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Pharmacology 101

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Benzodiazepines (diazepam, lorazapam, alprazolam 'pam' & 'lam') High TI-difficult to OD ... Alprazolam-Xanax. Halazepam-Paxipam. Barbiturates ... – PowerPoint PPT presentation

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Title: Pharmacology 101


1
Pharmacology 101
  • Drugs of Abuse

2
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

3
Part 1
  • What the Body does to the drug why thats
    important

4
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.

5
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

6
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

7
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

8
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

9
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

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
BAC
18
BAC Behavior
19
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

20
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

21
Chronic Alcohol Use- Side effects
  • Liver damage
  • Chronic insult ? reduced functional liver mass
    and local fluid retention (ascites)
  • Abdominal distention

22
Side effects
  • Pancreatitis
  • Acute and chronic
  • Can ? diabetes
  • Endocrine Imbalance
  • Diuretic effect ? volume depletion
  • Fetal alcohol syndrome

23
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

24
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

25
Part 2
  • What the drug does to your body/brain

26
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

27
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

28
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

29
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

30
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

31
Dose-Response Curves-Sedatives
32
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)

33
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

34
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

35
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.

36
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

37
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

38
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

39
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

40
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

41
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

42
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

43
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

44
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

45
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

46
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

47
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

48
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

49
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

50
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

51
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

52
Amphetamine/Cocaine Withdrawal
  • The Crash
  • Increased anxiety
  • Increased irritability
  • Depression
  • Need for sleep
  • Withdrawal shouldnt kill you.

53
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

54
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

55
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
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