Pharmacology 101

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Pharmacology 101

• Drugs of Abuse

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Basic Principles

• Pharmacokinetics
• What your body does to the drug
• Pharmacodynamics
• What the drug does to your body
• Psychotropic drugs
• Drugs that alter neurotransmission in the brain

• Tolerance
• Increasing amounts of the drug are needed to
  achieve desired response
• Dependence/ Addiction
• Psychological
• Cravings
• Physiological
• Physiological changes associated with drug
  withdrawal (e.g. delirium tremens w/ alcohol
  withdrawal

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Part 1

• What the Body does to the drug why thats
  important

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Pharmacokinetics

• ADME
• Absorption
• Drug has to be absorbed into bloodstream
• Distribution
• Drug has to be distributed to its target (where
  it will act)
• Metabolism
• Not all drugs will exert action, some be
  eliminated quickly-before eliminated, drug needs
  to be changed (metabolized) into a form that is
  easily eliminated or some drug are metabolized
  into active components
• Elimination
• Remaining drug or parts of drug will be
  eliminated via urine, feces, sweat, saliva.

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Administration

• Multiple ways to administer drugs
• Orally, safest, most popular slowest
• 20 minutes to site of action
• Intravenously, quickest most dangerous
• 15 seconds from arm to brain
• Inhalation-very quick, potentially dangerous both
  short term- (to the brain quickly) and long term
  (lung disease) but necessary if treating lung
  disorders-asthma
• Other routes
• Intramuscularly, rectally, sublingually,
  topically

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ADME Administration

• Route of administration
• absorption
• Large tissue surface area greater absorption
• Distribution
• More absorbed more distributed to brain
• Goal is to get Drug to brain
• Most direct route w/ greatest surface area for
  absorption fastest

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Absorption Distribution

• IV
• Into circulation to heart to brain (15 sec)
• Inhalation
• Into lungs
• Huge surface area for absorption
• Immediate path to distribution
• LungsgtHeartgtBrain
• Oral
• Large surface are for absorption
  (stomach-intestines)
• But has to go through liver first
• Job of liver is to prepare substances for
  elimination
• Most of oral drug lost to first pass metabolism
  is liver
• Most doesnt get distributed to brain

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Metabolism Elimination

• Metabolism
• Liver
• First pass metabolism (why oral administration
  not as effective as other routes)
• Prepare substances to be eliminated-
  biotransformation
• Enzymes in liver regulate metabolism
• Lots of inter-individual variation in liver
  enzyme activity
• CYTP450-major metabolizer
• Small molecules to kidneys
• Large molecules to feces or back into
  distribution for another round of action
• Elimination
• Kidneys
• Intestines

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Why ADME is Important

• Kinetic principles determine safety of drug
• Safety of drug related to dose response curve
• Amount of drug (dose) needed to generate a
  certain response
• From the dose-response curve we get the
  Therapeutic Index (TI)
• The greater the TI the safer the drug
• Drugs with TI under 10 are considered extremely
  dangerous-risk of overdose (OD) is high
• Alcohol has a TI 10
• LSD has a TI of gt600
• No reported deaths caused solely by LSD overdose

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Drug Safety

• Therapeutic Index
• LD50/ED50
• Lethal Dose
• Dose at which drug causes death in 50 (LD50)
• Effective Dose
• Dose at which drug cause response in 50 (ED50)

• ?TI ?risk of OD
• TI at 6 death occurs at 6X normal dose

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Elimination of Drug OD

• Drugs are metabolized prior to elimination
• Rate of metabolism/elimination shortens/prolongs
  response to drug
• Two types of metabolism
• First order
• Exponential based upon amount of initial dose
• Zero order
• Occurs at a set pace regardless of initial dose

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Metabolism

• First-order Kinetics
• Each pass through the liver eliminates ½ of the
  drug from the system
• Each drug has a half-life t ½ -how long to get
  rid of half the drug
• t ½ range from seconds to days
• Drugs w/ longer t ½ usually store in fat, bone or
  other tissue are released slowly over time
• Marijuana t ½ 20 hrs- 10 days depending upon
  amount potency of initial dose
• Elimination of a drug following first order
  kinetics usually requires 6 passes through the
  liver to be eliminated from circulation
• After 4 passes though the liver 94 of drug is
  eliminated

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Metabolism

• Zero order kinetics
• Drugs that follow zero order kinetics metabolize
  at a constant rate regardless of size of initial
  dose
• Risk of OD w/ large first doses
• Alcohol follows zero order kinetics
• Regardless of how much or how little you drink
  alcohol will metabolize at a constant rate

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Alcohol

• Big dumb stupid drug-need lots to get effect
• Small molecule, easily absorbed, distributes
  everywhere, gets to brain quickly
• Takes a lot of the drug (in comparison to other
  drugs) to exert a response
• Low TI high OD rate
• Zero order kinetics

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Alcohol

• 25-50mg of ethanol for every 100 mL of blood to
  get BAC of .025-.05-to get minimal response
• BAC-blood alcohol content
• .08 legal limit
• 1 drink (6 oz of ethanol) per 50lbs of person per
  hour

• 6 oz ethanol
• 1.5 oz of 80 proof liquor
• proof 2X ethanol content
• 80 proof 45 ethanol
• 6 oz of wine
• 12 oz of beer

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Alcohol Metabolism Binges

• Distribution
• 1 hour to 90 of alcohol into bloodstream
• B/c absorbed quickly in GI tract-minutes to brain
  initial effects
• Metabolized at rate of 1.5 oz of 80 proof p/hour
  or 1 beer p/hour
• 1 drink per/50lbs per hour to get BAC of .08
• Metabolizes _at_ 1 drink p/hour
• How much can you have per/hour stay w/in legal
  limit?
• How much can you drink per/hour before you kill
  yourself?
• BAC _at_ .4 LD50-death in 50 of population
• Alcohol poisoning-DEATH _at_ approximately 5X the
  legal limit
• Takes less if you dont drink, are taking other
  meds and/or have other medical conditions

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BAC
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BAC Behavior
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Alcohol Tolerance

• Repeated use of alcohol creates tolerance to drug
  cross tolerance to other drugs (sedatives)
• Combining alcohol sedatives ?response ?TI
  (takes less of either to kill yourself)
• With tolerance it takes increasing amounts of
  drug to get same response TI doesnt change
• But alcohol
• still metabolizes at constant rate
• still has narrow TI (LD50/ ED50) 10
• So as tolerance sets in use increases, risk of
  OD (alcohol poisoning) becomes greater b/c one
  approaches the upper limits of Lethal Dose in
  order to get desired response
• BAC can increase even after person has passed out
• Possible to ingest fatal amount of alcohol before
  passing out b/c it takes time for drug to get to
  brain

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Signs of Alcohol Poisoning

• Mental confusion, stupor, coma
• No response to pinching
• Vomiting while asleep
• Seizures
• Irregular reduced breathing less than 10
  breaths p/min w/ more than 10 sec between breaths
• Bluish tint to skin color
• Cold, clammy feel to hands

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Chronic Alcohol Use- Side effects

• Liver damage
• Chronic insult ? reduced functional liver mass
  and local fluid retention (ascites)
• Abdominal distention

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Side effects

• Pancreatitis
• Acute and chronic
• Can ? diabetes
• Endocrine Imbalance
• Diuretic effect ? volume depletion
• Fetal alcohol syndrome

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Alcohol Genetics

• Alcohol metabolism requires stomach liver
  enzymes from CYT P450 family-enzymes highly
  variable genetically influenced
• Alcohol dehyrdogenase (stomach)
• Acetaldehyde dehyrdogenase (liver)
• Alcohol dehydrongenase converts alcohol into
  Acetaldehyde
• Another liver CYTP450 enzyme-acetaldehyde
  dehydrogenase into acetic acid which is
  eliminated via urine
• Acetaldehyde-very toxic, induces vomiting
• Many Asians lack sufficient acetaldehyde
  dehydrogenase activity to fully metabolize
  alcohol begin vomiting more easily
• Many Indians have increased acetaldehyde
  dehydrogenase dont get sick as easily
• Acute high doses-binges of alcohol increase
  enzyme activity
• Chronic alcohol decreases enzyme activity-less
  enzyme more alcohol in system longer

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Kinetics of Other Drugs

• Sedatives
• Benzodiazepines (diazepam, lorazapam, alprazolam
  pam lam)
• High TI-difficult to OD
• Extremely long t ½ b/c metabolites
  (biotransformed substances are often active)
• Barbiturates
• Fast-asking, low TI-easy to OD
• Stimulants
• Amphetamine
• t ½ 10hrs depending upon dose
• (methamphetamine t ½ 5 hrs)
• Tolerance developed quickly
• TI low because of actions on heart
• Cocaine
• t ½ determined by route of administration
• Intranasal- 75 min.
• Oral- 48 min.
• Rapid tolerance
• TI low b/c actions on heart

• Hallucinogens
• LSD
• Rapid tolerance
• T ½ 4hrs
• Tolerance averted w/ 3-4 days between dosage
• Marijuana
• T ½ 20hrs-10 days
• Not physiologically addictive
• Narcotics/opioids
• Heroin
• Fast-acting, 4-5hrs of action, low TI (lt10) b/c
  fatally depresses HR respiration if given too
  much too quickly
• Rapid tolerance
• ED50 5mg, LD50 40-60mg

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Part 2

• What the drug does to your body/brain

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Pharmacodynamics

• All psychotropic drugs work by altering
  neurotransmission in brain
• All neurotransmitters have receptors in both the
  Central Peripheral Nervous Systems
• So all drugs will exert action in both the
  central peripheral nervous systems
• Actions in the peripheral nervous system are
  usually considered side-effects

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Tolerance, Dependence Withdrawal

• All Drugs of abuse involve tolerance, dependence
  withdrawal to some degree or another
• Tolerance need more to get the desired effect
• Dependence need to maintain drug levels to
  maintain functioning-offset withdrawal effects
• Withdrawal opposite of desired effect
• Sedatives
• Desired effect-relaxation sleep
• As tolerance increases need more to maintain
  relaxation initiate sleep
• Dependency involves preventing withdrawal effects
• Withdrawal- induces anxiety insomnia

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Peak Effects

• Some point after administration, a drug exerts
  its effect, the point at which the effect is
  strongest is the Peak Effect
• Repeated administration causes tolerance to a
  drug
• Tolerance delays diminishes peak effect
• Tolerance requires more drug to elicit the same
  peak effect

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Sedative-Hypnotics

• Sedatives-Hypnotics
• GABA agonists
• Decrease excitability of neurons
• Reduces heart-rate respiration
• parasympathomimetic
• Cross tolerance w/ alcohol
• Used in high doses for anesthesia
• Moderate doses for sleep
• Low doses for anti-anxiety (anxiolytic)
  anti-depressive

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Sedative-Hypnotics

• Benzodiazepines
• Moderate dependence with withdrawal symptoms
• Extended t ½-active metabolites
• Diazepam-Valium
• Oxapam-Serax
• Clorazepate-Thanxene
• Lorazapam-Ativan
• Prazepam-Centrax
• Alprazolam-Xanax
• Halazepam-Paxipam
• Barbiturates
• Highly addictive, short duration, rapid tolerance
• Withdrawal can be life threatening
• Thiobarbital-anesthestic fast acting ultra short
  duration-15 minutes
• Secobarbital-sleep induction, 1.5 hours duration
• Pentobarbital sedative, anticonvulsant,
  intermediate duration 4-6 hours

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Dose-Response Curves-Sedatives
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Sedative-Hypnotic Withdrawal Syndrome

• First 12-15 hours, patient appears to improve
• 16 hours
• Restless, anxious, tremulous, weak, abdominal
  cramping
• Vomiting, orthostatic hypotension, tremors,
  increased deep tendon flexion, convulsions
• Days 2-3
• Delirium, hallucinations (persecutory)
  disorientation to time place
• Once delirium starts cant be reduced by
  administration of other sedative hypnotics-has to
  run its course
• Includes hyperthermia (increased body temp),
  exhaustion, cardiovascular collapse sometimes
  death
• Depending upon type of drug, withdrawal symptoms
  reach peak severity at days 2-3 last upwards of
  a week ( in some cases, some of the symptoms
  may last several weeks)

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Sedative-Hypnotics

• Alcohol
• Large dose to get effect compared to other
  sedatives
• Addictive
• Rapid tolerance
• Low therapeutic index
• GABA agonist
• Additive effect when taken w/ other
  sedative-hypnotics
• Makes cell membrane more fluid-inhibits the
  movement of NA K across the membrane
• Prevents action potentials
• Decreases Glutamate (excitatory NT)-depresses NT
  even further
• Increase release of DA _at_ nucleus accumbens
  -reinforcement

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Alcohol Peak Effect vs. Peak BAC

• Feel more of alcohols behavioral effects before
  BAC levels reach peak concentration
• This means that we begin to feel less drunk
  before the alcohol has been metabolized

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Alcohol Withdrawal

• Symptoms begin 12-72 hours after last drink
• Tremors
• Nausea, vomiting, anxiety, sweating, abdominal
  cramps, hyperreflexia, increased BP w/
  orthostatic hypotension,
• Hallucinations, seizures, muscle weakness,
  increased body temp-sweating
• Day 3
• Exhaustion cardiovascular collapse
• The acute alcohol abstinence is self-limiting.
  If the patient does not die, recovery usually
  occurs within 5-7 days.

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Marijuana

• Leaves Buds used as far back as 2737
  BC-medicinally
• Last 100 years- recreationally
• Psychoactive component delta-9-tetrahydrocannabino
  l (THC)
• 30 metabolites
• Avg dose 20-30 mg

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Marijuanas Psychological Affects

• Impaired memory, speaking, problem-solving
• Lack of motivation
• Interestingly marijuana makes drivers more
  cautious (not better, but more cautious)
• Sedative
• Increased appetite
• Decrease pain

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Marijuana Site of Action

• Cannabinoid Receptors located through-out the
• Cerebral cortex
• Hippocampus (memory)
• Hypothalamus (hunger sleep)
• Amygdala (pleasure)
• Endogenous cannabis- neurotransmitter anandamide
  (Sanskrit word meaning internal bliss)
• Variable activity on almost all other NTs

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Marijuana Tolerance/Withdrawal

• Continued use-reverse tolerance-more sensitive to
  less
• With 10mg p/day tolerance doesnt usually develop
• Psychological not physical dependence unless
  using well above the norm
• Acute intoxication-increased HR conjunctival
  reddening of eyes

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Stimulants

• Stimulant effect on the CNS
• Three main categories
• Convulsants and respiratory stimulants
• Act on brain stem and spinal cord
• Little to no effect on mental function
• Exaggerated reflex excitability
• High doses ? convulsions
• Psychomotor stimulants (Amphetamines Cocaine)
• Affect mental function, behavior and motor
  activity
• Psychomimetics (Hallucinagens)
• Affect thought and perception, distort cognition
• Effects resemble psychosis

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Psychomotor stimulants

• Amphetamines and Related Drugs
• Amphetamine, methamphetamine, dexamphetamine,
  methylphenidate, fenfluramine, Ecstasy (MDMA)
• Release catecholamine, inhibit catecholamine
  reuptake
• Cocaine
• Inhibition of catecholamine reuptake
• Local anesthetic
• Methylxanthines
• Caffeine, theophylline
• Inhibit phosphodiesterase
• Adenosine type 2 receptor antagonists

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History-Amphetamines

• Amphetamines
• Sympathomimetic
• Synthesized in late 1800s
• Medical uses in 1920s -Benzedrine
• Asthma inhalers-bronchodilator
• Military used Benzedrine in WWII to help soldiers
  stay awake
• Discovered d-isomer more potent
• Developed Dexedrine
• Diet pill-suppresses appetite
• More modifications yielded methamphetamine
  (Desoxyn, Methedrine)
• Even more molecular modifications yielded
  methylphenidate (Ritalin), tranylcypromine
  (Parnate)
• Amphetamine injected w/ heroin-speed ball- speed
  (began as cocaine heroin together but as
  cocaine supplies diminished, amphetamines were
  substituted
• Methamphetamine-smoked ice or crystal meth

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Amphetamines

• Central effects
• Locomotor stimulation
• Run around more
• Behavioral changes
• Less attention paid to surroundings
• Exploratory behavior reduced
• Conditioned response altered
• No evidence of positive learning effects
• Aggression increased
• Impulse control declines
• Become busier, not brighter
• Improved performance in simple tasks

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Amphetamines

• Release biogenic amines
• Amphetamines
• NE and D most important for desired street effect
• Fenfluramine
• 5-HT release more pronounced
• Prevent reuptake
• Central effects
• Locomotor stimulation
• Euphoria, excitement
• Behavioral changes
• Anorexia (especially fenfluramine)
• Peripheral effects
• Sympathomimetic
• Increased BP, decreased GI motility

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Amphetamines

• Stereotypical Effects at high doses
• Repeated actions, inappropriate to environment
• Dose dependent
• Repetitions increase with dose
• Euphoria
• With IV administration orgasmic
• Confident, hyperactive, talkative, overtly
  sexual, reduced fatigue (physical, mental)
• Duration of Effect
• Related to PK, averages 3-6 hrs
• PK half-life 5 hrs to 30 hrs
• Routes of administration oral, inhalation,
  mucosal
• Metabolism
• P450 mediated

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Amphetamines

• Tolerance and dependence
• Tolerance
• Rapid for peripheral and anorexic effects
• Slower for central effects
• Dependence
• No true physical dependence
• Coming down unpleasant (catecholamine
  depletion)
• Sleep (deep, long), depression, anxiety, hunger
• Insistent memory of euphoria ? psychological
  dependence
• Binge use drugs

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Behavioral Effects of Amphetamines

• Performance enhancer _at_ low doses, impairs
  performance _at_ high doses
• Increased alertness
• Decreased fatigue
• Decreased appetite
• At high doses precipitates psychosis, stereotypic
  behaviors, aggression violence
• Rebound depression, suicidality upon withdrawal
• Rapid tolerance BUT increased sensitivity to
  psychotic effects
• If use elicits psychotic behavior, each
  additional use is going to be more likely rather
  than less like to elicit negative reaction

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Amphetamine Mechanisms of Action

• Increases release of catecholamines DA NE by
  increasing leakage of the neurotransmitters both
  at rest during action potential
• Inhibits reuptake (which means more has to be
  produced)
• Inhibits one of the enzymes that metabolize the
  neurotransmitters

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Cocaine

• Sympathomimetic
• Derived from coca leaf
• Freud used it to treat depression
  self-medicated
• In wine coca cola
• Local anesthesia-eyes
• Derivatives-lidocaine-topical anesthetic
• Rapid tolerance
• Highly addictive

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Cocaine

• Forms of administration
• Cocaine - HCl salt (H2O soluble)
• Intravenous
• With heroin (speedballs)
• Nasal inhalation
• Causes atrophy and necrosis of nasal septum
• Crack cocaine free base
• Smoked

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Cocaine

• Binges last 12 hours-several days w/ some users
  re-dosing every 15 min.
• Usually crash between binges
• Mood elevation, perceived increase in
  self-esteem, mental physical capacity
• Appetite sleep are decreased
• Increased sexual interest, impaired judgment,
  hyperactive

• Psychological Toxicity
• Hyper vigilance
• Paranoia
• Suspiciousness
• Aggressive homicidal against those perceived
  persecutory
• Physiological toxicity
• Myocardial infarction
• Arrhythmias
• Seizure

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Amphetamine/Cocaine Withdrawal

• The Crash
• Increased anxiety
• Increased irritability
• Depression
• Need for sleep
• Withdrawal shouldnt kill you.

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Opioids (narcotics)

• Heroin
• From the seeds of the poppy plant
• Metabolized into morphine
• 2x as strong as morphine
• 25X as strong as codeine
• Produce action by interacting w/ opioid receptors
  to activate endogenous opioids
• Enkephalins
• Endorphins
• Dynorphins

• CNS effects
• Analgesia (pain relief)
• Drowsiness
• Changes in mood-euphoria but also numbing
• Decreases diarrhea
• In pain free individuals
• Not always pleasant
• Induces vomiting
• Long term use
• Sexual impotence
• Constipation
• Insomnia
• Excessive sweating

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Opioid Withdrawal

• Begging/pleading for drug
• 8-12 after last dose
• Tearing
• Yawning
• Sneezing
• Sweating
• 12-14 hours
• Tossing restless sleep-several hours to days
• Upon waking still restless

• As the syndrome progresses (7-10 days to
  complete)
• Dilated pupils
• Anorexia
• Gooseflesh-cold turkey
• Violent yawning sneezing
• Pronounced weakness depression
• Nausea, vomiting diarrhea
• Increase BP HR, cold-sweats
• Abdominal cramps pain
• Muscle spasms-kicking the habit

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Caffeine

• Caffeine
• Behavioral Effects
• t ½ 5 hours
• Psychological mild physiological dependence
  withdrawal effects
• Increased alertness, attentiveness, decrease
  fatigue
• Too much-restlessness, jitters, anxiety
• Increase gross motor functioning, decreases fine
  motor skills
• Mechanism of Action
• Blocks adenosine receptors (chronic use causes
  up-regulation of receptors
• Vasoconstrictor
• Increases DA in nucleus accumbens-to some degree

• Average American 200-300mg p/day
• Negative effects/withdrawal at gt500mg p/day