Download Unit 4: Systemic Drugs

Unit 4: Systemic Drugs
12 days
April 6thand 7th: Opioid Analgesics
Opioid Analgesic Introduction
• Opioid analgesics are
found naturally
occurring in the opium
poppy
• Used historically as a
pain killer, sedative, and
recreationally
Opioid Analgesic Introduction
• Act on CNS to produce analgesic and euphoric
effects
• Arguably the most important drug in modern
medicine
Opioid Analgesic Introduction
• Also pose a huge
dependence and abuse
risk
What is Pain?
• Pain is defined as an unpleasant sensory or
emotional process often associated with
actual tissue damage
• When body tissue is damaged the afferent
nerve fibers are activated in the PNS
• These pain-sensing nerves are called
“nociceptive sensory neurons”
What is Pain?
• The pain signal is sent to the spinal cord, and specific
neurotransmitters are released that cause the pain
sensation
What is Pain?
• Naturally occurring endogenous
neurotransmitters control regulate the pain
and neurotransmitter release
• Drugs can mimic these endorphins, thereby
artificially reducing or eliminating pain
What is Pain?
• Opioids and endorphins inhibit pre-synaptic
release of pain-signaling neurotransmitters in
the spinal cord
• There are also pathways in the brain that can
be activated, which will trigger the release of
endorphins in the spinal cord and reduce pain
What is Pain?
• Pain is not only physical
• Often there is a psychological component,
which may lead to chronic pain with no
specific source
• Chronic pain is NOT successfully treated by
opiates, and is a major contributing factor to
opiate abuse and dependence
History
• Opium is extracted from
Papaver Somniforum
(sleeping poppy)
• Used to treat diarrhea,
coughs, constipation,
and insomnia
• Used to produce
euphoria, analgesia,
and sleep
History
• Even historically, abuse and recreational use
was common
• When opium was combined with alcohol the
substance was called ‘laudanum’ which means
“something to be praised”
• It was also called “the stone of immortality”
• Used as a cure-all for almost every know
disease
History
• In the early 1800’s
morphine was isolated
as the active ingredient
• Morphine was then
used and abuser
regularly
• After the U.S. Civil War,
opium addiction was
known as ‘soldier’s
disease’
History
• The invention of hypodermic needles in 1856 led to
users giving self-administered opium injections
History
• Concern over opium dependence and abuse
began to grow in the early 1900’s
• In 1914 the Harrison Narcotics Act was passed
in the U.S.
• This strictly controlled the use of most opium
products
History
• Nonmedical use of opioids was banned
• However, this did not stop the problem –
which still persists today
History
• The abuse of opioids is difficult to stop since
they produce pleasure and cause tolerance to
develop
• Continued use leads to physiological
dependence
History
• We as a society
cannot get rid of
all opiates
because they are
irreplaceable in
medicine
Terminology
• Opium = juice in Greek
• Opiate = drug extracted from the exudate of
the opium poppy (morphine and codeine)
• Opioid = any exogenous (outside originating)
drug, natural or synthetic, that binds to an
opiate receptor
• Endorphin = naturally occurring in the human
body substance that acts like morphine
Terminology
• Narcotic =
– from Greek word for ‘sleep’
– was originally used for all drugs that induced sleep
– now used for opioids
– Also used for other illegal drugs like cocaine and
marijuana
– Not used pharmacologically
Terminology
• Natural opioids
– Morphine and codeine
– Occur in nature in only 2 places
• The opium poppy
• The human body
• Semisynthetic opioids
– Produced from morphine
– Heroin
• Synthetic opioids
– Fentanyl
Opioid Receptors
• Opium receptor come in 3 types
• They are distributed throughout the CNS
• Some regions have all 3 types, others only
have 1
• Some regions have higher densities of these
receptors than others
• Little is known about the clinical significance
of this
Opioid Receptors
• Activation of receptors leads to respiratory
depression, spinal analgesia, bradycardia,
physical dependence, and euphoria
Opioid Receptors
• The opioid receptors were first isolated in the
1990’s
• They were purified, cloned, and sequenced
• Their three-dimensional structures were
modeled
• They are all G-protein coupled receptors
Opioid Receptors
• Each receptor has ~400 amino acids
• The 3 different types of receptors are ~60%
identical to each other
Opioid Receptors
• Endogenous endorphins and exogenous
opioids all work to activate opioid receptors
• Receptor activation causes reduction of or
inhibition of neurotransmitters
• This is mainly accomplished by inhibition of
the neurotransmitter release
Mu Receptors
• Response upon activation:
– Analgesia
– Respiratory depression
– Euphoria
– Reduced gastrointestinal motility
– Pupil constriction (miosis)
Kappa Receptors
• Response upon activation:
– Analgesia
– Dysphoria
– Psychotomimetic effects
– Miosis
– Respiratory depression
Delta Receptors
• Involved in analgesia at spinal and brain levels
• Further pharmacological effects are not clear
• Possibly play a role in emotional responses to
opioids
Types of Opioids
• Pure agonists
• Pure antagonists
• Mixed agonist-antagonists
• Partial agonists
Pure Agonists
• Bind to receptors like endogenous compounds
– Morphine
– Codeine
– Heroin
– Demerol
– Dilaudid
– Dolophine
– Numorphan
– Sublimaze
Pure Antagonists
• Have affinity for receptors but after attaching
do not change cell function
• Block access of endogenous compounds or
exogenous drugs
• Useful in opioid abuse treatment programs
– Narcan
– Trexan
– Revex
Mixed Agonist-antagonists
• Produces agonist effect at one receptor while
producing antagonist effect at another
• Usually has decreased efficacy, so not as good
at treating severe pain
– Nubain
– Stadol
– Talwin
– Dalgan
Partial Agonists
• Binds to opioid receptors but has a low
activity
• When given to a non-user, mild analgesia is
observed
• When given to a user, no analgesic effects are
seen
• Does not produce as much respiratory
depression (safer) as agonists (morphine)
– Buprene
– Ultram
April 13th and 14th: Morphine
Morphine
• 2 analgesics found in the opium poppy
– Morphine
– Codeine
• Less potent is codeine
– 0.5% of crude exudate
• More potent is morphine
– 10% of crude exudate
– No other drug is as effective an analgesic
– No drug is clinically superior to treating severe
pain
Morphine
•
•
•
•
Administered orally, rectally, or by injection
Absorption from GI is slow and incomplete
Injection is typically preferred
Can be administered directly to the spinal cord
or the peripheral nerves
– Avoids unconsciousness
– Avoids constipation
– Used for labor and delivery
– Used after surgery
Morphine
• During injection care must be taken
– Usually IV
– Can cause fatal respiratory depression
• Smoking also rivals the speed of IV injections
– More commonly raw exudate
– Not a typical route of morphine administration
Pharmacokinetics
• More water soluble than lipid soluble
• Slowly crosses the blood brain barrier
• Other opioids (heroin, fentanyl) cross much
faster
• Only ~20% of administered morphine reaches
CNS
Pharmacokinetics
• Morphine and other opioids reach all body
tissues
• This includes fetus
– Babies will have dependency
– Not teratogenic
– May cause fetal growth retardation
Pharmacokinetics
• Metabolized by the liver
– One of the metabolites is actually more than 10
times as potent as morphine as an analgesic
– Much of the ‘effect’ of morphine is actually this
metabolite
– Half life is 3 to 5 hours
– People with poor kidney function may experience
loner half lives, and therefore longer analgesic
effect
Pharmacokinetics
• Urine tests can detect morphine and codeine
• Heroin metabolizes to morphine and
acetylcodeine
– When both are present, heroin is suspected
• Drug tests can not differentiate between these
three
• Cough syrup and poppy seeds can cause
positive results
Pharmacological Effects
• Analgesia:
– Morphine causes indifference to pain
– It reduces the intensity of pain
– No loss of consciousness
Pharmacological Effects
• Euphoria:
– Morphine produces pleasant euphoric state
– Strong feeling of contentment, lack of concern
– Reinforcing
Pharmacological Effects
• These drugs are reinforcing because they
mimic the positive effect that is naturally
obtained from other essential activities
• Species-specific
• Eating, drinking, sex
Pharmacological Effects
• When a person is in withdrawal, they feel that
the withdrawal is life threatening
• Just as food or drink withdrawal would be
Pharmacological Effects
• Often users describe first time use in ecstatic
and sexual terms
• Constantly chasing the high
Pharmacological Effects
• Sedation:
– Morphine produces sedation
– Not as intense as the CNS depressants
– May cause person to dose
– Easily awakened
– Lack of concentration, apathy, complacency,
lethargy, and drowsiness
Pharmacological Effects
• Respiratory depression:
– Decreases the respiratory center’s sensitivity to
high levels of carbon dioxide
– Volume also decreases
– Breathing patterns are shallow and irregular
– Can stop breathing at high doses
– Typical cause of death from overdose
Pharmacological Effects
• Cough suppressant:
– Suppress the cough center in the brain stem
– Historically used as cough suppressant
– Codeine is most popular
– Today, less addictive drugs are used
– Opioids are inappropriate
Pharmacological Effects
• Pupillary constriction:
– Called miosis
– Occurs in the presence of analgesia
– Typical of opioid ingestion
Pharmacological Effects
• Nausea and vomiting:
– Stimulates receptors in the medulla
– These are the most characteristic, unpleasant side
effects
– Not life threatening
Pharmacological Effects
• Gastrointestinal symptoms:
– Relieve diarrhea
– Most important action of morphine outside the
CNS is on the intestines
– Intestinal tone increases, motility decreases, feces
dehydrates
– Cramping may occur
– Constipating
– Lomotil and Imodium – do not reach CNS
Pharmacological Effects
• Other effects:
– Morphine can release histamine
• Results in localized itching
• Can cause more severe allergic reaction
• Bronchoconstriction
– Affect white blood cell function
• Complex alteration in the immune system
• Avoid opioids with immune compromised patients
Tolerance and Dependence
• Characteristic of all opioids
• Use is limited because
– The development of tolerance
– Uncomfortable side effects
– Potential for abuse
Tolerance and Dependence
• The rate of tolerance development varies from
person to person
• Little is formed when opioids are used rarely
or intermittently
Tolerance and Dependence
• There is no top threshold of dose
Tolerance and Dependence
• Tolerance of one opioid leads to crosstolerance of all other opioids
• This does not extend to the sedative hypnotics
(alcohol and barbiturates)
Tolerance and Dependence
• Physical dependence is an altered state of
biology induced by a drug whereby
withdrawal of that drug is followed by a
complex set of biological events
Tolerance and Dependence
• Acute opioid withdrawal results in a decrease
in dopamine release by the body
• Also causes increased norepinephrine to be
released
• This is what Narcan does
Tolerance and Dependence
• Symptoms of withdrawal are typically
opposite the effects of the drug
Restlessness
Dysphoria
Drug craving
Sweating
Extreme anxiety
Depression
Irritability
Chills
Fever
Vomiting
Increased respiratory
rate
Cramping
Insomnia
Explosive diarrhea
Tolerance and Dependence
• One new radical technique is to allow rapid
withdrawal while under general anesthesia
• Therapy
• Support groups
• Medical support
Why do people abuse opioids?
•
•
•
•
Avoid the distress of stopping
The euphoria produced by the opioids
Preexisting pain that is alleviated
Preexisting psychopathy as a basis for initial
experimentation
• Deficient endorphin systems which are
corrected by opioid use
• Environmental cues and internal mood states
Why do people abuse opioids?
• Once abuse begins, the natural endorphin
system does become deficient
• Normal function and feeling requires
continued opioid presence
Why do people abuse opioids?
• Opioids are extremely important for palliative
uses
• Most doctors are willing to prescribe opioids
to terminal patients despite the fact that they
will develop tolerance and dependence
April 15th: Nonnarcotic, Antiinflammatory Analgesics
NSAIDs
• The second major type of analgesic are the
NSAIDs (nonsteroidal analgesic, antiinflammatory drugs)
• Act on the periphery of the nervous system
• Reduces pain and inflammation by interfering
with the formation of prostaglandin hormones
NSAIDs
• NSAIDs combine analgesic and antiinflammatory effects
• They do not bind to opioid receptors
NSAIDs
• They inhibit the enzyme cyclooxygenase
• This enzyme converts precursor molecules
into prostaglandins, so inhibiting it inhibits the
prostaglandin formation
NSAIDs
• There are two isomers of cyclooxygenase
– COX-1
• Primarily in the GI tract
• Also in blood platelets
– COX-2
• Less use in normal body functions
• Used when tissue is inflamed
• Also formed during arthritis
NSAIDs
• Most NSAIDs inhibit both cyclooxygenase
forms nonselectively
• This means they affect the GI, platelets, and
inflamed tissues
• Some new forms only target COX-2
NSAIDs
• Effects of most NSAIDS:
– Reduction of inflammation (anti-inflammatory)
– Reduction in body temperature (antipyretic)
– Reduction of pain (analgesic)
– Inhibition of platelet aggregation (anticoagulant)
• The typical NSAID is aspirin
• Most others are referred to as ‘aspirin-like’
• Their use is inhibited by GI irritation
• The typical COX-2 inhibitor is celecoxib –
called Celebrex
• Used to treat arthritis
Nonselective Cyclooxygenase
Inhibitors
• Aspirin:
– Between 10,000 and 20,000 tons of aspirin
consumed each year in the U.S.
– Most popular, and most effective
– Analgesic, antipyretic, anti-inflammatory
– Low intensity pain
– Exerts important effect on platelets
Aspirin
• Aspirin irreversibly binds to platelets
• Inhibiting them from aggregation, which
requires prostaglandins
• Platelets live for 8 to 10 days
• Used to reduce the risk of stroke and heart
attacks
Aspirin
• Aspirin increases oxygen consumption
• This causes build up of carbon dioxide
• This causes increased respiration rate
• One symptom of an aspirin overdose is
panting
Aspirin
• Side effects:
– Gastric upset
• Mild heartburn
• Gastric ulcers
– Poisoning
– Ringing in the ears
– Thirst
– Hyperventilation
– In rare cases, asthma attacks
Reye’s Syndrome
• Caused by using aspirin to treat viral diseases
(like flu or chickenpox)
• Potentially fatal
• Damages liver and brain
• Can be treated but must be caught early
• Early symptoms include rashes on palms of
hands and feet and severe vomiting
Acetaminophen
• Also known as Tylenol
• Also effective analgesic and antipyretic
Acetaminophen
• Does not have the negative side effects of
aspirin
• Not a good anti-inflammatory
– Not useful in treating arthritis
• Not an anticoagulant
• Safer for children – does not cause Reye’s
syndrome
Ibuprofen
• Analgesic, antipyretic, and anti-inflammatory
effects like aspirin
• Does not have the adverse effects of aspirin
• GI issues and ulcers have occasionally been
reported
Ibuprofen
• Not recommended for patients with bleeding
disorders
• Not recommended for pregnant women
• Not excreted in breast milk
• Generally more expensive than aspirin
April 20th, 27th, and 28th:
Hallucinogenic, Psychedelic Drugs, and
THC
Tetrahydrocannabinol
• Called THC, the active compound
• Found in the hemp plant, Cannabis sativa
• Commonly called marijuana
Tetrahydrocannabinol
• Other names are hashish, charas, bhang, ganja, and
sinsemilla
– Hashish and charas are made from the dried resinous
exudate of the female flowers, and are the most potent
• THC content from 10 – 20%
– Ganja and sinsemilla are made from the dried material in
the tops of the female flowers
• THC content from 5 – 8%
– Bhang and marijuana are made from the dried rest of the
plant
• THC content from 2 – 5%
Tetrahydrocannabinol
• Marijuana is a mild sedative hypnotic
• Does not depress respiration, and therefore is
not lethal, even in high doses (unlike alcohol
and benzodiazepines)
Pharmacologic Effects
•
•
•
•
•
Disruption in attention mechanisms
Impairment of short term memory
Altered sensory awareness
Analgesia
Altered control of motor movements and
posture
• Possibly immunosupression
Pharmacologic Effects
• THC binds to specific cannabinoid receptors
• Does not resemble other sedatives or
psychedelics structurally
History
• Use of Cannabis sativa dates back to 8,000
B.C.
– As hemp cord
•
•
•
•
In 2700 B.C. used in China medicinally
In 2000 B.C. used in India religiously
In 1850’s it was introduced to Western culture
1920’s portrayed as evil and linked with crime
– Outlawed
History
• 1930’s marijuana was considered a ‘narcotic’
• 1940’s public was convinced
– Induced violent crimes
– Led to heroine addiction
– Great social menace
• Today it is widely used by youth
– In 1997 ~35% of high school senior used
marijuana within the past year
– Daily use was estimated at ~4.6%
History
• Since 1996 several states have begun to vote
on medical use of marijuana
• Debate still ranges on whether:
– Medicinal use should be permitted
– What disorders it is appropriate to treat
– Recreational use should be permitted
– What age limits should be in place, if any
History
• THC was isolated in 1964
• It was later discovered that the body have
specific cannabinoid receptors
• In 1990 the receptor was isolated and cloned
• In 1999 a marijuana abstinence syndrome was
described
Pharmacokinetics
• Most marijuana in the U.S. has a THC content
less than 8%
• Most is between 4 and 6%
• The typical administration route is hand rolled
cigarettes
• Each cigarette has around 50mg of THC
• 25 to 50% of the THC is actually available in
the smoke
Pharmacokinetics
•
•
•
•
Absorption is rapid and complete
Behavioral effects occur immediately
Effects rarely last more than 4 hours
Peak plasma levels occur around 10 minutes
after smoking begins
Pharmacokinetics
•
•
•
•
Levels fall dramatically after 2 hours
Remain detectable for up to 12 hours
Heart rate and blood pressure increase
Skin temperature decreases
Pharmacokinetics
•
•
•
•
THC can also be administered orally
Absorption is slow and incomplete
Onset of action takes 30 to 60 minutes
Peak effects occur 2 to 3 hours after ingestion
• THC is 3x more effective when smoked
Pharmacokinetics
• THC is distributed to the organs of the body,
and accumulates well in areas with fatty tissue
• Therefore it readily penetrates the brain
• It also easily crosses the placental barrier
Pharmacokinetics
• The THC is broken down first into and active
metabolite, and then into an inactive one
(THC-COOH)
• This metabolite is excreted from the body
slowly, with a half life between 30 and 60
hours
• This means that urine tests for this metabolite
can be positive for days
Pharmacokinetics
• In individuals who chronically use THC or who
use high quantities infrequently, urine test
may be constantly positive
Pharmacological Effects in Animals
• In some animals THC creates a syndrome of
behavioral effects
• The naturally occurring cannabinoid and
cannabinoid receptors are essential in normal
neurological function
• When mice are altered to have no
cannabinoid receptors they have higher
mortality rates, lower activity levels, and
lower pain thresholds
Pharmacological Effects in Animals
• Marijuana disrupts the memory process
• It appears to impair both the encoding and
the retrieval processes
Pharmacological Effects in Animals
• THC decreases body temperature, calms
aggressive behavior, potentiates the effects of
barbiturates, blocks convulsions, depresses
reflexes
• In primates it dramatically reduces aggression,
and also decreases the ability to perform
complex behavioral tasks
• It also can induce hallucinations
Pharmacological Effects in Animals
• High doses can depress ovarian function
• Also decrease sperm production
• It also can disrupt appetite regulation, and
may lead to overeating
Pharmacological Effects in People
• CNS effects vary with dose, administration
route, and environment of the user
• Perception of time is usually altered
• Senses are typically enhanced
• Increased sense of well being and euphoria
• Relaxation and decreased anxiety
Pharmacological Effects in People
• Cognitive impairment
• Persists for several hours after the perceived
high
• Impairs performance while driving, at work, or
at school
Pharmacological Effects in People
• At high doses hallucinations may occur
• Also intensification of emotions
Pharmacological Effects in People
• At EXTREMELY high doses users have
experienced panic, paranoia, and depression
• Usually short
• Often triggered by pre-existing personality
disorders and/or schizophrenia
Pharmacological Effects in People
• Main adverse effect is the impairment on
learning, memory, and cognition
Pharmacological Effects in People
• In chronic users these issues may be
permanent
• When started before the age of 16:
– Have difficulty focusing and filtering out irrelevant
information
– Do not use acquired information to accurately
alter behavior
– Decreased psychospatial skills
• Poor routines
– Poor mental representations of the environment
Pharmacological Effects in People
• Long term effects on health are minimal when
compared with other drugs
• Often a gate-way drug, users trend toward
multidrug use
• Still employable
• May become a bigger problem in increasingly
technological societies
Pharmacological Effects in People
• An amotivational syndrome is also associated
with marijuana use
• This is the cause of the high ‘drop out’ rate of
users
• Loss of interest in goal oriented endeavors
Pharmacological Effects in People
• Cardiovascular system:
– Increase in heart rate
– Increase in blood pressure
– Dilated blood vessels in the cornea (bloodshot
eyes)
• Helps prevent heart attacks
Pharmacological Effects in People
• Pulmonary system:
– Does cause damage
– More tars than cigarettes
– Same carcinogenic compounds
– Bronchiole irritation and inflammation
• No evidence of lung cancers being caused
• Does not appear to cause COPD
Pharmacological Effects in People
• Immune system:
– May be suppressed
– Not well studied yet
– Probably insignificant
Pharmacological Effects in People
• Reproductive system:
– Decreased testosterone in males
– Decreased sperm production
– No reports of decreased male fertility
– Decreased FSH and LH in females
– Anovulatory cycles
Pharmacological Effects in People
• Does cross the placental barrier
• Probably should not be used during pregnancy
– Mild fetal growth retardation and maternal lung
damage
• Similar to smoking
• Little to no effect on 1 – 3 year olds
• After 4 years, children display increased
behavioral problems and decreased
performance in several areas
Pharmacological Effects in People
• There are no cases of overdoses or deaths
caused by THC
• The effective dose to lethal dose ration is
around 1:1000
Tolerance and Dependence
• Tolerance does not occur
• Until recently, physical dependence was not
thought to occur
– Not self administered by animals
– Newly defined marijuana withdrawal syndrome
includes restlessness, insomnia, anxiety,
depression, nausea, agitation, depression, and
many other symptoms
Tolerance and Dependence
• Defining elements of dependence:
– Preoccupation with the acquisition of the drug
– Compulsive use
– Relapse, or recurrent use of, the drug
Therapeutic Uses
• Appetite stimulant (AIDS patients)
• Anti-nausea and anti-emetic (chemotherapy)
• Cardioprotective (?) – reduce heart attacks
• Neuroprotective (?) – after strokes and head
trauma
• Should be a schedule 2 drug, not schedule 1
April 29th: Psychedelic Drugs
Psychedelic Drugs
• Commonly called hallucinogens
• Not exactly accurate, and includes a wide
array of different compounds
• Typically separate users from reality, and can
induce hallucinations
• Also alter mood, cognition ability, and
perception
Psychedelic Drugs
• Illusory phenomena and perceptual
distortions are actually more common than
true hallucinations
• Psychotomimetic = substance that mimics
psychoses or induces a psychotic state
• However, the behavior pattern is different
from people experiencing true psychotic
episodes
Psychedelic Drugs
• Phantasticum or Psychedelic = ability to alter
sensory perception
• More accurate for a wider range of drugs
• “any agent that causes alterations in
perception, cognition, and mood as its main
psychobiological action in the presence of an
otherwise clear sensorium” – Abraham, Aldridge, and Gogia
Psychedelic Drugs
• Does not include poisons or deliriants
• Deliriants = produce clouding of consciousness
and/or amnesia
Psychedelic Drugs
•
•
•
•
Many psychedelic agents occur naturally
Have been used since before recorded history
Inhaled, ingested, and worshipped
Many were thought to have magical
properties
• Mostly used by native peoples until the 1960’s
Psychedelic Drugs
• Advocated in the 60’s and 70’s to enhance
comprehension of the spiritual world,
promote personal awareness, and alter
perception
• Often part of the self seems to be a passive
observer of events
• Also used today for their intoxicating effect
Psychedelic Drugs
• Most psychedelic drugs resemble
neurotransmitters
• Three main classes:
– Anticholinergic
• Acetylcholine
– Catecholamine-like
• Norepinephrine
• Dopamine
– Serotonin-like
• Serotonin
Anticholinergic Psychedelics
• Scopolamine
• Acetylcholine receptor antagonist
• Blocks access of acetylcholine to receptors
Historical Use
• Scopolamine is found widely in nature
• High concentrations in:
– Atropa belladonna
• Belladonna or deadly nightshade
– Datura stramonium
• Jamestown weed, jimsonweed, stinkweed, thorn apple,
or devil’s apple
– Mandragora officinarum
• Mandrake
Atropa belladonna
• Deadly nightshade used extensively as a
poison throughout the Middle Ages
• Scientific name derived from Atropos – the
Fate who cuts the thread of life
• Belladonna = beautiful woman
– Comes from the ability of the drug to dilate the
pupils
– Thought to be beautiful
Datura stramonium
• Cause incapacitation of entire armies
– Marc Antony’s in 36 B.C. was defeated after
presumable eating the berries
– British soldiers defeated outside of Jamestown,
Virginia by settlers in the battle known as Bacon’s
Revolution
• This is how the name Jamestown weed came to be
Historical Use
• Leaves from these plants are often used to
prepare intoxicating beverages
• Still smoked occasionally
• Most contain both atropine and scopolamine
Pharmacological Effects
• Acts on the PNS
– Causes dry mouth, reduced sweating, dry skin,
increased body temperature, dilated pupils,
blurred vision, tachycardia, and hypertension
• Acts on the CNS
– Deliriant and intoxicant
– Low doses produce drowsiness, mild euphoria,
amnesia, fatigue, delirium, mental confusion, and
dreamless sleep
Pharmacological Effects
• Typically clouds consciousness and causes
amnesia
• At high doses psychiatric symptoms include:
– Hallucinations
– Restlessness
– Excitement
– Euphoria
– Disorientation
Pharmacological Effects
•
•
•
•
•
•
At VERY high doses
Confusion
Respiratory depression
Coma
Delirium
Stupor
Pharmacological Effects
• Not very popular because of the clouding of
consciousness and loss of memory
• Makes users “hot as a hare, blind as a bat, dry
as a bone, red as a beet, and mad as a hen”
April 30th: Catecholamine-like and
Serotonin-like Drugs
Catecholamine-like Psychedelics
• Norepinephrine and dopamine receptors
• These drugs structurally resemble
norepinephrine, dopamine, and
amphetamines
– Basic phenyl ring, an ethyl side chain with
attached nitrogen or amine ring
• Include mescaline, DOM or STP, MDA, MDE,
MDMA (ecstasy), MMDA, DMA, and drugs
from nutmeg
Catecholamine-like Psychedelics
• Known to produce:
– Enhanced emotional responses
– Sensory-perceptual distortion
– Altered perceptions of colors, sounds, and shapes
– Complex hallucinations
– Dreamlike feelings
– Depersonalization
– Somatic effects (tingling skin, weakness, tremor,
etc.)
Catecholamine-like Psychedelics
• Also found to produce alterations in brain
serotonin
• When serotonin receptors began to be
identified in the 1990’s it became known that
LSD is a serotonin receptor agonist
Mescaline
• Peyote is a cactus that grows in the SW U.S.
and Mexico
• Plant is cut and dried
• Dried portions are then ingested
• Psychedelic chemical is mescaline
Historical Use
• Use extends back to pre-Columbian times
• Used by Aztecs and Mexican natives in
religious rites
• Currently legal to use in the Native American
Church of North America
– Sacramental
– Religious use is not considered abuse
– Rarely abused by member of the church
– Legal in 23 states and according to the federal
government
Historical Use
• Mescaline identified in 1896
• Chemical structure outlines in 1918
• Made synthetically afterwards
Pharmacological Effects
• Orally taken, absorbs completely and rapidly
• Significant CNS concentration achieved within
1 to 2 hours
• After 3.5 to 4 hours a psychotomimetic state
– Main effects on the visual system
• Effects last for around 10 hours
• Does not appear to be metabolized before it is
excreted
Pharmacological Effects
• Visual hallucinations:
– Brightly colored lights
– Geometric shapes
– Animals
– Occasionally people
• Can also cause anxiety and tremors
Synthetic Amphetamine Derivatives
• DOM, MDA, DMA, MDE, MDMA
• Structurally similar to mescaline and
amphetamines
• Produce effects like both
– Moderate behavioral-stimulant
– Psychedelic effects
• Increase with dose and dominate
MDMA
• Methylene-dioxy-methamphetamine
• Ecstasy, XTC, or Adam
• Potent and selective neurotoxin in animals
– Damages pre-synaptic serotonin transporter
• Sense of disembodiment and visual distortion
MDMA
• Users are more psychologically disturbed and
impulsive than non-drug users
• Users were more impulsive than users of
other drugs
• Causes more or less positive emotional effects
• Negative somatic effects include high blood
pressure, jaw clenching, restlessness,
insomnia, and impaired gait
MDMA
• Use is increasing, especially in clubs
• Causes severe somatic effects similar to that
of stimulants
• Can be fatal
• Often used in conjunction with other drugs
Serotonin-like Psychedelics
• Includes lysergic acid diethylamide (LSD)
• Also psilocybin and psilocin (from Psilocybe
mexicana mushroom)
Serotonin-like Psychedelics
• One thought for how these drugs cause their
psychedelic effect is that they overwhelm the
pontine raphe
– This is a sorting station for incoming sensory
information
– Major center for serotonin activity
– Overloads brain circuits – when disrupted
LSD
• Became widely used and controversial during
the 1960’s and 1970’s
• Big changes occur with tiny doses
• Enhance self-awareness
• Alter internal reality
• Few changes in body physiology
Historical Use
• First synthesized in 1938
• Effects not known after animal trials
• Accidental ingestion led to awareness of LSD’s
effects in 1943
Pharmacokinetics
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Taken orally
Rapidly absorbed
Peak blood levels are reached in about 3 hours
Miniscule quantities needed for effective dose
Crosses all barriers
Largest concentration in the liver (where it is
metabolized)
Physiological Effects
• Rarely overdosed because the lethal dose is
280 times the effective dose
• Most deaths come from accidents, suicides, or
homicides
Psychological Effects
• Pupillary dilation and glassy eyed appearance
• Time is slowed or distorted
• Visual alterations are the most common
– Colors can be heard
– Sounds can be seen
• Mood swings may occur
– Can be dangerous
– May reach panic proportions
Psychological Effects
• Three main phases of LSD trip:
– Somatic phase
• CNS stimulation and autonomic changes
– Sensory phase
• Sensory distortions and pseudohallucinations
• Effects desired by user
– Psychic phase
• Maximum drug effect
• Changes in mood, perception of time, true
hallucinations, and psychotic episodes
• This is the ‘bad trip’ phase
Tolerance and Dependence
• Tolerance readily and rapidly develops
• Cross tolerance also occurs between LSD and
other psychedelics
• Tolerance is lost within several days of drug
use cessation
• Physical dependence does not develop
• Lab animals do not self administer LSD
Adverse Reactions
• Chronic or intermittent psychotic states
• Persistent major affective disorder
(depression)
• Exacerbation of preexisting psychiatric illness
• Disruption of personality or chronic brain
syndrome (burnout)
• Post-hallucinogenic perceptual disorder
(flashbacks of hallucinations)
May 11th and 12th: Phencyclidine
and Ketamine
Phencyclidine and Ketamine
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Phencyclidine (PCP or angel dust)
Psychedelic anesthetics
First used in anesthesia
Do not act on neurotransmitter receptors like
other psychedelics
Phencyclidine
• PCP was developed in 1956
• Stopped being used as a anesthetic because of
adverse reactions
– Agitation
– Excitement
– Delirium
– Disorientation
– Hallucinatory phenomena
• Resembled schizophrenia
Phencyclidine
• Still used as a veterinary anesthetic
• PCP appears as powder, tablets, and rock
crystals
• Most often smoked
• Sprinkled on tobacco or marijuana
Ketamine
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Developed in 1960
Less adverse effects than PCP
Still similar to schizophrenia
Both positive and negative effects
Reversible
Pharmacokinetics
• Well absorbed whether taken orally or
smoked
• Peak effects occur about 15 minutes after
smoking
• Maximum blood levels are reached about 2
hours after oral dose is taken
• Half life can range from 11 to 51 hours
• Appears in urine – need second confirmation
test because of false positives
Pharmacokinetics
• Lots of research being done with PCP,
ketamine, and schizophrenia
• Thought that if the drug mechanism of action
is understood, treatments for the disease can
be found
Psychological Effects
• PCP dissociates individuals from themselves
and their environments
• Induces an unresponsive state with analgesia
and amnesia
• Eyes remain open (blank stare)
• High doses induce a coma or stupor
• Most users avoid unconsciousness levels
Psychological Effects
• The disruption of sensory input can cause
behavioral reactions to be:
– Unpredictable
– Exaggerated
– Distorted
– Violent
Physiological Effects
• Blood pressure becomes elevated
• Does not cause respiratory depression at most
doses
• Users recover within 2 to 4 hours typically
• State of confusion may last for up to 72 hours
Physiological Effects
• HIGH doses can cause comas, seizure activity,
and respiratory depression
• Can be lethal
Side Effects and Toxicity
• Use may lead to severe anxiety, aggression,
panic, paranoia, and rage
• Also accidents like falls, burns, drowning,
driving accidents, and aggressive behavior
• Self inflicted injuries are common
• Restraints can also cause injury
• Users do not respond to pain
Tolerance, Dependence, and Abuse
• PCP is the only psychedelic drug selfadministered by monkeys
• This compulsive abuse pattern is also seen in
humans
Tolerance, Dependence, and Abuse
• Therapy includes:
– Minimizing sensory input
– Orally ingested active charcoal (binds PCP in
stomach)
– Physical restraint
– Sedation (benzodiazepine) or an antipsychotic