Pharmacology

1
Pharmacology
Lecture 1A

• Dr. Martha I. Dávila-García
• Course Coordinator
• Fall 2005

2
Introduction
 
  HOWARD UNIVERSITY    

• Syllabus
• Please read your syllabus carefully
• and consult it repeatedly.

3
Introduction

• What is pharmacology?
• Why do we need to take pharmacology?
• Significance of pharmacology to Dentistry

4
History of Pharmacology

• A history of pharmacology
• Ancient Times A series of scattered facts exists
  that speak of the early history of humankind's
  efforts to harness the healing properties of
  natural compounds. However, what we know for
  certain is that ancient peoples made extensive
  use of plant, animal and mineral sources for this
  purpose.

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History of Pharmacology

• The Ebers papyrus, written in Egypt in the 16th
  century B.C., lists the extensive pharmacopia of
  that civilization. Included in this are beer,
  turpentine, myrrh, , juniper

berries., poppy, lead, salt and crushed precious
stones. Also included were products derived from
animals, including lizard's blood, swine teeth,
goose grease, ass hooves and the excreta from
various animals. The effects of many of these
drugs on patients of antiquity can only be
imagined.
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History of Pharmacology

• From ancient China comes evidence of that
  culture's extensive efforts to heal through the
  use of natural products. The Pen Tsao, or Great
  Herbal, comprised forty volumes describing
  several thousands of prescriptions.

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History of Pharmacology

• Interestingly, the eastern herb Artemisia annua
  L. (wormwood), used in China since antiquity to
  treat fevers, is the source of the modern drug
  qinghaosu, which shows great promise as a modern
  anti-malarial compound.

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History of Pharmacology

• Antiquity to the modern eraThe ancients
  considered disease a consequence of demonic
  possession, or the wrath of god. Thus, in ancient
  times, the treatment of illness with natural
  products was invariably accompanied by religious
  rituals deemed essential to the healing process.

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History of Pharmacology

• With time, the thoughts returned to the
  appreciation that the natural products themselves
  held the power to cure.

Although, traditional remedies still generally
consisted of complex mixtures of distinct herbs
and minerals, perhaps only one of which possessed
any activity. Many poisonous mixtures were made.
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History of Pharmacology

• For example, the purple foxglove, Digitalis
  purpurea, was one of twenty herbs used in a folk
  remedy to treat dropsy in 18th century England.
  From the leaves of this plant was isolated the
  cardiac glycoside digitalis, a drug still used
  today to treat heart failure.

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History of Pharmacology

• Over time, as a more sophisticated view of
  illness evolved, an increasingly scientific
  approach to the isolation of drugs from natural
  products was taken. In the early 19th century,

morphine was isolated from the opium poppy
(Papaver somniferum) and the anti-malarial
compound quinine from the bark of the cinchona
tree (Cinchona officinalis).
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History of Pharmacology

• Materia Medica
• The ancient discipline of Materia Medica was
  born, devoted to understanding the origin,
  preparation and therapeutic applications of
  medicinal compounds.
• It postulated that
• Each disease has a unique cause for which there
  is a specific remedy.

• Each remedy has an identifiable nature or
  essence that is extracted from the natural
  product by chemical extraction.
• The administration of a remedy is based on
  testing the amount of drug needed to achieve an
  effect (dose-response).
• From Stata Norton

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History of Pharmacology

• In 1897, Felix Hoffman, a research chemist
  employed by the "Farbenfabrikin vorm. Freidr.
  Bayer and Co." synthesized acetylsalicylic acid.
  On February 1, 1899, Aspirin was registered as a
  trademark. On March 6th of the same year, this
  drug was registered with the Imperial Patent
  Office in Berlin. Aspirin quickly become popular

worldwide, and remains an important drug today.
(Interestingly, it was not until 1971 that Sir
John Vane discovered the mechanism of action of
aspirin, a feat that earned him the 1981 Nobel
Prize for Medicine.)
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History of Pharmacology
Paul Ehrlich described drug-receptor
binding Corpora non agunt nisi fixate. P.
Ehrlich (1908)   (Agents do not act unless they
are bound) In the United States, transformation
was marked by the creation of the American
Society for Pharmacology and Experimental
Therapeutics (ASPET) in 1908.
15
History of Pharmacology

• The modern eraThese, and additional advances in
  the fields of chemistry and physiology, lead to
  the birth of modern pharmacology in the latter
  half of the 19th century. Thus, Materia Medica
  evolved into the

experimental science of pharmacology, which is
devoted to understanding the physiological action
of these molecules.
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History of Pharmacology

• The 20th century has witnessed the discovery of
  a steady stream of important new drugs that have
  immeasurably improved the human condition.
• Not very long ago, vast numbers of humans
  perished prematurely or suffered an existence
  filled with pain due to the effects of infection
  or disorders that are now successfully treated.
• chemotherapy of cancer
• microbial infections
• diabetes
• hypertension
• depression
• AIDS

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Pharmacology

• DEFINITIONS
• Pharmacology is the study of how drugs exert
  their effects on living systems.
• Pharmacologists work to identify drug targets in
  order to learn how drugs work. Pharmacologists
  also study the ways in which drugs are modified
  within organisms.
• In most of the pharmacologic specialties, drugs
  are also used today as tools to gain insight into
  both normal and abnormal function.

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Pharmacology

• Divisions of Pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Pharmacogenomics

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Pharmacokinetics

• Is what the body does to the drug.
• The magnitud of the pharmacological effect of a
  drug depends on its concentration at the site of
  action.
• Absorption
• Distribution
• Metabolism
• Elimination

20
Pharmacodynamics

• Is what the drug does to the body.
• Interaction of drugs with cellular proteins,
  such as receptors or enzymes, to control changes
  in physiological function of particular organs.
• Drug-Receptor Interactions
• Binding
• Dose-Response
• Effect
• Signal Transduction
• Mechanism of action, Pathways

21
Pharmacogenetics

• Area of pharmacology concerned with unusual
  responses to drugs caused by genetic differences
  between individuals.
• Responses that are not found in the general
  population, such as general toxic effects,
  allergies, or side effects, but due to an
  inherited trait that produces a diminished or
  enhanced response to a drug.
• Differences in Enzyme Activity
• Acetylation polymorphism
• Butylcholinesterase alterations
• Cytochrome P450 aberration

22
Drugs
 
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• Drugs can be defined as chemical agents that
  uniquely interact with specific target molecules
  in the body, thereby producing a biological
  effect.

Drugs can be stimulatory or inhibitory
23
Drugs

• Drugs, as well as hormones, neurotransmitter,
  autocoids and toxins can make possible the
  transfer of information to cells by interaction
  with specific receptive molecules called
  receptors.

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Drugs

• Drugs interact with biological systems in ways
  that mimic, resemble or otherwise affect the
  natural chemicals of the body.
• Drugs can produce effects by virtue of their
  acidic or basic properties (e.g. antacids,
  protamine), surfactant properties (amphotericin),
  ability to denature proteins (astringents),
  osmotic properties (laxatives, diuretics), or
  physicochemical interactions with membrane lipids
  (general and local anesthetics).

25
Receptors

• Most drugs combine (bind) with specific receptors
• to produce a particular response. This
  association or binding takes place by precise
  physicochemical and steric interactions between
  specific groups of the drug and the receptor.
• Proteins
• Carriers
• Receptors
• G protein-linked
• Ligand gated channels
• Intracellular
• Enzymes
• DNA

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Endogenous compounds act on their Receptors
Neurotransmitter Neuropeptides Hormones Ions
http//www.morphonix.com/software/education/scienc
e/brain/game/specimens/neurotransmitters.gif
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Receptor
Classification of Receptors

• Pharmacological
• Mediator (i.e. Insulin, Norepinephrine,
  estrogen)
• Biophysical and Biophysical
• Second messenger system (i,.e. cAMP, PLC, PLA)
• Molecular or Structural
• Subunit composition (i.e. 5HT1A )
• Anatomical
• Tissue (i.e muscle vs ganglionic nAChRs)
• Cellular (i.e. Membrane bound vs Intracellular)

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Types of Receptors

• MEMBRANE BOUND RECEPTORS
• G-Protein-linked receptors
• Serotonin, Muscarinic, Dopaminergic,
  Noradrenergic
• Enzyme receptors
• Tyrosine kinase
• Ligand-gated ion channel receptors
• Nicotinic, GABA, glutamate
• INTRACELLULAR AND NUCLEAR RECEPTORS
• Hormone receptors
• Autocoid receptors
• Growth factors receptors
• Insulin receptors

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G Proteinlinked Receptors
http//www.sp.uconn.edu/bi107vc/images/anim/Sigtr
anRA.gif
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Enzyme-like Receptors
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Ligand-gated Ion-Channel Receptors
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Nuclear Receptors
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Drug-Receptor Interactions
Physicochemical and steric interactions

• 1)      Lipophilic
• 2)      Hydrophilic
• 3)      Ionic
• 4)      Hydrogen bonds
• 5)      Steric (stereospecificity) effects
• 6)      Electronic effect
• 7)      pK effects

34
Drug-Receptor Interactions
Chemical Bonds
Van der Waals Interactions
Hydrophobic Interactions
35
Drug-Receptor Interactions

• Drug-receptor interactions serve as signals to
  trigger a cascade of events. This cascade or
  signaling pathway, is a collection of many
  cellular responses which serve to amplify the
  signal and produce a final effect.
• Effectors are thus the molecules that translate
  the drug-receptor interaction into changes in
  cellular activity.
• ? ? ? ? ? ? ? ? ? ? ??? ?
  EFFECT
• DRUG DRUG RECEPTOR DRUG RECEPTOR
  EFFECTOR EFFECTOR
• INTERACTION
  COMPLEX
  SYSTEM
• STIMULUS BINDING ACTIVATION
  TRANSDUCTION AMPLIFICATION RESPONSE

SIGNALLING PATHWAY

36
Receptor Signaling Pathways

• Second Messengers
• Ions (Ca2, Na, K, Cl-)
• cAMP, cGMP, IP3, Diacylglycerol
• DNA binding Transcriptional regulation.
• Phosphorylated proteins and enzymes via tyrosine
  kinase receptors.
• Third Messengers
• Enzymes (PKC, PKA)
• Ions (Ca2, K)

37
Receptor Signaling Pathways
EFFECTORS
SECOND MESSENGER
cAMP cGMP DAG and IP3 Arachidonic acid NO and
CO Na, Ca2, K, Cl-

• Adenylate Cyclase (AC)
• Guadenylyl Cyclase (GC)
• Phospholipase C (PLC)
• Phospholipase A (PLA2)
• Nitric oxide Synthase
• Ions

38
Receptor Signaling Pathways
R
R
R
R
39
Receptor Signaling Pathways
40
Drug-Receptor Interactions

• Theory and assumptions of drug-receptor
  interactions.
• Drug Receptor interaction follows simple
  mass-action relationships, i.e. only one drug
  molecule occupies each receptor and binding is
  reversible (We know now there are some
  exceptions).
• For a given drug the magnitud of the response is
  proportional to the fraction of total receptor
  sites occupied by drug molecules.
• Combination or binding to receptor causes some
  event which leads to a response.
• Response to a drug is graded or dose-dependent.

41
Law of Mass Action

• When a drug (D) combines with a receptor (R), it
  does so at a rate which is dependent on the
  concentration of the drug and the concentration
  of the receptor.
• D drug
• R receptor
• DR drug-receptor complex
• k1 rate for association
• k2 rate for dissociation
• KD Dissociation Constant
• KA Affinity Constant
•   Read the Appendix at the back of
  lecture 1B

k1
D R ? DR
k2 k2 KD DR k1
DR 1 KA k1
DR KD k2 D R