Lesson 3: Aspirin D2 Wednesday, March 8 - PowerPoint Presentation

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Lesson 3: Aspirin

D2 Wednesday, March 8Slide3

Understandings

Aspirin

Mild

analgesics function by intercepting the pain stimulus at the source, often by interfering with the production of substances that cause pain, swelling, or fever.

Aspirin

is prepared from salicylic acid.

Aspirin

can be used as an anticoagulant, in prevention of the recurrence of heart attacks and

strokes

, and as a prophylactic.

Penicillin

Penicillins

are antibiotics produced by

fungi.

A

beta-lactam ring is a part of the core structure of

penicillins

.

Some

antibiotics work by preventing cross-linking of the bacterial cell

walls.

Modifying

the side-chain results in

penicillins

that are more resistant to the

penicillinase

enzyme. Slide4

Applications and Skills

Aspirin

Description

of the use of salicylic acid and its derivatives as mild analgesics.

Explanation

of the synthesis of aspirin from salicylic acid, including yield, purity by recrystallization,

and

characterization using IR and melting point.

Discussion

of the synergistic effects of aspirin with

alcohol.

Discussion

of how aspirin can be chemically modified into a salt to increase its aqueous solubility

and

how this facilitates its bioavailability.

Penicillin

Discussion

of the effects of chemically modifying the side-chain of

penicillins

.

Discussion

of the importance of patient compliance and the effects of the over-prescription of

penicillin.

Explanation

of the importance of the beta-lactam ring on the action of penicillin. Slide5

Analgesics – Reduce

P

ainSlide6

Pain

Pain is detected as a sensation by the brain when nerve messages are sent from various

pain receptors

located around the body. These receptors are themselves stimulated by chemicals known as

prostaglandins

, which are released from cells damaged by thermal, mechanical, or chemical energy. Slide7

Prostaglandins

Once released, prostaglandins also mediate the

inflammatory

response

by causing the dilation (widening) of blood vessels near the site of injury. In turn this can lead to swelling and increased pain. In addition, prostaglandins have an effect on the temperature regulation of the body that may result in increased temperature known as

fever

. Slide8

Mild Analgesics – Act

A

t

S

ource

Aspirin and non-steroidal anti-

inflammatory

drugs (NSAIDs) such as ibuprofen are

mild analgesics

.

Mild analgesics, such as aspirin and

paracetamol

, function by stopping the transmission of pain from source to brain as they intercept the pain stimulus at the source.

They act by preventing stimulation of the nerve endings at the site of pain and inhibit the release of prostaglandins from the site of injury.

They are non-narcoticSlide9

Mild Analgesics

Mild analgesics, such as aspirin and ibuprofen, prevent the production of

prostaglandins

in the body by inhibiting an enzyme known as

cyclooxygenase

(COX), which is a key enzyme in the synthesis of prostaglandins. Slide10

Strong Analgesics (Opioids) – Act

I

n

B

rain or CNS

Strong

analgesics such as

morphine

and

diamorphine

(

heroin

) work

by temporarily bonding to receptor sites (opioid receptors) to pain impulses in the brain or other parts of the central nervous system such as the spinal cord.

This prevents the reception of pain impulses i.e. blocking the signal without depressing the central nervous system.Slide11
Slide12

Mild or strong?

Mild analgesics eliminate pain at source

Strong analgesics alter our ability to perceive pain and act in the brain or CNS

Consider the relative value of these two approaches to pain management.Slide13

Development of Aspirin

Even back in the days of Hippocrates, people knew that chewing willow bark could reduce pain

In the 1800s, it was shown that the active ingredient was

salicin

which was converted into

salicylic acid

in the body; however ingesting salicylic acid causes people to vomit and tastes awful

In 1890 the Bayer Company in Germany made an ester derivative of salicylic acid, which was more palatable and less irritable to the body, while still being effective

as an

analgesic. It was named

aspirin

, in recognition of the plant

spirea

which produces

a similar compound. Slide14

Comparison

Salicylic Acid

AspirinSlide15

Aspirin (cont.)

Also, because it is effective in reducing fever, known as an

antipyretic

, and

inflammation

, it is used to provide relief from rheumatic pain and arthritis. Slide16

Synthesis

Made through esterification

Concentrated sulfuric acid or phosphoric acid is added to the reactants and the mixture is warmed gently. The aspirin product must then be isolated and

purified

from the mixture.

The product is

first

cooled to cause crystals to form, and then suction

filtered

and

washed with chilled water. Aspirin has a very low solubility in water at low temperature, so this process removes the soluble acids while not leading to the loss of the aspirin product.

Purification

involves a technique known as

recrystallization

. This involves dissolving the impure crystals in a minimum volume of hot ethanol, which is a better solvent

for impurities than aspirin. The solution is cooled slowly and aspirin crystallizesSlide17

Testing Purity

The purity of the product can be con

rmed

by

melting point determination

. Pure substances have well-

defined

melting points which are altered by the presence of impurities. Special apparatus is usually used to carry out this determination and the results are compared with data. Pure aspirin has a melting point of 138–140 °C, and salicylic acid has a melting point of 159 °C. A mixture would have a lower and less well-

defined

melting point. Slide18

Infrared Spectroscopy

Salicylic Acid

AspirinSlide19

Similarities

strong peaks from 1050 to 1410 cm

–1

due to C– O in alcohol/

ester

strong

peaks from 1700 to 1750 cm

–1

due to C= O in carboxylic

acid

both

have broad peaks from 2500 to 3000 cm

–1

due to OH in carboxylic acid

both

have peaks from 2850 to 3090 cm

–1

due to C– H (overlapping the broad

–

OH peak). Slide20

Differences

a second peak from 1700 to 1750 cm

–1

due to presence of ester group in

aspirin

a

peak from 3200 to 3600 cm

–1

in salicylic acid due to the presence of its –OH group;

this peak is not present in the aspirin spectrum. Slide21

Aspirin – Effects in Body

A

spirin

works by blocking the synthesis of prostaglandins.

Aspirin

is an

anticoagulant

, meaning it reduces the ability of the blood to clot.

Negative side-effects of aspirin include irritation and even ulceration of the stomach and duodenum, possibly leading to bleeding.

It is not recommended for children under 12 because its use has been linked to Reye’s syndrome, a rare and potentially fatal liver and brain disorder.

The physiological effects of aspirin are more acute when it is taken with ethanol in alcoholic drinks. This effect is known as

synergy

, and means that care must be taken when consuming alcoholic drinks alongside medication. Slide22

Synergism

Synergism

can happen when two or more drugs, given at the same time, have an

effect

on the body that is greater than the sum of their individual

effects

. In other words, certain drugs can increase the

effects

of other drugs when given at the same time.

When alcohol is taken with aspirin there is an increased risk of

hemorrhage

(bleeding) in the stomach. Slide23

Modification of Aspirin

Aspirin is available in many formulations, which include various coatings and buffering components. These can delay the activity of the aspirin until it is in the small intestine to help alleviate some of its side-effects.

Aspirin is taken orally and transported in the plasma of the blood in aqueous solution. It has a low solubility in water as it is a largely non-polar molecule. Its bioavailability can be increased by increasing its solubility in water through chemical

modification

. This involves reacting aspirin with an alkali such as

NaOH

or NaHCO3, so that it forms an ionic salt. Slide24

The type of reaction is addition–elimination (the

CH

3

CO group

is

added to aspirin and

ethanoic

acid is eliminated) and happens in the presence of a small amount of concentrated phosphoric (or sulfuric) acid catalyst.Slide25

Salt

Formulations that contain the salt of the acid are known as

soluble aspirin

or

dispersible aspirin

. Slide26

Let’s Practice

In an experiment to

synthesize

aspirin

, 5.60g

of salicylic acid (

M

r

138.13) was reacted with 8.00cm

3

of

ethanoic

anhydride (density 1.08 g cm

−3

) in the presence of a concentrated phosphoric acid catalyst.

5.21g

of a white solid was obtained at the end of the reaction. Calculate:

a

which reagent was in excess

b

the yield of aspirin. Slide27
Slide28

QuestionsSlide29

AnswersSlide30

Lesson 4:

Penicilin

D2: Wednesday, March 8, 2016Slide31

Antibacterial Drugs

All antibacterial drugs work by somehow being toxic to bacteria while being safe for humans

There are many

different

types of antibacterial drugs (

commonly called

antibiotics), but the most commonly prescribed are the

penicillins

.

Penicillin has a bicyclic structure

containing

a

β-lactam

ring (a cyclic amide that is part of a four-membered ring).This β-lactam ring is essential for the antibacterial activity of penicillin; if the ring is broken in any way, such as by acid or bacterial

enzymes,

the penicillin is no longer active. Slide32

Penicillin Action

The isolation and development of penicillin

occurred

before

there was any understanding of its chemical structure or its mode of action. It was the work of British biochemist Dorothy Hodgkin in 1945 using X-ray crystallography that determined the structure of

penicillin G

, the major constituent of the

mold

extract.

The five membered ring

containing a sulfur atom known as

thiazolidine

, attached to a four-membered ring containing a cyclic amide group, known as

beta-lactam

. This ring consists of one nitrogen and three carbon atoms, and is the part of the molecule responsible for its antibacterial properties. Slide33

Beta-Lactam Ring Slide34

Beta Lactam Rings

The bond angles in this ring are reduced to about 90°, despite the fact that because they have sp2 and sp3 hybridized atomic orbitals the atoms in the ring seek to form bonds with angles of 120° and 109.5° respectively. This puts a strain on the bonds, effectively weakening them. Consequently the ring breaks relatively easily, and this is the key to the molecule’s biological activity. Slide35
Slide36

Penicillin Action (cont.)

The action of these beta-lactam antibiotics is to disrupt the formation of cell walls of bacteria by inhibiting a key bacterial enzyme,

transpeptidase

. As the drug approaches the enzyme, the high reactivity of the amide group in the ring causes it to bind irreversibly near the active site of the enzyme as the ring breaks. Inactivation of the enzyme in this way blocks the process of cell wall construction within the bacterium because it prevents polypeptide cross-links from forming between the

mucopeptide

chains. Without these strengthening links, the cell wall is unable to support the bacterium, and so it bursts and dies. Slide37

Video

https://www.youtube.com/watch?v=

qBdYnRhdWcQSlide38

Penicillin G

The

first

penicillin to be isolated and

purified

was penicillin G (

benzylpenicillin

).

However

, this penicillin has a number of disadvantages, one of which is that it is easily broken down by stomach acid and must be given by injection. Scientists have overcome this problem by making derivatives of penicillin G that have

modified

side

-chains that

can resist stomach acid and be given by the oral route. Slide39

Bacterial Resistance

The widespread use of

penicillins

has resulted in the development of bacteria that have become resistant to their antibacterial

effects

–

this is

known as

bacterial resistance

and arises because of mutations

in the

DNA of bacteria to aid their survival. Some strains of bacteria have developed ways of counteracting the

effects

of certain

penicillins

by producing an enzyme known as

penicillinase

(a β-lactamase), which opens the β-lactam ring of the penicillin, rendering it inactive. Penicillin G is an example of a penicillin that is inactivated by

penicillinase

. However, scientists have now developed

penicillins

that are less sensitive to the

effects

of this enzyme by modifying the side-chain in the penicillin structure Slide40

Patient Compliance Issues

It is extremely important that

antibacterials

are taken according to a doctor’s instructions (called

patient compliance

) and that the whole course of treatment is taken. Otherwise failure to kill all the bacteria in the infection can lead to development of resistance in those bacteria that survive. Slide41

Overprescribing

Such widespread bacterial resistance is also due to the extensive

use of

antibacterials

, both for human use and for animals. Overprescribing of

antibacterials

for minor infections has increased the exposure of bacteria to the antibacterial agents and has increased the number of resistant

bacteria.Antibacterials

are also used extensively in animal feeds to lower the occurrence of infections in livestock

. These

antibacterials

are given to healthy animals and can result in the development of resistant bacteria that can be passed on to humans via meat and dairy products. Slide42

Antibiotic Resistance

https://www.youtube.com/watch?v=znnp-

Ivj2ekSlide43

Let’s PracticeSlide44

Answers