Transcript Chapter 1 Opener

Chapter 1 Opener
Psychopharmacology
• The emphasis of this discipline is on drug
induced changes in mood, thinking, and
behavior.
– Psychoactive Drugs
• Also interested in the mechanisms of
these effects.
– Neural
Drug action vs. Drug effect
• Drug action
– the specific molecular changes produced by a
drug
– Synaptic Effects
• Drug effects
– more widespread alterations in physiological
or psychological function.
Drug action vs. Drug effect
• Site of drug action can be very different
from the site of drug effect
– Atropine
• Placed in eye = dilates pupil
– near
– Morphine
• Placed in eye = no effect
• Taken internally = constriction of iris = pinpoint
pupils
– far
Drugs can have multiple effects
• Often act at a variety of target sites
• Therapeutic effects
– Desirable physical or behavioral changes
• Side effects
– Mildly annoying to distressing and possibly
dangerous
Therapeutic effects and side effects depend on the desired outcome
• Amphetamine-like drugs
• produce alertness, insomnia, increased
heart rate, and decreased appetite
– Narcolepsy
• Decreased appetite is side effect
– Weight control
• Insomnia is a side effect
Specific vs Nonspecific drug effects
• Specific drug effects
– the physical and biochemical interactions of a
drug with a target site in living tissue.
• Nonspecific drug effects
- Effects that are based on unique
characteristics of the individual.
- Mood, expectations, perceptions of the drugtaking situation.
Nonspecific drug effects
• Can make drug studies difficult.
• Two things must be controlled for
– Spontaneous recovery
– Placebo effects (demand characteristics)
Spontaneous recovery
• If a patient goes to a doctor to get medication
because they are depressed they are probably
very depressed.
• Perhaps more than they have ever been before.
• How likely is it that they will be this depressed in
a couple of weeks or months?
Demand Characteristics
• Placebo effects
– Beliefs about the drug
• Can cause effects even if the substance does not have that
specific effect
– Levine (1973)
• Ulcer patients given a placebo medication
• Group 1
– doctor assured patients the medication would provide relief
» 70% of patients felt better
• Group 2
– nurse described the drug as experimental
» 25% of patients felt better
Placebo effects
• Note: These effects are not just “all in the
person’s head.”
– Actual physiological and hormonal changes can occur
• Patients given a stimulant, but told it was a sedative.
– Decreased heart rate
– Patients can even become addicted
• The nonspecific (placebo) effects of drugs can
sometimes be more powerful than the specific
effects of the drug.
– Making it difficult to determine actual drug effects
Situational factors
• The alcohol “study” in North Carolina T.V.
station parking lot.
• Drugs work better if the patient likes the
physician
Control for drug experiments
• Double blind studies
• Can be difficult to achieve
– Side effects of drugs?
• Patients often guess better than chance which medication is
real
– Alcohol studies at UK
• Physicians asked to administer alprazolam,
imipramine, or placebo to panic attack patients
– 1 month in the patients and physicians were asked to
guess which group they were in.
• Patients = 83% correct about placebo vs. drug
• Doctors = 88%
– And better than chance at distinguishing which actual drug
Expectations of researchers? Experimenter Bias
• Meta analysis of double blind
antidepressant studies.
• When a drug is used as a control condition
for a new drug that is being tested
– One quarter to half as large of an effect than
when the drugs efficacy was initially tested.
Methods of Drug Administration
• Oral administration (PO)
– Per os (or per orem), literally "by mouth",
– Most popular route of administration
• Absorption
– The movement of the drug from the site of
administration into blood circulation
• Some drugs are absorbed in the stomach but
the majority are not absorbed until they reach
the small intestine
– Food in stomach (especially fatty) can slow
absorption rate
First-pass effect
• Drugs absorbed from stomach and
intestine goes directly to the liver prior to
general circulation
– Liver metabolism of the drug will reduce the
amount available
Intravenous (IV)
• Most accurate and most rapid
• IV cocaine
– Intense rush or flash of pure pleasure
– Lasts only about 10 minutes
• Also most dangerous
– On street = unknown dose
– Lack of sterile equipment
– Insoluble filler material may become trapped in small
blood vessels of the lungs
• Reduced respiratory capacity ---- death
Intramuscular (IM)
• Slower than IV
• More even absorption over time
– usually 10 – 30 minutes
Intraperitoneal (IP)
• Rare in humans
• Into abdominal cavity
• Rapid effects
– Not as rapid as IV
Subcutaneous (SC)
• Just under skin
• Absorption is usually slow and steady
• Drug containing pellets or capsules are
becoming more popular
– Implanon = contraceptive that protects for 3
years
Inhalation
• Very rapid absorption
– Capillaries of the lungs go straight to the brain
• Dangers of drugs themselves
• But also risk danger of harming the lungs
Topical application to mucous membranes
•
•
•
•
•
Nasopharynx
Colon
Vagina
Urethra
Cocaine addicts that have damaged the
nasal membrane may resort to application
of the drug in the rectum or genitalia.
Topical application (transdermal)
• Some drugs can be absorbed through the
skin.
– Skin patch
• Provides controlled sustained delivery of
the drug.
• Motion sickness
• Nicotine patch
Special injections
• Some drugs won’t cross blood-brain
barrier
• Epidural
– “on” the “duramater”
– Spinal anesthetics administered into the CSF
surrounding the spinal cord
• Micro injection
Factors affecting drug absorption
• Transport across membranes
– Cell membrane is a lipid bilayer
– This prevents many molecules from crossing the cell
membrane
• Lipid-soluble drugs
– Molecules that can cross the lipid bilayer
– Move by diffusion
• Heroin vs. Morphine
– Heroin has increased lipid solubility
• Thus it acts more quickly
• More potent
1.4 Cell membranes
Factors affecting drug absorption
• Surface area of the organ
– More in small intestine than stomach
– Also substances move more slowly in small
intestine
– Thus, rate stomach empties into small
intestine is a rate limiting factor of drugs taken
orally
• Take pill prior to meal and with fluids
– Move to intestine
Factors affecting drug absorption
• Individual differences
– Size – 150 lbs.
– Gender
Barriers to drug distribution
• Blood Brain Barrier
– Not complete
– Area Postrema (in medulla)
• Vomiting center
• Placental Barrier
– Barrier between blood circulation of pregnant
mother and fetus.
– Those drugs that cross this barrier are
potential teratogens (induce developmental
abnormalities).
1.6 Distribution of cerebrospinal fluid (Part 1)
1.6 Distribution of cerebrospinal fluid (Part 2)
1.7 Cross section of typical capillaries and brain capillaries
Receptors
• Ligand
– Any molecule that binds to a receptor with
some selectivity
• Most drugs bind to receptors on the
outside of cells
– What happens depends on the nature of the
receptor
• ionotropic
• metabotropic
– We will review this in a bit
Affinity vs. Efficacy
• Ligand and receptor act like a lock and key
• Affinity
– Those that “fit best”
– Attach most readily
– Stick together longer
• Efficacy
– How good of a job the ligand does at
producing an effect.
Agonists
• Agonists
– Neurochemicals that bind and cause a cellular
response
Antagonists
• Antagonists
• Neourochemicals that bind but don’t
produce a cellular response
– low efficacy – basically no efficacy
– take up space and prevent neurotransmitter
from producing its normal effect
1.11 Agonist and antagonist interactions with receptors
Types of agonists and antagonists
• Agonist
– Direct
• binds directly to and activates neurotransmitter receptors
– Indirect
• releases or enhances the action of a neurotransmitter
• Antagonist
– Direct
• aka receptor blocker: binds to the same receptor population as an
agonist but fails to activate the target receptors
– Indirect
• term rarely used
• more descriptive terms usually used
– Synthesis inhibitor
– Storage inhibitor
Autoreceptor actions
• Agonist with antagonistic action
– A drug that activates autoreceptors at the
terminal button
• Antagonist with agonist action
– SB-649915 = 5-HT1A and 5-HT1B
autoreceptor antagonist
– In combination with SSRIs may speed up
antidepressant action (scott et al., 2006).
Receptors can be modified in number
• Receptors have a life cycle
• Can be regulated
– Up regulation
• Chronic use of a receptor antagonist
– Down regulation
• Chronic use of a receptor agonist
• Takes 1 to 2 weeks
– May be why some therapeutic drugs take that long to
produce an effect
• Depression
• Schizophrenia
Dose response curves
• Threshold
– Dose producing smallest measurable
response
• ED100 …..ED = effective dose
– Dose that produces 100% response
(maximum)
• ED50
– The dose that produces half of the maximum
response
1.12 Dose–response curve
1.13 Dose–response curves for four analgesic agents
• Note that hydromorphine, morphine, and
codeine all produce the same ED100 and ED50.
– Probably because working at the same receptor
– They differ in potency, 2 mg, 10 mg, 100 mg.
– does that really matter?
– efficacy is the same
• Compare the curve for aspirin.
– ED100
– ED50
Therapeutic index = safety
• Compares ED50 to TD50
• TD50
– Toxic dose 50
– Sometimes use lethal dose 50
• LD50 (animal studies)
• TI (therautic index)
– TI = TD50/ED50
– The dose that produces toxic effects in 50% of the
population
– Divided by the dose that is effective for 50% of the
population
• Safe drugs have a very high TI
• Unsafe drugs have low TI
TI = TD50/ED50
• TI = TD50/ED50
• TI: 10mg/10mg = 1
100mg/10mg = 10
1000mg/10mg = 100
1.14 Comparison of ED50 and TD50
Biobehavioral effects of chronic drug use
• Tolerance
– Diminished response to a drug after repeated
exposure.
– Cross tolerance can occur
• Phenobarbital – anticonvulsant
• Takes larger dose if tolerant to alcohol
Tolerance
• Reversible = tolerance goes away if you stop using the drug
• Some forms of tolerance can develop quickly
– Acute tolerance – same dose of alcohol when you first get drunk can
produce greater effects than when your blood alcohol returns to that
level
• Tolerance does not develop equally for all effects
– Can be good if tolerance develops to side effects more quickly than for
therapeutic effects
– Can be bad if other way around – can cause increased drug use and
ED can become closer to TD
– Sensitization can also occur
Types of tolerance
• Metabolic
– Body gets better at breaking the drug down
• Pharmacodynamic
– Up regulation or down regulation of receptors
– Other cellular adjustments
• Behavioral
– Learning
• Contingent tolerance
– Before and after experiments
» Rats run treadmill under influence of alcohol
• Conditioned tolerance
– Siegel’s work
•
•
•
•
CS (context)
US (drug effect)
UR (compensatory response)
CR (compensatory response)
• State dependent learning
– Train
• Drug
• Saline
– Test
• Drug
• Saline
Goodwin et al. (1969)
•
•
•
•
Alcohol – Alcohol
Placebo – Alcohol
Placebo – Placebo
Alcohol – Placebo
– Alcohol – Alcohol was superior to Alcohol –
Placebo
1.19 Experimental design to test state-dependent learning
Review of iontropic vs. metabotropic receptors
• Ionotropic
– Ligand gated channels
• Na+?
• K+?
• Cl-?
• Metabotropic
– G protein-coupled receptors
3.9 Structure and function of ionotropic receptors
3.14 Summary of the mechanisms by which drugs can alter synaptic transmission
Drugs that stimulate synaptic transmission
•
Increase synthesis of NTs
–
–
•
Block enzymes that destroy NTs
–
•
Research drugs (couldn’t find any interesting ones)
Bind to post synaptic receptor and cause effects, or increase effectiveness of NT
–
•
Amphetamine – reverse transporter
Black widow venom – promotes release of ACh by interacting with the releasing proteins on
presynaptic membrane
Block Autoreceptor
–
•
MAO inhibitors (monoamine oxidase inhibitors)
Increase release from terminal buttons
–
–
•
Tryptophan (turkey; warm milk)
L-Dopa
Benzodiazepines = Valium
Block deactivation
–
–
–
SSRI = Prozac; Zoloft
SNRI = Effexor; Cymbalta
Cocaine
Drugs that inhibit synaptic transmission
•
Blocks synthesis of NTs
– AMPT – blocks production of DA – can increase symptoms of depression in lab.
•
Blocks storage/increases destruction of NTs
– Reserpine Blocks storage of monamines; used to treat high blood pressure;
depression can be a side effect
•
Prevent release of NTs
– Botulinum Toxin - Botulism (food poisoning). This toxin prevents the release of
Ach leading to paralysis and potentially death
• Small doses prevent wrinkles = Botox
•
Activate autoreceptor
– Aripiprazole – one action of this drug is that it Inhibits DA release by activating
the autoreceptor – used as an antipsychotic
•
Block receptor
– Some antipsychotic drugs. Drugs that block serotonin receptors are used to treat
the negative symptoms of schizophrenia (social problems, flattened affect).l