neurotransmitter GABA vs GLUTAMAT
Transcript of neurotransmitter GABA vs GLUTAMAT
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GABA, Glutamate, and
Sedative-Hypnotics
Jason Jerry, M.D.
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Introduction:
GABA is the major inhibitoryneurotransmitter in the CNS
GABAergic synapses account for 20-30%of all synapses in the brain
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 127.
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Introduction:
GABA receptors are of fundamentalimportance in the field of addiction as they
are stimulated by:Alcohol
Sedatives (benzodiazepines, barbiturates)
Inhalants Gamma Hydroxy Butyrate (GHB)
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Introduction:
Glutamate is the predominant excitatoryneurotransmitter in the CNS
Glutamate and GABA tend tocounterbalance one another to achievehomeostasis
For simplicitys sake, GABA can be thoughtof as the brakes and glutamate can bethought of as the accelerator
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GABAAReceptor:
Cl-
Threshold
Resting Potential
Hyperpolarization
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GABAAReceptors:
Comprised of five protein subunitssurrounding a trans-membrane channel
There are 16 distinct types of GABAreceptor subunits divided into severalmajor classes (alpha, beta, gamma, etc.)
Each major subunit class is further dividedinto isoforms (alpha1, alpha2, etc.)
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GABAAReceptor:
Cl-16 distinct types of GABAreceptor subunits dividedinto several major classes(alpha, beta, gamma, etc.)
The subunit composition ofthe GABAAreceptor
determines its pharmacologicproperties
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GABAAReceptors:
GABA bindingsite
BZD binding site
Receptorsubunit
Must haveand
Must haveand
Subunitisoforms
isoformsmust be1,2,3, or 5
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 127.
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GABAAReceptors:
Location Clinical implications
1Abundant throughoutcererbral cortex
-sedation
-amnesia
-ataxia
-anticonvulsant (--)
2Hippocampus,amygdala, cortex
-antianxiety
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 127.
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In normal brains, there is a balancebetween inhibition (GABA) and excitation
(Glutamate)
GABA Glutamate(Inhibition) (Excitation)
Introduction:
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Acute intoxication with sedative-hypnotics Effect: decreased anxiety, increased
sedation
(Inhibition) (Excitation)
Physiologic Effects of Sedative-
Hypnotics: Intoxication
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With chronic consumption, the braincompensates by increasing excitatory
glutamate activity
(Inhibition) (Excitation)
Physiologic Effects of Sedative-Hypnotics:
Adaptation & Homeostasis
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During acute sedative-hypnoticwithdrawal, the GABAergic effects of
alcohol are removed and the brainscompensatory increase in glutamateprevails
(Inhibition) (Excitation)
Physiologic Effects of Sedative-
Hypnotics: Withdrawal
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Cl-
Cl-Cl-
Cl-
Cl-
Cl-
GABAAReceptor
Action Potential
Threshold
Resting Potential
Hyperpolarization
GABA Receptors:
K+
Ca2+
GABABReceptors
X
Ca2+X
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Drugs in this class are used for amultitude of uses:
Anxiolysis (barbiturates, benzodiazepines)Anticonvulsants (barbiturates,
benzodiazepines)
Muscle relaxants (benzodiazepines, Soma )
GABAAAgonists:
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GABAAAgonists: History
1850s: Bromide is introducedas a sedative
Early 1900s: Barbituratesbecame available
1955: Meprobamate isdiscovered
Meprobamate is touted as asafer, less-addictive alternativeto barbiturates
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1959: Soma (carisoprodol) is born Soma was developed as a muscle
relaxant, but its major metabolite ismeprobamate
Soma is still widely used today, but does
have addictive potential
GABAAAgonists: History
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1957: Chlordiazepoxide (Librium), thefirst benzodiazepine, is discovered
1990s: Omega-1, non-benzodiazepine,hypnotics became available
Ambien , Sonata , Lunesta
GABAAAgonists: History
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Direct GABAAAgonists:
Do not require GABA to be present at itsreceptor in order to open the chloride
channel Tend to be more potent sedatives thanindirect agonists
Propofol and barbiturates are indirectagonists at lower doses and directagonists at higher dose
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Direct GABAAAgonists: Barbiturates
Ultrashort-acting: Thiopental (Pentathol )
Methehexital (Brevital )
Amobarbital (Amytal )
Short-to-intermediate-acting (T = 15-80hrs): Secobarbital
Pentobarbital
Long-acting (T = 80-120hrs): Phenobarbital
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Direct GABAAAgonists: Barbiturates
All of a low therapeutic index and are dangerousin overdose
Their anti-anxiety and sedating effects are
accompanied by central nervous systemdepression Barbiturates increase the metabolic activity of
liver enzymes
Still used in anesthesia induction, asantiepileptics, and in detoxification (GHB, BZDs,and occasionally ETOH)
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Indirect GABAAAgonists:
GABA must be bound to its receptor inorder for these substances to have an
effect They essentially facilitate the binding ofGABA to its receptor
Examples: benzodiazepines, zolpidem,ethanol, barbiturates (in lower doses),propofol (in lower doses)
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Abuse liability is greater with high-potency, short-acting benzodiazepines
with quick onset of actionAlprazalam (Xanax) is a prime example Diazepam (Valium) is long-acting, but
has a quick onset of action and has moreabuse liability than comparable long-actingbenzos
Indirect GABAAAgonists:Benzodiazepines
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Benzodizepine Dose Equivalents:
0
5
10
15
20
25
30
Xanax
Klo
nipin
Ativ
an
Valiu
m
Resto
ril
Lib
rium
Mg
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Physiologic dependence takes about twoweeks of daily use to develop
Tolerance to sedative effects developswithin two weeks
Rebound insomnia may occur with the use
of benzodiazepines
Indirect GABAAAgonists:Benzodiazepines
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Benzodiazepines vs. Barbiturates:
Benzodiazepines have a wider therapeuticwindow and are, therefore, safer thanbarbiturates
Barbiturates can act as direct agonists at higherconcentrations
Benzodiazepines influence the frequency of
opening of the chloride channel whilebarbiturates influence the duration of opening
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Endogenous Benzodiazepines
19861,4 BZDs isolated from bovinebrain(Sangameswaran et al. 1986)
1990BZDs isolated from human brains fromthe 1940s Naturally occuring diazepam, oxazepam, and
lorazepam have been found in humans, cows,
and pigs (Sand et al. 2000) Source is unknown
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Zolpidem (Ambien ), zaleplon (Sonata), and eszopiclone (Lunesta )
All have a rapid onset and short durationof action They selectively stimulate the omega-1
benzodiazepine receptor subtype
Decrease sleep latency, but do not affectsleep architecture
Indirect GABAAAgonists:Non-benzodiazepine hypnotics
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Zolpidem (Ambien ) has been shown tobe similar to a benzodiazepine in terms of:
Reinforcing effectsAbuse potential
Subjective effects
Performance impairment
Cases exhibiting abuse and withdrawalsymptoms have been reported
Indirect GABAAAgonists:Non-benzodiazepine hypnotics
Rush CR (1998). Behavioral pharmacology of zolpidem relative to benzodiazepines: A review. Pharmacology, Biochemistry andBehavior 61:253-269.
Cavallaro R, Regazzetti MG, Cavelli G et al. (1993). Tolerance and withdrawal with zolpidem [letter]. Lancet 342:868-869
Gericke CA & Ludolph AD (1994). Chronic abuse of zolpidem. Journal of the American Medical Association 272:1721-1722
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Evidence exists indicating that zaleplonmay also have abuse potential
Indirect GABAAAgonists:Non-benzodiazepine hypnotics
Rush CR, Frey JM, Griffiths RR (1999). Zaleplon and triazolam in humans: acute behavioral effects and abuse potential.Psychopharmacology 145:39-51.
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GABABAgonists:
Baclofen (A muscle relaxant). Gamma Hydroxy Butyrate (GHB) (A
performance-enhancing drug).
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Direct GABAAAntagonists:
Directly block the receptor, preventingGABA from binding
Examples include: cephalosporins,ciprofloxicin, penicillin, imipenem, nalidixicacid
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Indirect GABAAAntagonists:
Block the chloride ion channel or diminishthe effect that GABA has at its receptor
Examples include: flumazenil (Romazicon), clozapine, MAOIs, tricyclicantidepressants
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Summary:
GABAA Direct
Agonist
Indirect
Agonist
Direct
Antagonist
Indirect
Antagonist
Effect Do notrequirepresence ofGABA
Requirepresence ofGABA
Block GABAreceptor
Block chlorideion channel ordiminish effectof GABAagonists
Examples-Barbiturates
-Propofol
(Both athigherdoses)
-BZDs
-Zolpidem
-ETOH
-Barbiturates*
-Propofol*
-Cephalosporins
-Ciprofloxicin
-Penicillin
-Imipenem
-Nalidixic acid
-flumazenil(Romazicon )-Clozapine
-MAOIs
-Tricyclics
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Sedatives: DSM-IVTR Definitions:
Sedative Intoxication:Clinically significant maladaptivebehavior or psychological changes,temporally related to sedative ingestion,and at least one of the following:
1. Slurred speech
2. Incoordination
3. Unsteady gait
4. Nystagmus
5. Impairment in attention or memory
6. Stupor or coma
Source: American Psychiatric Association. DSM-IV-TR.American Psychiatric Association: Washington, DC; 2000.
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Sedative Withdrawal: Two or more of the following,developing within a few days of thecessation or reduction of heavy andprolonged sedative use:
Source: American Psychiatric Association. DSM-IV-TR.American Psychiatric Association: Washington, DC; 2000.
Sedatives: DSM-IVTR Definitions:
1. Autonomic hyperactivity
2. Tremulousness
3. Insomnia
4. Nausea or vomiting
5. Hallucinations or illusions
6. Psychomotor agitation
7. Anxiety
8. Grand mal seizures
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GABA Withdrawal: Clinical Effect
Symptoms generally appear within thefirst 24hrs of abrupt discontinuation of
short-intermediate half life benzodiazepine Symptoms may appear within 3-8 days
after abrupt discontinuation of a long
acting benzodiazepine
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 131.
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GABA Withdrawal: Taper
Sympt
omS
everity
Time
First Week Last Quarter
Long-Acting Short-Acting
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 131
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Pharmacologic Variables PredictingDifficult Benzodiazepine Withdrawal
High daily dose Short half-life
Longer duration of daily use More rapid taper (especially last half)
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 132
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Patient Variables Predicting DifficultBenzodiazepine Withdrawal
Diagnosis of Panic Disorder Higher levels of anxiety and depression
prior to taper Co-morbid substance abuse/dependence
history
Axis-II pathology
Graham, Schultz, et al. (2003) American Society of Addiction Medicine. P 132
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The End
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GABA Glutamate(Inhibition) (Excitation)
GABA Synthesis: