2. Lesson 6 pH Regulation in the Stomach
Tuesday, March 15, 2016

3. Understandings
Non-specific reactions, such as the use of antacids, are those that work to reduce the excess stomach acid.
Active metabolites are the active forms of a drug after it has been processed by the body.

4. Applications
Explanation of how excess acidity in the stomach can be reduced by the use of different bases.
Construction and balancing of equations for neutralization reactions and the stoichiometric application of these equations.
Solving buffer problems using the Henderson–Hasselbalch equation.
Explanation of how compounds such as ranitidine (Zantac) can be used to inhibit stomach acid production.
Explanation of how compounds like omeprazole (Prilosec) and esomeprazole (Nexium) can be used to suppress acid secretion in the stomach.

5. Your Gut
The gastro-intestinal tract, or gut, generates and maintains different pH environments along its length, which play an important role in controlling the activity of digestive enzymes.

6. Why so acidic?
Normally the pH in the stomach is between 1 and 2, owing to the production of hydrochloric acid by the millions of parietal cells that line the stomach. The stomach is maintained at such a low pH for two main reasons:
the acidic environment is not tolerated by the majority of microorganisms (e.g. bacteria) that may enter the digestive system with food – the low pH plays a role in the body’s natural defense against disease-causing microorganisms
the digestive enzymes in the stomach (e.g. pepsin, which breaks down proteins) require a low pH for optimum catalytic activity.

7. When It Goes Wrong
However, some factors, such as excess alcohol, smoking, caffeine, stress, and some anti-inflammatory drugs, can cause excess production of this acidic secretion, known as gastric juice. This can lead to the following problems:
acid indigestion – feeling of discomfort from too much acid in the stomach
heartburn – acid from the stomach rising into the esophagus (often called acid reflux)
ulceration – damage to the lining of the gut wall, resulting in loss of tissue and inflammation.
The term dyspepsia is used to refer to feelings of pain and discomfort in the upper abdomen, which include indigestion and heartburn.

8. Removing The Cause
In some cases, the first line of defense is to try to remove the cause; eating less, avoiding spicy foods, avoiding alcohol, reducing stress and reducing BMI
In some cases (for example, when you are teaching or taking IB Chemistry HL) you cannot remove all the stressors that cause indigestion and acid reflux. What to do?

9. Antacids
Antacids are used to treat these conditions. They are weakly basic compounds that neutralize acids, relieving the pain, discomfort or burning sensation and allowing repair of the mucous layer. In the case of peptic ulcers, neutralization of the acid prevents further erosion of the gut lining allowing ulcers to heal.
The most commonly used antacids are metal hydroxides, carbonates and hydrogencarbonates (bicarbonates):
magnesium hydroxide
aluminium hydroxide
calcium carbonate
sodium hydrogencarbonate (also called sodium bicarbonate).

10. Mix Of Salts
Some antacid preparations contain mixtures of two different antacids, such as magnesium compounds and aluminum compounds (usually magnesium and aluminum hydroxides).The rationale for using these two different antacids is that magnesium salts are faster acting and so work quickly to neutralize the acid, but aluminum salts have a slower and more prolonged effect, so the time interval between doses is increased. Also, magnesium salts in repeated doses can cause a laxative effect, but this is o set by aluminum salts which can induce constipation.

11. Equations Gas can cause flatulence!! calcium hydroxide,
Ca(OH)2(aq) + 2HCl(aq) → CaCl2(aq) + 2H2O(l)
magnesium hydroxide
Mg(OH)2(aq) + 2HCl(aq) → MgCl2(aq) + 2H2O(l)
aluminum hydroxide
Al(OH)3(aq) + 3HCl(aq) → AlCl3(aq) + 3H2O(l)
sodium hydrogencarbonate
NaHCO3(aq) + HCl(aq) → NaCl(aq) + H2O(l) + CO2(g)
sodium carbonate
Na2CO3(aq) + 2HCl(aq) → 2NaCl(aq) + H2O(l) + CO2(g)
Gas can cause flatulence!!

12. Side Effects
The gas released can cause bloating of the stomach and flatulence. To reduce this side-effect, antifoaming agents are often added to the formulation (dimethicone).
Some antacids also contain alginates which oat to the top of the stomach, forming a ‘raft’ which acts as a barrier preventing reflux into the esophagus.
Note that because antacids change the pH of the stomach, they can alter other chemical reactions, including the absorption of other drugs. Although they are over-the-counter drugs, they should not be taken for an extended period without medical supervision.

13. Why not strong bases like NaOH?
You’d cause harm to your stomach!

14. H2 Receptor Antagonists
The body is equipped with complex mechanisms to protect it from the self-harm that could result from uncontrolled release of stomach acid. Together these mechanisms ensure that gastric juice is released only when required – stimulated by the presence of food and distension (stretching) of the stomach walls. Several transmitters and chemical messengers called hormones are involved, and of these histamine is of specific interest.

15. Histamine

16. Histamine
Histamine has different functions in the body and several different receptor sites. In the stomach it stimulates secretion of stomach acid by interacting at receptors known as H2 (not to be confused with hydrogen gas!) in the parietal cells in the gastric glands.
This histamine interaction initiates a sequence of events, leading to the release of acid into the stomach lumen. This suggests that a possible target for a drug which will reduce stomach acid secretion would be to block the histamine–H2 interaction. Drugs which do this and which compete with histamine for binding at the H2 receptors are known as H2-receptor antagonists.

17. Zantac (Ranitidine)
Ranitidine (Zantac) is an example of an H2-receptor antagonist drug. It was developed from analogues of histamine using knowledge of the H2-receptor structure, and refined from earlier drugs to increase its potency. In many countries it is now available as an over-the-counter drug, but higher dosages need prescription.

18. Video

19. Proton Pump Inhibitors (PPIs)
In the last step of gastric acid secretion, the parietal cells in the gastric glands pump protons (H+) across their membranes and into the lumen of the stomach.
For each H+ ion pumped into the lumen, one K+ ion is pumped in the opposite direction so there is no charge build-up.
Movement of the ions occurs against their concentration gradients and so requires energy. This is provided by the hydrolysis of an energy carrier known as ATP, using the enzyme ATPase which is embedded in the cell membrane. The enzyme is therefore known as the H+/K+ ATPase or simply as a gastric proton pump.

20. Video

21. Omeprazole Got me through my first two years of teaching!
The first proton pump inhibitor was omeprazole, marketed as Prilosec, which was followed by the release of esomeprazole or Nexium when the patent for Prilosec expired in 2001.

22. Prilosec Nexium

23. Summary

24. Let’s Practice
Compare the volume of stomach acid (hydrochloric acid) of pH 1.50 that is neutralised by taking one indigestion tablet containing 1.00 g of calcium carbonate with one containing 1.00 g of sodium hydrogencarbonate.

26. Let’s Practice
Work out the volume of hydrochloric acid of pH 2.00 that reacts with: a 1.00g of aluminum hydroxide b 1.00g of magnesium hydroxide

27. Active Metabolites
Active metabolites are the active forms of drugs after they have been processed in the body.
We have already seen examples of drugs that are converted into a different form in the body – the form that causes the desired action of the drug.
codeine is converted into morphine in the body and it is the morphine that binds much more strongly to the opioid receptors than codeine, producing an analgesic e ect
omeprazole/esomeprazole are converted into di erent forms that are able to bind to proton pumps
aspirin is converted into the active form – salicylic acid. Salicylic acid cannot be taken orally because it causes severe irritation of the stomach lining, resulting in vomiting and gastric bleeding. Therefore it is taken in ester form; this causes much less gastric irritation but is converted back into the active analgesic in the body.

28. Reasons
There are many reasons for making a drug in a different form to that of the active metabolite and these include:
to avoid side effects – e.g. aspirin
to allow the drug to pass through cell membranes – the active form of omeprazole is charged and would not pass through the cell membrane into the parietal cells; diamorphine is another drug that fits into this category
to allow the drug to dissolve in water more easily – e.g. fosphenytoin
to target drugs to a particular area – for example, omeprazole again, where the active drug is formed only in the highly acidic conditions of the cells in the stomach lining.

29. Lesson 7: Buffers Revisited
Wednesday, March 16, 2016

30. Buffers
A buffer solution is one that resists changes in pH when small amounts of acid or alkali are added.
Biological systems are very sensitive to changes in pH. This is why complex buffering systems exist in cells that help to prevent major fluctuations in the pH.
REFER BACK TO ACID/BASE if you do not remember buffers!

31. Buffer Calculations
On Paper 2, you must write out an equilibrium equation to solve for buffers
On Paper 3, you can make the following assumptions:
The dissociation of the weak acid is so small that it can be considered to be negligible.
The salt is considered to be fully dissociated into its ions.
From this we can derive the Henderson-Hasselbalch equation to make these problems easier

34. Henderson-Hasselbalch
These equations, known as the Henderson–Hasselbalch equations, are given in section 1 of the IB data booklet. The beauty of these expressions is that they enable us to know the pH of a buffer solution directly from the following:
the Ka or Kb values of its component acid or base and
the ratio of initial concentrations of acid and salt used to prepare the buffer.

35. Let’s Practice
Calculate the pH of a buffer solution at 298 K, prepared by mixing 25 cm3 of 0.10 mol dm–3 ethanoic acid (CH3COOH) with 25 cm3 of 0.10 cm3 sodium ethanoate (Na+CH3COO–). Ka of CH3COOH = 1.8 × 10–5 at 298 K.

37. Let’s Practice
How would you prepare a buffer solution of pH 3.75 starting with methanoic acid (HCOOH) and NaOH?

38. Let’s Practice
How much 0.10 mol dm–3 butanoic acid solution and solid potassium butanoate should be used to make 1.00 dm3 of pH 5.00 buffer solution? State the assumptions made in the calculation.

46. More Problems
A student wants to make up a bu er solution of pH 7.7 using mol dm−3 solutions of HEPES (pKa = 7.5) and its sodium salt. Calculate how much of each solution must be used to make 500 cm3 of a buffer of pH 7.7
Therefore the volume of the HEPES solution required is 194 cm3 and that of the solution of its sodium salt is 306 cm3.

47. More Problems
What mass of solid sodium ethanoate must be added to cm3 of mol dm−3 ethanoic acid to produce a bu er solution of pH 4.00? Assume there is no change in volume when the sodium ethanoate is added.The pKa for ethanoic acid is 4.76.
0.285 g of sodium ethanoate must be dissolved in the ethanoic acid to produce a bu er solution of pH = 4.00.

53. 13  H2-receptor antagonists: block the binding of histamine, which prevents the reactions leading to stomach acid secretion. Proton-pump inhibitors: directly prevent the release of acid into the stomach lumen.