1. GASTROINTESTINAL AGENTS
Course code : PHR 107
Course name : Inorganic Pharmacy -II

2. GI Tract The human gastrointestinal tract is the stomach and intestine
sometimes including all the structures from the mouth to the anus
The GI tract always releases hormones to help regulate the digestive process.
These hormones, including gastrin, secretin, cholecystokinin .

4. Upper gastrointestinal tract
The upper gastrointestinal tract consists of the esophagus, stomach, and duodenum

5. Lower gastrointestinal tract
The lower gastrointestinal tract includes most of the small intestine and all of the large intestine.
Intestine:
Small Intestine: Has three parts:
Duodenum
Jejunum
Ileum

6. Large Intestine: Has three parts:
Caecum
Colon
Rectum

8. Hydrochloric Acid
Secreted by the parietal cells when stimulated by food
Maintains stomach at pH of 1 to 4
Secretion also stimulated by:
Large fatty meals
Excessive amounts of alcohol
Emotional stress

9. Functions of HCl: kills the bacteria in ingested food and drink,
softens fibrous foods
promotes the formation of pepsin that helps in digestion
Thus lack of HCl can cause gastrointestinal disturbances.

10. Peptic Ulcer Peptic ulcer may be located
- Lower end of the esophagus (esophageal ulcer)
Stomach (gastric ulcer)
Duodenum (duodenal ulcer)

11. Diagram showing peptic ulcer disease

13. Causes
an ulcer occurs when stomach acid eats away the inner lining of the digestive tract.
Normally, there is a layer of mucus to protect the gastrointestinal lining from the harsh acid.
But if there is excess acid or inadequate mucus, then the chances of developing an ulcer increases
Most experts agree that ulcers are either caused by bacteria or medications.

14. Helicobacter pylorus (H
Helicobacter pylorus (H. pylori) is one of the most common causes of peptic ulcers. H. pylori is a bacteria that lives within the protective mucus lining the stomach or small intestine, but it can also disrupt mucosal activity and lead to an ulcer.
NSAIDs such as aspirin can cause ulcers when used on a regular basis, as when used to prevent heart attack and stroke.

16. Gastrointestinal Agents
Any inorganic substances which can be used in gastrointestinal disorder are called gastrointestinal agent

17. Classification of inorganic gastrointestinal agents :
1. Products for altering gastric pH: A) Acidifying agents (induce acid secretion, e.g. histamine phosphate) B) Gastric Antacids, e.g. Al(OH)3, NaHCO3 2. Protectives for intestinal inflammation, e.g. bismuth subcarbonate. 3. Adsorbents for intestinal toxins, e.g. activated charcoal 4. Cathartics or laxatives for constipation, e.g. magnesium sulfate.

18. Achlorhydria Absence of HCl in the gastric secretions.
Patients with this condition fall into one of the following two groups:
A) Patients remain free of gastric HCl after stimilation with histamine phosphate.
Causes:
Subtotal gastrectomy
Atrophic gastritis (chronic gastritis with atrophy of the mucus membranes and glands)
Carcinoma of the stomach, etc.
Treatment:
Diluted HCl N.F. has been utilized.

19. B) Patients in whom there is normal lack of gastric HCl but will secrete it upon stimulation by histamine.
Causes:
Chronic nephritis (inflammation of the kidneys)
Chronic alcoholism
Tuberculosis
Hyperthyroidism
Treatment:
Administration of histamine phosphate.

20. Gastric hyper secretion:
When an excess amount of gastric HCl is secreted, the condition is called hyperacidity.
When hyperacidity develops, the results can range from gastritis (a general inflammation of gastric mucosa) to peptic ulcer (a specific circumscribed erosion).
Peptic Ulcer: Break in continuity of mucosa of any part of GIT caused by HCl and pepsin.

21. Antacids
Antacids are substances which reduce gastric acidity resulting in an increase in the pH of stomach & and duodenum.
It is itself basic in nature. Weak bases are used for this purpose.
e.g. Al(OH)3, Mg(OH)2, NaHCO3

22. Antacids Antacids are drugs that are widely used in
uncomfortable feeling from overeating,
heartburn
dyspepsia (indigestion)
Duodenal ulcer and
other non-specific GI symptoms.

23. Indications for antacids use:
Used to neutralize excess gastric hydrochloric acid associated with gastritis and peptic ulcer
Most antacids raised gastric pH to 4-5 (greatly reduce pepsin’s proteolytic activity)

24. Criteria of an ideal antacid:
The antacid should not be absorbable or cause systemic alkalosis.
The antacid should not be laxative or cause constipation.
The antacid should exert its effect rapidly and over a long period of time.

25. Criteria of an ideal antacid:
The antacid should buffer in the pH 4-6 range.
The reaction of the antacid with gastric hydrochloric acid should not cause a large evolution of gas.
NaHCO3 +HCi---›NaCi+CO2+H2O

26. Classification of antacids
There are two types of Antacids
- Systemic
- Non-systemic

27. Systemic antacids ---›soluble and readily absorbed e.g NaHCO3
Non systemic antacids ----› insoluble and not readily absorbed and does not produce systemic effects e.g. Al(OH)3, Mg(OH)2

28. Systemic antacids: It is soluble & systemically absorbed.
Capable of producing systemic alkalosis.
e.g. NaHCO3
Sodium carbonate is highly water soluble & potent neutralizer, but it is not suitable for peptic ulcer because of risk of ulcer perforation due to production of carbon dioxide in stomach.
It may lead to electrolyte disturbances, may lead to alkalosis, it may worsen edema and cause congestive heart failure because of sodium ion load (it causes sodium retention).

29. Sodium Bicarbonate (baking soda)
Highly water soluble
Rapid onset of action
Relatively short duration of action
Cause sharp increase in gastric pH (upto 7)
Large evolution of CO2 causes belching and flatulence
Readily absorbed, sodium retention

30. Products Sodium bicarbonate, U.S.P. XVIII
Usual dose: 300 mg to 2 g four times daily
Usual dose range: 300 mg to 16 gm daily

31. Non-systemic antacids :
The antacids which are insoluble and not significantly absorbed from the intestine into the systemic circulation due to formation of insoluble compound and will not disturb the acid – base balance of the body are referred to as non-systemic antacid.
Eg. Al(OH)3, Mg(OH)2, CaCO3
In case of CaCO3 , it is a potent antacid with rapid acid neutralizing capacity, but in long term use it can cause hypercalciuria, hypercalcemia and formation of calcium stone in kidney.( Renal Calculi )

32. Aluminum containing antacid
Widely used
Non-systemic
Buffer in pH 3-6 range
constipating

33. Aluminum hydroxide
Aluminum hydroxide recognized by USP in two physical forms
Aluminum Hydroxide Gel U.S.P XVIII:
white
viscous suspension
U.S.P permits suitable flavoring and antimicrobial agents.
Has a pH between 5.5 to 8.0

34. Dried Aluminum Hydroxide Gel U.S.P XVIII:
Is not a typical gel
White
Odorless
Tasteless
Amorphous powder
Insoluble in water & alcohol
Soluble in dilute mineral acids & alkali hydroxides

35. Acid neutralization by Al(OH)3 :
Al(OH)3 is considered as ideal antacid. It is soluble in acidic media. The overall mode of action of an Al-base antacid proceeds in a series of steps depending on the amount of antacid & the pH.
Antacid reacts with water to form a complex.
Al(OH)3 + 3H2O [Al(H2O)3. (OH)3]
Complex (Base)

36. Acid neutralization by Al(OH)3 cont….
The complex is soluble in acid media.
Base acid conjugated acid conjugated base
[Al(H2O)3. (OH)3] + H3O+ −> [Al(H2O)4. (OH)2]+ + H2O
[Al(H2O)4. (OH)2]+ + H3O+ −› [Al(H2O)5. (OH)] H2O
[Al(H2O)5. (OH)]++ + H3O+ −› [Al(H2O)6] H2O
Hexaquoaluminium
ion
This H3O+ acid is present in the stomach.

37. Side effects of antacid therapy: Acid rebound
If the gastric pH is raised too much acid rebound may occur since in an effort to maintain a lower pH, the stomach secretes additional hydrochloric acid which consumes the antacid.
The gastric contents including the antacid will be emptying into intestine .
The result is that an excess acid is secreted into the stomach, leading to a hyper acidic condition, which could further aggravate the ulcer.

38. AlCl3 + HCl pH Alkaline media Stimulation of oxyntic cells
Flow chart of Rebound acidity :
AlCl3 + HCl pH Alkaline media Stimulation of oxyntic cells
Secretion of HCl to balance the acidity
Then again Reaction occurs Need excess
rebound acidity & form alkaline media AlCl3
Stimulation of oxyntic cell Secretion of HCl Excess HCl
occurs (Rebound acidity)
Ulcer Infection of
stomach

39. Systemic alkalosis
If the antacid is sufficiently water soluble and is composed of readily absorbable ions, the antacids may be absorbed and exert its alkaline effects on body’s buffer systems.

40. Local effect in gastrointestinal tract
Antacids containing calcium and aluminum ions after being converted into soluble salts by gastric acid tend to be constipating
Those with magnesium salt tent to have a laxative effects

41. Commercial Preparation of Al(OH)3 gel :
Aluminum hydroxide gel is an aqueous suspension of hydrated aluminium oxide with different amounts of basic aluminium carbonate & bicarbonate.
When a hot solution of potassium alum is added slowly to a hot solution of Na2CO3, (at 700C), Al(OH)3 is produced.
Na2CO3+K2SO4. Al2(SO4)3+ H2O -- K2SO4+Na2SO4+Al(OH)3(ppt.) CO2

42. Method of Preparation :
It is prepared by dissolving sodium carbonate in hot water & the solution is filtered. To the filtrate add clear solution of alum (Aluminium salt, chloride or sulphate) in water with constant stirring.
Add more of water and remove all gas. The Aluminium Hydroxide precipitate out, collect the precipitate , wash and suspend in sufficient purified water.

43. Reaction occurred during preparation of Al(OH)3 gel:

44. Purification :
The ppt Al(OH)3 is washed thoroughly with hot water until it is free from SO4-2 ion which is confirmed with the addition of some BaCl2 to the filtrate.
Filtrate + BaCl2 -- BaSO4 (SO4-2 present)
-- No change (SO4-2 absent)

45. Disadvantages of Al(OH)3
Slow onset of action.
2. Phosphorous depletion (forms insoluble AlPO4 that results in increased phosphate excretion).
3. Osteomalacia (Softening of the bones due to a lack of vitamin D) & Osteoporosis (Thinning of bone tissue and loss of bone density over time).
4. Al(OH)3 may interfere with the absorption of other drugs by binding with them (e.g. tetracycline).
5. Can cause constipation.

46. Al(OH)3 is constipating
Reason : The product of the reaction of aluminium hydroxide and HCl is the water soluble astringent salt aluminium chloride that causes constipation.
Constipation Mechanism of Al(OH)3 :
Al(OH)3 + 3HCl ----- AlCl3 + 3H2O
Soluble
Cl  Reabsorbed

47. Magnesium containing antacids:
MAGNESIUM HYDROXIDE
White,fine odorless, amorphous powder.
It is practically insoluble in water and alcohol but soluble in dilute acids.
Used as laxatives in high doses.

48. MILK OF MAGNESIA
Suspension of magnesium hydroxide with 0.1 % citric acid and not more than 0.05 % of volatile oil suitable for flavouring purpose. Citric acid is added to minimize the interaction of glass and magnesium hydroxide
Very popular antacid and laxative.

49. Preparation of Mg(OH)2 :
They can be prepared by treating Mg salt with NaOH resulting Mg(OH)2 precipitate & Na salts.

50. Mechanism of action of Mg(OH)2 :
Mg(OH)2 is very less soluble & only goes into solution when there is acid & already contain minute amount of anion present in the stomach. In presence of acid Mg(OH)2 will dissolve the following way –
Mg(OH) acid Mg(OH)2
(solid) (dissolved)
Dissolved Mg(OH)2 Mg(OH)+ + (OH)-
Mg(OH) Mg++ + (OH)-

51. Mechanism of action of Mg(OH)2 cont…. :
proton from gastric HCl along with water & thus neutralizes the acid, leaving the counterpart Mg+2
HCl  H+ + Cl-
H2O + H  H3O+
(OH)- + H3O  2H2O
Now Mg binds with Cl- to form insoluble MgCl2 which is mainly responsible for laxative actions.
Mg Cl  MgCl2

52. Laxative mechanism of Mg(OH)2 :
The magnesium cation is responsible for the laxative action of magnesium containing antacids.

53. Advantages of Mg(OH)2 :
1. Fast onset of action.
2. No systemic alkalosis.
3. High ANC.
Disadvantages of Mg(OH)2 :
1. Short duration of actions.
2. Laxative
3. Hypermagnesia.
4. Contraindicated in kidney patients.
Dose of Mg(OH)2 :
300 mg to 600 mg as antacid per day. 2 to 4 gm as cathartic per day.

54. Acid Neutralizing Capacity (ANC)
Antacids are compared quantitatively in terms of their acid neutralizing capacity (ANC), defined as the quantity of 1 N HCl that can be brought to pH 3.5 in 15 minutes.
The time limit reflects the fact that some formulations may react with acid so slowly that a negligible amount is neutralized during the sojourn of the preparation in the stomach.

55. Milk of Magnesia :
Milk of Magnesia USP XVIII is a 7-8.5% w/w suspension of magnesium hydroxide, which may contain 0.1% citric and not more then 0.05% of a volatile oil or a blend of volatile oils, suitable for flavoring purpose.
It is a white, opaque, more or less viscous suspension from varying proportion of water usually separate on standing and has a pH of about 10.
Storage at temperature not exceeding 35◦C but not freezed.
Dose: As antacid: 5 ml four times a day,
As cathartic: 15 to 30 ml daily.

56. Why citric acid is added in the preparation of milk of magnesia ?
Milk of magnesia , USP is a suspension of magnesium hydroxide containing not less than 7% and not more than 8.5% of Mg(OH)2
For purposes of minimizing the alkalinity of milk of magnesia 0.1% citric acid is added.
Normally, Mg(OH)2 ionizes into Mg2+ & OH- ion. The citric acid (C6H8O7) upon addition reacts immediately to form magnesium citrate which ionizes to supply magnesium ion & citrate ion.
Mg(OH) Mg2++ 2 OH (i)
Mg3(C6H8O7) Mg2++ 2C6H8O (ii)
This increases the concentration of Mg2+ ions

57. As the aqueous suspension stands in contact with the glass container , additional hydroxide is formed from the hydrolysis of the sodium silicate of the glass.
Na4SiO4 + 3H2O  H3SiO Na+ +3OH-
As the pH increases, the law of mass action requires the reaction (i) be reversed and magnesium hydroxide reformed as the excess hydroxide from the glass is consumed.
Due to the presence of citric acid there are enough magnesium cations available to react with excess hydroxide from the glass container .
The end result is a product with a milder, less chalky taste. The alkalinity contributed by the glass container is like wise counteracted.

58. Advantages of antacid combinations:
Because no single antacid meets all the criteria for an ideal antacid, several products are on the market containing mixtures of antacids. Antacids are used commonly in combination for three reasons: 1. To combine fast and slow-reacting antacids in order to obtain a product with a rapid onset and relatively sustained action. E.g. Mg(OH)2 (having fast onset of action and short duration of action) and Al(OH)3 (having slow onset of action and prolonged duration of action) are used together in most of the antacid mixtures.

59. Advantages of antacid combinations (contd..)
2. To use one component to antagonize one or more side effects of another component. E.g. mixture of Mg(OH)2 (having laxative effect) and AL(OH)3/CaCO3 (having constipative effect) is done to balance the laxative and constipative effects. 3. To lower the dose of each component and minimize the possibility of certain adverse effects.

60. Examples of antacid combinations:
USP recognizes two dosage forms : a suspension and a tablet.
In either dosage form either aluminium hydroxide gel or magnesium hydroxide may predominate.
Alumina and Magnesium Oral suspension U.S.P XVIII contains the equivalent of 4% aluminium oxide (Al2O3 ) and 2% magnesium hydroxide Mg(OH)2 . Dose : 15ml four to six times a day.
Magnesia and Aluminium Oral Suspension U.S.P XVIII contains the equivalent of 2.2% aluminium oxide and 3.8% of magnesium hydroxide. Dose: 1 to 2 tablets four to six times a day.
Same for the two tablet forms.

61. Acid Indigestion Overeating Alcohol consumption Eating certain foods
When excess acid is produced a condition known as acid indigestion results.
If excess acid is forced into the esophagus acid reflux or “heart burn” results.
High acid concentrations can damage the stomach lining resulting in ulcers.
Causes of Acid Indigestion
Excess stomach acid results in a state of discomfort known as acid indigestion
Acid indigestion may result form a variety of factors including:
Overeating
Alcohol consumption
Eating certain foods
Anxiety
Smoking
Certain Drugs, i.e. Aspirin

62. What is heartburn?
Despite the name, heartburn has nothing to do with the heart. Heartburn is caused when stomach acid passes out of the stomach and up into the oesophagus (the tube that carries food from the mouth to the stomach).
The acid can irritate the surface of the oesophagus, leading to the burning sensation associated with heartburn. Health professionals prefer to use the term gastro-oesophageal reflux disease, or GORD, to describe this condition because it's a more accurate term than heartburn.

63. Systemic alkalosis:
Relatively too much base in the blood and body, an abnormal condition resulting from the accumulation of base or the depletion of acid.
 How systemic alkalosis is produced by antacids?
Antacid ↓
Neutralizes HCl .So, equivalent amount of intestinal HC03- remain neutralized & absorbed
HC03- absorption
Alkalosis
Kidney excrete excess HC03-
Urine become alkaline
Nephrolithiasis (Phosphate stone)
Renal damage

64. Causes, incidence, and risk factors
Milk-alkali syndrome
Milk-alkali syndrome is an acquired condition in which there are high levels of calcium (hypercalcemia) and a shift in the body's acid/base balance towards alkaline (metabolic alkalosis).
Causes, incidence, and risk factors
Milk-alkali syndrome is caused by drinking too much milk (which is high in calcium) and taking certain antacids, especially calcium carbonate or sodium bicarbonate (baking soda), over a long period of time.

65. Calcium deposits in the kidneys and in other tissues can occur in milk-alkali syndrome. High levels of vitamin D can worsen this condition.
In the past, milk-alkali syndrome was often a side effect of treating peptic ulcer disease with antacids containing calcium. It is rarely seen today, because newer, better medications that do not contain calcium are available for treating ulcers. A more common scenario today is when someone takes too much calcium carbonate in an attempt to prevent osteoporosis. This has been reported in persons who take as little as 2 grams of calcium per day.
Treatment
Treatment involves reducing or eliminating milk and other forms of calcium such as in antacids. If severe kidney failure has occurred, the damage may be permanent.

66. Simethicone Antiflatulents
Simethicon is a mixture of full methylated linear siloxane polymers containing repeating units of the formula [-(CH3)2 SiO2]n, stabilized with trimethylsiloxy end- bulking units of the formula [(CH3)3 SiO-] and silicon dioxide.
Translucent, gray, viscous fluid, Sp. gravity –
Use: Antiflatulent, gastric protective to deform gastric juice in order to decrease the tendency to gastro esophageal reflux.
Dose: mg (tablet) 4 times a day after each meal & at bedtime.

67. Adsorbents
They are chemically inert powders that have the ability to adsorb gases, toxins and bacteria.
The fine state of subdivision of these inert powders confers high adsorptive capacity upon them.
Adsorbents are used to remove a toxic substance before it can be absorbed into the body.
Two are currently official:
i) Kaolin N.F. and ii) Activated charcoal U.S.P

68. Kaolin N.F.:
kaolin N.F is a hydrate aluminum silicate. It occurs as a soft, white or yellowish white powder.
It has earthy or clay taste
It is insoluble in water, cold dilute acids, alkali hydroxides
Uses: It is medicinally used as adsorbents. It is of value chiefly in the treatment of diarrhoea. It supposedly adsorbs bacterial toxins that cause the diarrhoea.

69. Activated charcoal U.S.P XVIII:
It occurs as a fine, black, odorless and tasteless powder.
It is insoluble in water or the known
solvents.
Uses:
i) Activated charcoal is recommended
as a component of first aid kits and is
used as an antidote in certain types of poisoning. It will adsorb alkaloids and certain types of heavy metal.
Activated charcoal in a charcoal-to-poison ratio of 5:1 to 10:1 is usually administered as the pure powder dispersed in water.

70. ii) Charcoal has the ability to adsorb gases (such as ammonia, nitrous oxide, carbon monoxide, carbon dioxide, oxygen, nitrogen and hydrogen).
After oral administration it reduces the volume of intestinal gas.
Hence it is used for relief of gastrointestinal distress associated with indigestion.

71. Laxatives:
Laxatives are drugs that affect fecal consistency, accelerate the passage of feces through colon and facilitate elimination of feces from the rectum.
Traditionally, laxatives are divided into five groups:
Saline laxatives
Stimulant laxatives
Bulk-forming laxatives
Lubricant laxative
Fecal softener

72. Saline laxatives:
Saline laxatives act via their osmotic pressure to retain water in the colon. A number of magnesium salts as well as other sulfates and phosphates are used as saline laxatives.
These cations and anions are not absorbed from the GIT.
Consequently, when given orally in hypertonic solutions, they draw water from the tissue into the intestine, increase peristalsis and induce a profuse, watery stool.

73. It has also been shown that magnesium stimulates the release of endogenous cholecystokinin-pancreozymin , a hormone which causes the accumulation of fluid and electrolytes within the human small intestine. The laxative action may also result from this action.
Saline laxatives produce laxation with a latency of 6 to 8 hours in lower “laxative” doses.
Thorough fluid evacuation occurs in less than 3 hours when administered in higher “cathartic” doses. The cathartic dose is more effective when administered in an empty stomach.

74. Uses:
For emptying the bowel prior to surgical, radiologic and colonoscopic procedures.
Used as a useful adjunct in the elimination of some intestinal parasites.
Used as cathartics in some instances of poisoning.
Examples: MgSO4, Mg(OH)2, Mg-citrate, Na-Phosphate, etc.

75. Side effects :
Small amounts of these drugs may be absorbed in the blood causing occasional toxicity.
The absorption of magnesium may cause marked CNS depression while that of sodium worsens the existing congestive cardiac failure (CCF).

76. Magnesium Sulphate MgSO4.7 H2O Preparation:
Sulfur dioxide and air are passed into an aqueous suspension of the magnesium hydroxide, yielding magnesium sulfate.
Mg(OH)2 + SO2 + ½ O2 = MgSO4 + H2O
It is small colorless crystal, usually needlelike and has a cooling and bitter taste.
The intensity of the bitter taste may induce nausea and should be masked by taking the salt in citrus juices.

77. Uses:
An effective and widely employed saline laxative.
Treatment of oral poisoning.
Mechanism of action:
1) It acts via retention of water in the colon. Magnesium salt is not absorbed from the GIT.
Consequently, when given orally, they draw water from the tissue into the intestine, increase peristalsis and induce a profuse, watery stool.
2) Magnesium also stimulates the release of endogenous cholecystokinin-pancreozymin , a hormone which causes the accumulation of fluid and electrolytes within the human small intestine. Increased bulk promotes the motor activity of the bowel.

78. Stimulant laxatives:
They promote accumulation of water and electrolytes in the colonic lumen and stimulate intestinal motility.
The more commonly employed agents are cascara sagrada, senna, the diphenylmethane derivatives, etc.

79. Bulk forming laxatives:
The bulk-forming laxatives include a wide range of natural and semi-synthetic polysaccharides and cellulose derived from grains, seed husks, etc.
Methyl cellulose, carboxymethylcellulose are only partially digested.
The undigested portions are hydrophilic and swell in the presence of water to form viscous solution or gel.
The increased intra-luminal pressure reflexly
stimulates peristalsis,
diminishes colonic transit time and
produces soft gelatinous stool.

80. Lubricant Laxatives:
Mineral oil such as liquid paraffin, liquid petroleum, etc and vegetable oils.
-They lubricate the intestinal tract,
-soften the fecal contents and
-facilitate the passage of feces.

81. Fecal Softeners: Non-absorbable, non toxic.
They permit the intestinal fluids to penetrate the fecal mass more readily by reducing the surface tension.
Produce soft and easily passed stool.
Examples: Poloxamers, Castor oil etc.

82. Thank You