• certain aa's in the CNS bind post-synaptic receptors and act as inhibitory or excitatory neurotransmitters
• inhib/excitatory response is elicited by altering conductance of 1 or more ion-selective channels

• major inhibitory amino acid

• primary excitatory amino acid

• what most current drugs modulate

• widely distributed in CNS
• consists of protein subunits with a central ion channel
• have α,β, γ subunits families
• GABAA _{is targeted by largest # of drugs}

• 5 subunits, surround central Cl- ion pore that opens in presence of GABA
• Different receptor subtypes play distinct roles in specific neural circiuts

• expressed at lower levels than GABA_A 
• mostly in spinal cord
• targeted by only a few agents for spasticity

• affect arousal and attention, memory formation, anxiety, sleep, and muscle tone
• important mech for treatment of focal or widespread neural hyperactivity in epilepsy
• can act at pre- or post-synaptically

occur when the ligand binds to a different site on the receptor to either inhibit or potentiate response

• i.e. benzodiazepines act as + allosteric modulators by binding noncompetitively to ion channels activated by GABA, enhancing the net effect of GABA on channel conductance

• used for sedation, anxiolysis, hypnosis, neuro-protection following stroke or head trauma, control of epilepsy
• Tiagabine (Gabitril), Benzodiazepines, Barbiturates, Baclofen (GABA_B receptor agonist)

decreased activity 

moderates excitment

calms recipient

• produces drowsiness 
• facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electorencephalographic characteristics 
• recipient can be aroused easily from 

• can be benzodiazepines or non benzodiazepines

• All have similar pharm profiles, but differ in selectivity therefore variability among clinical usefulness of BZD agents

• sedation→hypnosis→stupor (as dose ↑)
• do not cause true gen. anesthesia b/c awareness usually persists, and relaxation to allow surgery cannot be achieved
• Used as pre-anesthetic to cause amnesia for events subsequent to admin.(Dose dependent)
• Hypnotic: effect different stages of sleep

cause respiratory depression especially in:

• high doses
• COPD
• if given with other resp. depressants (i.e opioids)

• minor in normal patients
• In diazepam inj, cardio and resp depressant effects may be caused in part by the propylene glycol vehicle present

• hepatic (CYP3A4) metabolized 
• many of their metabolites are pharm active with long t1/2. (cumulative effects with multiple doses)
• 
  

• structurally unrelated to BZD, but share similar mech of action
• more selecitve for α1 subunit of GABA receptor (thus more specific for sedation with fewer other BZD adverse effects: anxiolytic, muscle relaxant, amnesic effects)

Partial:

simple partial

Complex partial

Generalized: 

Absence (petit mal)

Myoclonic

Tonic-clonic (grand mal)

Febrile

Status epilepticus

I) mostly enhance Na+ channel-mediated inhibition

II) mostly inhibit Ca2+ channels

III) enhance GABA mediated inhibition

IV) Mixed actions

AED spectrum of activity

• Broad spectrum (reasonable initial choice)
• Narrow spectrum