Lecture 2

Classification and the Chemistry of Pharmaceutical Products

The Top Ten Drugs

1. Lipitor® (atorvastatin)

• This pyrrole derivative is a synthetic lipid-lowering agent for hyperlipidemia.

- to reduce elevated total and low-density ipoprotein (LDL) cholesterol levels.
- increases levels of high-density lipoprotein (HDL) cholesterol, (the "good"
cholesterol)
- prescribed for atheroschlerosis (hardening of the arteries), diabetes-related
blood-fat problems, preventing heart attacks and strokes, and reducing the
risk of cardiac bypass surgery. 1
2. Premarin® (conjugated estrogens)

• This is a mixture of female sex hormones (estrone, equilin, and 17a-

dihydroequilin).
• It is used to improve menopausal symptoms and problems.

• There is a decreased production of estrogens during menopause, which causes a

weight increase, hot flashes, and psychological problems. This mixture takes the
place of those estrogens.

• However, there is an increased risk of cancer of the uterus in women who take this
for more than a year.
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3. Synthroid® (levothyroxine)

• Levothyroxine (T4) is used to treat hypothyroidism (an underactive thyroid gland).

• Levothyroxine is one of two important thyroid hormones.

• It is converted into the second important hormone, liothyronine (T3), in the
body.

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4. Prilosec® (omeprazole)

• Omeprazole is an antiulcer drug. It is a proton pump inhibitor.

• This substituted benzimidazole inhibits gastric acid secretion to help acid/peptic

disorders and duodenal ulcers caused by an infection with a germ (bacterium).

• It interferes with the proton pump in the mucous lining of the stomach, the last
stage of acid production.

• It can turn off stomach acid in as little as one hour. Lansoprazole has a similar
structure.

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5. Norvasc® (amlodipine)

• Amlodipine is a calcium channel blocker used to treat hypertension.

• Calcium channel blockers block the passage of calcium, an essential factor in muscle
contraction, into the heart and smooth muscles.
• Such blockage interferes with the contraction (become smaller) of these muscles,
which in turn dilates the veins that supply blood to them. This reduces blood
pressure.

amlodipine

6. Glucophage® (metformin)

• This is an antihyperglycemic drug for non-insulin dependent diabetes.

• It is a blood glucose regulator. It lowers the amount of glucose produced by the
liver, reduces the amount of glucose absorbed from food, and helps cells use
glucose. metformin
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 ANTIBACTERIAL AGENTS (sulfa drugs and penicillins)

• Before the 1930s bacterial diseases were a major cause of death.

• Pneumonia and tuberculosis were major killers. Since the advent of the sulfa
drugs and penicillins many bacterial diseases have been controlled.

• Some of antibiotics, an antibacterial substance are produced by a living

organism such as a bacterium or fungus, rather than synthesized in the
laboratory.

• There are four general properties for a good antibacterial agent.

- It must be selective.
- Eliminating all species of bacteria from the body that may leave the patient
prone to super infection.
- It should kill bacteria rather than just prevent their multiplication; it should be
bactericidal rather than bacteriostatic.
- Bacteria should not develop resistance to the drug.
- Lastly, absorption of the drug into the body should be rapid and maintained
the desired level in the body for long periods.
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Sulfa Drugs (Sulfonamides)

• Sulfonamides (known as sulfa drugs) represent the best example of antibacterial

agents before the discovery of penicillin.

• In 1935, a red dye called Prontosil was discovered to have antibacterial

properties in vivo (i.e., when given to laboratory animals). No antibacterial effect was
observed in vitro (i.e., Prontosil could not kill bacteria grown in a test tube).

• This result remained a mystery until it was discovered that Prontosil was not the
antibacterial agent.

• It was found that the Prontosil was metabolized by bacteria present in the small
intestine of the test animal, and broken down to the active ingredient p-
aminobenzenesulfonamide, or sulfanilamide. He won the 1939 Nobel Prize in
medicine for this discovery.

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• The synthesis of a large number of sulfonamide analogues led to the following
conclusions:

1. The p-amino group is essential for the activity and must be unsubstituted
(R=H).
2. The aromatic ring and the sulfonamide group are both needed.
3. The aromatic ring must be para-substituted only.
4. The sulfonamide nitrogen must be secondary.

• Certain human genotypes are more susceptible to one type of sulfonamides than
others.

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The mode of action of sulfonamides

• They are bacteriostatic. Sulfanilamide mimics 7-aminobenzoic acid (PABA),

essential for incorporation into enzymes regulating bacterial growth but
nonessential for human growth.
• The bacteria mistake sulfur for carbon, form inactive enzymes, and cannot grow.
• If an alkyl, alkoxy, or other functional group is substituted for the p-amino
group all activity is lost. Groups at the ortho- and meta positions cause inactivity.

• Sulfa drugs have been largely replaced by antibiotics because they have a
relatively narrow antibacterial spectra, low potency, and cause rapid development
of resistance in the bacteria.

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Penicillin (Antibiotics)

• In 1929 Fleming discovered that certain molds contained antibiotics. This initial
report was studied in detail by Chain and Florey and all three won the Nobel Prize in
Medicine for 1945 because of their discovery of the penicillins.

• Over 30 penicillins have been isolated from various fermentation mixtures and over
2000 different R groups have been made synthetically.

• General structure shows that a four-membered ring amide, or -lactam, structure is

fused to a five-membered thiazolidine ring. The skeleton of the molecule suggests
that it is derived from the amino acids cytosine and valin.

five-membered
thiazolidine
ring

four-membered ring
amide, or -lactam

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The mode of action of penicillins

• They work by inactivating enzymes that are essential for cell wall development. As
a result, the bacteria are enclosed only by a fragile cell membrane and they do not
survive.
Corn steep liquor is a by-product of
corn wet-milling. A viscous concentrate of
corn solubles which contains amino acids,
vitamins and minerals, it is an important
Synthesis of penicillins constituent of some growth media.

• Although total syntheses of the penicillin have been reported, they are not
yet a feasible alternative to large-scale fermentation.
• Large tanks from 5,000-30,000 gal capacities are used.
• The mold grows best at 23-25C, pH 4.5-5.0.
• The fermentation broth is made from corn steep liquor with lactose and inorganic
materials added.
• Sterile air permits growth of the mold over a 50-90-hr period.
• The penicillin is separated by solvent extraction.
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• For years the most popular
penicillin was a natural one,
penicillin G, but it is not acid hydrolyze
stable. The strong acid in the
stomach leads to hydrolysis of
the amide side chain and a -
lactam opening and is
absorbed poorly through the
intestine.
.
• Penicillin G can be hydrolyzed
in the laboratory to 6-
aminopenicillanic acid, which
can be acetylated to the more
acid-resistant penicillin V and
ampicillin, both of which can be
taken orally.

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• Ampicillin has a broader spectrum of both gram-positive and gram-negative
antibacterial activity than G or V.

• Amoxicillin gives more complete absorption through the intestines and causes
less diarrhea. There is little or no effect of food on its absorption rate. It has
become the most important antibacterial.

• Both in ampicillin, or amoxicillin has an amino hydrophilic group.

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