Medicinal Chemistry - PowerPoint Presentation

Slide1

Medicinal Chemistry

D4

pH regulation of

the stomachSlide2

Understand that antacids can be used to reduce the amount of excess acid in the

stomach.

Understand that the action of antacids is non-specificWrite equations for neutralisation reactions involving different antacidsUnderstand how ranitidine (Zantac®) worksUnderstand how omeprazole (Prilosec®) and esomeprazole (Nexium®) workUnderstand what is meant by an active metaboliteSolve problems involving buff er solutions

Learning outcomes Slide3

Normal pH of stomach is 1 to 2Hydrochloric acid is produced in stomach by million if glands on the wall of the stomach.

Two reason for stomach to maintain low pH

The low pH plays a role in the body’s natural defense against disease-causing microorganismsThe digestive enzymes in the stomach (e.g. pepsin, which breaks down proteins) require a low pH for optimum catalytic activity.pH regulation of the stomachSlide4

Excess of acid in stomach Slide5

Excess of acid in stomach can damage mucous layer that protect the stomach wall.

This can result in the following

:Indigestion, heartburn and peptic ulcer indigestion – irritation of the stomach lining caused by excess acid producing pain or discomfort in the upper abdomen and/or nauseaheartburn (acid reflux) – acid from the stomach rising up into the esophagus causing a burning sensationpeptic ulcer

– erosion of part of the gut lining, caused by acid penetrating the mucous

layer. This is a serious condition if not treated can lead to internal bleeding.

Excess of acid in stomach Slide6

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:OvereatingAlcohol consumptionEating certain foodsAnxietySmoking

Certain Drugs, i.e. Aspirin

6Slide7

Antacid Compounds

Antacids are weak bases that are used to neutralize excess stomach acid

Most antacids are weak inorganic basesCommon examples includeCaCO3

NaHCO

3

Al(OH)

3

Mg(OH)2

MgO and Mg(OH)

2

(Milk of Magnesia)

7Slide8

Antacids are non-specific

and do not bind to protein receptors. They work by simply

neutralising excess stomach acid.Remember Slide9

Antacid Reactions

Antacids react with HCl in the stomach

Some common antacid reactions include: CaCO3 + 2 HCl  CaCl2

+ H

2

O + CO

2

NaHCO

3 + HCl  NaCl

+ H

2

O + CO

2

Al(OH)

3

+ 3 HCl

 AlCl

3

+ 3 H

2

O

Mg(OH)2 + 2 HCl  MgCl2 + 2 H2O MgO + 2 HCl  MgCl2 + H2O

9Slide10

Effect of Antacids

In addition to neutralizing excess stomach acid they may be helpful in preventing inflammation, relieving pain and discomfort, and allowing the mucus layer in the stomach lining to heal.

They are often used to treat ulcers by preventing the stomach acids from attacking the stomach lining allowing it to heal.

Mucus

Lining

10Slide11

Antacid Side Effects

Antacids

are relatively harmless but they can have minor contraindicationsMagnesium Compounds may cause diarrhea

Aluminum Compounds

may cause constipation and they also may interfere with the adsorption of phosphates in the formation of bones. This is more likely to be true if they are taken for an extended period of time

Carbonates

may generate carbon dioxide leading to bloating and flatulence.

11Slide12

Antacids are often combined with

alginates

and anti-foaming agents.Aliginates float on the stomach contents to form a neutralizing layer preventing reflux of stomach acids up into the esophagus. Hence they help to prevent acid reflux or heart burn.

Anti-foaming

agents

such as

simethicone (

dimethicone) prevent the formation of gases and reduce flatulence.

Alginates and Antifoaming Agents

12Slide13

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.ExampleSlide14

A pH of 1.50 corresponds to a concentration of H

+

(aq) of 10−1.50 = 0.0316 mol dm−3Because HCl is a strong acid it completely dissociates and the concentration of H+(aq) is equal to the original concentration of the acid.

Solutions Slide15
Slide16

SO

1.00

g of calcium carbonate therefore reacts with

significantly

more hydrochloric acidSlide17

a 3.85 dm

3

;

b 3.43 dm

3

Slide18
Slide19

Peptic ulcer

Peptic ulcer

It is a sore in stomach ( gastric ulcer ) or in upper part of small intestine (Duodenal ulcer)10 to 20 percent people suffer from peptic ulcerDisease is very painful and can fetalSlide20

Two main approaches to treat peptic ulcer

Stopping the production of acid

Preventing the release of acid into the stomachNote: Term H2 blocker or receptor will be used a lot. But it has nothing to do with H2 gasTreatment of Peptic UlcerSlide21

H2 Blockers

H2 blockers

impede acid production in the stomach by blocking the actions of histamine, a substance produced by the body that encourages acid secretion in the stomach. These drugs cannot cure ulcers, but in certain cases they are useful. They are effective only for duodenal ulcers, however, and have little effect on stomach (gastric) ulcers.

21Slide22

Ranitidine or Zantac® is

a drug that inhibits the production of acid.

RanitidineSlide23

It binds with receptor protein (histamine H2

-receptor) in cell membrane and stops normal chemical messenger (histamine) from binding with cell membrane.

Ranitidine stops production stomach acid.Ranitidine can be described as an H2-receptor antagonist because when it binds to an H2-receptor it does not cause activation of the receptor, but rather stops the naturally occurring molecule that does cause activation (the agonist) from binding. RanitidineSlide24

Proton Pump Inhibitors

Proton Pump Inhibitors reduce the production of acid by blocking the enzyme in the wall of the stomach that produces acid. Inhibitors do not neutralize excess acid but inhibit the initial production of hydrochloric acidThe reduction of acid prevents ulcers and allows any ulcers that exist in the esophagus, stomach and duodenum to heal.

24Slide25

Omeprazole (Losec®, Prilosec®) and esomeprazole (

Nexium

®) are proton pump inhibitors and work by preventing the release of acid from the parietal cells into the stomach.Omeprazole and esomeprazole

Esomeprazole is a stereoisomer of this Slide26

Protons are released from the parietal cell by the action of a proton pump. This is a protein complex that moves protons through cell membranes – being charged, protons cannot

diffuse

normally through a cell membrane made of mainly non-polar lipid molecules.These drugs are weak bases but are mainly in the un-ionised form at the pH of blood plasma. They are also mostly non-polar and therefore lipid-soluble so they can pass through the cell membrane of the parietal cells. Omeprazole and esomeprazoleSlide27

Inside the parietal cells the medium is much more acidic and the basic molecules get protonated. Protonation starts a series of reactions that changes the structure of the drug molecule into one that can bind irreversibly to the proton pump

and

so stop it from carrying out its function. The drugs are effective for an extended period of time – until the cell is able to make new proton pumps.Omeprazole and esomeprazoleSlide28

Active metabolites are the active forms of drugs after they have been processed in the body.

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 effectomeprazole/esomeprazole are converted into different forms that are able to bind to proton pumpsaspirin is converted into the active form – salicylic acid.Active metabolitesSlide29

To avoid side effects

– e.g.

aspirinTo allow the drug to pass through cell membranes. e.g Diamorphine To allow the drug to dissolve in water more easily – e.g. fosphenytoinTo target drugs to a particular area e.g omeprazole

Reasons

for making a drug in a

different

form to that of the active

metabolite.Slide30

A buffer solution is one that resists changes in pH when small amounts of acid or alkali are added

.

Buffer solutions

The graph in Figure

shows

the result of adding 10 cm

3

of 0.100

mol dm−3

hydrochloric acid in stages to 100 cm

3

of water (blue line) and to 100 cm

3

of a

buffer

solution (orange line).Slide31

A buffer solution consists of two components –

a

acid and a base. A weak acid and its conjugate base or A weak base and its conjugate acid. The base reacts with any acid added and the acid reacts with any base added. There must be reasonably large amounts of each present for the solution to function as a buffer.Components of BufferSlide32

Consider a general buffer containing acid, HA and base A−. The equilibrium that exists in this solution is

:

When acid is addedWhen a base is addedHow a buffer works Slide33

Henderson–Hasselbalch equation

:

pH calculation for a bufferSlide34

Worked

example

Calculate the pH of a buffer solution containing 0.0550 mol dm−3 CH3COOH (pKa = 4.76) and 0.0450 mol dm−3 CH3COO−.Slide35

Try thisSlide36

A buffer pH range can be calculated as pH=

pKa

-1 to pH = pKa +1 E.g a buffer dihydrogen Phosphate (pka 2.12) works effectively between 1.12 to 3.12.Outside this range buffer loses its ability to maintain constant pH.Buffer pH range