Transcript Elicited Behavior and Classical Conditioning

Pharmacology for the Health Sciences
Lecture 2b
Dr. Steven I. Dworkin
Dose-response curve The classic S-shape describes the gradual increase in biological
response that occurs with increasing doses of a dose (dose—receptor activation).Threshold
is the dose producing the smallest measurable response.The dose at which the maximum
response is achieved is the ED 100 (100% effective dose), while the ED50 is the dose that
effectively produces 50% of the maximum response
Dr. Steven I. Dworkin
Dose-Response Curve
•
Allows for the comparison of different drugs
– The relative position the curves for a drug on the x-axis indicates potency
• Reflects the affinity of each drug for the receptor that mediates the
measured response.
• Drugs may differ in affinity for the receptor but reaches the same
maximum on the y-axis, indicating that they have identical efficacy.
• Drugs that work by the same mechanism produce parallel curves.
• Curves that are shifted to the right are less potency.
– A lower-potency drug is frequently just as effective when a
higher dose is administered.
– The dose-response curve depends on the response that is being measured.
– A drug may be less potent for one response and more potent on
another.
Dr. Steven I. Dworkin
Dose—response curves for four analgesic agents Each curve represents the increase in
pain threshold (the magnitude of painful stimulus required to elicit a withdrawal response)
as a function of dose.The ED50 for hydromorphine, morphine,and codeine help compare
potency.The linear portions of the curves for the opiate analgesics are parallel, suggesting
they work through the same mechanism. Aspirin is not an opiate and relieves pain by a very
different mechanism of action, so the shape of the curve is distinct. In addition, aspirin's
maximum effectiveness never reaches the level of the opiates
Dr. Steven I. Dworkin
The therapeutic index calculates drug safety
•
•
•
•
•
•
•
Among the multiple responses to any drug, some are
undesirable or even dangerous side effects and need
to be evaluated carefully in a therapeutic situation.
For example, by drug A, which is prescribed to
reduce anxiety. The blue curve shows the number of
individuals who experience reduced anxiety at
various doses of the drug.
The purple curve shows the number of persons
suffering respiratory depression (a toxic effect) from
various doses of the same drug.
Comparing the ED50 for relieving anxiety (i.e., the
dose at which 50% of the population show reduced
anxiety) and the TD50 (50% toxic dose; the dose at
which 50% of the population experiences a particular
toxic effect) for respiratory depression.
The dose needed to provide significant clinical relief
to many patients (50%), almost none of the patients
would be likely to experience respiratory depression.
The drug has a relatively favorable therapeutic
index (TI = TD50/ED50).
In contrast, the dose of drug A that produces sedation
and mental clouding (red curve) is not very different
from the ED 50.
That small difference means that there is a high
probability that a dose effective in reducing anxiety
is likely to also produce significant mental clouding
and sedation, which may represent serious side
effects for many people who might use the drug
Dr. Steven I. Dworkin
Receptor antagonists compete with agonists
for binding sites
• Competitive antagonists
– Can be displaced from those sites by an excess of the agonist.
• Increased concentration of active drug can compete more
effectively for the fixed number of receptors.
– If the agonist and antagonist have similar affinities for the
receptor, then if 100 molecules of drug and 100 molecules
of antagonist were both present at the receptor, the
probability of an agonist acting on the receptor would be 1
to 1.
– If drug molecules were increased to 1000, the odds of
agonist binding rise to 10 to 1; at 1,000,000 agonist
molecules.
» The presence of the antagonist is of no consequence
to the biobehavioral effect measured.
Dr. Steven I. Dworkin
Receptor antagonists compete with agonists
for binding sites
• Non-competitive antagonists are drugs that reduce the effect of
agonists in ways other than competing for the receptor.
– A noncompetitive antagonist may impair agonist action by:
• Binding to a portion of the receptor other than the agonist
binding site
• Disturbing the cell membrane supporting the receptor
• By interfering with the intracellular processes that were
initiated by the agonist-receptor association.
– In general, the shape of the dose-response curve will be
distorted and the same maximum effect is not likely to be
reached.
• Biobehavioral interactions can also result in several different possible
outcomes
Dr. Steven I. Dworkin
Drug antagonism (A) The effect of a competitive antagonist (naloxone) on the analgesic effect of
morphine. The addition of a competitive antagonist essentially reduces the agonist's potency, as shown by
the parallel shift of the dose-response curve to the right. (B) In contrast, adding a non-competitive
antagonist usually produces a distinct change in the shape of the dose-response curve, showing that it
does not act at the same receptor site. Also, regardless of the increase in morphine, the maximum efficacy
is never reached.
Dr. Steven I. Dworkin
Receptor antagonists compete with agonists
for binding sites
•
Biobehavioral interactions can also result in several different possible
outcomes.
– Physiological antagonism involves two drugs that act in two distinct
manners but interact in such a way that they reduce each other's
effectiveness in the body.
• One drug may act on receptors in the heart to increase heart rate,
while the second may act on distinct receptors in the brain stem to
slow heart rate.
• Two agents may have additive effects if the outcome equals the sum
of the two individual effects.
• Finally, potentiation refers to the situation in which the combination
of two drugs produces effects that are greater than the sum of their
individual effects.
– Potentiation often involves issues of pharmacokinetics such as
altered metabolic rate or competition for depot binding, which
may elevate free drug blood levels in unexpected ways.
Dr. Steven I. Dworkin
Possible results of the interaction of two drugs (A) Physiological antagonism
results when two doses produce opposite effects and reduce each other's
effectiveness. (B) Additive effects occur when the combined dose effect equals the
sum of each alone. (C) Potentiation is said to occur when the combined dose effects
are greater than the sum of the individual dose effects
Dr. Steven I. Dworkin
Biobehavioral Effects of Chronic Drug Use
•
•
•
•
•
•
Many prescription and over-the-counter drugs are taken on a regular basis for
chronic medical or psychiatric conditions.
Drugs are taken for periods of weeks, months, or even years.
Recreational drugs also are most often used repeatedly rather than on only a
single occasion.
When a drug is used on several occasions (i.e., chronically administered),
changes in the magnitude of response to the drug frequently occur.
Most often the response diminishes with chronic use (tolerance), but
occasionally the effects are increased (sensitization).
In some cases, selected effects of a particular drug decrease while others
increase in magnitude.
– A good example is amphetamine
• Tolerance to decrease in food intake
• Sensitization to locomotor activity
Dr. Steven I. Dworkin
Repeated drug exposure can cause tolerance
• Tolerance is defined as a diminished response to drug administration
or a shift to the right in the dose effect-curve.
– In other words, tolerance has developed when increasingly larger
doses of a given drug must be administered to obtain the same
magnitude of biological effect that occurred with the original dose.
• Cross-tolerance is defined as the development of tolerance to one
drug that diminish the effectiveness of a second drug.
– For example, the effective anticonvulsant dose of phenobarbital is
significantly larger in a patient who has a history of chronic
alcohol use than in a patient who has not developed tolerance to
alcohol.
Dr. Steven I. Dworkin
Dr. Steven I. Dworkin
Drug Tolerance
• Some drugs induce tolerance relatively rapidly (LSD),
while others take weeks of chronic use (barbiturates) or
never cause significant tolerance (antipsychotics).
• In some cases tolerance even develops during a single
administration, as when an individual experiences
significantly greater effects of alcohol as her blood level
rises than she experiences several hours later when his
blood level has fallen to the same point.
• This form of tolerance is called acute tolerance.
• Also, it is important to be aware that not all biobehavioral
effects of a particular drug demonstrate tolerance equally.
Dr. Steven I. Dworkin
Tolerance
• Biobehavioral effects of a particular drug do not
demonstrate tolerance equally.
• Behavioral or context specific tolerance disappears in a
novel environment.
– Indicating the importance of behavioral and drug
history in the development of biobehavioral tolerance.
Dr. Steven I. Dworkin
Classical conditioning of drug-related cues Although
dose-taking equipment and the immediate environment is
initially a meaningless stimulus to the individual, its repeated
pairing with the dose (unconditioned stimulus; US), which
naturally elicits euphoria, arousal, or other desirable effects
(unconditioned response; UR), gives the dose-taking
equipment new meaning. Ultimately the equipment and
environment alone (now a conditioned stimulus; CS) could
elicit dose effects (conditioned response; CR) in the absence
of the dose.
Tolerance to morphine-induced hyperthermia
Following an identical series of prior morphine injections
(5 mg/kg SC for 10 days), rats were tested with a
morphine injection and changes in body temperature
were measured for the next two hours. One group of rats
was given the morphine in the same environment in
which they were previously treated ("Same"), and the
second group were tested in a novel environment
("Different").The animals treated in the same environment
show much less hyperthermia, which indicates tolerance
Dr. Steven I. Dworkin
Chronic drug use can cause sensitization
• Sensitization, sometimes called reverse tolerance, is the enhancement
of particular drug effects following repeated administration of the same
dose of drug.
– Prior administration of cocaine to animals significantly increases
motor activity and stereotypy (continuous repetition of a simple
action such as head bobbing) produced by subsequent stimulant
administration.
– Chronic administration of higher doses of cocaine has also been
shown to produce an increased susceptibility to cocaine-induced
catalepsy, in which the animal remains in abnormal or distorted
postures for prolonged intervals, as well as hyperthermia and
convulsions.
– Cocaine and amphetamine are examples of drugs that induce
tolerance for some effects (euphoria) and sensitization for others.
Dr. Steven I. Dworkin
Chapter Questions
•
•
•
•
•
•
•
•
•
1)What are the basic differences between pharmacokinetics and
pharmacodynamics?
2)What process are involved in the initiation of a drug effect?
3)Why do drugs have an effect on biologic systems or why are we influenced
by exogenous substances?
4)What are some of the differences between agonists and antagonists?
5)What is the importance of a curve that is shifted to the left on a dose-effect
curve?
6)What is the therapeutic index and why is it important?
8)When dose tolerance occur?
9)What is the difference between tolerance and sanitization?
10) Draw the dose–response curves for two drugs with the same efficacy,
given that drug A is twice as potent as drug B.
Dr. Steven I. Dworkin
Lecture Summary
•
•
•
•
•
The concept of the receptor is vital to pharmacology, as drugs have biological effects only because
they interact with receptors on target tissues.
Drugs or ligands that bind and are capable of changing the shape of the receptor protein and
subsequently alter cell function are called agonists.
The ligands that attach most readily are said to have high affinity for the receptor. Antagonists, in
contrast, are capable of binding and may have high affinity, but they produce no physiological
change, that is, they have little or no efficacy. Antagonists also prevent agonists from binding to the
receptor at the same moment, hence "blocking" agonist activity.
Rather than being fixed, the number of receptors changes to compensate for either prolonged
stimulation (causing down-regulation) or absence of receptor stimulation (up-regulation of receptors).
Pharmacologists study the relationship between drug, receptor, and biobehavioral effect by analyzing
dose–response curves.
The curves show the threshold dose at which biobehavioral effects can first be measured. With
increasing doses, the effect also increases in a linear fashion until the maximum effect is reached.
The ED50 is the dose that produces a half-maximal (50%) effect and is used to compare the potency
of drugs that produce similar biobehavioral effects. The more potent drug is the one that has the
lower ED50. Comparison of the ED50 with the TD50 (50% toxic dose) for a single drug helps us
calculate the therapeutic index. A large therapeutic index suggests that the drug is effective at low
doses but the toxic dose is high, making the drug relatively safe. A small TI suggests that there is not
much difference between the effective and toxic doses, so the drug is potentially dangerous.
Dr. Steven I. Dworkin
Lecture Summary
• Pharmacologists study the relationship between drug, receptor, and
biobehavioral effect by analyzing dose–response curves.
• The curves show the threshold dose at which biobehavioral effects can
first be measured.
• With increasing doses, the effect also increases in a linear fashion until
the maximum effect is reached. The ED50 is the dose that produces a
half-maximal (50%) effect and is used to compare the potency of drugs
that produce similar biobehavioral effects.
• The more potent drug is the one that has the lower ED50. Comparison
of the ED50 with the TD50 (50% toxic dose) for a single drug helps us
calculate the therapeutic index.
• A large therapeutic index suggests that the drug is effective at low
doses but the toxic dose is high, making the drug relatively safe.
• A small TI suggests that there is not much difference between the
effective and toxic doses, so the drug is potentially dangerous.
Dr. Steven I. Dworkin
Lecture Summary
• Receptor antagonists are competitive if they reduce the effects of an
agonist by binding to the same receptor and reducing agonist–receptor
interaction.
• This type of interaction reduces the potency of the agonist, as shown
by a parallel shift of the dose–response curve to the right. However, the
maximum effect is not altered, because raising the agonist
concentration can overcome the action of the antagonist.
• Noncompetitive antagonists impair agonist function by altering the
receptor at a modulatory site, by impeding the initiation of intracellular
processes, or by disturbing the membrane surrounding the receptor.
• Drugs can also interact by altering the biological effects beyond the
receptor's site of action. Drugs can produce physiological antagonism,
additive effects, or potentiation. In potentiation, the two drugs produce
effects greater than the sum of their individual effects.
Dr. Steven I. Dworkin
Lecture Summary
•
•
•
•
•
•
•
When drugs are administered on more than one occasion, the magnitude of
drug response often changes.
Most often chronic drug use leads to tolerance, that is, a diminished effect, but
in some circumstances drug effects increase with repeated use, a phenomenon
called sensitization.
Cross-tolerance may occur if repeated use of one drug reduces the
effectiveness of a second drug.
Although there are several types of tolerance, with distinct mechanisms,
tolerance in general is a reversible condition.
Tolerance is dependent on the dose and frequency of use, although some drugs
induce tolerance rapidly while others require longer treatment or never cause
tolerance at all.
Further, not all effects of a drug undergo tolerance to the same extent or at the
same rate.
Drug-disposition tolerance occurs when drugs induce the formation of the
liver's metabolizing enzymes. Increased enzyme action reduces the effective
blood level of the drug more rapidly, so the biobehavioral effect is reduced.
Dr. Steven I. Dworkin
Lecture Summary
• Pharmacodynamic tolerance depends on the compensation
of the nervous system to the continued presence of the
drug.
• Changes may include increases or decreases in receptor
number or other compensatory intracellular processes.
• Behavioral tolerance occurs when learning processes and
environmental cues contribute to the reduction in drug
effectiveness.
• Habituation, Pavlovian conditioning, and operant
conditioning can contribute to the change in drug response.
Dr. Steven I. Dworkin