600mg daily (providing

130-195mg/day of elemental iron).

Various other forms are also available. Adverse effects:-

common adverse effects of oral iron therapy includes nausea epigastric discomfort

abdominal cramps constipation and diarrhea

Usually dose related and can be over come by lowering the dose. Patients taking oral iron develops black stool.


17/36

Failure of oral iron Therapy:- Due to Poor patient compliance Persistent bleeding Wrong diagnosis Iron can not be absorbed from the intestine

The patient can not be relied on to take itsor Experiences intolerable Gut symptoms This

includes patient with various post gastrectomyconditions and previous small bowel resection,

inflammatory bowel disease, malabsorptionsyndromes ,advance chronic renal diseaseincluding hemodialysis and treatment witherythropoietin.


18/36

Parenteral iron therapy:-

This needs calculation of total

Iron requirement (mg) of the patient =4.4xbody wt (kg)xHb deficit (g/dl)

Intra.muscular iron:- iron sorbitol injection (50mg ofiron/ml) is an iron sorbital citric acid complex.

Rapidly absorbed

Stored in marrow and liver and bound to plasma globulin.

Excess unbound excreted in urine (about 30% of dose),when may turn black transiently at the time peak ironexcretion or only on standing for some hours.

Given deep IM , daily or on alternate days. By Z-technique


19/36

Intravenous Iron:- Iron dextran injection (ferric hydroxide complexed with

dextran; 50mg/ml) and iron sucrose injection (Ferrichydroxide complexed with sucrose; 20mg/ml) Administered by slow IV Not recommended for children IV route eliminates local pain and tissue staining.

Note:- Oral iron therapy should not be given 24 hours before I/

M injection begin, for 5day after the last I/V injection as itmay promote adverse reactions.

Adverse effects:-

Headache, light headedness, nausea, vomiting,myalgia, pressure sensation in the chest, hypotension,bronchospasm, and rarely anaphylaxis and death


20/36

Clinical Toxicity:- Acute iron toxicity:-

Almost exclusively seen in young children whoaccidentally ingest iron tablets. 10 tablet of any commonly available oral

preparations can be lethal in young children

Ferrous sulphate is the most toxic Young children poisoned with oral ironexperience necrotising gastro-enteritis with

Vomiting , abdominal pain, and bloody

diarrhoea followed by shock , lethargy anddysponea, then ultimately followed by severemetabolic acidosis ,coma and death.


21/36

Treatment should be prompt

To prevent further absorption of iron from gut:-

Do whole bowel irrigation or gastric lavage withsodium bicarbonate solu-to render iron insoluble,

give egg, yolk and milk orally to complex iron.

To bind and remove iron already absorbed:- Des- ferrioxamine injected IM 0.5-1g

(50mg/Kg)repeated 4-12 hourly required or

IV (if shock is present ) 10-15 mg/kg/hours; max

75mg/kg in a day till serum iron falls below300g /dl.


22/36

Supportive measures:- maintain fluid and electrolyte balance correct acidosis

support BP and respiration if convulsions occurs, give diazepam IV Chronic iron toxicity:- also K/a Hemochromatosis occurs when excess iron is deposited in heart, liver, pancreas, and

other organs.

Can lead to organ failure and death Commonly occurs in patients with inherited hemochromatosis and in

patients who receive may red cell transfusions over a long periodtime

Treated by:-

Intermittent phlebotomy but anemia should be absent If above, can not maintain then given des-ferrioxamine. Another alternative deferasirox


23/36

Vitamin B12:- Serve s as a co-factor for several essential bio-chemical reactions in

human. Deficiency leads to anemia, G.I symptoms, and neurological

abnormalities. The chief dietary source of vitamin B12 is microbially derived vitamin B12

in meat (especially liver),eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor to differentiate it from

intrinsic factor, a protein normally secreted by the stomach. The vitamin is avidly stored, primarily in the liver, with an average adult

having a total vitamin B12 storage pool of 3000-5000 mcg. Only trace amounts of vitamin B12 are normally lost in urine and stool. Because the normal daily requirements of vitamin B12 are only about 2mcg.

It would take about 5 years for all of the stored vitamin B12 to be exhaustedand for megaloblastic anemia to develop if B12 absorption stopped.

Vitamin B12 in physiologic amounts is absorbed only after it complexes withintrinsic factor, a glycoprotein secreted by the parietal cells of the gastric

mucosa. Vitamin B12 deficiency in humans most often results from malabsorption of

vitamin B12 due either to lack of intrinsic factor or to loss or malfunction ofthe specific absorptive mechanism in the distal ileum.


24/36

Pharmacodynamics:- Two essential enzymatic reactions in humans require vitamin B12


25/36

In one, methylcobalamin serves as an intermediate in the transfer ofa methyl group from N5-methyltetrahydrofolate to homocysteine,forming methionine

Without vitamin B12, the precursor of folate cofactors cannot occur.

As a result, a deficiency of folate cofactors necessary for severalbiochemical reactions involving the transfer of one-carbon groupsdevelops.

In particular, the depletion of tetrahydrofolate prevents synthesis ofadequate supplies of the deoxythymidylate (dTMP) and purinesrequired for DNA synthesis in rapidly dividing cells.

This is the biochemical step whereby vitamin B12 and folic acidmetabolism are linked, and it explains why the megaloblasticanemia deficiency can be partially corrected by ingestion ofrelatively large amounts of folic acid.

The other enzymatic reaction that requires vitamin B12 isisomerization of methylmalonyl CoA to succinyl CoA by the

enzyme methylamalonyl CoA mutase .


26/36

In vitamin B12 deficiency, this conversioncannot take place, and the substrate,methylmalonylCoA, accumulates.

The important point is that administrationof folic acid in the setting of vitamin B12deficiency will not prevent neurologicmanifestations even though it will largelycorrect the anemia caused by the vitaminB12 deficiency.


27/36

Clinical Pharmacology:- The most characteristic clinical manifestation of Vitamin B12

deficiency is megaloblastic anemia. Clinical findings are macrocytic

anemia, with leucopenia or thrombocytopenia a characteristichypercellular bone marrow.

The neurologic syndrome begins with paresthesias and weakness inperipheral nerves progresses to spasticity, ataxia, and other centralnervous system dysfunctions.

Once a diagnosis of megaloblastic anemia is made,determine

whether vitamin B12 or folic acid deficiency is the cause. This can usually be accomplished by measuring serum levels of the

vitamins. The Schilling test which measures absorption and urinary

excretion of radioactively labeled vitamin B12, can be used to furtherdefine the mechanism of vitamin B12 malabsorption

Common causes of vitamin B12 deficiency are pernicious anemia,partial or total gastrectomy, malabsorption syndromes, inflammatorybowel disease, or small bowel resection.


28/36

Pernicious anemia:- Pernicious anemia result from defective secretion of intrinsic factor

by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to

secrete intrinsic factor (as well as hydrochloric acid). Other rare causes of vitamin B12 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease.

Parenteral injections of vitamin B12 are required for therapy For patients with potentially reversible diseases, the under lying

disease should be treated after initial treatment with parenteral

vitamin B12. Initial therapy should consist of100-1000 mcg of vitamin B12

intramuscularly daily or every other day for 1-2 weeks to replenishbody stores.

Maintenance therapy consists of100-1000 mcg intramuscularlyonce a month for life.

If neurologic abnormalities are present, maintenance therapyinjections should be given every 1-2 weeks for 6 months beforeswitching to monthly injections.


29/36

Folic Acid:-

Also k/a pteroylglutamic acid

So named because it was discovered as a

bacterial growth factor present in spinachleaves.

One of the B-group vitamins

Reduced forms of folic acid are required for

essential bio-chemical reactions, that provideprecursors for synthesis of amino acids, purines,and DNA.


30/36

Functions:-

It self inactive, converted into the biologically

active coenzyme, tetra hydrofolic acid. Tetrahydrofolic acid is important in the bio-

synthesis of amino acids and DNA and therefore

in cell division.

The formyl derivative of tetrahydrofolic acid is

folinic acid and this is used to bypass the block

when the body fail to effect the conversion of

folic acid. Deficiency:- leads to megaloblastic anemia.


31/36

Occurrence and requirements:-

Widely distributed, especially in green

vegetables, yeast and liver

Adult daily requirement = 50-100g

Child daily requirement = 50 g

Body stores last about 4months.


32/36

Pharmacokinetics:-

Richest sources are yeast, liver kidney, and greenvegetables

. Normally, 5-20mg of folates are excreted in the urineand stool and are also destroyed by catabolism, soserum levels fall within a few days when intake isdiminished.

Because body stores of folates are relatively low anddaily requirements high, folic acid deficiency andmegaloblastic anemia can develop within 1-6 monthsafter the intake of folic acid stops.

Unaltered folic acid is readily and completely absorbed in

the proximal jejunum. Inside cells, N5 methyltetrahydrofolate is converted to

tetrahydrofolate by the demethylation reaction thatrequires vitamin B12.


33/36

Indications:- It is used to prevent or cure deficiency of folate

which are due either to a decreased supply or

to an increased requirement. Dietary deficiency :- commonest cause in india Due to increased requirement- as pregnancy. - increased demand for folic acid is also

observed in hyperthyroidism, rheumatoidarthritis, leukemia, hemolytic anemia, chronicinfections

Prevention of fetal neural tube defects (spina

bifida) Folic acid supplementation is taken beforeconception and during early week ofpregnancy.


34/36

Women hoping to conceive and had affectedchild are given folic acid =5mg/day.

To prevent 1st occurrence = 400 g/day

should be taken before conception or assoon as possible after diagnosis.

Taken for the first 12 weeks of pregnancy. Premature infants.

Drugs:- Anti-epilepsy drugs, particularly phenytoin,

primidone and Phenobarbital, causes amacrocytic anemia; they responds well to

folic acid. Anti- malarials as pyrimethamine, causesmacro-cytic anemia.


35/36

Contra- indication: - imprecisely diagnosedmegaloblastic anemia.

Haemopoietic growth factors:-

Stimulate both erythroid and myeloid cell lines. Potentially useful when ever there is cytopenia,

whether due to disease or to cyto toxicchemotherapy.

Erythropoietin:- Mainly produced in kidney in response to

hypoxia. Principal action to stimulate the proliferation,

survival and differentiation of erythrocyteprecursors. Anemia of chronic renal failure is largely d/t

failure of the diseased kidney to make enougherythropoietin.


36/36

Epoetin must be given S.C. or I/V. T1/2=4hours Self administration three times a week, dose adjusted by

response. Two preparations are available- epoetin alpha and

epoetin beta Effective in the anemia of chronic renal failure Rheumatoid arthritis Prematurity Cancer chemotherapy Zidovudine treated AIDS Adverse effects:- rise in BP and encephalopathy may

occur in some hypertensive patient.

drug treatment of anemia

Documents