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 drug-

taking 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: 10mg/10mg = 1

100mg/10mg = 10

1000mg/10mg = 100

TI = TD50/ED50

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 – Tryptophan (turkey; warm milk)– L-Dopa

• Block enzymes that destroy NTs– MAO inhibitors (monoamine oxidase inhibitors)

• Increase release from terminal buttons– Amphetamine – reverse transporter– Black widow venom – promotes release of ACh by interacting with the releasing proteins on

presynaptic membrane• Block Autoreceptor

– Research drugs (couldn’t find any interesting ones)• Bind to post synaptic receptor and cause effects, or increase effectiveness of NT

– 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