Major extra and intracellular electrolytes. Pharmaceutical Inorganic chemistry UNIT-II (Part-II)

Major extra and intracellular electrolytes. Pharmaceutical Inorganic chemistry UNIT-II (Part-II)
Electrolyte: Intracellular fluid
Interstitial fluid
Plasma (Vascular fluid)
Anionic electrolytes- HCO₃⁻, Cl⁻, SO₄²⁻, HPO₄²⁻
Cationic electrolytes- Na⁺, K⁺, Ca²⁺, Mg²⁺
Concentration of important Electrolytes:
Electrolytes used in the replacement therapy: Sodium
chloride*, Potassium chloride, Calcium gluconate* and Oral Rehydration Salt
(ORS), Physiological acid base balance.

1. Pharmaceutical Inorganic chemistry UNIT-II (Part-II) Major extra and intracellular electrolytes Presented By Ms. Pooja D. Bhandare (Assistant Professor) DADASAHEB BALPANDE COLLEGE OF PHARMACY BESA NAGPUR

2. Electrolyte is a substance that ionizes when dissolved in a suitable ionising solvent such as water. This includes most soluble acids, bases & gases. An electrolyte may be defined as concentrated if it has high concentration of ions or dilute if it has low concentration of ions. The electrolyte concentration is maintained constant in the body fluids. If a person undergoes surgery or remain ill or under undesirable condition for a long time, the body cannot maintain the electrolyte balance, then it is done by external administration which is termed as Replacement therapy. Electrolytes are used for the correction of acid-base balance in various body fluids. Electrolyte:

3. The electrolyte concentration of body fluids have been different in various body fluid compartments. They are 1. Intracellular fluid:- The fluid which is present inside the cell. Ex- Cytoplasm It constitutes 40-50% of body weight & its volume is 30 litres. 2 . Interstitial fluid:- The fluid which is present between the cells. It constitutes 12-15% of body weight & its volume is 10 litres. 3. Plasma (Vascular fluid):- The fluid which is present within the blood vascular system. This constitutes 4-5% of body weight & its volume is 3-5 litres. The fluids present in the interstitial & vascular compartments are referred to collectively as Extracellular fluid (ECF).

4. Electrolytic Fluid Compartments:  Body contain 60-70% of water Body Fluids Intracellular Fluid Extracellular Fluid (Fluid inside the cell) [45-50% of body weight ] Interstitial Fluid (Between the cell) [12-15% of body weight] Plasma or Vascular fluid (Fluid within blood vascular system) [4-5% of body weight]

5. Sodium & chloride are the main ions of ECF while potassium & phosphate are the major ions of ICF. The three fluid compartments are demarcated from each other by membranes which are permeable to water & certain inorganic & organic components present in the body fluids. These membranes do not permit the transfer of certain molecules like proteins. For certain ions like Na, K, Mg the membrane shows selective permeability. Thus the composition & concentration of various solutes in body fluids have been definite but different from one another. The body fluids are having various inorganic ions which are either anionic or cationic. Anionic electrolytes- HCO₃⁻, Cl⁻, SO₄²⁻, HPO₄²⁻ Cationic electrolytes- Na⁺, K⁺, Ca²⁺, Mg²⁺

6. Concentration of important Electrolytes

7. The fluid in each compartment is ionically balanced. Body has the capacity to adjust slight variations in electrolytic concentration of the fluid compartments. If concentration of electrolytes changes – water will migrate across the cell membrane to re-establish Osmotic equilibrium.

8. SODIUM – Location - extracellular compartment as a salt (90%). Normal plasma level- 136-142 mEq /L Normal intake of NaCl per day- 5-20g Daily requirement – 3-5g Excess quantity of salt consumed gets excreted in the urine. The sodium level in the blood is controlled by aldosterone. Food sources- table salt, milk, baking powder, meat & some vegetables . Functions- Regulates acid-base equilibrium. Along with chloride maintain osmotic balance of various fluids. Plays an important role in permeability of cell Transmission of nerve impulse.

9. 2. POTASSIUM – Normal intake of KCl-5-7g/day Daily requirement – 1.5-4.5g Sources- milk, certain vegetables, meat & whole grains. It is rapidly absorbed from diet & rapidly excreted through kidneys. Maintains electrolyte composition of various body fluids. Influences acid-base balance & water retention.cc

10. Condition Hyperkalaemia Hypokalaemia Elevated K⁺ levels Low K⁺ levels Reason Renal failure, Dehydration or shock, Addison’s disease Prolonged diuretic therapy, Inadequate intake, Severe diaphoresis, Use of laxative, vomiting, Excess insulin, Excess stress, Hepatic disease, Acute alcoholism Symptoms Apathy, Confusion, Numbness/ paraesthesia of extremities, Abdominal cramps, Nausea, Flaccid muscles, Diarrhoea, Oliguria, Bradycardia, Cardiac arrest Anorexia, Nausea, vomiting, Drowsiness, lethargy, confusion, Leg cramps, Muscle weakness, Hyperreflexia (overactive or overresponsive reflexes)., Hypotension, Cardiac dysrhythmias, Polyuria

11. 2. CALCIUM – The total calcium content in body is about 22g/kg body weight Daily requirement – 0.8g 99% of calcium is found in bones and 1% in ECF Sources- milk, cheese, green vegetables, eggs, some fish. It can be absorbed from all parts of small intestine by an active transport mechanism. Greater amounts of calcium are needed in children and during pregnancy, lactation The normal range for total plasma calcium – 2.2 to 2.6m mol /litre About half of this is bound to plasma proteins, a small fraction gets complexed with citrate and phosphate and remaining amount circulates in blood as ionised calcium Ionised calcium plays a vital role in the functioning of nerves, blood clotting and muscle contraction The level of calcium ions in plasma is regulated by parathyroid hormone and calcitonin

12. FUNCTIONS – Normal functioning of ANS and voluntary system For cardiac function Important factor in coagulation of blood For the formation of bones Muscle contraction and maintenance of muscle tone Transmission of nerve impulses across synapse Release of certain neurotransmitters(Ach)

13. Condition Hypercalcemia Hypocalcaemia Elevated Ca⁺² levels Low Ca⁺² levels Reason Hyperparathyroidism, Excess vit D intake Decreased calcium absorption, Hypoparathyroidism, vit D deficiency, Cushing’s syndrome, Osteoblastic metastasis Symptoms Fatigue, muscle weakness, constipation, Anorexia, Cardiac irregularities Titanic spasms, convulsions

14. 3. Magnesium – Second most abundant cation in the ICF The adult human body having 25gms of Mg about 54% is present in the bones along with P, Ca, about 45% is in ICF and about 1% is in ECF Daily requirement – 350mg Source – nuts, soyabeans , whole grains, sea foods Functions – (a). Activates enzymes which are involved carbohydrates and protein metabolis (b ). Important in neural transmission, myocardial function, neuromuscular activity ( c). Needed for the operation of Na⁺- K⁺- ATPase pump system ( d). It is a cofactor for phosphate transferring enzymes ( e). Constituent of teeth and bones

15. 4. Chloride – Major extracellular anion Total chloride ion present in the body – 50mEq/kg body wt. Daily requirement – 5 to 10g Source – common table salt It readily gets absorbed throughout GIT. Mainly excreted through urine & through skin during sweating. Functions – Chloride ion along with sodium ion maintain osmotic balance between different body fluids. Maintains charge balance between the body fluids i.e. ICF & ECF both as they can pass through all membranes. Maintains acid-base balance & also take part in the formation of gastric HCl . Maintains proper hydration.

16. Chloride Imbalance – Hypochloremia - due to metabolic acidosis diabetic mellitus & excessive vomiting. Hyperchloremia - due to dehydration Excess chloride intake CHF Severe renal failure

17. 5. Bicarbonate – Second largest anion in the ECF. Along with carbonic acid, it acts as one of the important buffer system in the maintenance of acid-base balance. A lack of bicarbonate causes metabolic acidosis while an excess of bicarbonate causes metabolic alkalosis.

18. 6. Phosphate – The phosphate ions such as H₂PO₄⁻, HPO₄⁻², PO₄⁻³ are the major anions of ICF. Among these HPO₄⁻² is most important for maintaining pH at 7.4. Normal plasma phosphate concentration is 1.7 to 2.6 mEq /litre. Almost 4/5 of the total body phosphate is present in teeth & bones along with calcium. Rest of the phosphate ion is covalently bound with lipids, proteins, carbohydrates, nucleic acids, ATP. Functions- Plays a vital role in maintaining pH of body fluids. HPO₄⁻² / H₂PO₄⁻ is an important biochemical buffer. Essential for normal bone & tooth development & proper calcium metabolism. Serum inorganic phosphate plays an important role in regulating erythrocyte glucose metabolism. Under normal conditions, deficiency of phosphate ions does not occur. However since the serum phosphate levels are usually correlated with serum calcium levels, any change in the normal serum calcium levels may result in change in normal serum phosphate levels

19. Hypophosphatemia – Seen in vit D deficiency (Rickets), hyperparathyroidism & lack of phosphate reabsorption by kidney tubule due to infections, cancer in patients consuming a large amount of antacids specifically Al(OH) ₃ Hyperphosphatemia- Occur due to inappropriate excretion as a result of renal failure, increase in absorption due to hypervitaminosis D & hypoparathyroidism. Hyperphosphatemia leads to formation of phosphatic urinary calculi ( a form of kidney stone).

20. ELECTROLYTE REPLACEMENT THERAPY It is also called as electrolyte replenisher . Due to serious symptoms of the loss of electrolytes, it is essential to maintain the normal level by external supply of electrolytes, this therapy is called as electrolyte replacement therapy. There are two types of electrolyte solutions are used in replacement therapy- I ) Electrolyte solution for rapid initial replacement- solutions contains electrolyte with concentration resemble with the electrolyte concentration found in extracellular fluids. II ) Electrolyte solution for subsequent replacement- lower concentration of electrolyte in solution.

21. 1 . Sodium replacement- The depletion of sodium cause various forms of hyponatremias. A patient who suffers severe symptoms cause by hyponatremia should receive either 3% or 0.9% sodium chloride solution, until severe symptoms resolve The main objective of replacement to raise the serum sodium concentration to 120 mEq /L. there are various sodium chloride preparations are available . 1. Sodium chloride : Formula: NaCl Molecular weight- 58.44 Standards : Sodium chloride not less than 99.0% and not more than 100.5% of NaCl , calculated with reference to the dried substance.

22. Method of Preparation: In laboratory it is prepared from common salt in water by passing hydrochloric acid gas. The crystals are precipitated out. Industrially it is prepared by 1) by evaporating purified saline (sea water) deposits & further purification. 2) and by purifying rock salt. It can also be prepared in laboratory in small scale by the acid-base reaction. In which strong acid ( HCl ) reacts with strong base ( NaOH ) & finally it gives sodium chloride . Properties: Physical properties: it is colorless crystals or white, crystalline powder. It is freely soluble in water & slightly more soluble in boiling water, practically insoluble in ethanol . Chemical properties: With oxidizing agent, it gets oxidized & liberates chlorine gas. 2Cl + MnO2 + 2H2SO4 Mn + 2SO4 + 2H2O +Cl2

23. Identifications : It gives reactions characteristics of sodium and chloride. Test of purity: It has tested for acidity and alkalinity, Ba, Ca and Mg, Fe and heavy metals, bromide, iodide, sulphate and loss on drying. Assay : The 0.1 g of substance is dissolved in 50ml of water in a glass stoppered flask. To it, 50ml of 0.1 N silver nitrate solution, 3ml of nitric acid, 5ml of nitrobenzene & 2ml of ferric ammonium sulphate solution are added. Now the solution is shaken well and is then titrated with 0.1 N ammonium thiocyanate solution until the water becomes reddish-yellow. Each ml of 0.1 N AgNO3 = 0.005844 g of NaCl . Storage : It is stored in tightly closed container in dry place as it absorb moisture . Uses: 1. it can be used as electrolyte replenisher , as it is isotonic solution. 2. In combination with other electrolyte & dextrose, it is used as dialysis solution in renal failure. 3. It is used as a saline diuretic in the form of enteric coated tablet.

24. Sodium chloride preparations: 1 . sodium chloride injection I.P ( normal saline) It contains 0.9% sodium chloride without any antimicrobial agent (PH 4.5-7.0) 2 . Sodium chloride hypertonic injection I.P- It contains 1.6% w/v sodium chloride (PH 5-7.5) 3 . Compound sodium chloride injection ( ringer solution ) It contain following ingredients: Sodium chloride-0.869 g Potassium chloride-0.030 g Calcium chloride-0.048 g Water for injection q. s. 100ml 4 . Bacteriostatic sodium chloride injection USP . It is sterile solution of sodium chloride (0.9% w/v) in water for injection containing suitable antimicrobial agent. It is used as sterile vehicle.

25. 5. Sodium chloride & Dextrose Injection I.P It is solution of dextrose & sodium chloride in water for injection containing no antimicrobial agent (PH 3.5-6.5). It is used as a nutrient & as an electrolyte replenisher . 6. sodium chloride tablet I.P It contain 95.0 to 105 % w/v of sodium chloride and is available in strength of 180, 300 & 500 mg of sodium chloride. It is used as an electrolyte replenisher . 7 . Sodium chloride and mannitol injection . It is sterile solution of sodium chloride and mannitol in water for injection. It is used as a diuretic agent.

26. 2. Potassium chloride Formula: KCl Molecular weight-74.55 Standard: potassium chloride contains not less 99.0% and not more than 100.5 % of KCl , calculated with reference to the dried substance. Preparation: 1. It is prepared from natural mineral, carnallite ( KCl , MgCl2.6H2O). The raw mineral is ground and then treated with hot water. The less soluble KCl precipitate out. The process is repeated till all the KCl is recovered from liquid. 2. On laboratory scale, it is prepared by action of HCl on potassium carbonate or bicarbonate. K2CO3 + 2HCl 2KCl + H2O + CO2 KHCO3 + HCl KCl + H2O + CO2 3. It can also be prepared in the laboratory in small scales by reacting potassium hydroxide (KOH) with hydrochloric acid ( HCl ). KOH + HCl KCl + H2O

27. Properties: It is colorless crystalline, or white crystalline powder; odorless. It has a saline taste. It melts at 772 C. the 10% aqueous solution is neutral to litmus. It is freely soluble in water; practically insoluble in ethanol and ether. Uses: It is used in prevention and treatment of potassium depletion and hypokalemia and diuretic-induced hypokalemia. Potassium chloride is sometimes used as an excipient in pharmaceutical formulations. It is used in diabetic ketoacidosis. It is used in hypertension, potassium supplementation results in reduction of both systolic and diastolic blood pressure.

28. Preparations of Potassium chloride: 1. Potassium chloride and Dextrose Injection: Potassium chloride and dextrose, intravenous infusion, is a sterile solution of potassium chloride and either anhydrous glucose, in water for Injections. 2. Potassium chloride, sodium chloride and dextrose Injection : Potassium chloride, sodium chloride and dextrose Injection intravenous infusion. 3. Bumetanide and slow potassium tablets: This preparation is official in BP 2007. It contains bumetanide and potassium chloride. They are formulated so that the potassium chloride is released over a period of several hours. 4. Sterile potassium chloride concentrate: It is sterile solution of potassium chloride in water for Injections.

29. 3. Calcium gluconate Formula: C12H22CaO14. H2O Molecular weight: 448.40 Structure: calcium gluconate is calcium D-gluconate monohydrate.

30. Physical properties:  White crystals, granules or powder, stable in air, does not lose its ( C12H22O14Ca. H2O) water of crystallization on drying.  Neutral to litmus paper . Chemical properties:  When treated with dil. HCl , it is decomposed into gluconic acid and calcium chloride . Method of Preparation :  It is prepared by boiling a solution of gluconic acid with Calcium carbonate.  Product is filtered and dried.

31. Assay :  Principles: Complexometric titration.  0.5 g sample is dissolved in warm water, cool and add 5 ml of 0.05 M MgSO4 and 10 ml of strong ammonia solution .  Titrant: 0.05 M Disodium EDTA  Indicator : Mordant Black II mixture.  End point: until deep blue color develops.  From the volume of 0.05 M disodium EDTA required, subtract the volume of the MgSO4 solution added for actual reading.  Factor : 1 ml 0.05 M disodium EDTA= 0.02242 g of Calcium gluconate. Uses : It is used in management of hypocalcemia and calcium deficiency state.  In insect bite: calcium gluconate 10 % solution, is given intravenously as an alternative to the use of conventional muscle relaxant, for the management of pain and muscle spasm associated with insect bite.  In severe acute hypocalcemia .

32. Preparations of calcium gluconate: 1 . Calcium gluconate injection: Calcium gluconate injection is a sterile solution of calcium gluconate in water for Injection. Not more than 5 % of the calcium gluconate may be replaced with a suitable calcium salt as stabilizing agent. 2 . Calcium gluconate tablets : Usual strengths: 325 mg; 500 mg; 650 mg; 1 g 3 . Effervescence calcium gluconate tablets:

33. Oral Rehydration Salts (ORS):- Oral rehydration therapy was developed in 1940 ORS came in market from 1970. Recommended by World Health Organization (WHO) Oral Rehydration Salts – is a fluid replacement for the condition called dehydration , electrolyte imbalance due to diarrhea . It works by increase the uptake of sodium and water by the intestine. Potassium is very important it promote the water and sodium absorption. A large number of formulation of oral rehydration preparations are available in market, which contains glucose, sodium chloride, potassium chloride, and either sodium bicarbonate or sodium citrate. These dry powder preparations are to be mixed in specific amount of water and are used for oral rehydration therapy.

34. ORS contains anhydrous glucose, NaCl , KCl & either NaHCO ₃ or Sodium citrate. These dry powder preparations are to be mixed in specific amounts of water along with certain flavouring gent and a suitable agent for free flow of the powder. These are used for oral rehydration therapy. In ancient times, homemade ORS is used which constitutes of 1 tablespoonful of salt, 2 tablespoonful of sugar in 1 litre of water. The following 3 formulations are usually prepared. When glucose is used, NaHCO ₃ is packed separately. The quantities given below are for preparing 1 litre solution.

35. The formula II & III are recommended by WHO & UNICEF for control in diarrhoeal diseases.

36. Physiological Acid-Base balance The number of hydrogen-ions present in the solution may be regarded as a measure of the acidity of the solution. But pH is related to negative logarithm of acidity of (H+) ion concentration . Thus, pH may be considered to measure the acidity of the solution. All body fluids have definite pH values which must be maintained within relatively narrow limits (within which the cells functions normally).The normal range of pH values of few selected fluids are:

37. The pH values of certain body fluids are:- The pH of blood of a healthy person remains constant around 7.35 If the pH of blood becomes low (high H⁺ concentration) acidosis results. If the pH of blood becomes high (low H⁺ concentration) alkalosis results. The range of pH of the blood compatible with life is 7-7.8. Since the kidneys help to remove excess acid from the body, urine can be quite acidic.

38. The intracellular fluids also have varying pH depending upon the types of the cell. For Eg in osteoblasts it may be slightly alkaline (pH 8.0) and in cells of prostate gland it may be acidic (pH 5.0). The individual pH in an organ is maintained by secretions of alkalis or acids to suit optimum level. The low pH in the stomach is best to the functioning of the enzyme pepsin present in gastric juice which breakdown proteins. Saliva has a pH range 6.4-7.4 which is the optimum value for the action of ptyalin (the enzyme present in saliva which initiates the digestion of carbohydrates) The metabolic process of the body cells produces acids or acidic substances (for eg . Carbonic acid from CO2 and water, sulphuric acid and phosphoric acid from, proteins and phosphoproteins , lactic acid and pyruvic acid from anaerobic metabolism) and alkalis (for eg . Bicarbonate ions from salt of organic acids c.f. citrate, lactate etc ) which tend to alter the pH of the tissue fluid and blood.

39. The term Alkalosis refers to excess removal of H+ from the body fluid, in contrast to the excess addition of H+, which is referred to as Acidosis . There are mainly three regulatory mechanisms which maintain the pH of the each system and equilibrium with one another. These are: Buffer of the body fluids 2. Respiratory mechanism 3. Renal regulation

40. 1. Buffer System: Buffers are the chemicals capable to maintain a constant pH. Buffer system is consists of a weak acid and the salt of that acid. They resist the rapid change in the pH of body fluid by converting strong acids and bases into weak acids and bases. Buffer is thus able to remove excess H+ from the body fluid but not from body. The major buffer systems existing in the body fluids are as follows : i . Carbonic acid-Bicarbonate Buffer system (H2CO3/NaHCO3 ): ii. Phosphate Buffer System (Na2HPO4/NaH2PO4 ): iii. Protein ( Hemoglobin ) Buffer System:

41. i . Carbonic acid-Bicarbonate Buffer system (H2CO3/NaHCO3 ): It occurs in plasma and kidneys. Important regulator of blood pH. If there occurs an excess of H+, the bicarbonate (HCO3-) ion acts as a weak base and accept H+ to form carbonic acid. They latter dissociate further to yield CO2 and water molecules . H+ + HCO3- H2CO3 H2O + CO2 While if there occurs shortage of H+, the carbonic acid (another compound of buffer system ) ionises to release more H+ and maintain the pH . H2CO3 H + + HCO3-

42. ii. Phosphate Buffer System (Na2HPO4/NaH2PO4): This buffer system mainly works in cells and kidneys and helps to maintain the physiological pH 7.4. Higher concentration of phosphate ions are found in intracellular fluid , thus consider as an important regulator of pH of cytosol. The system consists of monohydrogen phosphate/ dihydrogen phosphate (HPO42- / H2PO4- ) anions. If there occur an excess of H+, the monohydrogen phosphate ion acts as the weak base by accepting the proton HCl + Na2HPO4 NaCl + NaH2PO4 While dihydrogen phosphate ions can act as the weak acid and is able to neutralize the alkaline condition NaOH + NaH2PO4 H2O + Na2HPO4

43. iii. Protein ( Hemoglobin ) Buffer System: It is considered to be the most abundant buffer in body cells and plasma. Protein is compound of amino acids that are having at least one carboxyl group (COOH) and at least one amino (NH2) group. When there occurs an excess of hydrogen ions, the amino group acts as a base and accept the proton. Thus, proteins are able to serve both the functions of acid and base components of a buffer system due to its amphoteric nature. At physiological pH, histidine and cysteine are considered to be the most important amino acid buffer. Since hemoglobin which is a protein is composed of 37 histidine in the structure, it is effective physiological buffer.

44. 2. Respiratory mechanism: When respiration is decreased, there is an accumulation of CO2 in the body which used up the alkali reserve of the blood resulting in the acidosis . On the other hand, if thereis “over-breathing”, which results in excessive excretion of CO2, the condition of alkalosis may develop. Thus, acidity and CO2 increases are both powerful stimulants of respiratory mechanism and cause an increase in the rate and depth of respiration.

45. 3. Renal mechanism: Kidneys have the ability to form ammonia which combines with the acids produced during the protein metabolism and is excreted in urine. The pH of urine is highly variable between 4.8 to 8.0. Normally, it is towards acid side but varies with the nature of diet, exercise etc. While unstable H2CO3 is removed mainly by respiratory mechanism, the fixed acids like phosphoric, sulphuric and hydrochloric acids have to be remove through kidneys.

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