DRUGS OF ABUSE Part I

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DRUGS OF ABUSEPart I

• Martha I. Dávila-García, Ph.D.
• Howard University
• Department of Pharmacology

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Definitions

• I. Drug abuse.
• II. Drug dependence.
• A) Psychological dependence.
• B) Physiological dependence.
• III. Drug addiction.
• IV. Drug tolerance.

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I. Drug abuse

• Inappropriate and usually excessive,
  self-administration of a drug for non-medical
  purposes.
  
• Almost all abused drugs exert their effects in
  the CNS.
  
• Drugs with high abuse potential have a tendency
  to induce compulsive drug-seeking behavior.
  
• Preoccupation with the procurement and use of the
  drug may be so demanding as to decrease the users
  productivity.
  
• In addition, prolonged abuse may cause chronic
  toxicity.
  

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II. Drug dependence

• Repetitive use of substances that produce an
  optimal state of well being because of their
  positive reinforcing effects in the CNS.
  
• A) Psychological dependence.
• B) Physical dependence.

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II. Drug dependence

• A) Psychological Dependence
• Motivational component great subjective need,
  compulsion, drive to get the drug.
  
• Will take drug periodically.
• Although physical dependence for a drug may not
  occur, drug-seeking behavior is present.
  
• Habituation Just "like" the drug Drug effects
  serve as positive reinforcers.
  
• No tolerance increase.

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II. Drug dependence

• B) Physiological Dependence
• The body needs the drug for normal physiological
  function.
  
• Tend to increase dose because of tolerance.
• Physical withdrawal symptoms (negative
  reinforcement).
  
• Predictable group of signs and symptoms resulting
  from abrupt removal of a drug.
  
• Psychological dependence is also present.

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III. Drug addiction

• The drug-use and drug-seeking behavior of
  dependent individuals is maintained by the
  reinforcing central activity of the drug despite
  its negative social, psychological and physical
  consequences.
• Physiological effects, including negative
  reinforcers such as symptoms of withdrawal may
  also be involved.
  
• High tendency to relapse.

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IV. Drug tolerance

• After chronic use, the same amount of drug is
  insufficient to cause the desired effect and
  thus, more drug is used.
  
• A compensatory response.

Normal
Tolerance
EFFECT
Drug Dose
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IV. Drug tolerance

• A) Innate Tolerance
• 1. Sensitivity
• 2. Insensitivity
• B) Acquired Tolerance
• 1. Pharmacokinetic or metabolic
• 2. Pharmacodynamic or functional
• 3. Learned or behavioral

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V. Cross-dependence

• When a drug is administered to achieve the same
  outcome as that of another drug.
  
• i.e. heroin Û methadone.
• In a heroin user, methadone can be substituted
  for heroin in preventing the withdrawal syndrome.

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VI. Cross-tolerance

• When an individual has become tolerant to a drug
  and requires higher than normal doses of a second
  drug to have its effects.
  
• i.e. Barbiturates Û BDZ.
• Amphetamine Û cocaine.
• BARBs or BDZs Û Anesthetics.

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VI. Cross-tolerance

• In general there is cross-dependence and
  cross-tolerance between drugs of the same class,
  but not between drugs in different classes.
  
• Exceptions
• There is some cross-tolerance between
  sedative-hypnotics and volatile intoxicants thus
  a person tolerant to barbiturates will require
  more anesthesia than a non-tolerant person.
• LSD type drugs (tryptamine group) and
  phenylethylamines have cross-tolerance for each
  other but not with other hallucinogens.
  

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VII. Co-administration/Co-abuse

• Many of these drugs are used in combination with
  other drugs from one or more categories.
  
• Alcohol is used, for example, with almost
  everything else.
  
• Smoking (nicotine intake) is prevalent in
  patients using other drugs.
  
• Be aware of the possibility of combination of
  drugs when treating intoxication, withdrawal or
  overdose, each drug will require a specific
  treatment.

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Because of the diverse character of these drugs,
there is no single reason for their use, nor is
there an addictive personality".

• IT IS NOT NECESSARY TO HAVE A PREEXISTING
  EMOTIONAL OR PSYCHIATRIC PROBLEM TO BECOME DRUG
  DEPENDENT!!!
  

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VIII. Toxicology

• A) Tissue and organ toxicity
• - Usual dose vs overdose.
• - Acute use (respiratory depression - narcotics,
  coma-barbiturates cardiovascular effects and
  seizures-cocainearrhythmias-volatile
  intoxicants).
• - Chronic use (alcohol, tobacco).

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VIII. Toxicology

• B) Psychic toxicity
• - Acute use (bad trips, flashbacks -
  hallucinogens CNS stimulants).
  
• - Chronic use (alcohol, hallucinogens, stimulants
  reality distortion).

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VIII. Toxicology

• C) Behavioral toxicity
• - Amotivational syndrome, loss of productivity
  loss of psychomotor control, accidents,
  violence.
  
• - Acute use (alcohol, stimulants, PCP).
• - Chronic use (alcohol, CNS depressants,
  stimulants, hallucinogens, PCP).
  

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VIII. Toxicology

• D) Associated Diseases
• - Infections, AIDS, venereal diseases,
  tobacco-related fires, toxicity due to bad
  batches of drug (MPTP, PCP congeners), car
  accidents, big machinery accidents, other
  accidents, violent death.

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I. Animal Studies

• A) Drug-self administration
• Drugs as reinforcers in animals.
• High correlation with
• human dependence
• liability.

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Morphine/Heroin

• Self-Administration

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II. Brain Reward System

• Changes in brain function Reward Craving
• Involve the Dopaminergic System
• Mesolimbic pathwayVentral tegmental area (VTA),
  medial forebrain bundle, nucleus accumbens and
  the prefrontal cortex.
  
• Nigrostriatal pathway Sustantia nigra,
  striatum.
  
• Mesocortical pathway VTA, cingulate and frontal
  CTX.
  
• Tubero-Infundibular Arcuate N. in hypothalamus.

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THE DOPAMINERGIC SYSTEM
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THE MESOLIMBIC DOPAMINERGIC REWARD PATHWAY
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Tyrosine
Dopamine Synapse
Tyrosine
L-DOPA
DA
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Dopamine Reuptake System
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OPIOIDS or NARCOTICS

• Morphine, Codeine, Meperidine, Methadone
• I. Morphine, Heroin, Hydromorphone,Oxymorphone.
• A. Pharmacology
• - Heroin is very lipid soluble.
• - Short half-life (t½ 3 min).
• - Heroin 6-mono-acetyl morphine morphine

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OPIOIDS

• Desirable Effects Euphoria, sedation (wakeful,
  dreamy state "being on the nod"), relief of
  anxiety and various other forms of distress,
  analgesia.
• Depression of cough reflex.
• Subjective CNS effects Drowsiness, difficulty
  concentrating, apathy, decreased physical
  activity, lethargy, extremities feel heavy and
  the body feels warm.
• Undesirable Effects Dysphoria, dizziness,
  nausea, vomiting, constipation, biliary tract
  spasm, urinary retention.
  
• Therapeutic uses not related to analgesia

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OPIOIDS

• 1). Psychological dependence
• I.V. use preferred by most users rush or
  high
  
• Oral abuse meperidine.
• Emotional or motivational symptoms, craving.
• Iatrogenic addiction.
• 2). Physical dependence
• May develop on repeated use of therapeutic
  doses.
  
• Narcotic Abstinence Syndrome (Withdrawal).

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OPIOIDS

• Withdrawal, onset related to time-effect curve
  and t½ of narcotic.
  
• 6-8hr drug seeking behavior, restless,
  anxious.
  
• 8-12hr Pupils dilated, reactive to light
  increased pulse rate, blood pressure, yawning
  chills rhinorrhea lacrimation gooseflesh
  sweating restless sleep.
• 48-72 hrs (peak) All of the above plus
  muscular weakness, aches (cramps) and twitches
  nausea, vomiting and diarrhea temperature and
  respiration rate elevated heart rate and blood
  pressure elevated dehydration.
• Not life threatening, no convulsions, no
  delirium, no disorientation.
  

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OPIOIDS

• B. Concurrent or Substitute use
• Alcohol, sedatives or amphetamines
• C. Tolerance
• Yes, develops to almost effects except
  constipation and pupillary effects.
  
• Cross-tolerance and cross-dependence with other
  narcotics (Implication in narcotic addict need
  to increase dose to experience euphoria).
  
• High level of tolerance is possible huge amounts
  of drug can be tolerated after chronic use
  potential for overdose if relapse occurs and
  addict resumes with same high level of drug.
• Implications for chronic administration for pain.

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OPIOIDS

• D. Toxicology
• 1.Tissue and organ toxicity
• - Heroin lung with acute overdose.
• - No apparent tissue damage.
• 2. Psychic toxicity
• - Acute and chronic drive reduction.
• 3. Behavioral toxicity
• - Criminal behavior to obtain drugs.
• 4. Associated diseases/Death
• - Unsterile syringes AIDS, hepatitis, SBE,
  malaria, tetanus, localized infections, pulmonary
  infiltration of contaminants. Neuropathies.
  Violent deaths.
• E. Intoxication/Overdose
• 1. Disruption of central control of peripheral
  sympathetic activity.
  
• - respiratory depression brainstem DEATH
• - circulatory depression BP
• - pupils constricted
• - pulmonary edema
• 2. CNS depression
• - drowsiness sedation coma

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OPIOIDS

• E. Acute Intoxication/Overdose
• 1. Disruption of central control of peripheral
  sympathetic activity.
  
• - Respiratory depression apnea DEATH
• - Circulatory depression BP
• - Pupils constricted
• - Convulsions with propoxyphene and meperidine.
• - Arrythmias with propoxyphene.
• - Pulmonary edema
• - ? Reflexes
• 2. CNS depression
• Euphoria/dysphoria drowsiness sedation
  coma
  

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OPIOIDS

• F. Treatment
• Narcotic dependence is one of very few cases
  where there are partially effective
  pharmacological therapies.
  
• 1. Opioid replacement
• a. Methadone, Dolophin
• Long half-life produces a longer but less
  stressful withdrawal (although more prolonged).
  
• Onset 24hrs, peak 5-7 days.
• Lessens the highs and lows of withdrawal.
• Oral administration.

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OPIOIDS
Severity of Withdrawal
TIME
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OPIOIDS

• b. Clonidine, an agonist at a2 adrenergic
  receptors.
  
• Used to block autonomic signs and symptoms of
  withdrawal
  
• cramps
• nausea
• vomiting
• tachycardia
• sweating
• hypertension

ANS EFFECTS
Clonidine
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OPIOIDS

• c. Opiate Antagonists, cause precipitated
  abstinence.
  
• Long term maintenance of abstinence
  Naltrexone
  
• Longer half-life, oral, 3 times a week.
• Also used to control and reverse effects of
  therapeutically administered narcotics
  (anesthesia and labor).
  
• d. LAAM (L-a-acetyl methadol, methadyl acetate).
• Structurally similar to methadone. Longer-acting
  opiate. Taken orally in liquid form, lasts 72hrs
  (visits 3 X a week). "take home" medication.
  

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OPIOIDS

• e. Buprenorphine
• Partial agonists which substitutes for low doses
  of opioids but antagonizes high doses.
  
• Can be administered sublingually every 24-48
  hours as an alternative to methadone.
  
• Major problem in detoxification and maintenance
  of abstinence is the motivational component of
  the CNS effect, which is responsible for the
  drug craving sensations, also conditional
  dependence and social factors play an important
  role.

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OPIOIDS

• II. Codeine
• Codeine (Methylmorphine) Dihydrocodeine
  Hydrocodone (Dicodid, Hycodan) Oxycodone
  (Percodan).
  
• A. Pharmacology
• administered parentally.
  
• "Weak" opioids.
• Used as a cough suppressants (antitussive) and
  combined with aspirin and acetaminophen as
  painkillers.
  
• Dependence liability

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OPIOIDS

• III.Meperidine
• Meperidine (Demorol) Alphaprodine, (Nisentil)
  Fentanyl.
  
• A. Pharmacology
• - Less potent than morphine IM. More rapid
  onset, shorter duration. Similar to heroin.
  
• - Used in anesthesiology.
• - Dependence liability - Same as Morphine

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OPIOIDS

• B. Concurrent or substitute use - Yes. Other
  narcotics
  
• C. Tolerance Same as Morphine, Cross-tolerance
  with other narcotics
  
• D. Acute intoxication/Overdose Similar to other
  narcotics
  
• E. Withdrawal Same as Morphine
• F. Treatment None
• G. Mechanism of action m opioid receptors

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OPIOIDS

• IV. DESIGNER OPIOIDS
• Heroin-like drug MPPP contained MPTP impurities
  that caused Parkinson's like-symptoms in the
  young adults who used it by destroying DA
  neurons.
• China White alpha-methyl fentanyl deaths by
  overdose.
  
• 6000 times more potent than morphine.

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OPIOIDS

• G. Mechanism of action.
• 1. Anatomy of m opioid receptors nucleus
  accumbens (N. Acc.), ventral tegmental area
  (VTA), caudate, thalamus, cortex, spinal cord.
  
• 2. Actions in thalamus
• 3. Actions in spinal cord Analgesia
• 4. Actions at Mesolimbic dopaminergic system
  Reward.
  
• a. Inhibit the release of GABA at the VTA
• Desinhibition of DA DA activity

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OPIOIDS
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OPIOIDS
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CNS DEPRESSANTS

• I. Alcohol
• II. Sedative/hypnotics, Anxiolytics
• All are very addictive and cause withdrawal
  symptoms (mild anxiety, convulsions, seizures).
  
• All of these drugs create "lethal potentiation"
  when combined.
  
• Anxiolytics

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Alcohol

• A. Pharmacology
• Ethyl alcohol is created after the fermentation
  of the sugar of grains (beer) and fruit juices
  (wine). If distilled, they produce hard liquors
  (Whiskey, Brandy). In between are the fortified
  wines such as port, cherry and muscatel.
• Intake of alcohol begins during adolescence.
  Ninety percent of high school seniors have tried
  alcohol during their life times and 30 report
  daily use. Chronic abuse occurs much later.
• Alcohol is readily dissolved in water and lipids
  and thus distributes very evenly throughout the
  body. It crosses the blood-brain-barrier as well
  as the placenta without difficulty.

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Alcohol

• 1. Psychological Dependence
• Drug seeking behavior.
• 2. Physical Dependence
• - Hangovers are mini-withdrawals, probably due
  to a rebound of the depressed CNS.
  
• Cure for a hangover ? more alcohol
• ETOH is converted to acetaldehyde, which causes
  all the negative symptoms of hangovers, including
  dehydration, and headaches.

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Alcohol

• Withdrawal Syndrome Delirium Tremens
• Insomnia, tremulousness, REM rebound, reflexes
  are high, weakness, anorexia, orthostatic
  hypotension, sweating, agitation delirium, vivid
  auditory and visual hallucinations convulsions
  and seizures (probably caused by NMDA receptor
  number and hyperexcitability), may generate
  status epilepticus disorientation, paranoid
  delusions, hyperthermia dehydration,
  cardiovascular collapse, risk of death.

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Alcohol

• B. Concurrent or substitute use
• With most other drugs.
• Tranquilizers potentiate the effects of alcohol.
• Complications for treatment when there is
  concomitant narcotic addiction.

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Alcohol

• D. Toxicology
• 1. Tissue and organ toxicity
• Hangovers low blood sugar, dehydration.
• Acute use irritation of digestive system
• Chronic use cirrhosis of the liver, alcoholic
  hepatitis, cerebellar syndrome, alcoholic
  dementia, cancer of the mouth, throat and liver,
  vitamin deficiencies. In the fetus, it is a
  teratogen

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Alcohol

• Fetal Alcohol Syndrome
• Children exposed to alcohol in utero may exhibit
  a wide range of developmental disabilities and
  cognitive and behavioral deficits that reflect
  damage to the developing neurons. These effects
  may include mental retardation, attention
  deficit disorders, perceptual problems, memory
  and learning disabilities, and psychomotor
  dysfunction. Fetal Alcohol Syndrome (FAS), which
  is characterized by central nervous system
  impairments, growth retardation and
  characteristic facial dysmorphology is the most
  severe, manifestation of alcohol neuratogenesis.
• from NIAAA, Alcohol Alert, No. 13 1991

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Alcohol

• 2. Psychic toxicity
• - Korsakoffs Psychosis
• - Alcoholic dementia
• - Cerebellar syndrome
• - Epilepsy
• - As with other CNS Depressants
• Sluggishness, difficulty in thought, slowness of
  speech, poor comprehension, deterioration of
  memory and judgement, poor attention span.
  

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Alcohol

• 3. Behavioral toxicity
• More than half of all homicides are caused by
  alcohol.
  
• Overall the actions of alcohol in the CNS are
  very similar to those of other CNS depressants
  
• Desinhibition, aggression, loss of psychomotor
  control.
  
• Emotional liability, irritability, exaggeration
  of basic personality traits, hostile and paranoid
  ideas.
  
• Breakdown of ability to function, loss of
  decorum, quarrelsomeness, deterioration of work
  and family life, poor coordination and lapses of
  judgement favoring accidents, suicidal tendencies.

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Alcohol

• 4. Associated diseases
• - Chronic malnutrition
• E. Acute Intoxication
• - Slowed and slurred speech, ataxia, nystagmus,
  drowsiness coma, confusion reflexes are low,
  respiratory depression or apnea, low blood
  pressure death.

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Alcohol

• F. Treatment
• Disulfiram (antabuse) and CCC (citrate calcium
  carbamate) are acetaldehyde dehydrogenase
  blockers.
  
• Drinking alcohol with these drugs produces
  increased conc. of acetaldehyde and this make
  person sick. Sometimes tranquilizers and
  antidepressants are given to relieve the anxiety.
  DETOX is best in a hospital setting. AAA to
  prevent relapse.

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Alcohol

• ETHANOL (CH3CH2OH)
• Alcohol dehydrogenase
• ACETALDEHYDE (CH3CHO)
• Aldehyde dehydrogenase ½ Disulfiram
• ACETYL COENZYME A
• ø
• energy citric acid cycle
• ø
• carbon dioxide water

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Alcohol

• G. Mechanism of Action
• 1. Affects several ion channels
• a. NMDA receptor allosteric inhibitor.
  Physical dependence/withdrawal. Reinforcement.
  Behavioral desinhibition.
  
• b. GABAA receptor allosteric facilitator.
  Tolerance.
  
• c. 5-HT3 receptor sedative, antianxiety
  effects
  
• d. L-type calcium channel allosteric
  modulator
  

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Alcohol

• 2. CNS Control
• a. Alcohol effects in the cerebellum disturb
  equilibrium and posture.
  
• b. Alcohol effects in hippocampus disturb
  memory formation and retrieval.
  
• c. Alcohol in brainstem and medulla disturb
  respiratory centers.
  

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CNS DEPRESSANTS

Alcohol
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Sedative/Hypnotics

• I. Barbiturates
• II. Benzodiazepines
• III. Methaqualone

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Sedative/Hypnotics

• Can be procured readily from illicit sources.
• Patients experience rebound insomnia or anxiety.
  
  
• Gross binges of intoxication that last several
  days. Others ingest large quantities on a daily
  basis and remain chronically intoxicated
  
• Physiological consequences resemble those of
  alcohol intoxication.
  
• The person may feel a remarkable capability for
  coping with stress and anxiety, a general feeling
  of well being, may feel euphoric and stimulated.
  These latter effects (euphoria and stimulation)
  may be due to inhibition of inhibitory pathways.

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Sedative Hypnotics

• I). Barbiturates
• Used clinically as anticonvulsant, anti-anxiety
  drugs.
  
• phenobarbital (purple hearts)
• pentobarbital (yellow jackets)
• secobarbital (red devils)
• amobarbital (blue angels)

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Sedative Hypnotics

• II.) Benzodiazepines
• flurazepam Sleeping pills.
• flunitrazepam date rape drug.
• Diazepam (Valium) Tranquilizer.
• Chlordiazepoxide (Librium) Tranquilizer.
• Clonazepam anticonvulsant.
• They all cause sedation and muscle relaxation.
• Abuse may cause "BDZ-induced aggression".
• III.) Methaqualone (Quaalude) "Downer", works
  as Valium, seriously abused, very addictive.

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Sedative Hypnotics

• .

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Sedative Hypnotics

• Readily absorbed when taken orally or after
  parenteral administration.
  
• BARBs are more abused than BDZ.
• BARBs are favorite drugs used for suicide.
• Tolerance is slow and only partial.
• Lethal dose is quickly achieved if overdose
  w/BARBs.
  
• They are teratogenic if used during pregnancy
  (malformations of the limbs, facial features,
  CNS, heart, skeleton).
  

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Sedative Hypnotics

• 1. Psychological Dependence
• Preference for short acting vs long acting and
  for those with steep dose-response curves.
  
• 2. Physical Dependence
• 200 mg/day no effect.
• 400 mg /day, occasional EEG evidence of
  withdrawal, rebound insomnia.
  
• 600 mg/day, minor withdrawal.
• 80mg/day and higher, most patients have delirium
  and seizures.

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Sedative Hypnotics

• Withdrawal
• Minor tremors insomnia (REM rebound) high
  fever clonic blink.
  
• 12-16hrs minor symptoms plus abdominal cramps
  nausea and vomiting, o. hypotension Ý deep
  tendon reflexes.
  
• 24hrs pronounced weakness, course tremors (the
  shakes), hyperactive reflexes, early illusions
  and hallucinations.
  
• 48-72hrs convulsive seizures (rum fits) vivid
  auditory and visual hallucinations (the
  horrors), formication, agitation,
  disorientation, delirium, paranoid delusions.

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Sedative/ Hypnotics

• Withdrawal (cont)
• Hypothermia, dehydration,
• electrolyte imbalance, exhaustion,
  cardiovascular collapse. Threat to life.
  
• Time of onset and symptoms experienced varies
  with CNS depressant use, similar to alcohol
  withdrawal.
  
• Additive effect of sedative/hypnotics.
• Stabilization diazepam, chlordiazepoxide,
  phenobarbital (cross-dependence).
  
• Drug tapered off slowly prevention of onset
  (reversible only early in course).
  
• Relatively very large doses are needed.

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Sedative Hypnotics

• B. Concurrent or substitute use
• - May be lethal with other depressants.
• - Alcohol, amphetamines, cocaine. Not likely to
  abuse narcotics, but not vice-versa.
  
• C. Tolerance
• - Both drug disposition and pharmacodynamic
  tolerance exists to most CNS depressants
  
• - Tolerance of modest degree - lethal dose not
  greatly increased.
  
• - Cross-tolerance with alcohol, anesthetics and
  volatile intoxicants.

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Sedative Hypnotics

• E. Acute Intoxication
• - Pupils are normal BP and respiration are
  depressed nystagmus on lateral gaze tendon
  reflexes depressed ataxia slurred speech
  confusion coma shock. Death
• F. Treatment
• Treatment of overdose w/BDZs flumazenil (BDZ
  receptor blocker)
  

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Sedative/Hypnotics

• G. Mechanism of Action
• Major site of action is at GABAergic synapses.
• Inhibitory Synapse.
• GABA-A receptors Cl- Channels.
• Hyperpolarization.

BARBs
BDZs
GABA AGONISTS
?
?
?
?
?
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Sedative Hypnotics

• The GABA receptor is a pentameric structure that
  forms a Cl- channel.
  
• The receptor complex includes distinct binding
  sites for benzodiazepines, barbiturates and
  GABA-like substances.
  
• GABA transmission exerts an inhibitory effect on
  norepinephrine (NE), dopamine (DA), serotonin
  (5-HT), and acetylcholine (ACh) pathways.
  
• Barbiturates
• Prolong the opening of the channel associated
  with GABA
  
• binding, increase conductance.
• Benzodiazepines
• Facilitates the activity of GABA to open the
  channel.
  

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