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Technologies Associated with Pharmaceuticals (Drugs). 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.

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drugs
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

study of drugs
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
medicinal chemistry

Medicinal Chemistry

Drug Discovery

Drug Testing

Case Study

medicinal chemistry discovery of new drugs
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/drug+discovery

natural sources of drugs
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

discovery of drugs from natural sources
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/drug+discovery

process of drug testing
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/WHAT%20IS%20A%20CLINICAL%20TRIAL.html

clinical trials
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

case study of a drug
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

slide11

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

slide12

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.

Optimization

Development: current sales are about 80 billion tablets per year in US alone.

Snyder, Extraordinary Chemistry, Wiley, NY, 1992, 606

pharmacology

Pharmacology

Pharmacodynamics

Rational Drug Design

Analgesics

pharmacology14
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)
slide15

Pharmacodynamics - Basis for Drug Design

(Substrate)

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

slide16

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

slide17

Pharmacodynamics of Aspirin

*

**

Arachidonic acid

*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

slide18

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 C=O separated by one atom

Aspirin*

Ibuprofen*(Advil, Motrin)

Naproxen*(Aleve)

Acetaminophen(Tylenol, Datril)

*NSAID = non-steroidal anti-inflammatory drug

Suchocki, Chemistry, 2nd, Benjamin, 2004, 486

slide19

Steroidal Anti-inflammatory Drugs

Anti-inflammatory Steroids

Hydrocortisoneagonist

Cortisoneagonist

Helmprecht/Friedman, Basic Chemistry,McGraw Hill,NY,1977, 365-9

slide20

Analgesics that Filter Pain Signals at Brain

An Endorphin peptide

3

2

1

3

2

1

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

slide21

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

slide22

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

other drug targets
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
signal pathways
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/BiologyPages/S/Synapses.html

a drugs that inhibit nervous system signaling
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/BiologyPages/S/Synapses.html

slide26

Nervous System Signaling: Neurotransmitters

acetylase

Hill/Kolb, Chemistry for Changing Times, 8th, Prentice Hall, NJ, 1998, 596

slide27

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

slide28

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

slide29

Analgesics, Anesthetics, and Pain Relief

Suchocki, Chemistry, 2nd, Benjamin, 2004, 483

b endocrine signaling hormones
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
slide31

Production Sites for Hormones

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Endocrines.gif

slide32

Transportof Hormones

Receptors

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

slide33

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

slide34

http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.htmlhttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html

slide35

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

slide36

Steroid Sex Hormones - Lipids

Female Hormone

Male Hormone

Agonist

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

slide37

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

slide38

Female Hormone

Abortion Pill

Large extra ring makes RU-486 an antagonist for progesterone, i.e., occupies and blocks the progesterone receptor site, but causes no biological activity

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

slide39

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

slide40

Rational Drug Design

Sulfanilamide - antimetabolite that was the first antibiotic

Suchocki, Chemistry, 2nd, Benjamin, 2004, 459

slide41

Rational Drug Design

Replace one H of NH2 group

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

slide42

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

slide43

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.

slide44

Rational Drug Design

Current chemotherapy uses cyclophosphamide, which reduces nausea.

Joesten et al, Chemistry: Impact on Society,Saunders,Phildelphia,1988, 404

slide45

Rational Drug Design - drug designed for prostate cancer - currently in pre-clinical trials

N-mustard

Steroid

15 atom-chain

C&EN, ACS, 8/22/05, 38

slide46

Proposed Pharmacodynamics

Chem&Biol, Vol 12, 779-787, July, 2005

low success rate in drug development
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

causes of low success rate
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

slide49

Structural Complication

Mirror

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

slide50

Testing for Optical Isomers

View-1

View-2

Two views of the same molecule

Superimposable

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

slide51

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

slide52

Optical Isomers of Ibuprofen

Chiral atom

(Inactive)

(Analgesic)

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

slide53

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.

Receptor-1

Receptor-1

Mirror Image

Molecule

slide54

Chiral atom

Chiral atom

Optical Isomers of Thalidomide

Sedative

Teratogen (birth defects)

http://www.le.ac.uk/chemistry/teach/year1/LECT8_files/image014.gif

slide55

Optical Isomers of Thalidomide

http://colossus.chem.umass.edu/genchem/chem102/Articles/Article_Images/thalid3.jpg

slide56

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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