GABA and its receptors

1. Gamma amino butyric acid

2. HISTORY:
 Before 1883 known as a metabolite of
plants and microorganisms.
 1949 identified in animal tissue, not
incorporated in proteins.
 In 1950, further, GABA was discovered
to be an integral part of the mammalian
central nervous system.
 1953 first indications of an inhibitory
activity.

3. INTRODUCTION
• GABA (gamma- amino butyric acid) is the
major inhibitory amino acid transmitter of
the mammalian central nervous system and
it is present in some 40% of all neurons of
cortex.
• It is abundant in nigrostraital system, and
also occur in lower conc. n throughout the
grey matter.
• This channel mainly allows chloride influx
reducing its excitability, and thus classified as
an inhibitory neurotransmitter.

4. • The GABA system is the target of a wide
range of drugs active on the CNS-
• Anxiolytics ,
• sedative-hypnotics,
• General anesthetics, and
• Anticonvulsants

5. RECEPTORS

6. • A ligand gated receptor. Stimulation
results in increased permeability to Cl-
raising the postsynaptic membrane
threshold potential (inhibitory). This
receptor is a heterogenous pentamer
consisting of various numbers and types of
α, β and γ subunits.At least six different
αs, three different βs, three different γs
and other subunits have been identified.
GABAA receptor

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8. GABAA receptor (contd…)
• Different types and combinations of
subunits confer different pharmacologic
properties on different receptors;
• GABAA binding sites include:
• α subinits: BDZ receptor: Several subtypes
characterized including the BZ1 and BZ2
subtype.
• β subunits:binding of barbiturates and
picrotoxin.

9. Composition, Distribution, and Major Functions of GABAA Receptors
The major form of the GABAA receptor contains at least three
different subunits α, β, and γ, with likely combination of 2α, 2β, 1γ.

10. • Presynaptic linked to G proteins which
increase K+ conductance
(hyperpolarization), inhibits voltage-
senstive Ca++ channels (inhibition of
transmitter release)
GABAB receptor

11. GABAC receptor
• The GABAC receptor is less widely
distributed than the A and B subtypes.
• modulators (e.g., benzodiazepines and
barbiturates) seem not to interact with
GABAC receptors.
• GABAC receptors are found in the retina,
spinal cord, superior colliculus, and
pituitary.

12. Biosynthesis, Storage and Release
• GABA is directly biosynthesized from L-
glutamate by the action of glutamic acid
decarboxylase (GAD). L-glutamate is
available from α-ketoglutarate, a product
of glucose metabolism. Glucose is a normal
nutrient supplied to the CNS via the blood
.GABA is stored in synaptic vesicles and is
released in a Ca++-dependent manner
upon depolarization of the presynaptic
membrane

14. SYNTHESIS AND METABOLISM
vigabatrine

15. Termination
• Reuptake into presynaptic terminals
and/or surrounding glial cells is the
primary mechanism of termination.

16. Drug Affecting GABA Release

17. Baclofen
• Baclofen is a structural analog of (GABA)
and may exert its effects by stimulation of
the GABAB receptor subtype or inhibiting
GABA release.. Baclofen also has CNS
depressant properties as indicated by
production of sedation with tolerance,
somnolence, ataxia and respiratory and
cardiovascular depression.

18. • Baclofen is used to alleviate spasticity
resulting from multiple sclerosis,
particularly for the relief of flexor spasms,
concomitant pain, clonus and muscular
rigidity. It may be of some value in
patients with spinal cord injuries and
other spinal cord diseases.Baclofen may be
used intrathecally to manage severe
spasticity of spinal cord origin in patients
who are unresponsive to oral baclofen
therapy or who experience intolerable
CNS side effects at effective doses.
Baclofen contd…

19. • When introduced directly into the
intrathecal space, effective CSF
concentrations are achieved with
resultant plasma concentrations 100
times less than those occurring with oral
administration. Baclofen is well absorbed
(100%) orally and not metabolized to any
significant degree. It is excreted primarily
unchanged in the kidney, thus dose
adjustment in renal impairment may be
necessary!!!!
Baclofen contd…

20. GABA Reuptake inhibitors

21. Tiagabine developed from observations that
nipecotic acid possesses GABA reuptake
inhibitory activity. Tiagabine is indicated for the
adjunctive therapy for treatment of partial
seizures. This drug.reportedly binds to the GABA
reuptake protein, thereby blocking GABA uptake
into presynaptic neurons and permitting more
GABA to be available for receptor binding on the
surfaces of post-synaptic cells.
Tiagabine

22. • This suggests that tiagabine prevents the
propagation of neural impulses that
contribute to seizures by a GABA-ergic
action.

23. • Good absorption (95% - minimal first pass and peak plasma
levels within an hour. Food can reduce Cmax and Tmax
• Relatively high plasma protein binding (96%). Competitive plasma
protein binding interactions possible (i.e.Valproic acid)!!!
• Metabolism: Two metabolic pathways:
• 1) thiophene ring oxidation (cytochrome P450 3A) leading to the
formation of 5–oxo-tiagabine; and
• 2) glucuronidation. The 5–oxotiagabine metabolite does not
contribute to the pharmacologic activity of tiagabine.
• Elimination half-life of 7 to 9 hours.
Tiagabine contd…

24. Tiagabine contd…
• The elimination half-life decreased by 50% to 65% in
hepatic enzyme-induced patients with epilepsy
(carbamazepine, phenytoin, primidone and phenobarbital)
compared to uninduced patients with epilepsy.
• Approximately 2% of an oral dose of tiagabine is excreted
unchanged, with 25% and 63% of the remaining dose
excreted into the urine and feces, respectively, primarily as
metabolites.
• Potential Drugs interactions: Cytochrome inducers and
high plasma protein bound drugs!

25. • Inhibitors of GABA metabolism:

26. GABA-Transaminase (GABA-T) Inhibitors
• Vigabatrin is a second generation antiepileptic
which exerts its mechanism of action by
increasing brain GABA levels by inhibition of
GABA-transaminase-mediated metabolism via
suicide inhibition.
• Due to its structural similarity to the normal
substrate, vigabatrin is recognized at the active
site of GABA-T which initiates the
transamination reaction.

27. • Oral bioavailability: about 90%.
• Minimal first pass!
• Distribution: not bound to plasma
proteins and distributes into the CSF
• Metabolism: None (amino acid
derivative!!). Also not an inhibitor or
inducer or cytochrome isozymes!!!!
• Eliminated unchanged in the urine
(Amino acid derivative): Dose reductions
in renal impairment (CrCL <60 mL/min!)
Tiagabine contd…

28. Inhibitors of GABA metabolism: Succinic
Semialdehyde Inhibitors:
• Sodium Valproate (Valproic Acid)
• For use as sole and adjunctive therapy in the
treatment of simple and complex absence
seizures .
• Valproate sodium injection is indicated as an IV
alternative in patients for whom oral
administration of valproate products is
temporarily not feasible.

29. Sodium Valproate contd…
• Mechanism of Action: Prolongs the
recovery of voltage-gated sodium
channnels and thus inhibits neuronal
firing, and the T-currents of calcium
channels (thalamus).
• Also reported to inhibit GABA-
transaminase (aminotransferase) enzyme
involved in the degradation of GABA.

30. • peak plasma levels are attained in 1-8
hrs (formulation dependent).
• Valproate is highly plasma protein bound
(90%) as is typical for most organic acids.
• Because of its polarity CNS distribution is
low (10% of plasma concentration).
Sodium Valproate contd…

31. • Metabolism: CYP-mediated oxidation
• Elimination: 70% of a dose is excreted
renally, mainly as glucuronides
• t1/2- 15hrs
Sodium Valproate contd…

32. Drug Interactions:
1. GI Tract: Adsorbants (Charcoal, bile acid sequestrants) may
absorb valproate and reduce it's absorption (anion=cation
interactions with quaternary sequestrants)
2. Cytochrome inhibition by valproate may increase levels of other
drugs administered concurrently (phenobarbital, phenytoin,
carbamazepine, etc.
3. Cytochrome induciton by inducers (rifampin, phenobarbital,
phenytoin, carbamazepine) may incerase oxidative clearance of
valproate
4. Competitive plasma protein binding: Valproate may displace, or
be displaced, by other highly protein bound drugs, especially acids

33. Antiepileptic drugs

36. GABA and Sedative/Hypnotic
Drugs
 Sedative/Hypnotic are widely prescribed drugs worldwide.
 An effective sedative (anxiolytic) agent should reduce anxiety and
exert a calming effect.
 The degree of central nervous system depression caused by a
sedative should be the minimum consistent with therapeutic
efficacy.
 A hypnotic drug should produce drowsiness and encourage the
onset and maintenance of a state of sleep.
 Hypnotic effects involve more pronounced depression of the
central nervous system than sedation, and this can be achieved
with many drugs in this class simply by increasing the dose

37. Sedation
hypnosis
anaesthesia
Coma & death
CNSeffect
Increasing dose
Alcohol and barbiturates

38. Sedation
hypnosis
anaesthesia
Coma & death
CNSeffect
Increasing dose
Benzodiazepines & newer hypnotics

39. Molecular basis of GABAa receptor
• Species- knock out mice
• drug- benzodiazepines
• Expt-point mutation has
been inserted converting
histidine to arginine in
the α1 subunit.
• Result-resistance to both
the sedative and
amnestic effects of
benzodiazepines
• Species- knock out mice
• drug- benzodiazepines
• Expt-point mutation
has been inserted
converting histidine to
arginine in the α2 & α3
subunit.
• Result-resistance to
anxiolytic and muscle
relaxing effects

40. Barbiturates and GABA
• Barbiturates facilitate the actions of GABA
but in contrast to benzodiazepines—they
appear to increase the duration of the
GABA-gated chloride channel openings.
• At high concentrations,the barbiturates may
also be GABA-mimetic, directly activating
chloride channels. These effects involve a
binding site or sites distinct from the
benzodiazepine binding sites.
• Barbiturates are less selective in their actions
than benzodiazepines, because they also
depress the actions of the excitatory
neurotransmitter glutamate via binding to
the AMPA receptor.

41. GABA and alcohol
• Alcohols are CNS depressants with a
pharmacologic spectrum of action
overlapping those of the benzodiazepines
and barbiturates, known to act by
enhancement of GABAR.
• Long-chain alcohols have anesthetic
activity,

42. GABA and anaesthetic
• Progesterone was shown to produce rapid sedative activity,a
finding that led to the development of the clinical intravenous
steroid anesthetic, alphaxalone. Progesterone has anxiolytic and
anticonvulsant activity; discontinuation after long-term
administration leads to withdrawal signs that are clearly CNS
mediated these actions are mediated by the progesterone
metabolite, produced primarily in the adrenals but to some
extent in brain, 3-hydroxy-5--pregnane-20- one .The
neuroactive steroids act principally by binding directly to
membrane GABAA receptors and enhancing their function in a
manner resembling the barbiturates.

43. GABAA RECEPTORS ARE THE TARGETS OF
MANY CNS EXCITANTS
• Many naturally occurring and synthetic
convulsive agents are blockers of GABA-
mediated inhibition The prototypic GABAA
channel blocker picrotoxinin is isolated from
plants of the moonseed family, known as loco
weed, which causes occasional poisonings in
cows and even in people.
• this drug target appears to be the site of
action of the experimental convulsant
pentylenetetrazol (PTZ) and numerous
polychlorinated hydrocarbon insecticides,
including dieldrin, endosulfan,and lindane

44. Why Alzheimer’s drugs have failed?
With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus
are not fired up like they normally would be when a healthy person is learning
something new or remembering something already learned.