Tuesday Feb 27

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Tuesday Feb 27 Please read the book for
information regarding Inhalants and
Barbiturates EXAM I is Tuesday, Mar 6
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• Relevant GABAergic Drugs
• (Cannot increase GABA action by giving GABA
  does not cross the BBB.)
• CNS depressants - dose-related effects from calm
  to relaxation to disinhibition to drowsiness to
  sleep to anesthesia.
• Alcohol - today
• certain inhalants get from text
• anticonvulsant medications - today
• barbiturates sedatives anesthetics get from
  text
• Benzodiazepines - antianxiety drugs Thursday
• certain date rape drugs (GHB) get from text

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Alcohol Use During Pregnancy Effects on Fetus
and Child Teratology - study of abnormal
development Teratogen - an agent that causes
abnormal development Neurobehavioral Teratology
the study of abnormal brain and behavioral
development due to prenatal exposure to toxic
agents
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• X. Alcohol and Prenatal Development
• Readily crosses the placental membrane
• Developing embryo/fetus lacks detoxifying enzymes
• Alcohol interferes with normal developmental
  processes (reduces folic acid levels alters
  Vitamin A actions)
• Effects occur over a continuum from death,
  malformation, growth retardation, behavioral
  dysfunction
• Most research has focused on the severe end of
  the spectrum Fetal Alcohol Syndrome
• Fetal Alcohol Effects lesser effects than full
  syndrome may be physically normal but have
  learning or behavioral problems

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• Variables Governing Susceptibility
• Gestational Age at Exposure
• Genotype
• Amount consumed
• drinking frequency
• Among chronic alcoholics, 30-50 of infants have
  FAS.

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• Diagnosis of Fetal Alcohol Syndrome
• Minimal criteria
• Abnormalities in three areas
• Prenatal and/or postnatal growth retardation
• Central nervous system involvement
• Characteristic facial dysmorphology
• Major malformations heart and brain most common

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CNS Dysfunction Infants feeding problems
sleep problems irritable difficult to soothe
abnormal muscle tone Permanent reduced
intelligence behavioral abnormalities (reduced
inhibitory control social difficulties
increased activity) Alcohol is the 1
preventable cause of mental retardation.
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• Seizure Disorders
• Seizure abnormal neuronal activity resulting in
  excess activity
• 1 in 100 have Seizure Disorder
• Epilepsy 2 or more seizures (close together in
  time infrequent but severe)
• Causes
• brain architectural abnormality (wiring)
  neurons or glia - developmental
• neurochemical abnormality - transmitters or
  receptors (most attention to GABA and GLU)
• membrane abnormalities/channel abnormalities
• head injury stroke substance abuse disease
  toxicants

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• Types of Seizures
• Focal (partial)
• Restricted to one brain area
• 60 of people with seizure disorders have these
  alone or in combination with others
• Simple focal seizure remain conscious altered
  feelings, sensations (auras), thoughts
• Complex focal seizure loss or change in
  consciousness
• motor automatisms out-of-body experiences
  dreamlike state repetitive purposeful actions
  (continue activity they were engaged in at onset)
• Consistent symptoms within a person -
  stereotypies

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• 2. Generalized seizures
• Abnormal activity in both hemispheres
• May or may not lose consciousness
• May or may not have tonic-clonic seizure
• Absence seizures (petit mal) brief interruption
  in consciousness may seem to be staring off and
  lose train of thought
• Tonic seizures muscles contract (stiffen up)
  at max tone
• Clonic seizures repeated jerking of muscles on
  both sides of body
• Atonic loss of muscle tone may fall down or
  change posture
• Tonic-clonic seizures (grand mal) may cause
  loss of consciousness
• Types re often mixed in a single individual -
  gt50 have more than 1 type

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• Antiepileptic medications
• Marketed as efficacious for group that clinical
  trials were conducted on
• Some argued to be better for focal than
  generalized (CBZ for partial)
• In use, meds used across multiple types
• The med a person is on has as much or more to do
  with adverse reactions as efficacy.
• Trial and error required to find right med as
  well as right dose
• All have side effects on cognition and mood most
  on motor function (very dose and stage of
  treatment dependent)

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In general, 50 of patients achieve excellent
control on meds 30 improve 20 are
intractable. In general, side effects worse at
higher blood levels of med. In general, side
effects are worse with polydrug trt.
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Antiepileptic Medications 1. Barbiturates
Phenobarbital (Luminal) Binds to GABAA receptor
complex at barbiturate site enhances GABA action
upon GABA binding Inc duration of Cl- channel
opening 2. Benzodazepines Clonazepam
(Klonopin) Chlorazepate (Tranxene) Binds to
GABAA receptor complex at BZD site enhances GABA
action upon GABA binding Some BZDs used to treat
status epilepticus Diazepam (Valium) and
Lorazepam (Ativan) rectal gel available
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Mechanisms of Action of Antiepileptic
Medications 3. Phenytoin (Dilantin) mephenytoin
(Mesantoin) Ethotoin (Perganome) Less CNS
depression than barbiturates Keeps Na channels
open longer and prolongs refractory period
following an action potential 4. Carbamazepine
(Tegretol) Slows rate of recovery of neuron after
firing by interfering with Na channels 5.
Ethosuximide (Zarontin) Reduces Ca entry into
neuron and interferes with neurotransmitter
release
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Mechanisms of Action of Antiepileptic
Medications 6. Valproic acid Depakote
Depakene Prolongs the recovery of Na channels
after action potential occurs Increases GABA
production and release stimulates synthesis and
breakdown 7. Trimethadione Tridione Inhibits
incoming Ca
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Newer Anticonvulsants and How They May
Work Lamotrigine (Lamictal) appears to block
sodium and calcium channels Gabapentin
(Neurontin) appears to increases GABA levels
and to block calcium channels Topiramate
(Topimax) multiple appears to block sodium and
calcium channels to increase GABA levels and to
bind with the GABAA receptor to block calcium
channels to block certain Glutamate receptors
(AMPA) Oxycarbazepine (Trileptal) - appears to
block sodium and calcium channels Zonisamide
(Zonegran) - appears to block sodium and calcium
channels and to bind with the GABAA receptor
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Individual Differences in Response Several
relevant genes have been identified that alter
drug metabolism. For several medications, poor
metabolizers and ultrafast metabolizers have been
identified. Relevant to administered dose dosing
schedule drug interactions risks for adverse
effects immediate and long term Identifying
those at risk helpful to patient to drug
approval and marketing
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• Certain relevant genes
• CYP2D6
• Homozygous for particular allele poor
  metabolizers
• Some have gene amplification ultrarapid
  metabolizers
• This enzyme involved in metabolism of many
  psychoactive drugs anticonvulsants
  anxiolytics cardiac meds antipsychotics
• 1 of Japanese are poor metabolizers vs 5-10 of
  white North American or European as well as
  African
• Ultrametabolizers 1-2 Swedish and German vs
  20 Saudi Arabia Ethiopia also high among those
  in Spain
• 2. CYP2C19
• Asian 13-23 poor metabolizers vs 2-5 whites

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Use of Anticonvulsant Meds During Pregnancy
Effects on the Fetus/Child
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• Early Human Studies of the Teratogenicity of
  Anticonvulsant Medications
• examined the effects of polytherapy (mostly
  hydantoins and barbiturates)
• focused on malformations and growth impairments
• reported non-systematic observations of
  developmental delay and intellectual impairments
• did not control for important demographic
  variables

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• Prenatal exposure to anticonvulsants increases
  risks (3X-4X) for
• major malformations (cleft lip/palate heart
  defects neural tube defects)
• microcephaly
• growth reduction
• midface hypoplasia
• digit/nail hypoplasia

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Fetal Anticonvulsant Syndrome
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Picture of hypoplastic nails
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• Phenobarbital Monotherapy
• major malformations (cleft lip/palate heart
  defects)
• microcephaly
• growth reduction
• midface hypoplasia
• digit hypoplasia
• Major malformations in 5-8
• Major plus minor in 20-30
• (Holmes et al, 2001 2004)

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MGH Anticonvulsant Study 1997 -
2006 Phenobarbital, Carbamazepine, or
Hydantoin Aims 1) to determine the effects of
gestational monotherapy on the childs cognitive
and socio-emotional characteristics 2) to
quantitatively examine the effects upon midface
and digit hypoplasia 3) to examine the
relationships between structural and functional
effects
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• Criteria for Inclusion
• maternal seizure history
• monotherapy throughout pregnancy
• willingness of both parents to participate
• normal intelligence in both parents
• singleton birth
• English as first language of child

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• Criteria for Exclusion
• Mothers
• occurrence of tonic-clonic seizures during pg.
  
• maternal exposure to other teratogenic drugs or
  illnesses
• Children
• neurologically-relevant birth complications
• neurologically-relevant illnesses or injuries
• orofacial malformation
• auditory or visual impairment

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• Matching of Exposed and Control Cases
• age
• sex
• socioeconomic status
• parental education

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• Neurobehavioral Evaluations of the Children
• maternal administration of the Behavioral
  Assessment Scale for Children and the Child
  Behavior Checklist
• examiner-blinded administration of a
  comprehensive neuropsychological battery of tests
  to the child (the WISC-III selections from the
  K-ABC, the Stanford-Binet IV, the CELF, Wechsler
  Memory Scale for Children)
• Goal to determine the childs general mental
  ability as well as abilities across processing
  areas

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General Mental Ability on WISC-III Phenobarbital