Inorganic Pharmaceutical Chemistry

Lec3: Essential and Trace Ions

By:Zaid Al-Obaidi

Assistant Lecturer in Pharmaceutical Chemistry

MSc Pharmaceutical AnalysisSheffield, UK

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Essential and Trace Ions:• The ions, to be discussed, have specialized

biochemical functions.

• They are not found in the general electrolytereplacement preparations.

• At least two of them, iron and iodine, show a defineddeficiency syndrome.

• Specific deficiency symptoms for some of the othersare seen in animals other than humans.

• Ions to be discussed:

Iron.

Copper.

Sulfur.

Iodine.2

Iron:• Importance:

1. Iron is present in some form whereverrespiration occurs in higher animals.

i. It is essential to the elementary metabolic processesin the cell.

ii. In the respiratory chain, iron functions as anelectron carrier. Iron is responsible for the transportof molecular oxygen in higher organisms.

• Both of these functions depend on the ability of ironto exist in coordination compounds in differentstates of oxidation and bonding.

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Body Components Containing Iron:

OccurrenceIron Bound

As

Mode of

LinkageFunction

Iron Content

Total% of Body

Iron

Blood

System

Haemoglobin Heme 02 Transport 3 g 65.4

Plasma Transferrin Fe Transport 4 mg 0.1

Tissues

Functional

Iron

(Myoglobin,

Cell Hemes)

HemeCell

Respiration650 mg 13.9

Storage Iron

Ferritin Iron Pool

1 g 21.5Hemosiderin Detoxication

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Iron absorption

• There are three hypotheses of the controlof intestinal iron absorption :

Mucosal block hypothesis.

Active transport hypothesis.

Iron-chelate hypothesis.

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Mucosal block hypothesis

• Iron absorption regulated and controlledby the existence of apoferritin.

• The dietary or administered iron isreduced to ferrous form (Fe2+) whichdiffuses into the mucosal cell where it isoxidized and then combined withapoferritin to ultimately form the stableiron carrying protein, ferritin.

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Mucosal block hypothesis• As ferritin iron crosses the cell and then

released to be reduced again to ferrous ironwhich diffuses across the serosal cell (cover theintestine) and eventually oxidized to ferric iron(Fe3+) and combined with the iron-transportprotein (transferrin).

• In this form it is transferred to the liver forstorage or to the bone marrow for use in hemesynthesis for erythrocyte production.

• This hypothesis does not stand against saturationi.e. no maximum limit of absorption has beendemonstrated with increased iron doses.

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Mucosal block hypothesis

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The active transport hypothesis:

• Like in the mucosal block mechanism, Fe2+

enters the mucosal cell by diffusion where itcombines with endogenous low mwt ligands orit stored as ferritin.

• Iron absorption regulated and controlled byregulation the amount of cellular energyavailable for active transport (ATP).

• To cross the serosal membrane into the bloodspecific transport system linked to ATP.

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The active transport hypothesis:

• Once past the serosal membrane the rest stepsare the same as explained by the mucosal blockhypothesis.

• One of the most points against this hypothesis isthe fact that iron movement (absorption) is notaffected by an anaerobic condition, where asother known active transport processes (e.g.Na+)are vitally affected.

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The active transport hypothesis:

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The iron chelate hypothesis:

• This hypothesis indicates that iron absorptiondepends on the availability of endogenous orexogenous chelating agents which are able tobind either Fe2+ or Fe3+ to form soluble lowmwt complexes.

• Within the cell the iron can be transferred toother endogenous ligands or stored as ferritin.

• The major attributes of this theory are that noredox reactions or Metabolic energyrequirements are directly involved.

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The iron chelate hypothesis:

• Points against this hypothesis:

a) It is not rally clear that low mwt chelates arepresent in the GIT cells.

b) The assumption that both Fe2+ and Fe3+ are equallycomplexed for diffusion into the mucosal cell is noteasy to understand especially when the Fe2+

absorption is more than Fe3+. (Due to poor solubilityof Fe3+ salts as compared to Fe2+ salts).

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The iron chelate hypothesis:

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Iron requirements:

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Standard formula:

Total milligrams of iron needed =

Patient's wt. (kg) × [normal Hb value (g%) ̶ Patient's Hb value (g%)] × 2.5

Official Iron Products:• Ferrous Fumarate U.S.P. (Mol. Wt. 169.9, Fe = 55.8 a.m.u)

• Iron content: (32.8% elemental iron)

• It has been assumed that Ferrous Fumarate is lessirritating than ferrous sulfate if one administersequivalent doses of iron.

• One of the useful attributes of this salt is itsresistance to oxidation on exposure to air.

• In this respect it may be superior to both ferroussulfate and ferrous gluconate.

• Usual Dose: 200 mg(the equivalent of 65 mgof elemental iron) two orthree times a day.

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Official Iron Products:• Ferrous Gluconate, N.F. (Mol. Wt. 482.18, Fe = 55.8 a.m.u)

• Iron content: (11.6% elemental iron)

• Ferrous gluconate was a great improvement asit has good bioavailability.

• It is doubtful if it is any less irritating thanferrous fumarate or sulfate when equivalentdoses of iron are administered.

• Usual Dose: 300 mg

• Elemental iron= ?

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Official Iron Products:• Ferrous Sulfate, U.S.P. (FeSO4.7H20; Mol. Wt. 278.02, Fe = 55.8 a.m.u) (20% iron)

• Ferrous Sulfate oxidizes readily in moist air to form brownish yellowbasic ferric sulfate [approximate formula Fe4(0H)2(SO4)5).

• For this reason the U.S.P. carries the italicized warning: Note-Do notuse Ferrous Sulfate that is coated with brownish yellow basic ferricsulfate.

• Ferrous sulfate is the most widely used oral iron preparation and isconsidered as the drug of choice for treating uncomplicated iron-deficiency anaemia.

• It can be irritating to the gastrointestinal mucosa due to the astringentaction of soluble iron, but it is probably no more irritating than anyother iron salt when equivalent doses are used.

• Although there are a large number of ferrous sulfate tablets on themarket, they can vary as to the potential bioavailability of the iron.Usual Dose: 300 mg, this equivalent to ??mg of elemental iron.

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Official Iron Products:

• Iron Dextran Injection, U.S.P. (Imferon®)

• Iron Dextran Injection U.S.P. is a sterile, colloidalsolution of ferric hydroxide [Fe(OH)3]complexed with partially hydrolysed dextran(glucose polymer) of low molecular weight, inWater for Injection.

• It is used only in confirmed cases of severe iron-deficiency anaemia where oral therapy iscontraindicated or ineffective, or if the patientcannot be relied upon to take oral medication.

• It should not be used in a prophylactic manner.

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Official Iron Products:• Iron Dextran Injection, U.S.P. (Imferon®)

• Anaphylactic (severe allergic response) reactions, includingthree deaths, have been reported.

• A recent study indicates that iron dextran is effective in irondeficiency anaemia only when the bone marrow iron storesare depleted.

• In iron-deficiency anaemia Usual Dose: Intramuscular, theequivalent of 100 mg of iron once a day.

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Copper:

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• It is required for many enzymes, for synthesis ofhaemoglobin and for normal bone formation.

• Unlike iron it is believed that most of the population obtainthe sufficient amount of copper from food, water, andcooking utensils. thus copper supplements are probably notnecessary.

• Copper is solubilized in stomach acid and absorbed fromthe stomach and upper small intestine, from intestinecopper moves into the blood where it exists first as copperalbumin complex, then goes to the liver where the copper iseither stored, incorporated into ceruloplasmin, or excretedin the bile.

• Copper is found in the brain in form of cerebrocuprein , inblood cells as erythrocuprein.

Copper:

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Several roles in metabolism have been attributed to copper :

Copper is utilized in haemoglobin formation.

Copper is required to prevent anaemic conditionsthrough:

1. facilitate iron absorption.

2. Stimulates enzymes involve heme and globin biosynthesis.

3. Could involve in metabolism of stored iron.

Copper is important in oxidative phosphorylation (ATPproduction) .

Copper is associated with the formation of aortic elastin.

Copper is a component of tyrosinase, an enzymeresponsible for conversion of tyrosine to the blackpigment, melanin.

Wilson's disease:• More common, although still rare ( 4 or 5 per million).

• A condition of excess copper storage.

• Wilson's disease is of genetic origin, beingtransmitted by an autosomal recessive gene.

• Patients have increased copper levels in liver,brain, kidney, and cornea.

• The symptoms are hepatic cirrhosis, braindamage and demyelination, and kidney defects.

• Treatment is usually done by diet and by use ofthe chelating agent penicillamine.

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Sulfur

• Sulfur is widely distributed throughout the bodyas sulfhydryl groups of cysteine, disulfidelinkages in protein from cystine and sulfate saltsand esters found in mucopolysaccharides andsulfolipids, Dietary sulfur comes from thesesame groupings found in plant and animalfoodstuffs.

• The minimum daily requirements are 2-3 g.

• Currently there seems to be no need for dietarysupplements of sulfur.

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Sulfur

• Sulfur has been used therapeutically sinceantiquity and, during that time, certain welldefined uses emerged.

• These are:

1. Cathartic action.

2. Parasiticide in scabies.

3. Stimulant in alopecia.

4. Fumigation.

5. Miscellaneous skin diseases.

6. Sulfides have been used for many years asdepilatories.

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Iodine (Iodide)

• Iodide is an essential ion necessary for thesynthesis of the two hormones produced bythe thyroid gland, triiodothyronine (T3) andthyroxin (T4).

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Iodine (Iodide)

• Internally iodine or iodide can be administered , sinceiodine is reduced to iodide in the intestinal tract but morecommon iodide salts are administered because ofsolubility reasons.

• Iodine have :

1. biochemical role in thyroid hormone formation.

2. pharmacological action as:a) Fibrinolytic agent.

b) Expectorant .

c) Bactericidal agent.

• The usual daily iodine requirement for an average male is140 micrograms and female about 100 micrograms.

• Lack of sufficient iodine in diet result in an enlargement ofthyroid gland.

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Iodine (Iodide)• When iodine is administered its uptake is governed

by three principle factors:I. The character of local thyroid tissue because abnormal

thyroid tissue (tumorous) has a slower uptake of iodideand a lower content of iodine than normal tissue.

II. Blood level of inorganic iodide ,because of high levelkeeps the iodine at high level in the colloids thus using uponly a small part of the administered iodide.

III. The level of TSH in blood which is hormone secretedpituitary gland which stimulate uptake of iodide by thegland ,incorporate iodine into thyroxin and stimulaterelease thyroid hormones from the gland.

• Excess of iodide inhibit release of TSH and decreaseproduction of thyroid hormones.

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Official Iodine Products

• Strong Iodine Solution, U.S.P. (Lugol's Solution)

– Contains 5 g of iodine and 10 g of potassium iodideper 100 ml total volume.

– It is a transparent liquid having a deep brown colourand odour of iodine.

– Category: Source of iodine.

– Usual Dose: 0.1 to 0.3 ml three times a day.

– Usual Dose Range: 0.1 to 3 ml daily.

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References:

• Inorganic Medicinal and Pharmaceutical Chemistry by Block, Roche Soine and Wilson, 1986.

• Wilson and Gisvold Textbook of Organic medicinal and Pharmaceutical chemistry, Delgado JN, Remers WA, (Eds); 12th edition, 2011.

• National Center for Biotechnology Information. PubChem Compound Database; CID=198008, https://pubchem.ncbi.nlm.nih.gov/compound/198008 (accessed Oct. 2, 2015).

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