Alcohol Pharmacokinetics Absorbsion

Alcohol Pharmacokinetics Distribution

– 95% enzymatically metabolized by alcohol
dehydrogenase (ADH)
• 85% metabolized by liver
• 15% in GI by gastric alcohol dehydrogenase
– It is metabolized at a rate of 10 cc of 200
proof/ hr
– 5% excreted in breath
– Drinking on an empty stomach decreases first
pass metabolism and increase BAC’s

Some drugs decrease alcohol dehydrogenase
levels – aspirin, heartburn meds

• Reversible druginduced brain syndrome
• Liver damage
• Korsakoff’s syndrome
– Caused by alcohol induced thiamine deficiency

that leads to brain damage
• Digestive difficulties
• Tumor promoter

• Close in structure to GABA
• GHB can be synthesized in the brain
• Produces sedation and anesthesia
• Club drug, date-rape drug
• Schedule 1
• Effects include euphoria, relaxation, and
social disinhibition
– Higher doses cause lethargy, ataxia,
dizziness, death

• Activation of pre/postsynaptic GABAb
receptors
• Could also be a GHB receptor
– Shows a strong affinity for an unknown
receptor

• Opium – Juice or extract from poppy flower
• Opiate – Compounds found in extract
• Morphine
• Codeine
• Opioid

– A natural or synthetic drug that binds to the opiate
receptor and produces agonist effects
– Analgesia

– Mu receptors (mu-1 and mu-2)
     • Mu-1 receptors are supraspinal and are responsible for the central
interpretation of pain
     • Mu-2 are located throughout the CNS and control respiratory depression, spinal analgesia, euphoria, and physical dependence
     • PAG, brain stem, caudate, thalamus, spinal cord
– Delta
     • Poor analgesics and low addictive potential
     • Modulate mu receptors
     • Nucleus accumbens and limbic structures
– Kappa
     • Modest analgesia, little respiratory depression, and  very little dependence
     • Miosis (pinpoint pupils)
     • Activation may antagonize mu receptors
     • Basal ganglia, PAG, hypothalamus, cortex, spinal cord

• Analgesia
       – Reduces intensity of pain by inhibiting the
release of pain signaling transmitters
• Euphoria
      – Drug reinforcement
      – Activate mu receptors in the mesolimbic
dopamine system
      – Opiods reduce the inhibition exerted by
GABAergic neurons on dopaminergic neurons
in the VTA (see figure 9.8)

Morphine - Pure agonists

Heroine - Pure agonists

Buprenorphine (Buprenex) - opioid partial agonist-antagonists,

naloxone - opioid antagonists

     • Typical routes of absorption
– Intranasal, inhalation, oral, iv
     • Absorption rate depends on the route of
administration
– Very little is absorbed when snorted
– Smoking has a much higher rate of absorption
     • Distribution
– Rapid and complete
– Brain levels can exceed plasma levels

• Cocaine has an interesting interaction with
EtOH
• The enzymatic breakdown of EtOH and
benzolecgonine produces a unique ethyl
ester
   – Cocaethylene
    Biologically as active as cocaine at blocking DAT
    Increases effect, withdrawal, dependence, etc
    Half-live is 2 ½ hours

• Potentiates DA, NE, and 5-HT
• Blocks active reuptake of all 3
• Research has focused mainly on DAT
• Increased dopamine levels in the nucleus
accumbens and other mesolimbic
structures leads to inhibitory actions,
decreases discharge rates
     – Leads to the euphoria and behavioral
         reinforcing properties of cocaine

• 25 – 100 mg
• The nontoxic physiological effects are
     – Increased alertness, motor hyperactivity
     – Tachycardia, vasoconstriction, hypertension
     – Pupil dilation, hyperthermia
• Psychological effects
     – Euphoria, giddiness, enhanced self consciousness –
lasts ~ 30 minutes
     – 2nd stage: lessened euphoria, anxiety – 60-90 minutes
– 3rd stage: enhanced long-term anxiety – lasts for
hours

• Tolerance develops rapidly
• Sexual dysfunction
• Stokes, seizures, dementia, brain damage
• Aortic rupture, heart attacks, arrhythmias
    – Occur with prolonged use or single use
• Nasal and pulmonary hemorrhage

• 1-2 mg/kg of bw
• No euphoric effects
• Anxiety, paranoia
• Toxic paranoid psychosis
• Hallucinations

• Chronic use produces severe psychiatric disturbances
    – Affective disorders, schizophrenia-like syndromes,
personality disorders
• Pregnancy
    – Same detrimental physiological and psychological
problems with the fetus as seen with an adult
• Treatment
    – Antiwithdrawal agents
    – Anticraving agents
    – Treatment of comorbidity

• Sympathomimetic agents
    – Mimic the action of adrenaline
• Originally a therapeutic option
    – 1935-1946
    – Used to treat schizophrenia?
• Today only used for narcolepsy and ADHD
    – Sometimes to maintain alertness
    – Major drug of abuse

• Facilitate release of DA and NE from presynaptic terminals
• Blocks reuptake
• Behavioral stimulate properties caused by increased DA in the mesolimbic system
• High dose stereotypical behavior caused by increased DA in the basal ganglia
• Peripheral effects caused by NE

• Depends on the amount and the specific form taken
• Low doses
    – Increase bp, decrease heart rate, increase wakefulness, improve performance, dexterity and fine
motor skills may be impaired
• Moderate doses
    – Tremor, restlessness, agitation
• High doses
    – Sterotypical behaviors, repetition, paranoid delusions

• Synthetic or natural compounds that are similar to
AMPH
• Increase levels of monoamines
• Little is know about the base pharamacology
– Do not cross the BBB well, this will be changed in
future versions

– Similar levels of behavioral and physiological effects
• Taken orally, nasally, inhalation or injection

• Oral administration
• Rapid absorption
     – Blood levels reached in 30-45 minutes
     – Peak at 2 hrs
• Hepatic, (liver) metabolism
• ½ life 3.5-5 hours in adults
    – Smoking decreases ½ life
    – SSRI can also alter metabolism

• Main effects
    – CNS stimulant
    – Cardiac, respiratory, and diuretic effects
• Has been used for the treatment of asthma, narcolepsy, migraines, pain
• Psychostimulant produces alertness
    – Occur after 100-200mg
    – Impairs fine motor skills, timing, and math
• High dosage 1.5g (12 cups)
    – Produces anxiety, agitation, tremors
    – Lethal at 10g
    – The anxiogenic effect is increased in those with             anxiety disorders
• Peripheral vasodilator, CNS vasoconstrictor

• Clinical syndrome
    – Characterized by CNS and peripheral effects
    – Produced by overuse
• CNS symptoms
    – Anxiety, agitation, insomnia, mood changes
• Peripheral symptoms
    – Tachycardia, hypertension, cardiac arrhytmias,
gastric disturbances
• Dose related
    – 500-1000mg

• Adenosine antagonist
    – A1, A2A, A2B, A2A
    – Most potent for A1, A2A
    – Form a diffuse depressant system
    – Decrease discharge rate of neurotransmitters
        DA, Ach, Glut, NE
        A1 inhibit release of DA, ACh and Glut
        A2A activation inhibits DA and antagonizes GABA

• Safety of caffeine during pregnancy has not been fully studied
• Dose dependent
• Higher dosages have been shown to cause growth retardation and spontaneous abortion
• High use prior to pregnancy has an elevated incidence of spontaneous abortion

• Chronic use associated with habituation and tolerance
• Likely to produce withdrawal symptoms
    – Headache, drowsiness, fatigue, low mood state
    – May also include craving, impairment in                             concentration, intellect, motor skills
• Mild dependency

• One of the 3 most widely used psychoactive drugs
    – Caffeine and EtOH are the others
• Few or no therapeutic applications
• Primary active ingredient in tobacco
• 9 in 10 smokers addicted by age 21
• 3 million adolescent smokers in U.S. alone

• Easily absorbed through many routes
• Typical dose 0.5-2.0 mg/ cigarette
• 20% is absorbed, amount of absorption is regulated by smoker
• Metabolism by hepatic (liver) enzymes
• ½ life 2 hrs

• Has strong effects on the CNS, PNS, heart, and other
structures
• Initially produces nausea and vomiting
• Stimulates release of ADH from the hypothalamus
increasing fluid retention
• Reduces muscle tone
• Shown to increase/improve
     – Psychomotor activity
     – Cognitive function
     – Attention
     – Memory
• Higher dosages induce nervousness, tremor, panic
disorder

• Seems to have antidepressant effects
• High level of comorbidity with ADHD and
depression
• Strong reinforcing effects early on
     – DA activation in midbrain
     – Fade with long term use
• Used to avoid withdrawal
• Increase heart rate, blood pressure

• Activation of nicotinic receptors
    – PNS effects, direct effects on ACh
    – CNS effects
• Not only activates ACh, but also DA and glutamate
• DA effects in mesolimbic, mesocortical regions
    – VTA, nucleus accumbens, forebrain
    – Behavioral reinforcement, stimulant and                         antidepressant effects
• ACh and glutamate effects in the CNS are primarily related to cognitive enhancement

• Does not seem to produce tolerance
• Does produce physiological and psychological dependence
• Withdrawal – abstinence syndrome
    – Craving, irritability, anxiety, anger, weight
           gain, insomnia, restlessness, etc
    – Can last for months
    – Increase in caffeine use

• Toxicity does not come from nicotine
• It comes from tar and the other compounds (>4000) in cigarettes
• Cancer causing
• Reduces your life by 14 minutes a cigarette
• Carbon monoxide lowers O2 levels in the
heart, leads to heart disease and stroke
    – Increases heart rate, hardens arteries, etc

• Pulmonary disease
    – Smoker’s syndrome
    – Emphysema
    – Decreased efficacy of pulmonary immune system
• Cancer
    – Nicotine is not carcinogenic
    – BDPE is a metabolite of one of the most potent
        mutagenic and carcinogenic agents known
• Damages a cancer suppressor gene
• Passive smoke is bad
• Smoking and pregnancy is bad

• Nicotine replacement therapies
     – Very effective
     – Gum & patches
     – Buproprion hydrochloride (Zyban)
• All methods have similar effectiveness

• 8000 B.C. first record of hemp cord
• Comes from the plant Cannabis sativa
     – Contains 60 compounds knows as cannabinoids
     – Main psychoactive properties come from
          Δ9-tetrahydrocannabinol (THC)
• Interesting history of use and regulation
     – early 19th century: use spread from China and the Middle East to Europe
     – Came to USA in the early 1900’s
     – Marihuana tax act, 1937
• Most heavily used illicit drug in USA

• A typical joint contains 0.5 to 1 g of cannabis, normal THC content is 4%, that gives you 49 mg of active THC per joint
• Only about 20% is absorbed
• Absorption is quick and establishes plasma levels
rapidly
• Metabolized by liver, metabolites stored in lipids
• Oral admin is more variable, 1st pass metabolism
knocks a lot out

• Serum level falls quickly over about 2 hrs
• However, body elimination is much slower
• The t1/2 of THC is 20-30 hrs
• A single use can be detected more than 2
weeks later

• CB1 and CB2
• CB1 being the CNS
receptor
• Metabotropic
    – Inhibition of cAMP and Ca2+ channels, K+

        channel activation
    – Occur presynaptically

• Inhibits the release of many neurotransmitters
• Ach, dopamine, NE, 5-HT, glutamate, GABA
• SR 141716 is a CB1 antagonist
     – Allows us to study how the receptors affect

          behavior
• Why do we have a pot receptor in the brain?
     – For the endocannabinoids of course

• Anandamide, 2-AG, etc
• “bringers of inner bliss”
• Are too lipid soluble to be stored in vessicles, so they are made and released as needed.
• Elevating iCA2+ levels starts production
• Retrograde messenger

• So how are you going to study it clinically?
     – I guess if you got, you use it
• Potency dependent
     – Buzz, high, stoned
     – Lightheaded, dizzy, progressing to euphoria, on to

          calm, dreamlike state
     – Higher levels produce perceptual distortions and

          hallucinations
     – Can induce anxiety, flashbacks, similar to LSD
     – There are no confirmed, published deaths from

          cannabis only poisoning, but allergies have been

          reported
• Physiological responses include increased blood flow, flushing, elevated heart rate, eating
• Antagonism with SR 141716 blocks most of these effects so they are based on CB1 action

• Intoxication produces deficits in thought and verbal behavior
• Does not produce amnesia but impairs cognitive performance
     – Inhibitory action in the hippocampus
• Strong psychomotor failure as well
• Hypoalgesia
• Have very strong reinforcing properties

• Has adverse effects on health
• Although it can be clouded in politics
     – Greater use correlated with poor school

          performance
• Dose-dependent effect on memory impairment
• Amotivational Syndrome
     – “stoned and stupid”
• Health effects not really studied much
     – Bad for the lungs, sperm and immune system
• Does have valid clinical applications
     – Marinol(dronabinol) and nabilone (analog of THC)
     – Cancer, AIDS wasting syndrome, pain, glaucoma,

          spastic disorder

• K2 like compounds (spice, Red X Dawn, etc)
• Bind strongly to CB1 and CB2, more so that THC

     (full agonist vs partial agonist)
• Developed in the mid 1990 as therapeutic agents
• Increase heart attack risk
• Increased risk for psychiatric illness and suicide

• Anticholinergics
     – Scopolamine
• Catecholamine-like
     – Mescaline
     – DOM, MDMA
• Serotonin-like
     – LSD
     – DMT
     – Psilocybin
• Psychedelic anesthetics
     – PCP
     – Ketamine

• Found in several common plants
     – Deadly nightshade, stinkweed, jimsonweed
     – Plants have been used for centuries for ceremonial

          purposes and murder
     – These plants also contain atropine
• Often used for their intoxicating effects
• Also dilates pupils

• Antagonizes Ach receptors
• Pharmacological effects
     – PNS Effects
• Produces an anticholinergic syndrome
     – Dry mouth, increased temp, dilated pupils,

          hypertension
• CNS Effects
     – A deliriant and intoxicant
     – In low doses produces drowsiness, euphoria,

          amnesia, mental confusion
     – Increases in dose produce hallucinations,

          disorientation, euphoria
     – Toxic doses produce a “toxic psychosis”

• Catecholamine-like psychedelic
     – Peyote
     – Used by Native Americans in many different rituals
     – Structurally similar to norepinephrine
     – Full agonist of 5-HT2A receptors
• Pharmacology
     – Rapid oral absorption
          Levels peak at 2 hrs and effects take place 3-4           hrs after administration, hallucinations can last           10 hrs
     – Produces visual hallucinations, limb spasms,

          anxiety

• DOM, MDA, DMA, MDE, TMA, MDMA
• All structurally similar to mescaline and methamphetamine
• They have moderate stimulant effects at low doses, psychedelic effects appear at higher dosages
• High potency and toxicity

• A potent and selective serotoninergic neurotoxin
• Damages SERT
• There are a variety of physical and psychological side effects

• Are all structurally similar to 5-HT
• LSD
     – Has strong effects even at very low doses
     – Binds to the 5-HT2A receptor
     – Has agonistic and antagonistic effects
     – Also a partial D2 agonist
     – Produces a multitude of physiological and     

          psychological effects
     – Tolerance develops rapidly but fades without

          continued use
     – Dependency does not seem to be a problem

• Psychedelic compounds found in several species of mushrooms
• Effect lasts for 6-10 hrs
• Hallucinations and sensory distortions similar to LSD
• 5-HT2A agonist
• Can produce a schizophrenia like psychosis

• Structurally dissimilar to other psychedelic agents
• Do not involve 5-HT, DA, or Ach
     – Phencyclidine (PCP)
• developed as an anesthetic, but was later dropped
• A noncompetitive NMDA antagonist
     – Ketamine
• Similar properties as in PCP
• NMDA antagonist
     – Dextromethorphan
• Antitussive medication in some cough syrups
• Opiate-like actions, is NMDA noncompetitive antagonist

• Low doses
     – Mild agitation, disinhibition, disturbances in

          cognition and judgement
• Moderate doses
     – Coma, stupor, hypertension
• Other effects include anxiety, aggression, panic
attacks
• Can be habit forming
• Ketamine produces analgesia
• Have led to insights in schizophrenia

Alcohol Pharmacokinetics Absorbsion

Alcohol Pharmacokinetics Distribution

– 95% enzymatically metabolized by alcohol
dehydrogenase (ADH)
• 85% metabolized by liver
• 15% in GI by gastric alcohol dehydrogenase
– It is metabolized at a rate of 10 cc of 200
proof/ hr
– 5% excreted in breath
– Drinking on an empty stomach decreases first
pass metabolism and increase BAC’s

Some drugs decrease alcohol dehydrogenase
levels – aspirin, heartburn meds

• Reversible druginduced brain syndrome
• Liver damage
• Korsakoff’s syndrome
– Caused by alcohol induced thiamine deficiency

that leads to brain damage
• Digestive difficulties
• Tumor promoter

• Close in structure to GABA
• GHB can be synthesized in the brain
• Produces sedation and anesthesia
• Club drug, date-rape drug
• Schedule 1
• Effects include euphoria, relaxation, and
social disinhibition
– Higher doses cause lethargy, ataxia,
dizziness, death

• Activation of pre/postsynaptic GABAb
receptors
• Could also be a GHB receptor
– Shows a strong affinity for an unknown
receptor

• Opium – Juice or extract from poppy flower
• Opiate – Compounds found in extract
• Morphine
• Codeine
• Opioid

– A natural or synthetic drug that binds to the opiate
receptor and produces agonist effects
– Analgesia

– Mu receptors (mu-1 and mu-2)
     • Mu-1 receptors are supraspinal and are responsible for the central
interpretation of pain
     • Mu-2 are located throughout the CNS and control respiratory depression, spinal analgesia, euphoria, and physical dependence
     • PAG, brain stem, caudate, thalamus, spinal cord
– Delta
     • Poor analgesics and low addictive potential
     • Modulate mu receptors
     • Nucleus accumbens and limbic structures
– Kappa
     • Modest analgesia, little respiratory depression, and  very little dependence
     • Miosis (pinpoint pupils)
     • Activation may antagonize mu receptors
     • Basal ganglia, PAG, hypothalamus, cortex, spinal cord

• Analgesia
       – Reduces intensity of pain by inhibiting the
release of pain signaling transmitters
• Euphoria
      – Drug reinforcement
      – Activate mu receptors in the mesolimbic
dopamine system
      – Opiods reduce the inhibition exerted by
GABAergic neurons on dopaminergic neurons
in the VTA (see figure 9.8)

Morphine - Pure agonists

Heroine - Pure agonists

Buprenorphine (Buprenex) - opioid partial agonist-antagonists,

naloxone - opioid antagonists

     • Typical routes of absorption
– Intranasal, inhalation, oral, iv
     • Absorption rate depends on the route of
administration
– Very little is absorbed when snorted
– Smoking has a much higher rate of absorption
     • Distribution
– Rapid and complete
– Brain levels can exceed plasma levels

• Cocaine has an interesting interaction with
EtOH
• The enzymatic breakdown of EtOH and
benzolecgonine produces a unique ethyl
ester
   – Cocaethylene
    Biologically as active as cocaine at blocking DAT
    Increases effect, withdrawal, dependence, etc
    Half-live is 2 ½ hours

• Potentiates DA, NE, and 5-HT
• Blocks active reuptake of all 3
• Research has focused mainly on DAT
• Increased dopamine levels in the nucleus
accumbens and other mesolimbic
structures leads to inhibitory actions,
decreases discharge rates
     – Leads to the euphoria and behavioral
         reinforcing properties of cocaine

• 25 – 100 mg
• The nontoxic physiological effects are
     – Increased alertness, motor hyperactivity
     – Tachycardia, vasoconstriction, hypertension
     – Pupil dilation, hyperthermia
• Psychological effects
     – Euphoria, giddiness, enhanced self consciousness –
lasts ~ 30 minutes
     – 2nd stage: lessened euphoria, anxiety – 60-90 minutes
– 3rd stage: enhanced long-term anxiety – lasts for
hours

• Tolerance develops rapidly
• Sexual dysfunction
• Stokes, seizures, dementia, brain damage
• Aortic rupture, heart attacks, arrhythmias
    – Occur with prolonged use or single use
• Nasal and pulmonary hemorrhage

• 1-2 mg/kg of bw
• No euphoric effects
• Anxiety, paranoia
• Toxic paranoid psychosis
• Hallucinations

• Chronic use produces severe psychiatric disturbances
    – Affective disorders, schizophrenia-like syndromes,
personality disorders
• Pregnancy
    – Same detrimental physiological and psychological
problems with the fetus as seen with an adult
• Treatment
    – Antiwithdrawal agents
    – Anticraving agents
    – Treatment of comorbidity

• Sympathomimetic agents
    – Mimic the action of adrenaline
• Originally a therapeutic option
    – 1935-1946
    – Used to treat schizophrenia?
• Today only used for narcolepsy and ADHD
    – Sometimes to maintain alertness
    – Major drug of abuse

• Facilitate release of DA and NE from presynaptic terminals
• Blocks reuptake
• Behavioral stimulate properties caused by increased DA in the mesolimbic system
• High dose stereotypical behavior caused by increased DA in the basal ganglia
• Peripheral effects caused by NE

• Depends on the amount and the specific form taken
• Low doses
    – Increase bp, decrease heart rate, increase wakefulness, improve performance, dexterity and fine
motor skills may be impaired
• Moderate doses
    – Tremor, restlessness, agitation
• High doses
    – Sterotypical behaviors, repetition, paranoid delusions

• Synthetic or natural compounds that are similar to
AMPH
• Increase levels of monoamines
• Little is know about the base pharamacology
– Do not cross the BBB well, this will be changed in
future versions

– Similar levels of behavioral and physiological effects
• Taken orally, nasally, inhalation or injection

• Oral administration
• Rapid absorption
     – Blood levels reached in 30-45 minutes
     – Peak at 2 hrs
• Hepatic, (liver) metabolism
• ½ life 3.5-5 hours in adults
    – Smoking decreases ½ life
    – SSRI can also alter metabolism

• Main effects
    – CNS stimulant
    – Cardiac, respiratory, and diuretic effects
• Has been used for the treatment of asthma, narcolepsy, migraines, pain
• Psychostimulant produces alertness
    – Occur after 100-200mg
    – Impairs fine motor skills, timing, and math
• High dosage 1.5g (12 cups)
    – Produces anxiety, agitation, tremors
    – Lethal at 10g
    – The anxiogenic effect is increased in those with             anxiety disorders
• Peripheral vasodilator, CNS vasoconstrictor

• Clinical syndrome
    – Characterized by CNS and peripheral effects
    – Produced by overuse
• CNS symptoms
    – Anxiety, agitation, insomnia, mood changes
• Peripheral symptoms
    – Tachycardia, hypertension, cardiac arrhytmias,
gastric disturbances
• Dose related
    – 500-1000mg

• Adenosine antagonist
    – A1, A2A, A2B, A2A
    – Most potent for A1, A2A
    – Form a diffuse depressant system
    – Decrease discharge rate of neurotransmitters
        DA, Ach, Glut, NE
        A1 inhibit release of DA, ACh and Glut
        A2A activation inhibits DA and antagonizes GABA

• Safety of caffeine during pregnancy has not been fully studied
• Dose dependent
• Higher dosages have been shown to cause growth retardation and spontaneous abortion
• High use prior to pregnancy has an elevated incidence of spontaneous abortion

• Chronic use associated with habituation and tolerance
• Likely to produce withdrawal symptoms
    – Headache, drowsiness, fatigue, low mood state
    – May also include craving, impairment in                             concentration, intellect, motor skills
• Mild dependency

• One of the 3 most widely used psychoactive drugs
    – Caffeine and EtOH are the others
• Few or no therapeutic applications
• Primary active ingredient in tobacco
• 9 in 10 smokers addicted by age 21
• 3 million adolescent smokers in U.S. alone

• Easily absorbed through many routes
• Typical dose 0.5-2.0 mg/ cigarette
• 20% is absorbed, amount of absorption is regulated by smoker
• Metabolism by hepatic (liver) enzymes
• ½ life 2 hrs

• Has strong effects on the CNS, PNS, heart, and other
structures
• Initially produces nausea and vomiting
• Stimulates release of ADH from the hypothalamus
increasing fluid retention
• Reduces muscle tone
• Shown to increase/improve
     – Psychomotor activity
     – Cognitive function
     – Attention
     – Memory
• Higher dosages induce nervousness, tremor, panic
disorder

• Seems to have antidepressant effects
• High level of comorbidity with ADHD and
depression
• Strong reinforcing effects early on
     – DA activation in midbrain
     – Fade with long term use
• Used to avoid withdrawal
• Increase heart rate, blood pressure

• Activation of nicotinic receptors
    – PNS effects, direct effects on ACh
    – CNS effects
• Not only activates ACh, but also DA and glutamate
• DA effects in mesolimbic, mesocortical regions
    – VTA, nucleus accumbens, forebrain
    – Behavioral reinforcement, stimulant and                         antidepressant effects
• ACh and glutamate effects in the CNS are primarily related to cognitive enhancement

• Does not seem to produce tolerance
• Does produce physiological and psychological dependence
• Withdrawal – abstinence syndrome
    – Craving, irritability, anxiety, anger, weight
           gain, insomnia, restlessness, etc
    – Can last for months
    – Increase in caffeine use

• Toxicity does not come from nicotine
• It comes from tar and the other compounds (>4000) in cigarettes
• Cancer causing
• Reduces your life by 14 minutes a cigarette
• Carbon monoxide lowers O2 levels in the
heart, leads to heart disease and stroke
    – Increases heart rate, hardens arteries, etc

• Pulmonary disease
    – Smoker’s syndrome
    – Emphysema
    – Decreased efficacy of pulmonary immune system
• Cancer
    – Nicotine is not carcinogenic
    – BDPE is a metabolite of one of the most potent
        mutagenic and carcinogenic agents known
• Damages a cancer suppressor gene
• Passive smoke is bad
• Smoking and pregnancy is bad

• Nicotine replacement therapies
     – Very effective
     – Gum & patches
     – Buproprion hydrochloride (Zyban)
• All methods have similar effectiveness

• 8000 B.C. first record of hemp cord
• Comes from the plant Cannabis sativa
     – Contains 60 compounds knows as cannabinoids
     – Main psychoactive properties come from
          Δ9-tetrahydrocannabinol (THC)
• Interesting history of use and regulation
     – early 19th century: use spread from China and the Middle East to Europe
     – Came to USA in the early 1900’s
     – Marihuana tax act, 1937
• Most heavily used illicit drug in USA

• A typical joint contains 0.5 to 1 g of cannabis, normal THC content is 4%, that gives you 49 mg of active THC per joint
• Only about 20% is absorbed
• Absorption is quick and establishes plasma levels
rapidly
• Metabolized by liver, metabolites stored in lipids
• Oral admin is more variable, 1st pass metabolism
knocks a lot out

• Serum level falls quickly over about 2 hrs
• However, body elimination is much slower
• The t1/2 of THC is 20-30 hrs
• A single use can be detected more than 2
weeks later

• CB1 and CB2
• CB1 being the CNS
receptor
• Metabotropic
    – Inhibition of cAMP and Ca2+ channels, K+

        channel activation
    – Occur presynaptically

• Inhibits the release of many neurotransmitters
• Ach, dopamine, NE, 5-HT, glutamate, GABA
• SR 141716 is a CB1 antagonist
     – Allows us to study how the receptors affect

          behavior
• Why do we have a pot receptor in the brain?
     – For the endocannabinoids of course

• Anandamide, 2-AG, etc
• “bringers of inner bliss”
• Are too lipid soluble to be stored in vessicles, so they are made and released as needed.
• Elevating iCA2+ levels starts production
• Retrograde messenger

• So how are you going to study it clinically?
     – I guess if you got, you use it
• Potency dependent
     – Buzz, high, stoned
     – Lightheaded, dizzy, progressing to euphoria, on to

          calm, dreamlike state
     – Higher levels produce perceptual distortions and

          hallucinations
     – Can induce anxiety, flashbacks, similar to LSD
     – There are no confirmed, published deaths from

          cannabis only poisoning, but allergies have been

          reported
• Physiological responses include increased blood flow, flushing, elevated heart rate, eating
• Antagonism with SR 141716 blocks most of these effects so they are based on CB1 action

• Intoxication produces deficits in thought and verbal behavior
• Does not produce amnesia but impairs cognitive performance
     – Inhibitory action in the hippocampus
• Strong psychomotor failure as well
• Hypoalgesia
• Have very strong reinforcing properties

• Has adverse effects on health
• Although it can be clouded in politics
     – Greater use correlated with poor school

          performance
• Dose-dependent effect on memory impairment
• Amotivational Syndrome
     – “stoned and stupid”
• Health effects not really studied much
     – Bad for the lungs, sperm and immune system
• Does have valid clinical applications
     – Marinol(dronabinol) and nabilone (analog of THC)
     – Cancer, AIDS wasting syndrome, pain, glaucoma,

          spastic disorder

• K2 like compounds (spice, Red X Dawn, etc)
• Bind strongly to CB1 and CB2, more so that THC

     (full agonist vs partial agonist)
• Developed in the mid 1990 as therapeutic agents
• Increase heart attack risk
• Increased risk for psychiatric illness and suicide

• Anticholinergics
     – Scopolamine
• Catecholamine-like
     – Mescaline
     – DOM, MDMA
• Serotonin-like
     – LSD
     – DMT
     – Psilocybin
• Psychedelic anesthetics
     – PCP
     – Ketamine

• Found in several common plants
     – Deadly nightshade, stinkweed, jimsonweed
     – Plants have been used for centuries for ceremonial

          purposes and murder
     – These plants also contain atropine
• Often used for their intoxicating effects
• Also dilates pupils

• Antagonizes Ach receptors
• Pharmacological effects
     – PNS Effects
• Produces an anticholinergic syndrome
     – Dry mouth, increased temp, dilated pupils,

          hypertension
• CNS Effects
     – A deliriant and intoxicant
     – In low doses produces drowsiness, euphoria,

          amnesia, mental confusion
     – Increases in dose produce hallucinations,

          disorientation, euphoria
     – Toxic doses produce a “toxic psychosis”

• Catecholamine-like psychedelic
     – Peyote
     – Used by Native Americans in many different rituals
     – Structurally similar to norepinephrine
     – Full agonist of 5-HT2A receptors
• Pharmacology
     – Rapid oral absorption
          Levels peak at 2 hrs and effects take place 3-4           hrs after administration, hallucinations can last           10 hrs
     – Produces visual hallucinations, limb spasms,

          anxiety

• DOM, MDA, DMA, MDE, TMA, MDMA
• All structurally similar to mescaline and methamphetamine
• They have moderate stimulant effects at low doses, psychedelic effects appear at higher dosages
• High potency and toxicity

• A potent and selective serotoninergic neurotoxin
• Damages SERT
• There are a variety of physical and psychological side effects

• Are all structurally similar to 5-HT
• LSD
     – Has strong effects even at very low doses
     – Binds to the 5-HT2A receptor
     – Has agonistic and antagonistic effects
     – Also a partial D2 agonist
     – Produces a multitude of physiological and     

          psychological effects
     – Tolerance develops rapidly but fades without

          continued use
     – Dependency does not seem to be a problem

• Psychedelic compounds found in several species of mushrooms
• Effect lasts for 6-10 hrs
• Hallucinations and sensory distortions similar to LSD
• 5-HT2A agonist
• Can produce a schizophrenia like psychosis

• Structurally dissimilar to other psychedelic agents
• Do not involve 5-HT, DA, or Ach
     – Phencyclidine (PCP)
• developed as an anesthetic, but was later dropped
• A noncompetitive NMDA antagonist
     – Ketamine
• Similar properties as in PCP
• NMDA antagonist
     – Dextromethorphan
• Antitussive medication in some cough syrups
• Opiate-like actions, is NMDA noncompetitive antagonist

• Low doses
     – Mild agitation, disinhibition, disturbances in

          cognition and judgement
• Moderate doses
     – Coma, stupor, hypertension
• Other effects include anxiety, aggression, panic
attacks
• Can be habit forming
• Ketamine produces analgesia
• Have led to insights in schizophrenia