Transcript Antianemeic drugs final

Antianemeic drugs
Agents to Tr anemia
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• Hematopoiesis: production of erythrocytes,
platelets, & leukocytes from stem cells in ! BM.
• Require a constant supply of 3 essential
nutrients:
- Iron
- Vitamin B12
- Folic acid
+ hematopoietic GFs.
Anemia: deficiency in O2-carrying erythrocytes.
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Anti-anemic drugs
In iron deficiency & other hypochromic anemia:
- Iron
- Pyridoxine, Riboflavin, Copper
In megaloblastic anemia:
- Vit B12
- Folic acid
Hematopoietic GFs
- Erythropoietin (in chronic RF).
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Agents used to Tr anemia
1- Iron:
Iron deficiency is ! most common cause of
chronic anemia.
Total Body Iron
4 g in ! adult male
2.5 g in ! adult female
Source: meat & green vegetables.
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• Iron forms ! nucleus of ! iron-porphyrin heme
ring, w together e globin chains forms Hg.
• Hg reversibly binds O2 (delivery).
• Iron deficiency causes: small erythrocytes e
insufficient Hg are formed: microcytic
hypochromic anemia.
PK:
• All of ! iron used to support hematopoiesis is
reclaimed from catalysis of ! Hg in senescent /
damaged erythrocytes.
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• Dietary requirements are small & easily available in food.
Iron absorption:
Actively absorbed in duodenum & proximal jejunum.
In ! ferric (+++) form & is complexed to other organic & inorganic
molecules.
! acid in ! stomach & hydrolytic enzs in small intestine release !
iron from these complexes.
It is then reduced to ! ferrous (++) form (more readily absorbed).
Abs is increased by: glucose, amino acids & ascorbic acid.
& decreased by : phosphate bicarbonate bile acids,
antacids & tetracycline.
Heme iron in meat Hg & myoglobin can be absorbed intact.
Iron in vegetables & grains, tightly bound to organic cpds; <
available for abs.
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• Excess iron: stored in mucosal cell as ferritin,
a water-soluble complex.
Distribution:
Iron is transported in ! plasma bound to
transferrin, a β globulin binds 2 molecules of
ferrous iron. ! iron is transported to ! marrow
for use /storage.
! transferrin-iron complex enters maturing
erythroid cells by a specific R mechanism.
transferrin conc increased in Iron store
depletion & iron deficiency anemia.
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Storage:
When free iron levels are H, apoferritin is
produced to sequester iron & protect organs
from toxic effect of excess free iron.
Iron is stored in intestinal mucosal cells & as
ferritin, in macrophages in liver, spleen, &
bone.
Elimination:
No mechanism for excretion
Small amounts in feces & bile.
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A- Use of iron:
- Tr of iron deficiency anemia
- Prevent anemia in increased iron requirement:
- premature infants,
- children during rapid growth periods,
- pregnant & lactating women,
- increased bld losses & iron (heavy
menstruation),
- patients e chronic kidney D & Tr e GF
erythropoietin (parenteral iron is preferred).
- Malabs, inadequate iron abs, GIT bleeding,
gastrectomy & severe small bowel D.
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B- Tr
Iron deficiency anemia is Tr e oral/ parenteral
iron.
po iron if GIT is normal.
1- Po iron: 200 – 400 mg for 3-6 months.
Forms: FERROUS sulfate, gluconate, fumarate
or succinate.
All are effective & inexpensive.
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• SE:
N, epigastric discomfort, abdominal cramps,
constipation/ diarrhea & black stools.
Rx: lower ! dose/ taking ! tablet immediately
after/ e meal.
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2- Parenteral iron:
(postgasrectomy, small bowel section,
inflammatory bowel D, noncompliance of po,
malabs syndrome, marked bld loss &
advanced chronic renal D).
• Iron dextran: stable complex of ferric OH &
low molecular wt dextran (IM/ IV infusion).
Advantage of IV: eliminates local pain & tissue
staining (SE: IM). + allow delivery of entire iron
dose.
• Also Iron sorbitol (IM)
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SE: headache, light-headness, fever, arthralgia,
N, V, back pain, flushing, urticaria, B.spasm.
Rare: anaphylactic & death.
Also dextran can cause hypersensitivity rxs.
• Alternative preparations:
Iron-sucrose complex & iron Na+ gluconate
complex. ONLY (IV) less hypersensitivity than
dextran.
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A- Acute iron tox: Causes:
Signs & symptoms:
Necrotizing gastroenteritis, V, abdominal pain,
bloody diarrhea, followed by shock, lethargy, &
dyspnea. + severe metabolic acidosis, coma &
death.
Tr:
- Whole bowel irrigation/ gastric lavage: 1%
NaHCO3.
- Antidote: Deferoxamine (Desferroxamine),
potent iron-chelating agent, bind absorbed iron
& promote its excretion in urine & feces
(intragastric, IM, SC, IV infusion).
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• Chronic iron tox:
Overload / hemochromatosis, result when
excess iron is deposited in ! hrt, liver,
pancreas, & other organs. It can lead to organ
failure & death.
Causes:
patients e inherited hemochromatosis
(excessive iron abs;; tissue damage),
& in patients who receive many RCs
transfusions over a long period of time as
chronic hemolytic anemia (thalassemia).
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Tr: intermittent phlebotomy: Removing one unit
of bld every wk until all excess iron is
removed.
Or parenteral deferoxamine (less efficient, more
complicated, expensive, & hazardous).
• Recent oral iron chelator: deferasirox.
Effective as deferoxamine at reducing liver
iron conc & more convenient.
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2- Cyanocobalamin = Vitamin B 12 (extrinsic F)
CoF for several essential biochemical rxs.
Deficiency;; anemia, GI symptoms, & neurologic
abnormalities.
Chemistry:
porphyrin-like ring e a central cobalt atom
attached to nucleotide.
Source: Meat (liver), eggs, & dairy products.
For therap use: Cyanocobalamin &
hydroxycobolamin.
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PK:
Stored mainly in liver
Normal daily requirement: 2 -3 mcg.
For its abs, it makes a complex e intrinsic F, a glycopt secreted
by ! parietal cells of ! gastric mucosa. + R mediated transport
system in ! lumen.
Must be converted to active forms b4 abs: Deoxyadenosylcobalamin & methyl-cobalamin.
Vit B12 deficiency results from malabs of Vit B12 due to lack/loss/
malfunction of intrinsic F.
This intrinsic F may be absent in gastrectomy & pernicious
anemia.
Nutritional deficiency (rare).
Route of administration: mainly: parenteral,, IM
Or po/ aerosol.
Excretion: kidney
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• Pharmacodynamics:
2 essential enzymatic rxs require Vit B12:
1- Methylcobalamin: as intermediate in ! transfer
of methyl gp from N-methylTHF to
homocysterine, forming methionine.
! depletion of THF prevents synthesis of
adequate supply of deoxythymidylate (dTMP)
& purines required for DNA synthesis.
Tr by Vit B12 & folic acid.
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2- Isomerization of methylmalonyl-CoA to
succinyl CoA by methylmalonyl-CoA mutase.
In vit B12 deficiency: methylmalonyl-CoA
accumulate.
Neurologic manifestations due to disruption of
methionine synthesis. Tr by Vit B12 only.
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• Clinical pharm:
Deficiency of vit B12:
- Megaloblastic anemia (macrocytic anemia +
leukopenia &/ thrombocytopenia)
- Hematologic abnormalities
- Hypercellular BM e accumulation of
megaloblastic erythroid.
- Neurologic syndrome: paresthesia &
weakness in peripheral nerves, spasticity, &
ataxia.
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• Causes of vit B12 deficiency:
- Pernicious anemia (Defective secretion of
intrinsic F by ! gastric mucosal cells).
- Partial/ total gastrectomy
- Malabs syndrome, inflammatory bowel
syndrome or small bowel resection.
- Damage of distal ileum that absorb vitB12intrinsic F complex,
- Surgical resection of ! ileum.
TR: Vit B12.
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Tr: parenteral inj of vit B12. Available as:
1-Cyanocobalamin
2-Hydroxycobolamin is preferred (more highly
pt bound: longer DOA).
Uses:
1- Pernicious anemia
2- Neurologic abnormalities
3- Gastrectomy
4- Cyanide poisoning.
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• Initial therapy: 100-1000 mcg of vit B12 IM
daily or every other day for 1-2 wks
• Maintenance: 100-1000 mcg IM once a month
for life.
• Oral dose of 1000 mcg of vit B12 in pernicious
anemia who refuse or cannot tolerate ! inj.
• After parenteral, ! vit can also administered as
a spray/ gel.
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Adverse effect of Vit B12
1- Allergic hypersensitivity rxs
2- Arrhythmia secondary to hypoK.
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3- Folic acid (FA):
Reduced form of FA: THFA is essential for !
synthesis of amino acids, purines, & DNA.
Its deficiency is uncommon.
deficiency of THFA causes anemia, congenital
malformations in newborns & occlusive
vascular D.
Chemistry:
FA is pteroglutamic acid, composed of a
heterocycle (pteridine), P-aminobenzoic acid +
glutamic acid.
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• FA can undergo reduction, catalyzed by
DHFRase… dihydroFA … THFA.
• Vit B12 is required for activation of FA
(demethylation).
• PK:
Source: yeast, liver, kidney, & green vegetables.
5-20 mg of folates are stored in liver.
Route: po
Converted to mono-glutamyl form then absorbed
in ! proximal jejunum .
Excreted in urine & stool.
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• Pharmacodynamics:
THFA CoF participate in one-C transfer rx.
Produce dTMP needed for DNA synthesis.
N-methyleneTHF is required for ! vit B12dependent rx that generate methionine from
hemocysteine.
THF COF: donate 1 C unit during synthesis of
purine.
Preparations:
1- Synthetic FA (tablets/ parenteral)
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2- Folinic acid (active form).
•
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FA Deficiency is caused by
Malabs & inadequate dietary intake of folate.
Alcohol dependence
Liver D
Clinical Pharm:
• Folate deficiency; megaloblastic anemia.
(1 mg po daily): reverse megaloblastic anemia, restore
normal serum folate, & replenish body store of folate.
- Prophylactically: Pregnant women & patients e
hemolytic anemia have increase folate requirements
& may become FA-deficient, esp if their diets are
marginal.
- Maternal FA deficiency: fetal neural tube defect as
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spina bifida.
- Patients who require renal dialysis.
- Drugs: Methotrexate, trimethoprim &
pyrimethamine inh DHFRase: deficiency of
folate CoFs;; megaloblastic anemia.
- Long term use of phenytoin
- H risk patients (FA supplementation):
pregnancy, premature infants, hemolytic
anemia, liver D, & renal dialysis.
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4- Hematopoietic Growth Factors:
Glycopt hormones regulate ! proliferation &
differentiation of hematopoietic progenitor cells
in BM.
Produced by recombinant DNA technology.
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• Erythropietin (epotein):
PK:
- IV/ SC
- T1/2: 4-13 hr in patient e chronic RF.
- Produced in ! Kidney
- Not cleared by dialysis.
- Given 2-3 times weekly.
- Darbepoetin α: glycosylate form, longer t1/2.
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Pharmacodynamics:
1- Stimulate erythroid proliferation &
differentiation by interacting e specific
erythropoietin Rs on RC progenitors.
2- Induces release of reticulocytes from BM
3- Tissue hypoxia stimulate erythropoietin
synthesis.
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• Clinical Pharm/ Uses:
1- Anemia + chronic RF
Erythropoietin 50-150 IU/kg, IV/SC: improve !
hematocrit (in 10 days) & Hg level (in 2-6 wk) &
eliminate ! need for transfusion
+ Iron & FA.
2- Anemia in HIV patients & zidovudine (anti HIV).
3- Anemia in cancer patients.
4- Anemia due to BM disorders. As in patients e
aplastic anemia & other BM failure states, & multiple
myeloma.
5- Anemias associated e chronic inflammation (RA)
7- Anemia of prematurity
8- Accelerate erythropoiesis after phlebotomies.
9- Misused by athletes to increase O2 delivery &
performance.
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• Adverse effects &Toxicity:
1- Rapid increase of hematocrit & Hg: HTN &
thrombosis.
2- Seizure, headache
3- Transient influenza-like syndrome
4- Mild allergic rxs.
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