Chapter 12
Health & Medicine
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How does the healthy body work?
How do different types of medications work?
How is nuclear chemistry used as a medical tool?
How are new pharmaceuticals developed?
Medicinal Chemistry
Pharmaceuticals: therapeutic substances intended to prevent, moderate, or cure
illnesses.
Medicinal chemistry: the science that deals with the discovery or design of new
therapeutic chemicals, and their development into useful medicines.
The father of medicine, Hippocrates (460–370 BC), considered tuberculosis to be the
most deadly disease, but modern medicine can now treat tuberculosis with
antibiotics.
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Equilibrium
Biochemical reactions are almost always reversible:
A ⇌ B
When the concentrations of products and reactants are constant, the system is at equilibrium.
We can define the equilibrium constant, Keq, as the ratio of product concentrations to reactant
concentrations:
Keq =
[B]
[A]
If Keq > 1, then the concentration of the product is favored; if Keq < 1, then the reactants are
favored:
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The Reaction Quotient
For a general reversible reaction: a A + b B ⇌ c C + d D
We may define the following expression for the equilibrium constant:
[C]c[D]d
Keq =
where the system is at equilibrium
[A]a[B]b
The current ratios of [products]/[reactants], which may or may not be at equilibrium, is referred
to as the reaction quotient, Q:
Q=
[C]c[D]d
where the system may or may not be at equilibrium
[A]a[B]b
When Q = K, the system is at equilibrium; when Q < K, more products are formed to reach
equilibrium; when Q > K, more reactants are formed to reach equilibrium:
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Thermodynamics vs. Kinetics
Thermodynamics: the relative energy of the reactants with respect to products.
Kinetics: how fast the rate of conversion of reactants to products takes place.
If a higher energy barrier must be overcome in order to form products, the reaction will take
place more slowly (kinetics). However, the overall energy will be the same after the reaction has
taken place (thermodynamics).
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Buffers
To keep our bodies in equilibrium, we need to maintain a constant pH level in our tissues, blood,
and interior compartments of our cells.
Buffers are systems that respond only gradually or slightly to an external influence, and are
composed of acids and bases that are able to react and neutralize external acidic/basic species.
Acids may be strong, which indicates their dissociation reaction is not reversible (Keq is very
large):
HCl(aq) + H2O(l) → H3O+(aq) + Cl−(aq)
Acids may also be weak, which indicates their dissociation reaction is reversible (it only weakly
dissociates, with a very small Keq):
HF(aq) + H2O(l) ⇌ H3O+(aq) + F−(aq)
For these weak acids, such as hydrofluoric acid, HF, there is a considerable amount of
undissociated HF present, as well as its conjugate base, F.
A conjugate base reacts with the conjugate acid, H3O+, to form HF via the reversible reaction.
Conjugate acid: has one more proton, H+, than the original reactant base (H2O in the above
reaction).
Conjugate base: has one fewer proton than the original reactant acid.
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The Effect of Buffers
Recall that pH = −log [H+]
Therefore, the pH of a pure water solution, with [H+] = 1  107 M is 7.0
If only 0.05 mole of HCl is added to 1.0 L of pure water, the pH drops to:
pH = −log[0.05 M] = 1.3
If a buffer is present, which contains 0.1 M HF (a weak acid) and 0.1 M NaF (the conjugate base of
HF), the pH may be calculated using the Henderson-Hasselbalch equation:
pH = pKa + log
[conjugate base]
[weak acid]
where: pKa = log[Ka] (Note: Ka is the equilibrium constant, Keq, for the weak acid)
For HF, pKa is 3.14, so the pH of the buffer is:
pH = 3.14 + log
[0.1]
= 𝟑. 𝟏𝟒
[0.1]
If the same 0.05 mole of HCl is added to 1.0 L of this buffered solution, the pH drops to:
pH = 3.14 + log
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[0.1 – 0.05]
= 𝟐. 𝟔𝟔 (MUCH less pH drop relative to HCl added to pure water)
[0.1 + 0.05]
The Buffer Capacity
A buffer is most useful when the solution’s pH is equal to the pKa value.
A buffer will resist against additions of acids or bases up to ±1 pH unit around the value of pKa.
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Dissociation Constants
Acid (name)
Conjugate Base
(name)
pKa
Ka
HCOOH
(formic acid)
HCOO
(formate ion)
3.8
1.78  104
CH3COOH
(acetic acid)
CH3COO
(acetate ion)
4.8
1.74  105
H3PO4
(phosphoric acid)
H2PO4
(dihydrogen
phosphate ion)
2.1
7.24  103
H2PO4
(dihydrogen
phosphate ion)
HPO42
(hydrogen phosphate
ion)
6.9
1.39  107
HPO42
(hydrogen phosphate
ion)
PO43
(phosphate ion)
12.4
3.98  104
H2CO3
(carbonic acid)
HCO3
(bicarbonate ion)
6.3
5.1  107
HCO3–
(bicarbonate ion)
CO32
(carbonate ion)
10.3
5.62  10–11
NH4+
(ammonium ion)
NH3
(ammonia)
9.3
5.62  10–10
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Carbon Compounds
Organic Chemistry—the study
of carbon compounds.
There are over 12 million
known organic compounds.
Why carbon? Carbon has the
remarkable ability to bond in
multiple ways.
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Molecular Structures
Isomers are molecules with the same chemical formula (same number and kinds of
atoms), but with different structures and properties.
n-butane and iso-butane are isomers, each having a chemical formula of C4H10.
There are various representations for molecules, such as structural formulas, lineangle drawings, ball-and-stick formulas, or space-filling models:
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Molecular Representations
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Benzene Representations
Many molecules, including aspirin, glucose, and dopamine, have carbon atoms
arranged in a ring.
Rings most commonly contain five or six carbon atoms; many pharmaceutical drugs
and biomolecules contain 6-membered rings based on benzene, C6H6.
The benzene structure has two resonance forms, which alter the position of single and
double bonds. The actual structure of benzene features a hybrid of the two resonance
forms, which is drawn as dashed lines or a circle.
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Functional Groups
Functional groups—
arrangements of groups of
atoms which impart
characteristic physical and
chemical properties.
The presence and orientation
of functional groups are
responsible for the action of
all drugs. See Chapter 9 for
more info on functional
groups.
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Thyroxine: A Vital Hormone Precursor
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Enantiomers
Chiral molecules have 4 different
groups attached to a central
atom.
A chiral molecule and its nonsuperimposable mirror image are
a special kind of isomer called
enantiomers.
Enantiomers have identical
physical properties.
The only way we can tell them
apart is by seeing their effect on
plane-polarized light.
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Enantiomer Binding
However, the body can tell them apart. Two enantiomers will bind to receptor
sites very differently, and will therefore have different actions in the human
body.
One enantiomer fits into a receptor site, while the other does not. The
molecule on the right will have (possibly) no effect on the human body.
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Life via Protein
Function
Life depends on four major classes of
macromolecules: lipids (fats),
polysaccharides (sugars), nucleic acids,
and proteins.
Lipids: provide calories and comprise
the cellular membrane that controls
the passage of components into/out of
the cell.
Polysaccharides: vital for energy
storage, cellular structure, and
signaling.
Nucleic acids: regulate information in
your cells and are responsible for
heredity.
Proteins: contribute to the structure of
cells, guide chemical transformations,
and form conduits for signaling
between systems.
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Respiration
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The body uses glucose, a simple monosaccharide sugar, as a universal fuel across cells and
tissues.
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The combustion of glucose occurs via respiration, which requires oxygen and generates
carbon dioxide and water – same as traditional combustion reactions.
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Cellular respiration requires at least 25 enzymes located in 3 distinct cellular compartments.
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Glycolysis is the first stage of respiration, which converts intracellular glucose into 3-carbon
sugars. This step operates even in the absence of oxygen (anaerobic respiration), required for
many lower-order microorganisms such as yeast and bacteria.
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Remaining stages of respiration require oxygen and produce carbon dioxide. Each molecule
of glucose can be converted into 32 molecules of adenosine triphosphate, ATP.
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ATP is the chemical fuel of choice for many transformations in the cell.
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Hormones
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Cells do not spontaneously use glucose; this
is triggered by chemical signals known as
hormones, which are produced in endocrine
glands.
Hormones have a wide range of functions
and have diverse chemical compositions and
structures.
Thyroxine is a hormone secreted by the
thyroid gland, which is essential for
regulating metabolism.
Insulin is a hormone secreted by the
pancreas, which helps the body carry a
stable quantity of glucose through the blood.
Most hormones require receptors on the
cells they affect. This is designed to respond
perfectly and selectively to only one type of
hormone. The receptor changes in shape,
allowing the hormone to dock but not pass,
while still permitting information to be
transferred through the cellular membrane.
Binding Models
Small molecules must have the correct type of
functional groups to bind with high affinity and
specificity to a receptor protein, or within an
enzyme active site.
Three models describe possible binding modes:
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Lock-and-Key: the exact shapes of both
molecules are set before binding occurs.
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Induced Fit: molecules shift into the correct
position only upon binding.
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Conformational Selection: one of the
interacting partners switches between threedimensional shapes before the binding
event.
Steroids
Steroids perform many functions in the body:
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Function
Example Molecules
Regulation of secondary sexual
characteristics
Estradiol (an estrogen)
Testosterone (an androgen)
Regulation of the female
reproductive cycle
Progesterone
Regulation of metabolism
Cortisol
Digestion of fat
Cholic acid
Component of cellular
membranes
Cholesterol
Stimulation of muscle and bone
growth
Gestrinone
Trenbolone
Cholesterol
The structure of all steroids is based on a 17-carbon molecular framework, containing four rings:
The steroid cholesterol is required for the body to manufacture hormones, build cell walls, and
produce bile acids, which are essential for the breakdown and digestion of fats. Skin cells contain
a lot of cholesterol, making them highly water-resistant. However, too much cholesterol leads to
heart disease.
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Pain Relief from
Chemical Extraction!
In the 1760s, willow bark was evaluated as a
pharmaceutical precursor.
Small amounts of yellow, needle-shaped
crystals were extracted from willow bark, which
was separated into two components, only one
of which reduced fevers and inflammation:
salicyl alcohol.
Once in the body, metabolism converts salicyl
alcohol into salicylic acid. This was widely used
to treat pain, fever, and inflammation, but had a
very unpleasant taste and stomach irritation.
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Aspirin
Neutralization of the carboxylic acid group in salicylic acid with a base resulted in a salt
that had fewer side effects, and improved its water solubility and shelf life.
However, further modifications of its chemical structure were sought to remove most
side effects such as nausea. The reaction of salicylic acid with acetic acid resulted in
acetylsalicylic acid, which was given the trade name “Aspirin”. This molecule contains
an ester functional group.
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Drug Discovery—Serendipity
Sir Alexander Fleming, a British bacteriologist was working with Staphylococcus, a
bacteria.
A colleague working in same building was working with Penicillium notatum, a fungus
that produces penicillin.
Through a series of chance occurrences, penicillin was discovered!
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Classification of Drugs
Drugs may be broadly classified as:
• Those that cause a physiological response in the body (aspirin
anticancer drugs, morphine)
• Those that kill foreign invading organisms (antibiotics,
antifungal agents)
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Structure-Activity Relationship
The functional groups and their placement in three-dimensional space
determines to a large degree a molecule’s biological activity.
The portion of a molecule that determines the biological effects of a drug is
called the pharmacophore.
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Combinatorial Chemistry
Combinatorial chemistry is the systematic creation of large numbers of small
molecules in “libraries” that can be rapidly screened in vitro for potential new drugs.
The benefits of using combinatorial chemistry:
1. Many molecules can be created at a rapid rate.
2. The cost of the procedure is much cheaper than traditional molecule synthesis.
3. Large libraries of bioactive lead compounds can be produced relatively
inexpensively.
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