neurotransmitter GABA vs GLUTAMAT

8/21/2019 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



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GABAAReceptors:

Location Clinical implications

1Abundant throughoutcererbral cortex

-sedation

-amnesia

-ataxia

-anticonvulsant (--)

2Hippocampus,amygdala, cortex

-antianxiety



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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


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


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



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1957: Chlordiazepoxide (Librium), thefirst benzodiazepine, is discovered

1990s: Omega-1, non-benzodiazepine,hypnotics became available

Ambien , Sonata , Lunesta



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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


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


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



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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)



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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



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The End


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GABA Glutamate(Inhibition) (Excitation)

GABA Synthesis:

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neurotransmitter GABA vs GLUTAMAT

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