Unit 4: Systemic Drugs 12 days. April 6 th and 7 th : Opioid Analgesics.

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


• Act on CNS to produce analgesic and euphoric effects

• Arguably the most important drug in modern medicine


• 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

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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

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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

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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


• Euphoria:– Morphine produces pleasant euphoric state– Strong feeling of contentment, lack of concern– Reinforcing


• These drugs are reinforcing because they mimic the positive effect that is naturally obtained from other essential activities

• Species-specific• Eating, drinking, sex


• When a person is in withdrawal, they feel that the withdrawal is life threatening

• Just as food or drink withdrawal would be


• Often users describe first time use in ecstatic and sexual terms

• Constantly chasing the high


• 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


• 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


• 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


• Pupillary constriction:– Called miosis– Occurs in the presence of analgesia– Typical of opioid ingestion


• Nausea and vomiting:– Stimulates receptors in the medulla– These are the most characteristic, unpleasant side

effects– Not life threatening


• 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


• 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


• The rate of tolerance development varies from person to person

• Little is formed when opioids are used rarely or intermittently


• There is no top threshold of dose


• Tolerance of one opioid leads to cross-tolerance of all other opioids

• This does not extend to the sedative hypnotics (alcohol and barbiturates)


• 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


• 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


• Symptoms of withdrawal are typically opposite the effects of the drugRestlessnessDysphoriaDrug cravingSweatingExtreme anxietyDepressionIrritability

ChillsFeverVomitingIncreased respiratory rateCrampingInsomniaExplosive diarrhea


• 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


• Once abuse begins, the natural endorphin system does become deficient

• Normal function and feeling requires continued opioid presence


• 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, Anti-inflammatory Analgesics

NSAIDs

• The second major type of analgesic are the NSAIDs (nonsteroidal analgesic, anti-inflammatory 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 anti-inflammatory 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


• 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%


• 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


• Marijuana disrupts the memory process• It appears to impair both the encoding and

the retrieval processes


• 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


• 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


• Cognitive impairment• Persists for several hours after the perceived

high• Impairs performance while driving, at work, or

at school


• At high doses hallucinations may occur• Also intensification of emotions


• At EXTREMELY high doses users have experienced panic, paranoia, and depression

• Usually short• Often triggered by pre-existing personality

disorders and/or schizophrenia


• Main adverse effect is the impairment on learning, memory, and cognition


• 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


• 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


• 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


• Cardiovascular system:– Increase in heart rate– Increase in blood pressure– Dilated blood vessels in the cornea (bloodshot

eyes)

• Helps prevent heart attacks


• 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


• Immune system:– May be suppressed– Not well studied yet– Probably insignificant


• Reproductive system:– Decreased testosterone in males– Decreased sperm production– No reports of decreased male fertility– Decreased FSH and LH in females– Anovulatory cycles


• 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


• There are no cases of overdoses or deaths caused by THC

• The effective dose to lethal dose ration is around 1:1000


• 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


• 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


• 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


• Typically clouds consciousness and causes amnesia

• At high doses psychiatric symptoms include:– Hallucinations– Restlessness– Excitement– Euphoria– Disorientation


• At VERY high doses• Confusion• Respiratory depression• Coma• Delirium• Stupor


• 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


• 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.)


• 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


• 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


• 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

• 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


• 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 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

• 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

• 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


• 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


• The disruption of sensory input can cause behavioral reactions to be:– Unpredictable– Exaggerated– Distorted– Violent


• 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


• 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 self-administered 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

Unit 4: Systemic Drugs 12 days. April 6 th and 7 th : Opioid Analgesics.

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Transcript of Unit 4: Systemic Drugs 12 days. April 6 th and 7 th : Opioid Analgesics.