Download Basic Neuroanatomy

Patrick Foley PharmD, BCPP, BCPS
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Prescription Drug Abuse
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Sedative-hypnotics
 Barbiturates
 Benzodiazepines
Stimulants
 Analgesics
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In the middle of the 19th century, bromide and
chloral hydrate replaced alcohol and opium for
sedation
Barbiturates replaced these in the early 1900s
Finally the latest improvement were the
benzodiazepines in the 1960s
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Affect neurons in a way that causes
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A state of calm, relaxation, drowsiness, and
eventually sleep
Also called tranquilizers and anxiolytics (antianxiety)
Largely represented by the barbiturates and the
benzodiazepines
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All carry the risk of inducing physical and
psychological dependence
Large degree of tolerance occurs from liver
enzyme induction
Cross tolerance common between barbiturates
Fits the criteria (from previous 2 slides)
for a sedative-hypnotic drug
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First introduced into medicine in 1912
Barbiturates were the drug of choice for anxiety
and insomnia from 1912 to about 1960
Barbiturates are classified based on
their pharmacokinetic properties
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Absorbed from oral and rectal routes to
varying degrees
Onset of action is 10-60 minutes following oral
ingestion
Onset is almost immediate to 5 minutes
following intravenous administration
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Broken down slowly in the liver
20-30% unchanged in the urine
Remainder is metabolized first and then
excreted in the urine
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3-6 hours after IV injection
6-8 hours after oral ingestion
Ranges from 3 hours to 6 days
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Have a low degree of selectivity and a small
therapeutic index (dangerous)
DO NOT have analgesic properties
Barbs are cognitive inhibitors causing sedation
and depressing memory function
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Sleep patterns are markedly disturbed
Suppress dreaming
Rebound REM sleep occurs with
withdrawal
Behavioral and motor depression are
similar to that seen with alcohol
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Drowsiness
Impair motor, and intellectual performance
and judgment
Additive to alcohol in their effects
Sedative doses have minimal effects on
respiration
Overdose amounts profoundly depress
respiration
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Induction of drug-metabolizing enzymes
Adaptation of neurons in the brain to the
presence of the drug
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Normal doses used in medicine can induce
physical dependence
Withdrawal from high doses may result in
hallucinations, restlessness, disorientation, and
life-threatening convulsions
These drugs are prone to abuse because they
relieve anxiety and produce a state of euphoria
Carry the same abuse potential as barbiturates
 Ethchlorvynol, Methylprylon, Methaqualone
(Quaalude®), Meprobamate , Chloral Hydrate
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Originally used as anxiolytics, daytime sedatives, and
hypnotics
Interchangeable pharmacologically with Barbiturates
Rarely used today
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Became available in early 1960’s
15 have been released in the US market
Became the most widely used class of drugs in
the 60’s
Their tendency to produce dependency as time
went on has limited their use
Currently still marketed for use as
sedatives/hypnotics, anxiolytics, muscle
relaxants, IV anesthetics, and anticonvulsants
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Still widely considered drugs of choice for
short term treatment of acute anxiety
Behavioral therapies and antidepressants have
replaced them for treating chronic anxiety
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Well absorbed orally with peak blood levels
occurring in about 1-2 hours
Many metabolized to active metabolites prior
to being metabolized to in-active compounds
Occurs mainly in the liver
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Mostly eliminated in the urine after being
metabolized
Ranges from one hour to greater than 3 days
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Agonist of the GABA-benzodiazepine chloride
complex
Work as anxiolytics by stimulating GABA’s
action in the Limbic system
Anxiolysis occurs because the Amygdala is
depressed and this is the brain center largly
associated with fear and anxiety
GABA stimulation in the Cerebral Cortex
accounts for side effects such as sedation,
increased seizure threshold, and muscle
relaxation
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Stimulation of GABA receptors in the Cerebral
Cortex and Hippocampus leads to mental
confusion and amnesia
Mild muscle relaxation occurs due to anxiolysis
and GABAergic effects in the spinal cord, brain
stem, and cerebellum
Stimulation of nerves in the Ventral
Tegmentum and Nucleus Accumbens accounts
for the behaviorally rewarding aspect
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Acute anxiety
Sedative/hypnotic
Muscle relaxant
Antegrade amnesia
Panic attack
Alcohol withdrawal
Seizure disorders
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Rohypnol® is Flunitrazepam
Not marketed in this country
Exhibits “Mickey Finn” like action
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Side effects include
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Sedation, drowsiness, ataxia, lethargy, mental
confusion, motor and cognitive impairments,
disorientation, slurred speech, amnesia, and
worsening of dementia
When used for insomnia, some people have a
paradoxical agitation effect
Appears to be a ceiling to the respiratory
depressant effect and therefore is not as serious
a concern as the Barbiturates
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Especially associated with extended use (>3
weeks)
Rebound increases in insomnia, restlessness,
agitation, irritability, seizures, and
hallucination
Most withdrawal symptoms subside within 1
to 4 weeks
Those prone to dependence show a pattern of
multi-drug abuse
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Freely crosses the placenta
Increased number of fetal abnormalities when
taken during the first trimester
Excreted in breast milk leading to
accumulation in the infant
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Increase behavioral activity
Elevate mood
Increase motor activity
Increase alertness
Decreases sleepiness
Increase brain metabolic activity
Increase neuronal activity
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Stimulate the monoamine neurotransmitters
dopamine, norepinephrine, and serotonin
Stimulate the nucleus accumbens (the reward
center)
Area of the brain associated with
behavioral reinforcement, compulsive
abuse, and drug dependency
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Developed in the 1930’s
Had 39 purported uses up until 1946
Currently used for:
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Narcolepsy
ADHD
Weight loss
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Absorption - well absorbed orally
Distribution - quickly to the brain where levels
reach 80% of serum levels
Metabolism - extensively in the liver to inactive
metabolites, though not to the same extent as
cocaine
Excretion - 17-73% unchanged in the urine with
remainder at inactive metabolites, they are
detectable for 48 hours
Half-life – 10.5 hours
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Sympathomimetic agents
which mimic actions of
adrenaline
Exert most CNS effects by
stimulating release of
norepinephrine and
dopamine from presynaptic
nerve terminals
PNS effects are caused by
increased norepinephrine
levels
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Behavioral stimulation and
increased psychomotor
activity is mediated by
amphetamine’s effect on
dopamine receptors in the
meso-limbic system
Much of its pharmacological
activity is like cocaine
Potency =
methamphetamine>dextroa
mphetamine>amphetamine
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Peripherally causes:
Hypertension
 Tachycardia
 Bronchodilation
 In general, induces
fight or flight pattern
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CNS causes:
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Potent psychomotor
stimulation
Increased alertness
Euphoria
Excitement
Wakefulness
Reduced sense of
fatigue
Loss of appetite
Mood elevation
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Additional to low
dose effects include:
Stimulate respiration
 Slight tremors
 Restlessness
 Insomnia
 Agitation
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Chronic users:
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Stereotypical
behaviors
Sudden outbursts of
aggression and
violence
Paranoid delusions
Severe anorexia
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Psychosis
Weight loss
Skin sores
Progressive deterioration in social, personal,
and occupational affairs
Amphetamine psychosis with paranoid
ideation (especially seen with
methamphetamine abuse)
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Occur at doses as small as 20-30mg
Some people tolerate doses >400mg
Primary toxicity usually occurs due to chronic
use
Acute toxicity outside of CNS due to
hypertension which leads to MI and stroke
Acute toxicity in the CNS includes psychosis
and hyperthermia
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Do not have the amphetamine nucleus, but
share the same action of potentiating
sympathomimetic actions
Include such OTC’s as ephedrine, found in Mahuang, and pseudoephedrine, found in
sudafed
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Regular release tablets have half-life of 2-4 hours
Several sustained-release tablets available
Pharmacodynamically it increases the synaptic
concentration of dopamine by blocking the presynaptic
dopamine transporter and also by slightly increasing
dopamine release presynaptically
If injected IV, an individual would experience a
Cocaine-like high, but the slow uptake into the brain
when given orally would limit its degree of positive
reinforcement
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Inhibits reuptake of serotonin, norepinephrine,
and (to some extent) dopamine
Used as an anti-obesity drug with modest
results
Rapidly metabolized in the liver to active
metabolites that are responsible for its
pharmacologic action (prodrug)
Metabolites reach a peak at 3-4 hours in plasma
Half-life of 14-16 hours
Drug does not appear to have significant abuse
potential
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Nonamphetamine psychostimulant with
unknown MOA
May potentiate excitatory glutamate
neurotransmission and inhibit GABA activity
Used for narcolepsy
Recently FDA approved for use by truck
drivers as a stimulant
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Nonamphetamine behavioral stimulant
Inhibits presynaptic norepinephrine
transporter
Developed as an antidepressant
Used to treat ADHD
Pain relief
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Opioids
Non-opioids
Adjuvant agents
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Most important drug in medicine for the relief
of severe pain
Work by mimicking the actions of endogenous
endorphins to suppress pain
Derived from opium in early 1800’s
Used extensively during Civil War subsequent
to the invention of the hypodermic needle
Access was restricted by the Fed’s with the
Harrison Narcotic Act of 1914
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Mu
Kappa
Delta
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Pure agonists
Pure antagonists
Mixed agonistantagonists
Partial agonists
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Results in both analgesia and euphoria
Prone to cause dependency
Examples: morphine, methadone, heroin,
fentanyl
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Produce agonist effect at one receptor and an
antagonist effect at another
Clinically useful drugs are Kappa agonists and
weak mu antagonist
Have a ceiling to their analgesic effects
Can precipitate withdrawal in opiate addicts
Example: pentazocine (Talwin)
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Binds to an opioid receptor but has low
intrinsic activity
Exert analgesic activity but have a ceiling to
their effect
Example: buprenorphine (Suboxone)
No other drug has shown to be more
effective for treating severe pain
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GI absorption is slow and erratic
From rectum is adequate
IV can produce profound respiratory
depression
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Morphine crosses BBB slowly
Only about 20% reaches brain
Fentanyl and Heroin cross BBB much faster
The flash or rush that heroin produces is due to
the rapidity with which it reaches the brain
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Morphine - in the liver to an active metabolite
called morphine-6-glucuronide
Metabolite of morphine is 10-20 times more
potent than parent compound
Heroin - in liver to morphine
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Via the urine
Morphine can be detected in the urine for 2-4
days post Heroin dose
Morphine - 2 to 4 hours
Ranges from 10 minutes to 30 hours for all pure
opioid agonists
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Analgesia
Euphoria
Sedation and anxiolysis
Respiratory depression
Cough suppression
Pupillary constriction
Nausea and Vomiting
GI symptoms
Other effects
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Morphine produces intense analgesia and
indifference to pain
Occurs without loss of consciousness
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Includes feeling of contentment, well being,
and lack of concern (important part of efficacy
and reinforcing properties)
Euphoric effects are less intense with repeated
use
Body produces endorphin which is its own
“Morphine” and responsible for the “runner’s
high”
Activate mu receptors in the meso-limbic
reward system which causes reinforcing effects
of opioids
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Produces anxiolysis, sedation, and drowsiness
Sedation is not as deep as that of CNS
depressants
Prominent mental clouding with apathy,
complacency, lethargy, and sense of tranquility
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Morphine causes profound respiratory
depression
Single most important acute side effect of
morphine and usually the one implicated as the
cause of death in overdoses
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Morphine as well as other mu and kappa
agonists cause pupillary constriction
Morphine stimulates mu receptors in the
CRTZ of the medulla causing vomiting
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Cause histamine release local itching
Adversely affects white blood
cells
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Development of tolerance with repeat use is a
feature of all opioids
Tolerance is mediated by activation of
glutamate NMDA receptors which counteract
opioids actions at mu receptors
Clinically, morphine doses may be increased
from a starting dose of 50-60mg per day to
500mg per day in as little as 10 days
Tolerance to one opioid leads to cross-tolerance
of all opioids
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Leads to profound reduction in the release of
dopamine in the nucleus accumbens and a
threefold increase in norepinephrine
Symptoms of withdrawal are the opposite of
the pharmacologic effects
Magnitude of the withdrawal symptoms is
directly related to the dose and frequency of
the opiate taken
Withdrawal is not considered to be life
threatening
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Buprenorphine (Suboxone, Subutex)
Works much like methadone does in treating
opiate withdrawal
Does not have the reinforcing properties that
methadone does
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Methadone
LAAM
Simply replace the shorter acting opiate and
are decrease the dose over time
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Codeine
Heroin
Hydrocodone (Vicodin, Lortab)
Hydromorphone (Dilaudid)
Oxycodone (Percocet, Oxycontin)
Oxymorphone
Meperidine (Demerol)
Methadone
LAAM
Propoxyphene (Darvon)
Fentanyl
Sufentanil
Alfentanil
Remifentanil
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Occurs naturally in opium
Usually used in combo with Acetaminophen or
aspirin for mild to moderate pain relief
Metabolized to morphine
Ceiling to its effectiveness as an analgesia that
morphine does not have
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Both structurally related to morphine
6-10 times more potent than morphine
Causes somewhat less sedation
Causes equal amounts of respiratory
depression
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Structurally different than morphine
Synthetic opioid
1/10th as potent as morphine
Produces similar type of euphoria
Equally as likely to produce dependence when
compared to morphine
Produces more excitatory side effects than
morphine such as tremors, delirium, hyperreflexia, and convulsions
Withdrawal reactions occur more rapidly due
to its shorter half-life
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Synthetic mu agonist with a pharmacological profile
similar to morphine
Very effective PO
Extended duration of action in suppressing withdrawal
symptoms
Methadone maintenance programs that prescribe an
average daily dose >50mg/day have higher retention
rates and lower illicit drug use rate
Even when doses are adequate, 1/3rd of patients will
still experience withdrawal
Has half-life of about 24 hrs
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Structurally similar to methadone
Less potent than codeine but more potent than
aspirin
Large doses demonstrate opioid-like effects
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Short acting IV opioid agonists related to
meperidine
Fentanyl is available as patches, injectable
solution, and oral lozenges
80 to 500 times as potent as morphine
Profoundly depresses respiration
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Buprenorphine
(Suboxone/Subutex)
Tramadol (Ultram)
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Semi synthetic which has limited stimulation of mu
receptors
As a partial agonist there is a limit to its analgesic
effects
Has limited ability to produce euphoria and
respiratory depression
Administration routes include PO, or IV
Subutex® (C-III) is indicated for opioid withdrawal
Suboxone® (C-III) contains buprenorphine and the
antagonist naloxone and is used for maintenance
treatment for opioid dependence
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Partial agonist at mu receptors
Blocks presynaptic uptake of norepinephrine
and serotonin
As a partial agonist it exhibits a ceiling to its
analgesic effects
Limited potential for abuse ad respiratory
depression
Many side effects which limit its usefulness
including drowsiness, vertigo, nausea,
vomiting, constipation, and HA
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Week mu agonists
Most analgesic effect comes from affinity for kappa
receptors
Quite limited in its analgesia producing abilities
Good for moderate pain relief
Ceiling to analgesia effectiveness
Produce acute withdrawal in opioid dependent
individuals
High incidence of psychomimetic side effects such as
dysphoria, anxiety reactions, and hallucinations
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Pentazocine (C-IV) (Talwin)
Butorphanol (C-IV) (Stadol)
Nalbuphine (Rx) (Nubain)