Noor abu zaid 1 - HUMSC

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Noor abu zaid

Copyright © 2018 Wolters Kluwer • All Rights ReservedTareq Saleh ©

Drugs for AnemiaPharmacology and Toxicology

HLS ModuleSecond Year Medical Students

Tareq Saleh, MD, PhDFaculty of Medicine

The Hashemite University


Specific Intended Learning Objectives

By the end of these lectures the students should be able to:

1. List the different approaches utilized for the treatment of anemia based on its classification.2. Describe the main characteristics of iron preparations, their therapeutic indications,

pharmacokinetics, and major adverse effects.

3. Describe the mechanism of action of folic acid and vitamin B12, their therapeutic indications andmajor adverse effects.

4. Understand the role of erythropoietin in the treatment of anemia, therapeutic guidelines, andmajor adverse effects.

5. List pharmacological therapy utilized for the treatment of neutropenia.

6. Describe the role of hydroxyurea in the treatment of sickle cell anemia, its mechanism of actionand overall contribution to disease outcome.

Associated with anemia caused by nutritional deficiency

Very important hormone that involved in hematopoiesis, it’s secreted mainly from the kidney, so it’s naturally occurring hormone, but we also have pharmacological preparation of erythropoietin is used to treat certain types of anemia.

Reduced numbers or counts of WBCs, it’s very dangerous because it reflects reduced immunity so high susceptibility to infectious exposure.


Reference in Textbook

Chapter 42: Drugs for Anemia (pp: 565-571)


Anemia

“decreased (below-normal) plasma hemoglobin concentration resulting from decreased RBCs or abnormally low hemoglobin/blood volume”

Do Decreased Hb levels affect the function of Hb? Remember that Hb is responsible of transport and delivery of oxygen to the tissues that require, which is the main function of RBCs.. so decreasing Hb levels results in reducing the oxygenation of the tissues which leads to pathological/clinical features of anemia.

Keep in your mind that, anemic patient may develop symptoms (symptomatic) or may not (asymptomatic), so this means that diagnosis of anemia is laboratory diagnosis not clinical diagnosis, so you have to measure Hb level.

The most frequent cause

How can we determine that this state is anemia or this person is anemic, based on what? Anemia describes significant reduction of Hb, this decreased level it depends on many factors and specific guidelines, like: age (neonates, adults, elderly), gender (male, female), the environmental factors and lifestyle (smoking, chronic smokers are usually expected to have higher levels of Hb concentrations).


Signs and Symptoms of Anemia

High sensitivity to cold temperature

All the time, which is not normal


Classification of Anemia

At the beginning the treatment of anemia has been by blood transfusion. But treatment becomes advanced, advancement of anemia depends mainly in knowing the types of anemia, so anemia can be classified in too many ways ( according to the cause, symptoms, severity, age, etc..), one of the most important classification is according to the mean corpuscular volume of RBC, which divides anemia into 3 types (microcytic, normocytic, macrocytic)

Keep in your mind that ALL these 3 types have decreased Hb levels, but they differ in the mean corpuscular volume (it may be normal, below normal, higher than normal).

Replacement the whole blood


Agents Used to Treat Anemias

• Iron• Folic acid• Cyanocobalamin and

hydroxocobalamin (vitamin B12)• Erythropoietin and darbepoetin• Hydroxyurea• Transfusion of whole blood

According/depending in the cause

By replacing iron like: red blood cells maturation Hb synthesis

Using Vitamin B12 supplements

Mainly in sickle cell anemia

Effective in most of anemia states.


Iron


Iron

• Storage (liver, spleen, bonemarrow, intestinal mucosa):ferritin (iron-protein complex)

• Transport (to the bone marrow):transferrin

Iron is a natural element but we can also prepare it as a pharmacological agent to work as a drug by qualifying.

We obtain iron from diet, daily diet contains about 10-20 mg of iron, 90% of this amount are lost in fesses and only 10% is absorbed. 75% of the absorbed iron transport into the bone marrow that is required for Hb synthesis and erythropoiesis, (the rest used in liver function spleen function, etc), if the available absorbed iron is abundant to carry and Hb synthesis then the excess amount will be stored in tissues (liver, spleen, bone marrow, lymph nodes and more importantly in the cells of the intestinal mucosa “epithelium and endothelium of the gastrointestinal tract”. stored iron will be in the form of iron protein complex “ferritin”, also transported iron through the blood stream will be in the form of iron protein complex “transferrin”.


Iron Deficiency Anemia

• Most common nutritional deficiency

• Negative iron balance: depletion of iron stores and/or inadequate intake.

• Examples: acute/chronic blood loss, menstruation, accelerated growth in children…..

Symptoms: pallor, fatigue dizziness, shortness of breath, etc.. + Koilonychia (curved/concave/spoon-shaped nails), pica (tendencies to eat non food elements, not very common), angular Glossitis.

Imbalances between iron intake and iron uses/consumptions.


Iron

Mechanism of action:• Replace deficient iron levels

• 150-180 mg/day elemental iron (2-3 doses/day)

Remember always that In the treatment we have to follow specific guidelines. Rate of correction (iron replacement) depends on how much iron becomes absorbed, and this is differ according to the route ( how you given.. orally/ IV).

This is the most effective range that we should follow to get the best results in treatment, nor higher nor below.

About 50 mg every 8 hours.


Iron

Pharmacokinetics• Given orally or IV• Gastric acidity keeps iron in the

ferrous form: Fe → Fe+2

• Main site of absorption: duodenum• Extent of absorption depends on

iron stores

Iron absorption firstly occurs in the gut, specifically in the duodenum (the first more proximal part of the small intestine), absorbed rate usually 10%-30%, it depends mainly on the amount of stored iron (the less storage, the more absorption)

The main way, in the majority of cases.

The ultimate treat goal is to give the patients 150 mg of iron divided in 3 doses per day, why we cannot exceed this therapeutic range? 1- risk of toxicity (hemosiderosis due to iron accumulation), 2- if given orally, the gut has the ability to absorb only about 10% of the dietary iron, this means that even increased dose will not give you higher bioavailability or 100% absorbed amounts.


Iron

Oral preparations

❑Ferrous sulfate❑Ferrous fumarate❑Ferrous gluconate❑Polysaccharide-iron

complex❑Carbonyl iron

Takes weeks to replenish stores

Parenteral preparations

❑Iron dextran❑Sodium ferric gluconate❑Ferumoxytol❑Ferric carboxymaltose❑Iron sucrose

faster

Intravenous iron given when oral iron is not tolerated or in combination with erythropoietin (hemodialysis or chemotherapy)

These are the first line therapy, not the IV route.

In severe anemic states

Treatment with oral therapy is irritant


Most frequently/ commonly used.

This means that 100mg of this drug contains 20mg of iron, so you must give 750mg to reach the therapeutic dose (which is 150mg divided into 3 doses per day


Iron

Adverse effects• GI disturbances: pain, constipation, nausea, diarrhea• Dark stool (most common side effect)• Hypersensitivity/anaphylaxis (iron dextran)

IV iron should be used cautiously in patients with active infections. Why?

Must be tested before using.

Iron should be used with caution in patient with active bacterial infection, because iron may promote microbial growth and disrupt the body’s neutrophil immune response.


Iron toxicity

• Excessive iron can result in toxicities• Usually results from frequent blood transfusion• Treatment: deferoxamine (used for chelation of iron in both acute

and chronic toxicity.)

Like in treatment of thalassemia, this lead to build up of iron which is a toxic


Folic Acid (Folate)


Folic acid (Folate)

• Causes of folate deficiency:1. Increased demand (e.g., pregnancy, lactation)2. Poor absorption (e.g., intestinal pathology)3. Alcoholism4. Drugs:❑ Dihydrofolate reductase inhibitors, e.g., methotrexate, trimethoprim❑ DNA synthesis inhibitors, e.g., azathioprine, zidovudine❑ Drugs that reduce folate absorption, e.g., phenytoin, phenobarbital

Folic acid is important in: cellular proliferation and replication (by the synthesis of purine and pyrimidine, so DNA synthesis), it acts as a cofactor “reduction factor”, the active form of folic acid is the tetrahydrofolic acid (it responsible of the reduction reaction and then facilitate the biochemical pathway conversion of (what into what)? Homework. And according to it, the enzyme that catalyze that reaction is called “tetrahydrofolate reductase” to keep it in the reduced form because it’s important in the purine pyrimidine synthesis. So folate deficiency means there’s no purine pyrimidine synthesis appropriate, no DNA synthesis appropriate, so no cell proliferation appropriate. The most affected tissue by folic acid deficiency is the highly proliferative tissue such as the bone marrow, which leads to reduced RBCs then anemia.

I googled it, so hope this is the answer.


Folate deficiency

Folic acid deficiency →↓ synthesis of purines and pyrimidines →

megaloblastic anemia


Folic acid (Folate)

• Absorption: jejunum• Oral folic acid is not toxic (even at high doses)• Rare hypersensitivity to IV injection

Noor abu zaid 1 - HUMSC

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