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Technologies Associated with Pharmaceuticals Drugs

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Title: Technologies Associated with Pharmaceuticals Drugs


1
Technologies Associated with Pharmaceuticals
(Drugs)
2
Drugs
  • Drug - substance, other than food or water, that
    affects how a body functions
  • Medicine or pharmaceutical - drug beneficial to
    human health
  • 25,000 prescription drugs and 300,000
    non-prescription drugs available in US

Suchocki, Chemistry, 2nd, Benjamin, 2004, 452
3
Study of Drugs
  • Two major components medicinal chemistry and
    pharmacology
  • Medicinal chemistry - the discovery,
    identification, synthesis, development of new
    drugs and optimization of existing drugs
  • Pharmacology - study of how chemical substances
    interact with living systems

4
Medicinal Chemistry
  • Drug Discovery
  • Drug Testing
  • Case Study

5
Medicinal Chemistry - discovery of new drugs
  • In the past most drugs have been discovered
    either by identifying the active ingredient from
    traditional remedies or by serendipitous
    discovery
  • Rational drug design is the approach of
    synthesizing drugs based on similarities in
    molecular structures.

http//encyclopedia.thefreedictionary.com/drugdis
covery
6
Natural Sources of Drugs
  • Most common natural sources of drugs are plants,
    animals, and fungi
  • 3000 new drugs are discovered annually from
    components of plants
  • Only 5000 plants out of estimated 250,000 have
    been studied exhaustively as drug sources
  • More than half of all plants exist solely in the
    tropical rain forests that are rapidly being
    destroyed by slash/burn agriculture

Suchocki, Chemistry, 2nd, Benjamin, 2004, 452
7
Discovery of Drugs from Natural Sources
  • Identification of new active compounds (called
    hits) by screening natural materials (plants,
    animals, fungi,etc) for desired biological
    properties
  • Optimization - synthetic modification of hits to
    obtain maximum potency and selectivity with
    minimum toxicity
  • Development - large scale production and
    formulation needed for clinical trials

http//encyclopedia.thefreedictionary.com/drugdis
covery
8
Process of Drug Testing
  • Preclinical trials on animals to establish safety
  • Then 4 phases of clinical trials on humans
  • Phase I - small group (20) of healthy humans
    determine safety pharmacokinetics (how drug is
    absorbed, metabolized, excreted) and
    side-effects
  • Phase II - several hundred persons with disease
    randomized/blinded trials using placebos ED50,
    TD50, therapeutic indices determined

http//www.huntington-study-group.org/WHAT20IS20
A20CLINICAL20TRIAL.html
9
Clinical Trials
  • ED50, effective dose - dose that produces
    therapeutic effect in 50 of test subjects
  • TD50, toxic dose - dose that produces specific
    unwanted side-effect in 50 of test subjects
  • Therapeutic index TD50/ED50 Large index means
    highly effective with low toxicity (rare)
  • Phase III - several thousand persons with
    disease risks/benefits fully assessed if
    approved by FDA goes on market
  • Phase IV - monitor for long-term effects
    determine pharmacodynamics of drug (how its acts
    on disease)

Waldron, Chemistry of Everything,Pearson,2007,
518-519
10
Case Study of a Drug
  • In 400 BC, Hippocrates, Father of Medicine, used
    an extract, prepared by boiling bark from a
    willow tree in water, to reduce fevers and pain
  • This folk remedy was used for centuries, but was
    not scientifically studied until 1827 when an
    active component, salicin, was isolated

Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
604
11
Salicin from willow bark reacts with water to
produce glucose and salicyl alcohol. In the
body, salicyl alcohol is oxidized to salicylic
acid which is the active substance that reduces
fever (antipyretic), pain (analgesic), and
inflammation (anti-inflammatory agent) in humans
Identification
(Metabolic change)
(Metabolite)
Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
605
12
Although salicylic acid reduces pain, fever, and
inflammation, it is far too corrosive to tissues
in the stomach to be taken internally by most
people. In 1893 Felix Hofman, a chemist working
for the Bayer firm in Germany, converted
salicyclic acid to acetylsalicylic acid which can
be better tolerated by most people.
Development current sales are about 80 billion
tablets per year in US alone.
Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
606
13
Pharmacology
  • Pharmacodynamics
  • Rational Drug Design
  • Analgesics

14
Pharmacology
  • Pharmacokinetics - what the body does to a drug
    how a drug is absorbed, metabolized, and
    eliminated by body
  • Pharmacodynamics - what a drug does to body
    common targets of drugs are substances involved
    in metabolic pathways (enzymes) or substances
    involved in signaling pathways (nervous system or
    endocrine system)

15
Pharmacodynamics - Basis for Drug Design
The model used to explain how drugs function is
essentially the same lock/key model that was used
to explain enzymes
Complementary forces (polarities and H-bonding
potentials)
Complementary topographies (sizes and shapes of
portions of surfaces of drug and of receptor
molecules)
Schaumberg, Concerning Chemistry,
Wiley,NY,1974,226 and 229
16
Drug Actions Based on Drug/Receptor Model
Drug
Drug can be an agonist (drug which fits and
activates a specific receptor) or antagonist (a
drug that fits and deactivates a specific
receptor by blocking receptor from its natural
substrate)
Staniski et al, Chemistry in Context,4th,McGraw
Hill, IA,2003, 407
17
Pharmacodynamics of Aspirin
Prostaglandins are biochemicals that initiate a
pain signal, inflammation, and fever.
Analgesic - a drug that enhances the ability to
tolerate pain without abolishing nerve
sensations. Aspirin is an antagonist - it fits
and blocks the enzyme site, thus decreasing
prostaglandin production.
Suchocki, Chemistry, 2nd, Benjamin, 2004, 485
18
Rational Drug Design of Other Analgesics
Drug design is based on QSAR - quantitative
structure activity relationships. Drugs that have
the same key donor groups in the same relative
locations in their structures likely form the
same drug/receptor complex and will exhibit
similar activities.
Analgesics have a benzene ring and CO separated
by one atom
Ibuprofen(Advil, Motrin)
Naproxen(Aleve)
Aspirin
Acetaminophen(Tylenol, Datril)
NSAID non-steroidal anti-inflammatory drug
Suchocki, Chemistry, 2nd, Benjamin, 2004, 486
19
Steroidal Anti-inflammatory Drugs
Helmprecht/Friedman, Basic Chemistry,McGraw
Hill,NY,1977, 365-9
20
Analgesics that Filter Pain Signals at Brain
Endorphins are present in brain in low
concentrations. Their function is to temporarily
filter out pain signals when under high stress
without interfering with other sensory signals.
QSAR both endorphin and morphine have benzene
ring and N separated by 3 C atoms. Morphine
functions as an agonist.
Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-10-11
21
Rational Drug Design
Structures of drugs can be modified to increase
effective-ness and reduce side effects
Crosses blood-brainbarrier faster thanmorphine
Snyder, Extraordinary Chemistry, Wiley, NY,1992,
611,612,618
22
Rational Drug Design
Keep removing structural parts of the drug
molecule until the irreducible minimum structure
required for drug activity is determined. A new
drug can then be synthesized containing the
active donor site with other functional groups to
adjust polarities of bonds in active site.
Schwartz et al, Chemistry in Context,Brown,
IA,1994,308
23
Other Drug Targets
  • Typically a drug target is a key molecule
    involved in a particular signaling pathway or a
    metabolic pathway that is specific to a disease
  • Signaling pathways involve two types of signal
    carriers chemical or a combination of electrical
    and chemical

24
Signal Pathways
  • A. Endocrine system chemical signaling in which
    substances (hormones) are secreted into blood by
    endocrine glands and carried by blood to the
    responding cell
  • B. Nervous system combination of chemical and
    electrical signaling in which electrical impulses
    to and from the brain are transmitted via the
    central nervous system

http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/S/Synapses.html
25
A. Drugs that Inhibit Nervous System Signaling
  • Nerves are tissues that carry electric signals to
    and from the brain
  • Unlike wires, nerves are not continuous but have
    tiny fluid-filled gaps called synapses
  • The transmission of the nerve signal across
    these gaps is by means of small molecules called
    neurotransmitters (usually water soluble peptides
    or amines)

http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/S/Synapses.html
26
Nervous System Signaling Neurotransmitters
27
Neurotransmitters and Catalysts
Neurotransmitters depend on catalysts for their
formation and degradation. Catalyst can be
blocked by an antagonist drug. Drugs that block
neurotransmission are called anesthetics.
Hill/Kolb, Chemistry for Changing Times, 8th,
Prentice Hall, NJ, 1998, 596
28
Rational Drug Design
QSAR acetylcholine has carbonyl and substituted
amine functional groups separated by several
atoms. Molecules having similar structures can
block catalysis needed for neurotransmission
(antagonists)
Cocaine
Novocaine
Xylocaine
Snyder, Extraordinary Chemistry, Wiley, NY,1992,
620
29
Analgesics, Anesthetics, and Pain Relief
Suchocki, Chemistry, 2nd, Benjamin, 2004, 483
30
B. Endocrine Signaling Hormones
  • Water soluble hormones proteins, peptides,
    modified amino acids, amines
  • Lipid soluble hormones steroids
  • Hormones are extremely potent
  • Can isolate only 5 mg of testosterone (male
    hormone) from 1 ton of bull testes or 12 mg of
    estradiol (female hormone) from 4 tons of pig
    ovaries

31
Production Sites for Hormones
http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/E/Endocrines.gif
32
Transportof Hormones
Biomolecules are large, but only a small portion
of a biomolecule (receptor) is involved in
signaling
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
33
Mechanism of Signaling by Water Soluble Hormones
Water soluble hormones (proteins) act on surface
receptors and do not enter the cell
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
34
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
35
Mechanism of Signaling by Lipid Soluble Hormones
Lipid soluble hormones (steroids) pass through
the cell membrane, form a receptor-steroid
complex that enters nucleus of cell and activates
a specific gene
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
36
Steroid Sex Hormones - Lipids
Norethinodrone mimics progesterone and sends a
false message that a pregnancy has been
established thus stopping ovulation
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 407-408
37
Safe Estrogen Mimics - the Pill used since 1960
These two estrogen agonists are the components of
the first birth control pill called Enovid.
Long-term usage has shown them to be relatively
safe.
Hill/Kolb, Chemistry for Changing Times, 8th,
Prentice Hall, NJ, 1998, 554
38
Female Hormone
Progesterone activity is essential for
implantation of the embryo in uterine cells,
without this activity, the developing embryo is
spontaneously aborted
Schwartz et al, Chemistry in Context,Brown,
IA,1994,316
39
Drugs that Inhibit Metabolic Pathways
(Anti-metabolites)
Folic acid is required to maintain strength of
cell walls. Bacteria synthesize folic acid
enzymatically using PABA.
Humans obtain folic acid from food and do not
synthesize it. The bacterial enzyme can be
blocked by a drug of proper design.
Suchocki, Chemistry, 2nd, Benjamin, 2004, 458
40
Rational Drug Design
Sulfanilamide - antimetabolite that was the first
antibiotic
Suchocki, Chemistry, 2nd, Benjamin, 2004, 459
41
Rational Drug Design
Substituting R groups for H on amine group
changes polarities and hence strength of forces
binding drug/receptor complex. Over 5000
derivatives were made and studied.
Hardwick/Knobler, Chemistry Man and Matter,
Ginn, MA,1970, 444
42
Nitrogen Mustard - antimetabolites that was the
first drug used in cancer chemotherapy
Nitrogen mustards are less toxic nitrogen
derivatives of highly toxic mustard gas
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 404
43
Pharmacodynamics
N-mustard covalently links the two strands of DNA
together making it impossible for cell division
to occur since DNA cannot replicate. The covalent
cross-link, -CH2-CH2-N-CH2 -CH2- ,
isrepresented by the black rectangle. Functions
as an antimetabolite which interferes with
replication.
44
Rational Drug Design
Current chemotherapy uses cyclophosphamide, which
reduces nausea.
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 404
45
Rational Drug Design - drug designed for prostate
cancer - currently in pre-clinical trials
15 atom-chain
CEN, ACS, 8/22/05, 38
46
Proposed Pharmacodynamics
ChemBiol, Vol 12, 779-787, July, 2005
47
Low Success Rate in Drug Development
  • 1/50 tested shows promising bio-activity
  • 1/100 modifications of these is useful
  • 1/10 of these successfully passes clinical trials
    and becomes a market-able drug
  • Low success rate (and high legal costs) translate
    to high cost to consumer

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-2
48
Causes of Low Success Rate
  • Drug must have appropriate solubility
    characteristics (fat versus water)
  • Drug must be reasonably resistant to chemical
    degradation in the body
  • Drug must not interfere with any other aspects of
    biochemistry of the body
  • Drug must have a specific structure to be able to
    elicit a specific response

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-2
49
Structural Complication
Optical Isomers - two different drugs with same
atoms, same bonds, but different spatial
orientations
Levomethorphan is an addictive analgesic
prescription drug, while Dextromethorphan is
non-addictive and can be sold over-the- counter
as a cough suppressant. What is the structural
difference?
Schwartz et al, Chemistry in Context,Brown,
IA,1994,303,410
50
Testing for Optical Isomers
View-1
View-2
Superimposable
Two views of the same molecule
Superimposable means that the structures match -
i.e., they have the same kinds of atoms in the
same locations when the structures are placed on
top of each other.
If structures are superimposable, they represent
different views of the same molecule and are not
isomers.
Bettleheim/March, Organic and Biochemistry,2 nd,
Saunders, PA, 1995, 253
51
Testing for Optical Isomers
Isomer-I
Isomer-2
Non-superimposable
Two different molecules
Molecules that are non-superimposable mirror
images to each other are two different molecules
and are called optical isomers.
Any molecule containing a chiral carbon atom (one
that has four different groups bonded to it) has
two optical isomers.
Bettleheim/March, Organic and Biochemistry,2 nd,
Saunders, PA, 1995, 251
52
Optical Isomers of Ibuprofen
Ibuprofen has a chiral carbon Which carbon atom
is the chiral C-atom?
Only one of the two isomers is physiologically
active.
The same reaction that produces L-ibuprofen also
produces D-ibuprofen so that a 50-50 mixture
(called racemic mixture) is obtained.
Over-the-counter ibuprofen is the racemic
mixture.
Why don't optical isomers have the same
properties?
Schwartz et al, Chemistry in Context,Brown,
IA,1994,303,410
53
Drug molecules that exist as optical isomers do
not fit the same receptor site and hence do not
have the same therapeutic properties. One may be
useful while the other may be either harmless
(ibuprofen) or could have other properties such
as annoying or even dangerous side-effects.
Mirror Image
Molecule
54
Optical Isomers of Thalidomide
Sedative
Teratogen (birth defects)
http//www.le.ac.uk/chemistry/teach/year1/LECT8_fi
les/image014.gif
55
Optical Isomers of Thalidomide
http//colossus.chem.umass.edu/genchem/chem102/Art
icles/Article_Images/thalid3.jpg
56
Taxol - drug used in treating breast cancer
Number of optical isomers 2n where n number
of chiral carbon atoms in the molecule. The more
chiral centers in a molecule, the more difficult
it is to manufacture the drug.
Taxol has 1024 optical isomers!
http//adeviq-spin.mega.com.pl/taxolred.gif
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