Barbiturates, General Anesthetics, and Antiepileptic Drugs

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Barbiturates, General Anesthetics, and
Antiepileptic Drugs

• Laureen Trail
• Spring 2003

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History

• Humans have always sought ways to induce sleep,
  relieve stress and anxiety
• Natural CNS depressants
• Alcohol
• Morphine (opium alkaloid)
• Manufactured CNS depressants
• Phenobarbital (1912) 1st barbiturate
• 1912-50 many tested/marketed
• Dominated market until 1960

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Action Sites and Mechanisms

• Early understanding -
• Depressed neuronal pathways in brain
  stem/cerebral cortex
• Severe depression DEATH
• Present day
• Reduced metabolic and brain electrical activity

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Neurotransmitters Receptor Sites

• Glutamate (excitatory)
• Reduce excitatory activity
• GABA (inhibitory)
• Augment inhibitory activity
• Barbiturates/benzodiazepines bind here

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GABA Site
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GABAA Site Action

• Binding to GABAA receptors
• Facilitates GABAA-induced neurotransmission
• Channel opens, influx of Cl- ions,
  hyperpolarization
• Reason for sedative-hypnotic anesthetic effects
  of barbiturates, benzodiazepines, anesthetics,
  other depressants

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Barbiturate Problem

• Barbiturates can open Cl- channel
• without GABA
• Possibility of extreme toxicity in overdose!

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Uses of Barbiturates

• Only 10 of depressant prescriptions
• Lethal in overdose
• Narrow therapeutic-to-toxic range
• High potential for tolerance, dependence, abuse
• Dangerous interaction with other drugs
• Still used as anticonvulsant, intravenous
  anesthetics, death inducing, brain protection
  (head injury), psychiatric sedation

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Sedation-Induced Brain Dysfunction

• Blackout is antegrade amnesia
• All sedatives can produce Alzheimer-like amnesia
• Dementias produce characteristic patterns

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Mental Status Exam

• Used to evaluate mental functioning
• Five areas affected in dementia
• SENSORY clouded disorientation to
  time/place
• MEMORY forgetfulness, loss of ST
• INTELLECT depressed reasoning
• JUDGMENT altered insight
• AFFECT wide mood swings
• Severe in elderly STOP MEDS!

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Specific CNS Depressants
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Barbiturates

• Primary prescription for anxiety, insomnia from
  1912-1960
• Associated with suicides, accidental overdose,
  dependence/abuse, dangerous drug interactions
• Still prototype for drug comparison

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Pharmacokinetics

• Wide range of half-life 3 min to 120 hrs
• Redistribution in body
• Fast-acting gtgt lipid (fat) soluble results in
  seconds
• Long-actinggtgt water soluble slower to
  penetrate CNS (20-30 minutes)
• Metabolized in liver eliminated through
  kidneys
• Urinalysis detects 30 hours to weeks

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Pharmacological Effects

• With lowered anxiety, also sedation
• Not analgesic no sleep/sedation with moderate
  pain
• Suppressed dreaming during REM
• Cognitive inhibition
• Changes in thinking, judgment, motor skills,
  behavior over hours or days

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Affects on Other Systems

• Respiratory
• Low dose none
• High dose suppression gtgt death
• Few effects at low dosage
• Cardiovascular, gastrointestinal
• Liver - drug stimulates enzymes that metabolize
  it gtgtgt tolerance

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Psychological Effects

• Depressed behavior
• Cognitive/Motor inhibition akin to alcohol
  inebriation gtgt impaired driving
• Low dose reduced anxiety OR emotional
  withdrawal, aggression or violence
• Set/setting determines positive or negative
  response
• High doses general behavioral depression, sleep

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Adverse Reactions

• Side effects
• Drowsiness intellectual/motor impairment
• Effects like alcohol dont need to be
  drunk
• OVERDOSE no antidote, only life support

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Tolerance

• Two ways to induce tolerance
• 1) Liver enzymes metabolize drug
• 2) Neurons in brain adapt to drug
• Primarily sedative effects
• Narrow safety margin for brain stem depression

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Physiological Dependence

• Wide range of effects
• Low dose sleep difficulties
• High dose hallucinations, restlessness,
  disorientation, life-threatening convulsions

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Psychological Dependence

• Pleasurable effects
• Reduced anxiety
• Sedation
• Euphoria
• Lead to compulsive use and abuse

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Effects in Pregnancy

• Mixed results in testing anticonvulsants
• Some show harm to fetus, others none
• Best to avoid during pregnancy, but
• Need to prevent seizures that could harm fetus

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Misc. Nonbarbiturate Sedative-Hypnotic Drugs

• Most obsolete, not used or prescribed
• Methaqualone (Quaaludes) 1970s, 80s
• Love Drug ?? NOT!
• Opposite effect like alcohol set and setting
  gave it the reputation
• Meprobamate (Equanil, Miltown) 1950s
• 1st non-barbiturate tranquilizer
• Less respiratory suppression

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Misc. Drugs, cont.

• Chloral Hydrate (Noctec) since 1880s
• Metabolized like alcohol
• Tolerance like barbiturates
• Bedtime sedative for elderly
• Mickey Finn (w/alcohol) 1st date rape drug

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Misc. Drugs, cont.

• Paraldehyde precedes barbiturates
• By-product of ethyl alcohol metabolism
• Used to treat DTs
• Dependence toxicity for stomach, liver, kidneys

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General Anesthetics

• Potent CNS depressants
• General anesthesia most severe state of
  intentional drug-induced CNS depression
• opioid narcotic volatile anesthetic
• (no pain unconsciousness)
• Depression of all CNS functions
• - sedation, sleep, depressed reflexes, amnesia,
  unconsciousness

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Route of Administration

• Inhalation gases or volatile liquids
• Nitrous oxide dentistry
• Abuse with canned whipped cream sniffing
• hypoxia (Oxygen deprivation)
• brain damage
• Injection Thiopental (Pentothal) barbiturate
• Propofol and others resemble GABA N.T.

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GHB

• Gamma-hydroxybutyrate
• Naturally occurring 4-carbon molecule
• in mammal brains
• Structure like, synthesized from GABA
• Anesthetic in other countries
• Use in sleep disorders, alcohol and opioid
• dependence

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GHB Abuse

• Euphoriant makes you feel good!
• Common date rape drug
• Doesnt enhance body building or sex!
• Effects disinhibition, excitement, drunkenness,
  amnesia
• Dangerous overdose stupor, delirium,
  unconsciousness, coma
• NO ANTIDOTE only life support

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Antiepileptic Drugs

• Epilepsy CNS disorders of brief, chronic ,
  reoccurring seizures (brain electronic
  disturbance) assoc. with brain lesions
• How drugs suppress seizures
• Limit neuron firing at sodium channels, block
  depolarization
• Reduce GABA metabolism, aid GABA release from
  presynaptic neurons

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Research Findings

• Multiple effects of drug sedation, anxiolytic,
  antiepiletic, antimanicgtgtgtgtgt
• Help several disorders bipolar, explosive
  psych. disorders, mania
• Reinforces previous knowledge
• Stabilizes neurons by aiding inhibition or
  limiting excitation

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Traditional Antiepileptics

• Barbiturates (Phenobarbital) still used
  occasionally, but hard on children (hyperactivity
  learning problems)
• Hydantoins (Dilantin) - common use as
  anticonvulsant
• Benzodiazepines (Clonazepan) anticonvulsant,
  hard on children (personality changes and
  learning problems)

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Modern Antiepileptics

• Resemble GABA act on GABA receptors
• Inhibit glutamate action brain protection
  from hypoxia ischemia
• NEWEST CLASS Epalons - steroid derivatives
• No hormonal action, but traditional effects
• Bind to steroid-sensitive GABAA receptors

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Antiepileptics and Pregnancy

• Stillbirth and infant mortality rate higher
• Antiseizure meds in early months increase birth
  defects
• Balance danger of seizures with possible birth
  defects discontinue meds or move to single drug
  at lowest effective dose

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Benzodiazepines and Second Generation Anxiolytics

• Laureen Trail
• University of Idaho
• Spring 2003

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History

• Benzodiazepines (BDZ) introduced in 1960s
• 40 years - drug of choice
• Still widely used 1 in 5 prescriptions
• Many properties anxiolytic, sedative,
  anticonvulsant, amnestic, relaxant
• Anxiolytic synonymous with BDZ
• Newer antidepressants rapidly replacing

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Effects

• Safer than barbiturates
• much less respiratory depression
• - lg. doses rarely fatal (except w/alcohol)
• CNS toxicity in chronic use/high doses
• - headaches irritability, confusion, impaired
  memory, depression

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Mechanism of Action

• BDZs - agonists of GABA-BDZ-Chloride receptor
  complex, facilitate GABA binding
• Action gtgt aids influx of Cl- ions gtgt
  hyperpolarization of postsynaptic neuron gtgt
  excitability depressed

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Sites of Action

• MRIs, PETs research - fear and anxiety
  responses in amygdala, orbitofrontal cortex,
  insula
• Decreased GABAergic function gtgt
• elevated anxiety states

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Pharmacokinetics

• 15 BDZ derivatives used in U.S.
• -differ in pharmacokinetics parameters
• a. Metabolism rates to active intermediates
• b. Plasma ½ life of parent active metabolite
  long- or short-acting

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Familiar BDZs

• Long-acting (6)
• Valium Librium (50-100 hrs.)
• Intermediate-acting (4)
• Ativan ProSom (10-50 Hrs.)
• Short-acting (5)
• Halcion Xanax (1.5-35 hrs.)

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Absorption gtgtgt Excretion

• BDZs taken orally well absorbed
• Peak plasma concentration gtgt I hour
• Most psychoactive drugs metabolized to inactive,
  water-soluble product
• Exceptions for some BDZs
• Some long-acting ones transformed to long-acting
  metabolites
• - nordiazepam 60 hrs.

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Problem Population

• CAUTION with elderly patients!
• Metabolize BDZs much more slowly
• -up to I month to eliminate single dose
• BDZs can easily cause dementia
• -too often overlooked in elderly

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Pharmacological Effects

• BZDs facilitate GABA-induced neuron inhibition at
  GABAA receptors in many CNS areas
• Complete agonists dependably aid GABA binding
• Partial agonists bind to subgroups of GABAA
• receptors

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Specific Sites and Actions

• Cerebral cortex and hippocampus
• - Mental confusion and amnesia
• Amygdala, orbitofrontal cortex insula
• - Alleviation of anxiety, agitation and fear
• Spinal cord, cerebellum brain stem
• - Muscle relaxation (also anxiolytic)
• Cerebellum and hippocampus
• - Antiepileptic action
• Ventral tegmentum and nucleus accumbens
• - Rewarding behavioral effects (depend/abuse)

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Uses and Effects of BDZs

• Severe anxiety relief PRIMARY
• - usually psychological relief leads to
  physiological relief
• Sedative hypnotic effect for insomnia
• - fast-acting no daytime sedation
• - long-acting some daytime sedation
• Muscle relaxant - direct physiological relief or
  indirect with psychological relief

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Uses and Effects, cont.

• Amnestic effect - before or during surgery
• Panic Attacks and Phobias (controversial)
• Somewhat effective Serotonin-type
  antidepressant better
• anxiety relief, minimal side effects, patient
  compatibility
• --- impaired psychomotor and alertness,
  potential for dependence/abuse

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Uses and Effects, cont.

• Anticonvulsant - secondary medication
• - Effective at raising seizure threshold
• Treatment of Alcoholism
• - alcohol substitute in treating withdrawal
• - helps reduce relapse rate

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Side Effects and Toxicity

• Usually dose-related effects of intended actions
  sedation, drowsiness, ataxia, lethargy, mental
  confusion, amnesia, onset/extension of dementia
• High doses mental/motor dysfunctiongtgt
• hypnosis
• HALCION controversial paradoxical effects
  agitation, aggression, disinhibition,
  hallucinations

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Side Effects/Toxicity, cont.

• Alone even high doses no respiratory
  suppression
• Successful suicides rare
• BDZ alcohol highly toxic gtgtgt fatal

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Complex Side Effects

• Sleep pattern disturbances
• Daytime sedation or night time rebound insomnia
  related to long or short action
• Impaired motor abilities - especially driving
• Irrational self-assessment about effects
• Cognitive deficits learning, academic,
  psychomotor interference
• DISCONTINUATION gtgtgt normal function

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Tolerance-Dependence-Withdrawal

• Extended periods of use gtgtgt dependence
• Withdrawal symptoms rebound and intensified
  anxiety, insomnia, restlessness, agitation,
  irritability
• Rare hallucinations, psychosis, seizures
• Abuse patterns typical of polydrug users

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BDZs and Pregnancy

• BDZs and metabolites freely cross placenta
• - small but possible risk of fetal damage
• Near delivery, high-dose mothers risk
  BDZ-dependence/withdrawal in infants
• floppy infant syndrome

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Unique Antagonist

• Flumazenil (Romazicon) high-affinity binding to
  GABAA complex but shows no activity!
• Blocks access of active BDZs to produce reverse
  effect
• Used as antidote for BDZ overdose - short ½ life
  an advantage

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Second-Generation Anxiolytics

• Not benzodiazepines, but similar agonist activity
  at GABA receptors
• Zolpidem (1993) sedative and sleep pattern
  normalizer short ½ life mild to moderate side
  effects stronger in elderly
• (strong nausea discourages suicide attempts)
• Zaleplon Zopiclone (1999)
• Primarily hypnotics w/o rebound insomnia
• Agonist qualities similar to Zolpidem

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Partial Agonists

• Desired anxiolytic effects without usual side
  effects, rebound anxiety, or physical dependence
  - 5 studied in Europe
• Alpidem anxiolytic, little sedation, no alcohol
  reaction
• Etizolam potent anxiolytic, low side effects
• Imidazenil anxiolytic, minimal cognitive
  disruption and side effects
• Abecarnil rapid anxiolytic effects, low
  physical dependence
• Bretazenil anxiolytic and antipsychotic,
  minimal side effects and dependence

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Serotoninergic Drugs as Anxiolytics

• Role of serotonin neurotransmission in anxiety
  behavioral disinhibition
• Recent interest focused on presynaptic
  transporters and postsynaptic 5-HT1A and
• 5-HT3 receptors fear area of the brain,
  rich in 5-HT1A receptors, studied in mice

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Serotonin Agonists

• Serotonin 5-HT1A agonists known collectively as
  second-generation anxiolytics
• Buspirone (BuSpar) marketed in 1986 unique
  anxiety relief

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Buspirone Properties

• 1.Anxiolytic w/o sedation, drowsiness, hypnosis
  minimal amnesia, mental or psychomotor impairment
• 2. Doesnt enhance CNS depressant effects of
  alcohol, sedatives, BDZ
• 3. No cross-tolerance, cross-dependence with
  BDZs no addiction/abuse potential
• 4. Additional antidepressant effect potential for
  depressive disorders w/anxiety (weak agonist)

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Busipone, cont.

• 5. Slow onset/subtle effects works for patients
  who can tolerate delayed gratification
• 6. May augment beneficial effects of
  psychotropics
• 7. May reduce some negative effects of
  developmental disorders in children

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Serotonin Reuptake Inhibitors

• Rapidly becoming meds of choice for variety of
  anxiety disorders
• Slow onset but effects compare favorable w/BDZs
  without dependence
• Serotonin receptor antagonists also under studied
  for anxiety