Transcript and drug

DRUGS AND BEHAVIOR
PSYCHOLOGY 305
GARY L WENK
PROFESSOR
PSYCHOLOGY & NEUROSCIENCE
http://faculty.psy.ohio-state.edu/wenk/
ORDER OF LECTURE TOPICS
Introduction to Pharmacology
Principles of Drug Action
Acetylcholinergic System Drugs
Catecholaminergic System Drugs
Serotonergic System & Related Hallucinogens
CANNABINOIDS
GABAergic System: Alcohol, Barbiturates and
Benzodiazepines
OPIATES
OTC Drugs
One guiding principle: everyone is treated consistently.
No extra credit for any reason.
There are two major exams: mid-term and final
You know when they are. So no excuse for not being able to
study during the weeks prior to the exam.
Exams are not given early or later than the specified day.
If you miss an exam for any reason you get a zero for that exam.
Exams will only cover material that is presented in class.
If I do not cover a topic in class it will not be on an exam.
http://faculty.psy.ohio-state.edu/wenk/
Be courteous of your fellow students.
You may come in late, leave early, sleep, eat, drink, read the newspaper, text
message your friends, listen to your iPod, …
Just do it quietly and do not disturb other students who are trying to pay
attention to the lecture.
http://faculty.psy.ohio-state.edu/wenk/
This course is about the brain, not the drugs.
The effects of drugs upon the brain can
teach us how the brain works.
If the book differs from anything I say.
-- I am right & the book is wrong.
Bring it to my attention.
Some of you may know more about selected drugs or
certain issues than I do. Contribute your knowledge to the
class (and to me) and correct me if I say something
incorrect.
I will try to always define the boundaries of the grey
areas of my knowledge as well as that of the scientific
community.
The drugs that I will discuss are psychoactive.
The term "psychopharmaceutical" first
appeared in 1548 in the title to a collection of
prayers of consolation, and prayers for the
dead, called: "psychopharmakon, hoc est:
medicina animae."
The term here related to spiritual medicine,
which was to be used in miserable and
hopeless situations in life.
The word "pharmakos" originally meant scapegoat;
a pharmakos was a person who was sacrificed as
a remedy for whatever maladies another person
might have been experiencing. Around 600 BC
the term came to refer to medicine, drug or poison.
Naturally occurring psychoactive agents are
fundamental to most cultures and the
routine use of stimulants and depressants is
so pervasive in most western societies that
most of us don't even consider such
substances to be drugs, but rather an actual
nutrient. Indeed, the border between drug
and nutrient is blurring.
How many people can get through the day without
the assistance of the “natural drugs” coffee, tea,
tobacco, alcohol, cocoa, or their illegal cousins
marijuana, cocaine, or heroin?
I want you to keep in mind that anything you take
into your body should be considered a drug,
whether it's obviously nutritious or not.
Our ancestors were very aware of these
properties and sought them out for remedies for
a variety of illnesses.
The use of plant and synthetic products as
medicine is but one in a long line of
revolutions that occurred to alter culture and
the way we view drugs.
The first revolution:
-- treatment of communicable diseases.
Pasteur and Koch (19th century) developed
vaccines against measles and other disorders.
This introduced us to drug taking on a large scale.
The second pharmacological revolution resulted
from the evolution of sulpha drugs: penicillin, and
the broad spectrum antibiotic agents.
The third pharmacological revolution was the
advent of tranquilizers for the treatment of the
mentally ill (1950's).
First time that compounds were widely used for their
effect on the mind and not on the body.
The fourth pharmacological revolution is still in progress.
Development of oral contraceptives. Their impact cannot yet
be predicted. Over 10 million American women now using
oral contraceptives.
The most important point - for the first time, potent chemicals
are being widely used by healthy people because of their
social convenience.
The evolution of our view of drugs that affect the brain
continues with the introduction of cognitive enhancing drugs
and neuroprotectants.
4 basic principles
First: drugs per se are not "good" or "bad". When drug
abuse is talked about, it is the behavior, the way the drug is
being used, that is being referred to as bad. Drugs are
simply chemicals!
Second: every drug has multiple effects, they act in many
different areas of the brain and may have different effects
than intended.
Third: the effects of a drug depend on the amount taken.
Varying doses can change the magnitude and the character
of the drug effect. This is called a dose-response effect.
Fourth: (possibly the most difficult to document) the
effects depend in part on the individual's history and
expectations of the drug taking experience.
Conclusion: essentially it means that every drug
experience is a mix of three ingredients: the drug itself, the
individual taking the drug, and the setting in which the drug
is taken.
How are we protected? The FDA and its history
In 1929 the US. Post office forced pharmacist Harold Watkins to stop
promoting his lucrative weight loss formula.
Harold was jobless after the stock market crash and throughout the
depression.
He was eventually hired by the S.E.. Massengill company Bristol,
Tennessee. In July 1937 Harold was asked to find a solvent for the new
anti-biotic sulfanilamide.
The drug was very effective against gonorrhea, meningitis and strep
throat. However the tablets were too big and difficult to swallow,
especially for children.
Harold was instructed, as the company's chief chemist, to make it into a
liquid.
Harold chose the solvent diethylene glycol, a sweet syrupy liquid.
Sometimes used as anti-freeze
Harold held a degree in pharmaceutical chemistry but was not aware that this
solvent could be a deadly poison at certain doses.
Harold added to the solution saccharin, caramel, amaranth, raspberry extract.
Harold tasted the concoction himself and with no further tests sent it to the
manufacturing laboratories.
By September 1937 the lab had shipped 240 gallons of "elixir sulfanilamide." By
October of the same year almost 12 gallons had been prescribed.
In that year, 107 children died after taking the elixir.
Samuel E. Massengill insisted his company was blameless, but fired Watkins
anyway. The government could only charge Massengill and his company with
improper labeling since the nation's food and drug law was so feeble at that
time.
Within months the food drug and cosmetic act had cleared both houses and in
June 1938 president Franklin D. Roosevelt signed it into law.
This act is still enforced today and requires drug makers to prove all new
products safe and effective.
On January 10, 1939 Samuel E. Massengill was elected president of the Bristol
chamber of commerce. Watkins, morose at this time, retreated to his home
and read of the election of Massengill. A brief notice appeared in the Bristol
Herald Courier a week later.
"Harold Cole Watkins, 58, retired chemist, was found dead Tuesday morning
in the kitchen of his home, a discharged 38 caliber automatic pistol lying
near his body. He had been shot once through the heart."
Introduction to Pharmacology
Principles of Drug Action
Acetylcholinergic System Drugs
Catecholaminergic System Drugs
Serotonergic System & Related Hallucinogens
GABAergic System: Alcohol, Barbiturates and
Benzodiazepines
Cannabinoid System
OTC Drugs & Sleep
Principles of drug action
The part of the body where the drug acts to produce its effect is called the drug's
"site of action."
Drugs differ in their site of action.
The effects of a drug provide clues to its site of action.
For example: drugs that effect sleep, alter activity in the reticular activating
system.
Another clue to site of action is afforded by the unequal distribution of
neurotransmitters in the brain.
For example: dopamine is highly concentrated in the basal ganglia, which
controls movement. Therefore, administration of drugs that affect the dopamine
system may affect disorders of movement, such as in Parkinson's disease.
For a drug to produce an effect it must achieve an
Adequate Concentration at its site of action.
Relevant factors are
1) The route of administration
2) The amount administered
3) The extent and rate of absorption from the area of
administration
4) Distribution within the body
5) Binding or localization in tissues
6) Biotransformation
7) Excretion
Characteristics of the drug
1)Molecular size and shape
2)Solubility at site of its absorption
3)Degree of ionization
4)Relative lipid solubility of ionized and nonionized forms
1) Route of administration
Enteral vs. Parenteral routes of administration
Enteral routes include oral, rectal and sublingal. Drugs
administered by enteral routes reach the liver before going
into general circulation.
This makes it possible for the drug to be metabolized by liver
enzymes prior to being absorbed into the bloodstream for
general circulation.
Rectal route is useful when oral ingestion is precluded by vomiting or
when the patient is unconscious. About 50% of the drug passes
through the liver; thus this way is even better than orally. However
absorption is often irregular and incomplete.
The exception is the sublingual administration.
Drugs given by this route do not go through the liver first.
For this reason, nitroglycerin is given sublingually (or as a
tongue spray).
It is non-ionic, very lipid soluble, and very potent.
Venous drainage from the mouth is to the superior vena
cava and thus avoids the liver.
Absorption after ingestion is effected by pH
gradient between the drug and absorbing
surface.
In the stomach, which is highly acidic, acidic
drugs are absorbed while basic drugs tend to
accumulate.
In the intestine, which is only slightly acidic,
basic drugs are better absorbed than acidic
drugs.
Effect of
ionization
on drug
absorption
Intestinal contents affect absorption:
E.G., High fat increases absorption of anti-fungal drugs and fat soluble
vitamins and drugs.
The quantity of food in the stomach is also important.
E.G., Animals that were food deprived 24 hours prior to phenobarbital
treatment were anesthetized by the same dose which only effected
50% of the animals that were on a free feeding diet.
The onset of the anesthesia was short, and its duration longer.
For fastest absorption and strongest most predictable effects, most
drugs should be taken on an empty stomach.
Orally administered drugs are primarily absorbed through
the small intestine.
The passage of drugs from the stomach to the intestine is
effected by the temperature of the solution, size of
particles and pH of stomach
Stability of the drug in the intestines is an important
consideration. Must be resistant to low pH and digestive
processes.
Injection and inhalation are called parenteral
routes.
This means by route other than via the intestines,
including intravenous, subcutaneous, and
intramuscular routes.
If a drug increases the blood flow into its own
region, it enhances its own rate of absorption.
Conversely: if a drug constricts blood vessels in
the region, it closes down its own absorption into the
body, e.g.. Cocaine.
Topical applications
Mucous vs. Skin surfaces
Mucous membranes - fast absorption.
Skin - few drugs can readily penetrate the intact skin. Absorption is
usually proportional to surface area over which they are applied and to
their lipid solubility.
Dermis is freely permeable to many drugs. Consequently, systemic
absorption occurs more readily through abraded, burned, or denuded
skin.
Inflammation can also enhance absorption.
Hydrated skin is more permeable than dry skin.
Suspending the drug in oily vehicle and rubbing onto skin can also
enhance absorption- known as inunction. (Inner forearm)
Distribution
After a drug is absorbed, it must be transported to its site of
action. For most behaviorally active drugs, the site is the brain.
Well vascularized areas will have highest concentration of
drug. -- Brain receives 20% of blood flow from heart.
The elderly also have reduced cardiac output and increased
circulation time all of which may impair the distribution of
drugs. The consequence is an increased latency of onset,
and prolonged action of the drug because it is not rapidly
removed from its site of action.
• Partition coefficient the relative affinity of a
drug for either lipid or water
environments.
• This determines how fast a drug will pass
out of the gut, across barriers into the
brain.
E.G., Heroin, (diacetylmorphine) is more
soluble in lipid than is morphine, and thus
penetrates into brain tissue more readily and a
quicker onset of action Speed of entry into the brain is the basis of its
euphoric effect.
Acetyl groups are removed first before it is
active.
Size and degree of ionization of a
molecule effect its entry rate into the brain.
Effect of
ionization
on drug
absorption
Ionization factor ionization depends
the properties of the drug, i.e.. How
easily it is ionized by the solution it is
in. This depends upon the pH of the
solution.
(pH is negative log of H+ ion
concentration; e.g.. 10-7m is
0.0000001 moles/liter, the negative
log is 7.0, pH is 7.0)
• The extent of ionization of a drug is
expressed as the pKa of the drug.
• pKa is equal to the pH of the aqueous
solution in which the drug is 50%
ionized.
• E.G., Weak acids ionize more readily
in alkaline solutions, and weak bases
ionize more readily in acidic
solutions.
Effect of
50%
ionization
on drug
absorption
Principle of Ion Trapping
• Drugs and their metabolites get trapped
inside or outside of membranes and can
not move across.
• This is due to the presence of an electric
charge on the drug
Once a drug is
“caught” outside
of the blood,
inside of the
kidneys,
It is not reabsorbed and
will be excreted
with the urine.
Ionized drugs are transported out of the blood into the
kidney compartment where the pH can vary due to
what you’ve eaten recently.
Kidney
Ionized drugs carry a
charge, this charge
attracts water molecules
and makes the drug
“bigger” preventing it
from getting back into the
blood.
• Before getting to the brain, a drug must
pass 2 barriers
• (1) plasma proteins and (2) blood-brain
barrier.
• They prevents drugs from diffusing out of
the bloodstream.
• Blood-brain barrier.
• Many drugs administered outside of
the CNS are unable to enter the brain.
• The BBB is made up of many
parts. Most important may be the
peculiar type of capillaries that are in
brain. Tight junctions, no fenestra, no
pinocytosis, presence of thick
basament membrane
• Astrocytic process cover the
basament membrane.
Blood-brain capillaries
The BBB is an obstacle for CNS therapy and a serious
bottleneck in drug development for CNS diseases.
The BBB is an obstacle for CNS therapy and a serious
bottleneck in drug development for CNS diseases.
Theoretically, the amount of randomly selected drugs having
bioavailability in the CNS is less than 2% of small molecules
and practically 0% of large molecules.
The BBB is an obstacle for CNS therapy and a serious
bottleneck in drug development for CNS diseases.
Theoretically, the amount of randomly selected drugs having
bioavailability in the CNS is less than 2% of small molecules
and practically 0% of large molecules.
These numbers are also reflected by the drugs currently
available for CNS diseases. Of over 7,000 potential drugs in
the comprehensive medicinal chemistry database, only 5%
can enter the brain.
The BBB is an obstacle for CNS therapy and a serious
bottleneck in drug development for CNS diseases.
Theoretically, the amount of randomly selected drugs having
bioavailability in the CNS is less than 2% of small molecules
and practically 0% of large molecules.
These numbers are also reflected by the drugs currently
available for CNS diseases. Of over 7,000 potential drugs in
the comprehensive medicinal chemistry database, only 5% of
all drugs treat the CNS.
The typical CNS-active drug is very small in size with an
average molecular mass of 0.36 kDa and is used for treatment
of a very limited number of diseases, such as affective
disorders, schizophrenia, epilepsy, and chronic pain.
• Transport is carrier - mediated.
• The BBB is selectively permeable.
• -- Reduces flow of water soluble or
ionized molecules.
• -- Does not impede lipid-soluble or
un-ionized molecules.
• The blood-brain barrier is composed of
a number of lipophylic
elements. Therefore, drugs soluble in
lipids enter the brain more easily than
water-soluble drugs.
Astrocyte
Astrocytes are an important component of the
blood brain barrier.
Astrocytes
conduct
nutrients and
drugs from the
blood to the
neurons and
transport waste
products away
to the blood and
CSF.
• The BBB is not intact everywhere.
• Area postrema (vomiting center, projectile
vomiting), mediam eminence in
hypothalamus, pineal gland
• The blood-brain barrier is not permeable to
the neurotransmitters.
• 1) conserves transmitters within the
nervous system
• 2) isolates brain from exogenously
produced transmitter substances
Plasma Proteins
The distribution of many drugs is slowed because
they combine readily with proteins within the
blood plasma.
• This prevents the drug from diffusing out of the
bloodstream.
• An equilibrium is eventually reached between the
unbound drug and the plasma protein drug
complex.
• Drugs vary in their strength of binding to plasma
proteins.
• The elderly and people with impaired
kidney or liver functions often have
reduced levels of plasma proteins. As a
result, there is less binding and the drug
effects may be more intense.
Once a drug has entered the brain
The site of action is at the synapse
Within the synapse, the site of action is often
a receptor protein.
• Receptor binding a receptor is a
physiological entity.
• The cells response to a drug is
proportional to the fraction of receptors
occupied = law of mass action.
D + R = DR -- pharmacological effect
Transmitter
Receptor
Receptors
live on the
surface of
the neuron
Actions at Receptors
• Agonist: binds to receptors and produces
pharmacological action.
• Antagonist: binds to receptors but
produces no pharmacological action
Agonist and antagonist interactions with receptors
• Two functions of a receptor:
• 1) ligand-binding domain, 2) effector domain.
•
Intracellular action: promote synthesis or release of an
intracellular regulatory molecule - second messenger.
• E.G. Receptor stimulated adenylate cyclase - to synthesize the
second messenger cyclic AMP. cAMP acts within the cell to
stimulate camp-dependent protein kinases which catalyze the
phosphorylation of numerous enzymes.
• E.G. Receptor-controlled calcium entry. Binds to Ca-dependent
regulatory protein calmodulin- forms Ca-calmodulin complex.
• E.G. Multiple second messengers - receptor-stimulated
phosphoinositol (PI) turnover.
Cell Nucleus
A complex
cascade of
changes
amplify the
effects of the
receptor
within the
neuron.
Regulation of receptors:
• Desensitization - following continued
stimulation of receptors.
• (Also called down regulation)
• Super sensitivity - following continued
blockade of receptors or loss of
neurotransmitters.
Dose-response
• Describes the amount of
pharmacological effect for a given
concentration (dose).
• Maximum Response = receptors are
fully occupied
Dose–response curve
Drug-receptor Interactions
• Potency determined by the affinity of drug for
the receptor, as well as accessibility of drug to
receptor site (which involves absorption,
distribution, biotransformation, and excretion).
• Potency only determines the drug dose.
• Otherwise, not a particularly important
issue.
Potency does not alter maximum effectiveness
of drug. Drugs of different potency that
affect same receptor site will have same
effect, simply give more drug.
Potency does not correlate with clinical
superiority.
• Maximal efficacy: the maximal effect
produced by a drug. Determined by drugs
inherent properties, reflected as a plateau
in dose-effect curve.
•
Efficacy can be limited by undesired side
effects that limit the amount or use of the
drug, regardless of its efficacy.
• Efficacy and potency are not necessarily
correlated - so don't confuse them
• Therapeutic index
• Toxic dose for 50% of people/
effective dose for 50% of people.
• TD50/ED50.
Dose–response curves for four analgesic agents
Comparison of ED50 and TD50
• Termination of drug effects:
• Redistribution away from the site of action
is one mechanism for terminating drug
action. Most drugs are, however,
metabolized within the liver and excreted
by the kidneys. Metabolism may take
place in the plasma, kidneys and other
tissues, but most occur within the liver.
• Liver is the largest organ in the body and
serves several functions besides
metabolism. It has several different
enzyme systems for metabolizing drugs.
• Primary effect of the metabolic process is to convert
fat soluble substances into water soluble substances
which are more easily excreted by the kidneys.
• Most common type of transformation is oxidation.
• Others include conjugation to a larger molecule
which is water soluble.
• E.G., To glucuronide, gylcine, sulfate and acetyl groups.
• Oxidation by cytochrome p450 which is concentrated
in the liver. Levels of p450 depend upon the need for
this enzyme.
• Only a few types of chemical
transformations are actually involved.
• Enormous diversity of drug types that exist.
• The liver does far more than convert active
compounds into inactive ones that are more
readily excreted.
• Some drugs are metabolized into more active
substances
• E.G. Codeine - about 10% of administered
codeine is metabolized to morphine which is
much more powerful.
• Certain pathological states can alter an
individual's response to certain drugs.
• E.G., Metabolic enzymes may be deficient in
certain conditions.
• Infants -have a poorly develop glutathione
system.
• Can't metabolize aspirin or Tylenol very well,
so should alternate when given.
• Some drugs influence the metabolism of other
drugs.
• E.G., By stimulating or inhibiting the oxidation
system.
• In general, the more rapidly a drug is
metabolized, the lower the blood levels and
the smaller the drug effect.
• Occasionally, a non-toxic drug may be
metabolized by the liver into a carcinogenic
compound. (hot dogs with sodium nitrite need
ascorbic acid)
Excretion
• Drugs can be excreted in urine, feces,
expired air, sweat, and the milk of a nursing
mother.
• Primary excretory pathway is via the kidneys.
• Some drugs are excreted unchanged:
E.G., Nitrous oxide via the lungs;
E.G., The active agents in the hallucinogenic
mushroom amanita muscaria via the kidneys -common custom among users to collect the urine
excreted by the people who have eaten the
mushroom.
The rate at which a substance is excreted is pH
dependent.
-- Drugs that are basic are excreted most rapidly
when the urine is acidic, whereas acidic drugs are
excreted faster when the urine is alkaline.
E.G., Cigarette smokers may regulate their nicotine
intake via their food consumption.
Increased excretion of nicotine leads to increased
cigarette smoking.
Since nicotine is excreted more slowly when the urine
is alkaline (nicotine is basic).
Smokers who take extra vitamin C smoke more than
those who take bicarbonates for GI distress.
• Eating also effects urinary pH. The urine
becomes more acidic about 30 minutes
after eating, then grows more alkaline for
hours. Smokers routinely light up after
meals as their nicotine levels are reduced
by the acidified urine.
• Therefore, if you want to quit smoking and
not feel the effects of low nicotine in your
blood system, it helps if you take low
doses of sodium bicarbonate. (...and stop
eating)
• Heavy breathing also blows off CO2 and
increases blood pH.
• This accelerates the removal of nicotine
from the brain.
• Three blood pH buffers. Plasma proteins,
hemoglobin and carbonic acid :
• HCO3- + H+ <=> H2CO3 <=> CO2 + H2O
loosing CO2 moves equation to the right
and lowers H+ ion concentration, pH
increases.
• Excretion rate is given as half-life of drug
in body –
• The time required for body to reduce
plasma concentration by half.
Rebound Effects
The withdrawal of drugs that modify
physiological or behavioral systems is often
accompanied by changes in the opposite
direction of the original compound. The
always brain pushes back.
E.G. The euphoria induced by cocaine and
amphetamine is often a prelude to severe
depression.
E.G. Alcohol and barbiturates suppress dreaming and
REM sleep and also reduce the vividness of
dreams. During withdrawal, dream time and
vividness of the dreams are increased.
Responsiveness to Drugs:
4 Important Influences
Our response to drugs is influenced not only by
our metabolism of them, but also our
compliance with the prescriptions as written
by the physician.
However, there are 4 important factors which
influence responsiveness to drugs that are
important for compounds which have
behavioral effects.
First Organismic Factor is Age
• Children are often hyperactive to drugs
because of incomplete development of
metabolic enzyme systems.
• Older people may be hyperactive because
of impaired metabolic excretory
mechanisms.
• In some young species, there may also be
an undeveloped blood-brain barrier.
• According to US government: 120,000 older people
are afflicted annually by mental impairment induced
by psychoactive drugs given to them by their
physician.
• 32,000 fall and break hips because they are dizzy
from prescription tranquilizers and sleeping pills.
• According to the inspector general Richard
Kusserow of the US Health & Human Services Dept.
• At least 200,000 elderly are hospitalized each year
because of the drugs they take!!
• Older people also take a greater number of drugs
Second Organismic Factor is Weight
Dose must be adjusted to the weight of the
drug recipient.
This is usually calculated on the basis on the
number of milligrams of drug/kg of body wt.
Third Organismic Factor is Biological Rhythms
Physiological systems undergo rhythmic variations
and activity. This is true in single cell
organisms.
Responsiveness to drugs is rhythmic in
nature. Humans that are on a typical 24 hour
schedule where they sleep between midnight
and 8 am are maximally susceptible to drugs
between the hours of 9:30 and 11:30 in the
evening.
I.E., A dose which that is effective or non-toxic in
the morning, could be lethal if given during the
evening.
Fourth Factor Is Personality
Many personality variables effect
responsiveness to drugs. This argument
was best described by Wilder in his law of
initial value.
• Each person has an initial level of
excitation; the degree of response depends
upon this initial level.
• E.G., euphoria is observed in patients
suffering from pain, anxiety, or tension
when they are given small doses of
morphine.
• A similar dose given to a happy, pain-free
individual often precipitates mild anxiety and
fear.
• Stuporous catatonic patients often respond
with a burst of animation and spontaneity to
intravenous injections of barbiturates.
• Finally, sedative drugs create more anxiety in
outgoing, athletic people, as compared to
passive intellectual types.
• The tendency is that people who respond
strongly to one drug tend to respond strongly to
others.
• Response of patient is also affected by
importance of symptom being treated.
Treatment of trivial symptoms of syndrome
may be worse than not treating the patient.
• Physiological state: pathological and
physiological conditions modify drug
actions. Alterations in renal or hepatic
functioning are likely to have an effect as well
as our vitamin deficiencies. However, even
normal alterations of physiological function
influence drug activity. Examples are as
follows.
• Aspirin lowers body temperature in febrile
individuals, but does not effect body
temperature when it is normal.
• The toxicity of both caffeine and
amphetamine is increased in mice when
they have been deprived of water.
• Respiratory depression that is produced by
morphine is reduced by pain, so much so,
that pain is often inflicted on victims of
morphine overdose as a therapy, at which
time it acts as an antidote to morphine in
the same way that during pain morphine is
an antidote to the pain.
• Genetics: different strains of mice metabolize drugs
at different rates.
• There is also an obvious sex difference in metabolism
of compounds.
• Morphine controls pain much better in men than
women.
• Ibuprofen is more effective in men than women.
• Anti-rejection drugs are cleared from women faster so
they reject more organs than men.
• Sometimes, certain individuals may possess a genetic
complement which will have tragic consequences
under normal conditions.
• E.G., A case of a young boy who died after receiving
general anesthetic. When his sister subsequently
required an operation, she was given the same
anesthetic and also died.
Drug variables
A very important drug variable is the (1) dose
response curve.
Many compounds have vastly different effects when
administered at different concentrations.
E.G., Although barbiturates are effective for
inducing sleep, small doses induce excitement
and increase sensitivity to pain.
Repeated administrations of the same drugs. If a
drug is administered chronically in doses that
exceed the amount removed from the body by
metabolism and excretion, cumulative effects can
occur.
• Tolerance may also develop with many
drugs.
• Tolerance is the progressive requirement
with chronic use for higher drug doses to
produce a given effect.
• Tolerance can be viewed as an attempt by
the body to return to homeostasis,
equivalent to the drug free condition.
• Cross tolerance- develops among related
drugs.
• E.G. between mescaline and LSD. (The
reverse is also true.)
Sensitization - when responsiveness to a
drug increases with repeated
administrations.
E.G. Marijuana, amphetamine, cocaine,
barbiturates, and morphine.
Withdrawal: the abstinence syndrome.
Set of behaviors and physiologic symptoms
that occur when drug treatment is
withdrawn from a person who has
developed a tolerance to the drug.
Physical Dependence:
Craving for substances as a result of
pharmacodynamic tolerance. (Neurochemical
adjustment of brain to presence of drug.)
Physical dependence is defined as an adaptive
state that manifests itself by intense physical
disturbances when the administration of a drug is
suspended.
Psychological Dependence:
Psychological dependence is defined as a condition
in which a drug produces a feeling of satisfaction
and a psychic drive that requires periodic or
continuous administration of the drug to reduce
pleasure or to avoid discomfort.
Physical and psychological dependence is typically called addiction. Over
time these effects can have cumulative negative effects on physiology and
general health related to changes in lifestyle and diet and due to legality of
the drug being used.
Why do you think the appearance of these people changed so much?
Bioavailability
Refers to the effectiveness with which a
drug is absorbed. All preparations that
contain identical amounts of active
ingredients are not equally utilized.
Bioavailability depends significantly upon the
manufacturer of a drug. (Remember: 250
ingredients with 200,000 variations)
Dosage Regimen
To maintain a steady state level of a drug,
administration should be at uniform intervals
equal to the drug's biological half life.
Drug levels that are too low will be ineffective
while those that are too high may be toxic.
E.G. A drug with a half life of 8 hours should be given
at 8 hour intervals.
Expectation plays an
important role in how we
respond to drugs that affect
the brain:
We call this…
THE PLACEBO EFFECT
The Placebo Effect
Size and Color are Important
Placebo Effect
Placebos play an important part in medical
practice. Placebo effect may have greater
implications for psychotherapy than any other
form of treatment because both psychotherapy
and the placebo effect function primarily
through psychological mechanisms.
Placebos influence both selective and
objective measures.
E.G., Study of patients with bleeding ulcers: half were told by a doctor that
they were given a new drug which would undoubtedly produce relief;
The other half was told by nurses that they would receive a new experimental
drug with uncertain effects.
In fact, both groups received a placebo.
The dopamine being released leads to reduced binding of the radioactive
drug to the dopamine receptors in the caudate nucleus.
Treatment with placebo increased the release of dopamine
and decreased the number of dopamine receptors within the
caudate nucleus of patients with Parkinson’s Disease.
de la Fuente-Fernandez et al.,2001.
Placebo effects depend in part on the condition that’s being treated.
Placebo doesn’t affect diabetes; there’s no
placebo effect on blood sugar levels.
Pain reducing placebo seems to be about
half of the response to active pain reducing
medications. This is true regardless of
whether the active medication is aspirin or
morphine, meaning that placebo morphine
is significantly more powerful than placebo
aspirin.
For depression the placebo response
ranges from 60 to 80 percent of the
response to the medication.
Placebo effects occur faster than “real” drug effects!
Figure 1. Areas in which the magnitude of placebo analgesia correlated with gray matter
density
Schweinhardt, P. et al. J. Neurosci. 2009;29:4882-4887
Copyright ©2009 Society for Neuroscience
Figure 2. Areas in which the dopamine-related trait variable correlated significantly with
gray matter density
Schweinhardt, P. et al. J. Neurosci. 2009;29:4882-4887
Copyright ©2009 Society for Neuroscience
NIH Press Release
May 2002
Placebo, Antidepressant May Lift Depression Via Common Mechanism
Both groups, placebo (top) and drug (bottom) shared a pattern of increased
activity in the cortex (e.g., prefrontal, posterior cingulate) and decreased activity in
limbic regions (e.g., subgenual cingulate), which the researchers suggest is
necessary for therapeutic response.
Participants viewed images taken
from paintings either of a woman
depicted by Leonardo da Vinci, left,
or of the Virgin Mary, right, before
and during applications of painful
electrical pulses.
Devout Catholics reported feeling peaceful and secure, as well as thinking about
compassion and other religious concepts, while viewing the Virgin Mary. They rated
that image as especially helpful in coping with pain. Non-religious participants
reported no advantage from either image in dealing with pain.
Pain relief for Catholics was accompanied by activity in the right ventrolateral
prefrontal cortex, a brain region linked to pain relief associated with emotional
detachment and perceived control over pain. This brain response was not observed
in the non-religious volunteers.
Wiech, K., et al. In press. An fMRI study measuring analgesia enhanced by religion as a belief
system. Pain.2008
"cure for Dyspepsia, Low Spirits, Nervousness, Heartburn, Colic Pains, Wind in
the Stomach or Pains in the Bowels, Headache, Drowsiness, Kidney and Liver
Complaints, Melancholy, Delirium Tremens, and Intemperance."
Next: Acetylcholine