Transcript Introduction to Pharmacology

Introduction to Pharmacology
Dr. SA Ziai
Pharmacology
• Pharmacology can be defined as the study of
substances that interact with living systems
through chemical processes, especially by binding
to regulatory molecules and activating or
inhibiting normal body processes.
• These substances may be chemicals administered
to achieve a beneficial therapeutic effect on some
process within the patient or for their toxic
effects on regulatory processes in parasites
infecting the patient.
Toxicology
• Toxicology is the branch of pharmacology that
deals with the undesirable effects of chemicals
on living systems, from individual cells to
humans to complex ecosystems
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.
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.
Galen’s Influence on Medicine lasted
>1500 years…
present day language reflects Galen’s influence:
“phlegmatic personality” … “a bilious person”
“melancholy” … “in good humor”
Some of Galen’s “remedies” for righting these
imbalances were based on ancient practices (e.g.
bloodletting)
By 1737, 73 per cent of patients at the British Royal
Infirmary experienced bloodletting as part of their
treatment…
popularity peaked in the early 19th century through the
use of leeches
Precursors to “Scientific” Drug Development
“Chymical remedies” – 16th century remedies
based on ideas of the Swiss physician Philippus
Aureolus Theophrastus Bombastus von
Hohenheim (1490-1541), better known as
PARACELSUS
-- he held Galen in contempt
Started in 1623, the “medicinal garden” of Oxford
University was growing over 600 native plants
and over 1000 plants from all over the world by
1650
• Around the end of the 17th century, and
following the example of the physical sciences,
reliance on observation and experimentation
began to replace theorizing in medicine
• Materia medica—the science of drug
preparation and the medical use of drugs—
began to develop as the precursor to
pharmacology.
• In the late 18th and
early 19th centuries,
François Magendie, and
later his student Claude
Bernard, began to
develop the methods of
experimental
physiology and
pharmacology.
• Advances in chemistry and the further
development of physiology in the 18th, 19th,
and early 20th centuries laid the foundation
needed for understanding how drugs work at
the organ and tissue levels.
History of Pharmacology
• Paradoxically, real advances in basic
pharmacology during this time were
accompanied by an outburst of unscientific
claims by manufacturers and marketers of
worthless "patent medicines."
• Not until the concepts of rational therapeutics,
especially that of the controlled clinical trial,
were reintroduced into medicine—only about 60
years ago—did it become possible to accurately
evaluate therapeutic claims.
• Unfortunately, manipulation of the legislative
process in the United States has allowed many
substances promoted for health—but not
promoted specifically as "drugs"—to avoid
meeting the Food and Drug Administration
standards
• During the last half-century, many
fundamentally new drug groups and new
members of old groups were introduced.
• The last three decades have seen an even
more rapid growth of information and
understanding of the molecular basis for drug
action.
Pharmaceutical Industry
• Much of the recent progress in the application
of drugs to disease problems can be ascribed
to the pharmaceutical industry and specifically
to "big pharma," the multibillion-dollar
corporations that specialize in drug discovery
and development.
August 10, 1897: Felix
Hoffmann, a chemist working
at Farbenfabriken vorm.
Friedr. Bayer & Co., recorded
in his laboratory logbook that
he had succeeded in
acetylating salicylic acid into
a chemically pure and stable
form of acetylsalicylic acid
(ASA). (easier to “stomach” in
its acetylated form)…
Within the same month (in fact
only two weeks later Felix
Hoffmann in acetylates morphine
into diacetylmorphine…
Pharmacogenomics
• or pharmacogenetics is the study of the
genetic variations that cause differences in
drug response among individuals or
populations.
• Gene therapy
• knockout mice
• Knockdown
• Knockin
The Nature of Drugs
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Agonist
Antagonist
Receptor
Chemical antagonist
Hormones
Xenobiotics
Poisons "the dose makes the poison" Paracelsus
Toxins
The Physical Nature of Drugs
• Drugs may be solid at room temperature (eg,
aspirin, atropine), liquid (eg, nicotine,
ethanol), or gaseous (eg, nitrous oxide).
• A number of useful or dangerous drugs are
inorganic elements, eg, lithium, iron, and
heavy metals.
• Many organic drugs are weak acids or bases.
• To interact chemically with its receptor, a drug
molecule must have the
– appropriate size
– electrical charge
– shape
– atomic composition
Drug Size
• The molecular size of drugs varies from very
small (lithium ion, MW 7) to very large (eg,
alteplase [tPA], a protein of MW 59,050).
• However, most drugs have molecular weights
between 100 and 1000
• To have a good "fit" to only one type of
receptor, a drug molecule must be sufficiently
unique in shape, charge, and other properties,
to prevent its binding to other receptors.
Drug Reactivity and Drug-Receptor
Bonds
• Drugs interact with receptors by means of
chemical forces or bonds. These are of three
major types:
• Covalent
– Aspirin, DNA-alkylating agents
• Electrostatic
– Ionic, hydrogen bond, van der waals
• Hydrophobic
Drug Shape
Dissociation Constants (Kd) of the
Enantiomers and Racemate of
Carvedilol.
Form of Carvedilol
R(+) enantiomer
S(–) enantiomer
R,S(±) enantiomers
αReceptors (Kd, nmol/L) βReceptors (Kd, nmol/L)
14
16
11
45
0.4
0.9
Enantiomers
• Transport
• Duration of action
• As a result, many patients are receiving drug
doses of which 50% or more is less active,
inactive, or actively toxic.
Intrinsic efficacy is independent of affinity for
the receptor.
Agonists, Partial Agonists, and Inverse
Agonists
• Constitutive activity
• Full agonists
• Partial agonists
– Pindolol
• Intrinsic efficacy
• Neutral antagonism
• Inverse agonists
Competitive & Irreversible Antagonists
• The degree of inhibition produced by a
competitive antagonist depends on the
concentration of antagonist.
• Clinical response to a competitive antagonist
depends on the concentration of agonist that
is competing for binding to receptors.
Irreversible antagonists advantages
and disadvantages.
• The duration of action of such an irreversible
antagonist is relatively independent of its own
rate of elimination and more dependent on
the rate of turnover of receptor molecules.
• If overdose occurs, however, a real problem
may arise
• Duration of Drug Action
– The action may persist after the drug has
dissociated
– Drugs that bind covalently to the receptor site
• Acetylcholinesterase inhibitors
Macromolecular Nature of Drug
Receptors
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Regulatory proteins
Enzymes
Transport proteins
Structural proteins
Concentration-Effect Curves &
Receptor Binding of Agonists
Potency & maximal efficacy
• Potency refers to the
concentration (EC50) or dose
(ED50) of a drug required to
produce 50% of that drug's
maximal effect
• Potency of a drug depends
in part on the affinity (Kd) of
receptors for binding the
drug and in part on the
efficiency with which drugreceptor interaction is
coupled to response.
Potency & maximal efficacy
• The clinical effectiveness
of a drug depends not on
its potency (EC50), but on
its maximal efficacy and
its ability to reach the
relevant receptors
• This ability can depend on
its route of
administration,
absorption, distribution
through the body, and
clearance from the blood
or site of action
Quantal Dose-Effect Curves
Quantal Dose-Effect Curves
• median effective dose (ED50): the dose at which 50%
of individuals exhibit the specified quantal effect
• median toxic dose (TD50): the dose required to
produce a particular toxic effect in 50% of animals
• median lethal dose (LD50): If the toxic effect is death of
the animal
• therapeutic index: One measure, which relates the
dose of a drug required to produce a desired effect to
that which produces an undesired effect and in animal
studies it is usually defined as the ratio of the TD50 to
the ED50
Graded vs. quantal dose-effect curve
• Both curves provide information regarding the
potency and selectivity of drugs; the graded
dose-response curve indicates the maximal
efficacy of a drug, and the quantal dose-effect
curve indicates the potential variability of
responsiveness among individuals.
Receptor-Effector Coupling
• Coupling: The transduction process that links
drug occupancy of receptors and
pharmacologic response
• Coupling efficiency is also determined by the
biochemical events that transduce receptor
occupancy into cellular response
Spare Receptors
• Spare receptors: nonlinear occupancy-response
coupling
• Myocardial cells are said to contain a large proportion
of spare adrenoceptors.
• Β-adrenoceptor activation promotes binding of
guanosine triphosphate (GTP) to an intermediate
signaling protein and activation of the signaling
intermediate may greatly outlast the agonist-receptor
interaction
• In such a case, the "spareness" of receptors is temporal
• The receptors may be spare in number
Signaling Mechanisms & Drug Action
Intracellular Receptors for LipidSoluble Agents
• Steroids
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Corticosteroids
Mineralocorticoids
Sex steroids
Vitamin D
• Thyroid hormone
• Lag period of 30 min. to
several hrs
• Persist for hrs or days
Ligand-Regulated Transmembrane
Enzymes
Protein tyrosine kinase
Serine kinase
Guanylyl cyclase
Ligand-Regulated Transmembrane
Enzymes
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Insulin
Epidermal growth factor (EGF)
Platelet-derived growth factor (PDGF)
Atrial natriuretic peptide (ANP)
Transforming growth factor- β(TGF-β)
– Inhibitors (eg, trastuzumab, cetuximab)
– Other inhibitors are membrane-permeant "small
molecule" chemicals (eg, gefitinib, erlotinib)
• many other trophic hormones
• Receptor down-regulation (endocytosis of receptors)
• EGF and cancer
Cytokine Receptors
Janus-kinase (JAK) family
STATs (signal transducers and activators of transcription)
Cytokine Receptors
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Growth hormone
Erythropoietin
Interferons
other regulators of growth and differentiation
Ligand- and Voltage-Gated Channels
• The natural ligands are
acetylcholine,
serotonin, GABA, and
glutamate.
• Time in milliseconds
• Phosphorylation and
endocytosis
G Proteins & Second Messengers
G Proteins & Second Messengers
• Norepinephrine may encounter its membrane
receptor for only a few milliseconds.
• GTP-bound Gs may remain active for tens of
seconds
• The duration of activation of adenylyl cyclase
depends on the longevity of GTP binding to Gs
rather than on the receptor's affinity for
norepinephrine.
G Proteins and Their Receptors and Effectors
G Protein
Gs
Gi1, Gi2, Gi3
Receptors for
β-Adrenergic amines, glucagon,
histamine, serotonin, and many
other hormones
α2-Adrenergic amines, acetylcholine
(muscarinic), opioids, serotonin, and
many others
Golf
Odorants (olfactory epithelium)
Go
Neurotransmitters in brain (not yet
specifically identified)
Acetylcholine (muscarinic),
bombesin, serotonin (5-HT1C), and
many others
Photons (rhodopsin and color opsins
in retinal rod and cone cells)
Gq
Gt1, Gt2
Effector/Signaling Pathway
↑Adenylyl cyclase→ ↑cAMP
Several, including:
↓Adenylyl cyclase→↓ cAMP
Open cardiac K+ channels→↓
heart rate
↑Adenylyl cyclase→↑cAMP
Not yet clear
↑Phospholipase C→↑IP3,
diacylglycerol, cytoplasmic Ca2+
↑cGMP phosphodiesterase→↓
cGMP (phototransduction)
GPCRs
serpentine
Receptor Regulation
Receptor Regulation
β-arrestin binding accelerates endocytosis of receptors
The activated GRK
phosphorylates
serine residues in the
receptor's carboxyl
terminal tail.
A receptor phosphatase is present at high
concentration on endosome membranes
Cyclic Adenosine Monophosphate
(cAMP)
• Mobilization of stored energy (the breakdown of
carbohydrates in liver or triglycerides in fat cells stimulated
by β-adrenomimetic catecholamines)
• conservation of water by the kidney (mediated by
vasopressin)
• Ca2+ homeostasis (regulated by parathyroid hormone)
• Increased rate and contractile force of heart muscle (βadrenomimetic catecholamines)
• Regulates the production of adrenal and sex steroids (in
response to corticotropin or follicle-stimulating hormone)
• Relaxation of smooth muscle, and many other endocrine
and neural processes.
cAMP
Competitive inhibition of cAMP
degradation is one way caffeine,
theophylline, and other methylxanthines
Calcium and Phosphoinositides
• Triggered by GPCRs &
Tyrosine kinase
• At least nine structurally
distinct types of protein
kinase C have been identified
• IP3 is inactivated by
dephosphorylation
• DAG is either phosphorylated
to yield phosphatidic acid,
which is then converted back
into phospholipids, or it is
deacylated to yield
arachidonic acid
Cyclic Guanosine Monophosphate
(cGMP)
• cGMP signaling in only a few cell types
• In intestinal mucosa and vascular smooth
muscle, the cGMP-based signal transduction
mechanism closely parallels the cAMPmediated signaling mechanism
• ANP & NO
• Nitroglycerin and sodium nitroprusside
• Sildenafil
cGMP
Interplay among Signaling Mechanisms
• cAMP and IP3 counteract each other in
smooth muscle contraction
• cAMP and phosphoinositide second
messengers act together to stimulate glucose
release from the liver
Phosphorylation: A Common Theme
• Amplification : the attachment of a phosphoryl group
to a serine, threonine, or tyrosine residue powerfully
amplifies the initial regulatory signal by recording a
molecular memory
• Flexible regulation: differing substrate specificities of
the multiple protein kinases regulated by second
messengers provide branch points in signaling
pathways that may be independently regulated
• Inhibitors of protein kinases have great potential as
therapeutic agents, particularly in neoplastic diseases