Transcript File - Riske Science

Lesson 3: Aspirin
D2 Wednesday, March 8
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.
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.
Analgesics – Reduce Pain
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.
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.
Mild Analgesics – Act At Source
• 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-narcotic
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.
Strong Analgesics (Opioids) – Act In
Brain 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.
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.
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.
Comparison
• Salicylic Acid
• Aspirin
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.
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
crystallizes
•
•
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.
Salicylic Acid
Infrared
Spectroscopy
Aspirin
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).
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.
Aspirin – Effects in Body
• Aspirin 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.
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.
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
The type of reaction is addition–elimination (the
CH CO group is added to aspirin and ethanoic
3
acid is eliminated) and happens in the presence
of a small amount of concentrated phosphoric
(or sulfuric) acid catalyst.
Salt
• Formulations that contain the salt of the acid
are known as soluble aspirin or dispersible
aspirin.
Let’s Practice
• In an experiment to synthesize aspirin, 5.60g
of salicylic acid (Mr 138.13) was reacted with
8.00cm3 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.
Questions
Answers
Lesson 4: Penicilin
D2: Wednesday, March 8, 2016
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 βlactam ring (a cyclic amide that is part of a fourmembered 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.
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 fourmembered 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.
Beta-Lactam Ring
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.
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.
Video
• https://www.youtube.com/watch?v=qBdYnRh
dWcQ
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.
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
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.
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
Antibiotic Resistance
• https://www.youtube.com/watch?v=znnpIvj2ek
Let’s Practice
Answers