Transcript Introduction to Pharmacology - Home

Pharmacodynamics
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
The New York Tomes, February 20, 2005
For Pain Management, Doctors Prescribe Caution
By MARY DUENWALD
"All of us have been reacting to the news as it comes
forward, as to whether some of our tools will be taken off
the market," said Dr. Raymond Gaeta, an anesthesiologist
who directs Stanford's pain management clinic. "This is
good news for patients over all. Clearly there are side
effects with every medication, but it's really important to
weigh the potential side effects versus the benefits for an
individual patient."
Transmembrane Signaling
Katzung, 2-8
Molecular Drug Targets
Target
Drugs
opioid receptors
morphine, naloxone
b receptors
albuterol, metoprolol
estrogen receptors
ethinyl estradiol, tamoxifen
voltage gated Na+ channels
lidocaine
acetylcholinesterase
neostigmine, organophosphates
cyclooxygenase
aspirin
catecholamine reuptake
cocaine
Drug/Receptor Interactions
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Glucocorticoid Action
Katzung, 2-9
Epidermal Growth Factor Receptor
Katzung, 2-10
Ion Channels
Katzung, 2-12
G-Protein Coupled Receptors
Katzung, 2-12
Graded Responses
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Concentration-Response Curve
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Quantal Dose-Response Curve
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Affinity and Potency
How well does the drug bind to the receptor?
Drug A
Drug B
% Positive respnose
(analgesia)
100
50
0
ED50
Drug A
ED50
Drug B
Dose of Compound
Potency
Fentanyl
M orphine
% Positive respnose
(analgesia)
100
50
0
0.1 mg
10 mg
Dose of Compound
Efficacy
How well is the receptor/transduction process activated?
% Measured Effect
100
Full Agonist
Partial Agonist
50
Antagonist
0
Dose of Compound
Efficacy and Opioid Analgesics
% Measured Effect
100
M orphine
Severe Pain
Codeine
Moderate Pain
50
Aspirin
Naloxone
0
Dose of Compound
Mild Pain
Therapeutic Index
• The relative safety of a drug is sometimes expressed as
a therapeutic index (TI)
• Ratio of the dose of the drug lethal in 50% of a tested
population (LD50) to the dose of the drug therapeutically
effective in 50% of the tested population (ED50)
TI=
LD50
ED50
% Animals Showing Effect
Therapeutic Index
Analgesia
100
Death
50
0
3 mg
600 mg
Drug Interactions
• Antagonism
– pharmacological (heroin and naloxone)
– physiological (norepinephrine and acetylcholine)
• Additive effect
– morphine and fentanyl
• Synergistic effect
– alcohol and diazepam
Drug Interactions
Addition
Synergy
Measured Effect
Antagonism
A B
A+B
A B
A+B
A B
A+B
Competitive Antagonism
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Partial Agonists
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Some Drug Interactions are Favorable
LeWitt P. N Engl J Med 2008;359:2468-2476
Tolerance
Definition:
– decreased effectiveness of a drug that results from
repeated drug exposure
– necessitates an increase in the dose of the drug in
order to maintain a given level of effect
Related Terms:
– cross-tolerance (morphine/fentanyl)
– tachyphylaxis
Different Types of Tolerance
Metabolic:
– Repeated administration of alcohol induces the enzyme
alcohol dehydrogenase --> increased metabolism leads
to a decreased drug effect
Pharmacodynamic:
– Repeated administration of morphine produces
changes to opioid receptors and second messenger
systems
Behavioral:
– Development of tolerance can be influenced by
learning and conditioning processes
Drug Dependence and Withdrawal
Definition:
– Continual exposure to a drug produces physiological
adaptations at the cellular level (physical dependence)
– Cessation of drug administration can results in a
rebound effect --> withdrawal syndrome (e.g., heroin
withdrawal)
Related Term:
– psychological dependence