PHARMACOLOGY OF DRUGS FOR ANEMIADr.Datten Bangun MSc.SpFKDept.Farmakologi & TherapetikFak.Kedokteran UHNM E D A N

ANEMIAAnemia can be defined as a reduction in thehemoglobin,hematocrit or red cell number.

In physiologic terms an anemia is any disorderin which the patient suffers from tissuehypoxia due to decreased oxygen carryingcapacity of the blood

HematinicsThese are drugs used to treat anemia

IronVitamin B12, CyanocobalaminFolic acidErythropoietin

*TYPES OF ANEMIAVarious classifications:Examples: Iron deficiency anemia ---- microcytic , hypochromic Megaloblastic anemia ---- macrocytic , normochromic due to Vit. B12 or Folic Acid deficiency Anemia due to decreased Erythropoietin as in chronic renal failure

Causes of Anemia1. Diminished production and or replacement of red blood cells.

2. Excessive breakdown and loss of red blood cells.

Hemodilution while not a cause of anemia, it does cause an anemia-like effect.

1. Diminished Production/Replacement of RBCs Anemia'sMicrocytic anemia deficiency of FeRBCs appear pale and smaller, and we see more reticulocytes in circulation. Can be caused by the chronic use of aspirin, which irritates the stomach GI blood loss.

Normocytic anemia deficiency of ErythropoietinCaused by compromised renal function.

Macrocytic Anemia- deficiency of folic acid and B12 Diminished cell division and release of larger cells in circulation.

2. Breakdown of RBCs AnemiaBleeding: can be due to an ulcer or in females blood loss due to their menstrual cycle

Use of drugs that irritate the GI tract (aspirin)

Hemolysis (Hemolytic Anemia) can be caused by:Autoimmune disease Mechanical (heart valves, microvascular disease) Toxins (e.g., snake venom)

Anti anaemic DrugsHaematopoiesis: it is the production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells.The haematopoietic machinary reside in the bone marrow in adults.It requires a constant supply of essential nutrients iron, vit B12, folic acid and presence of hematopoietic growth factors

*

ANTI-ANEMIC DRUGS

Drugs effective in iron deficiency and other hypochromic anemias: Iron Pyridoxine , Riboflavin , Copper Drugs effective in megaloblastic anemia: Vitamin B12 Folic Acid Hematopoietic growth factors: Erythropoietin

IRON FACTS

All body cells need iron. It is crucial for oxygentransport, energy production, and cellular growthand proliferation.

The human body contains an average of 3.5 g ofiron (males 4 g, females 3 g).

The typical daily normal diet contains 1020 mg ofiron. Only about 10% of dietary iron is absorbed (12 mg/day).

Anti anaemic DrugsIron: Total quantity of iron in the body is 4-5G, 65-70% in the form of Hb in RBC, 4% in myoglobin, 1% in various heme compound, 15-30% stored in the form of ferritin and hemosiderin in RE system, liver, spleen, intestinal mucosa and bone marrow

*IRON

Preparations: Oral: Ferrous sulphate Ferrous gluconate Ferrous fumarate , etc. Parenteral: Iron dextran ---- i.m or i.vIron Sorbitol ----- i.m only.

*Pharmacokinetics

Absorption ---- depends on requirements iron stores Ferrous (Fe++) / ferric (Fe+++) form pH Vitamin C Chelators or complexing agents Malabsorption syndrome

Iron transport

Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin. Transferrin is a carrier protein that plays a role in regulating the transport of iron from the site of absorption to virtually all tissues. Transferrin binds only two iron atoms. Normally, 2045% of transferrin binding sites are filled (measured as percent transferrin saturation [TS]).

Iron transport

Ferritin molecules store thousands of iron atoms within their mineral core. When excess dietary iron is absorbed, the body responds by producing more ferritin to facilitate iron storage.

Importance of IronIron forms the nucleus of the iron-porphyrin heme ring, This with globin chains forms hemoglobin.

Function of Haemoglobin:

Reversibly binds oxygen and provides the criticalMechanism for oxygen delivery from the lungs to other tissues.

In the absence of adequate iron, small erythrocyteswith insufficient hemoglobin are formed, giving rise toMicrocytic hypochromic anemia

*Acute Oral toxicity (overdose ; poisoning)

Necrotizing gastroenteritis with ---- vomiting, abdominal pain, bloody diarrhea Shock , lethargy & dyspnea Severe metabolic acidosis Coma Death

*

Acute Oral toxicity (overdose ; poisoning):(Contd.)

Treatment: Whole bowel irrigation Desferrioxamine (Deferoxamine) orally --- for Unabsorbed iron Parenteral ( i.m. , i.v. ) --- for iron absorbed

Desferrioxamine + ferric iron Ferrioxamine --- excreted in urine and bile.

*Chronic iron toxicity (iron overload): (Contd.)

Hemosiderosis: a focal or general increase in tissue iron stores without associated tissue damage

Hemochromatosis: associated with tissue damage

*Chronic iron toxicity (iron overload)(Contd.)Treatment:

Intermittent Venesection (Phlebotomy)---- when there is no anemia

Chelation (Desferrioxamine) ---- for transfusional overload

*Adverse effects of Parenteral iron therapy Local pain & tissue staining (brown discoloration of tissue overlying the injection site). Headache , light-headedness , fever , arthralgias,

nausea , vomiting , back pain , flushing , urticaria, bronchospasm , & ,

Rarely anaphylaxis & death

*VITAMIN B12 Chemistry Porphyrin-like ring with a central cobalt atom & nucleotide. Cobalamins = various organic groups covalently bound to cobalt atom Cyanocobalamine hydroxycobalamin & other cobalamins (found in food sources) are converted to active forms Deoxyadenosylcobalamin &methylcobalamin

* Active forms of vitamin B12 in human: Deoxyadenosylcobalamin Methylcobalamin Vitamin B12 available for therapeutic uses: Cyanocobalamin Hydroxycobalamin

Hydroxycobalamin --- is preferred because it is highly protein-bound & therefore remains longer in the circulation.

*Pharmacokinetics

Absorption: Intrinsic factor (IF) --- a glycoprotein , secreted by parietal cells of gastric mucosa IF-Vit.B12 Complex --- absorbed by active transport in the distal ileum

Transported in plasma bound to the glycoprotein transcobalamin II & is taken up by tissues where required & stored in hepatocytes

*Pharmacokinetics (Contd.)

Route of administration

Mostly ------ Parenteral ---- i.m.

Oral

Aerosol

*Pharmacokinetics (Contd.)

Elimination:

not significantly metabolized

pass into bile

Enterohepatic circulation

Excreted via kidney

*Features of Vitamin B12 deficiency

Impairment of DNA synthesis affects all cells but most apparently RBCs.

Megaloblastic Anemia

GI symptoms

neurologic abnormalities

*

Features Vitamin B12 deficiency (Contd.)

Neurological abnormalities : Degeneration of brain and spinal cord (Subacute combined degeneration ) and peripheral nerves. Symptoms may be psychiatric & physical.Paresthesia & weakness in peripheral nervesspasticity, ataxia, & other CNS dysfunction

*Uses Pernicious (addisonian) anemia After partial or total gastrectomy Malabsorption syndromes Insufficient dietary intake

Hydroxycobalamin (Not cyanocobalamin) Tobacco Amblyopia Cyanide toxicity

*Adverse effects

Allergic hypersensitivity reactions Antibodies to hydroxycobalamin-transcobalamin II complexArrhythmias secondary to hypokalemia

*FOLIC ACID (PTEROYLGLUTAMIC ACID; VITAMIN B9) Is inactive Active form is ---- tetrahydrofolic acid

*Pharmacokinetics Route of administration ----- usually oral

In diet ---- Polyglutamate form For absorption ---- must be converted to --- Mono-glutamyl form Absorbed mostly --- in proximal jejunum

*Functions Is required for synthesis of Amino acids , purines, pyrimidines, & DNA ; & therefore in the cell division

*Features of folic acid deficiency Mitotically active tissues such as erythroid tissues are markedly affected.

Anemia Congenital malformations --- neural tube defects ( e.g., spina bifida) Vascular disease

*Vitamin CVitamin C deficiency can cause megaloblastic anemia

*UsesPrevention & treatment of folic acid deficiency Dietary insufficiency (e.g. in elderly) Pregnancy & lactation to prevent --- Congenital malformations --- neural tube defects ( e.g., spina bifida) High red cell turn over --- e.g. in hemolytic anemias --- Premature infants Malabsorption syndromes

*Uses (contd.) Drugs Antiepileptics ---- enzyme inducers Phenytoin Primidone Phenobarbitone Antimalarials pyrimethamine Methotrexate FOLINIC ACID (not folic acid)

*Uses (contd.) Myelofibrosis Exfoliative dermatitis Rheumatoid arthritis Malignant disease , e.g., lymphoma Chronic hemodialysis

*Adverse effects Generally well tolerated Rarely --- G.I. Disturbances hypersensitivity reactions Status epilepticus may be precipitated

* ERYTHROPOIETIN (EPOTEIN)

a glycoprotein hormone produced : 90% --- by peritubular cells in kidney remainder --- by liver and other tissues is essential for normal reticulocyte production synthesis is stimulated by hypoxia synthesized for clinical use ---- by --- recombinant DNA technology

*Pharmacokinetics Route of administration --- S.C. or I.V. Plasma t1/2 ---- 4 - 13 hrs in patients with chronic renal failure.

Not cleared by dialysis

*Mechanism of action

increases rate of stem cell differentiationincreases rate of mitosis in red cell precursors, blast-forming units, colony forming cells. increases release of reticulocyte from marrowincreases Hb synthesisits action requires adequate stores of iron

*UsesAnemia associated with chronic renal failurepremature infantsAnemia during chemotherapy of cancerAnemia of AIDS (which is exacerbated by zidovudine treatment) to increase the yield of autologous blood before donation Anemia of chronic inflammatory conditions such as rheumatoid arthritisMISUSED --- by sports people

*Adverse effects Usually due to excessive increase in hematocrit increase blood pressure thrombosis seizures headache hypertensive crises with encephalopathy-like symptoms clotting in dialyser

*Adverse effects Transient influenza-like symptoms ------ chills & myalgias iron deficiency transient increases in platelet count hyperkalemia skin rashes pure red cell aplasia --- discontinue the drug antibodies to epoetins

*Precautions / contraindications hypertension should be well controlled seizures thrombocytosis ischemic vascular disease iron , folic acid , vit. B12 supplements may be needed heparin during dialysis

*Monitor hematocrit blood pressure platelet count serum potassium

********