Topic 3: BENZODIAZEPINES

Question 1

GABAa receptor

Answer 1

1.ligand-gated ion channel
2.pharmacological target: sedatives & hypnotics
3.
MUSCIMOL: AGONIST at the GABA-binding site
BICUCULLINE:ANTAGONIST at the GABA-binding site
PICROTOXIN:blocks the channel directly
BENZODIAZEPINES, BARBITURATES: positive allosteric modulators.

Question 2

MUSCIMOL

Answer 2

•AGONIST OF GABA-binding site

act on GABAa receptor

Question 3

BICUCULLINE

Answer 3

•ANTAGONIST OF GABA-BINDING SITE

Question 4

PICROTOXIN

Answer 4

• Blocks the channel directly( the GABAa receptor which its ligand-gated ion channel)

Question 5

BENZODIAZEPINES(BZD) & BARBITURATES

Answer 5

• Positive allosteric modulators
→Have an effect on the receptor by binding at different site on the protein.
→able to enhance the binding affinity of the ligand , and thus able to increases the activity of the GABAa receptor

Question 6

Actions of positive modulation of GABAergic neurotransmission( increasing doses)

Answer 6

•ANXYOLITIC: (reduce anxiety without influencing motor and mental function)
→lowest dose
→(not fully distinguishable from sedation)
•HYPNOTIC:(resembles the natural state of sleep , induce drowsiness)
→moderate dose
•GENERAL ANESTHESIA:
→higher dose
•COMA, DEATH:
→toxic dose

Question 7

Additive synergism of GABAergic neurotransmission

Answer 7

→with sedatives , ethanol

Question 8

Additional actions of GABAergic sedative hypnotics

Answer 8

• Antiepileptic actions
• Skeletal muscle relaxant action
• Amnesia

Question 9

Anxiety

Answer 9

•disorders involving anxiety are the most common mental disorders
•unpleasant state of tension, apprehension (=anxiety or fear that something bad it will occur)or uneasiness
•physical symptoms involving the SY system activation
→tachycardia
→sweating
→trembling
→palpitations
•some of them may cause some sedation, due to that they used as HYPNOTIC AGENT also

Question 10

Benzodiazepines

Answer 10

•most frequent used SEDATIVE-HYPNOTICS
•replace BARBITURATES and MEPROBAMATE in the treatment of anxiety and insomnia .
(act as a positive allosteric modulator for GABAa receptor)

Question 11

Mechanism of action of GABAergic neurotransmission

Answer 11

•benzodiazepine or omega receptor: binding site at the GABAa receptor(γ-aminobutyric acid)
•compose of 5 subunits(2α, 2β,1γ) , able to span the postsynaptic membrane.
•Benzodiazepines(BZD=drug) able to bind to a site other than the GABA-binding site , at the interface of the α-γ subunit
→subtypes: BZD1(α1-subunit) and BZD2(α2-subunit)

Question 12

Action of BZD

Answer 12

•positive allosteric modulators of GABAa receptor
•BZD(bind to BZD binding site)–>promote the GABA to bind to GABA-binding site–>opening of ion channel–>Cl- ions pass through the pore
•the influx of Cl- ions causes hyperpolarization of the neutron and decreases the neurotransmission , by inhibiting the formation of Action potential.
•BZD: do not substitute GABA but able to enhance the effect of GABA without directly activating the GABA receptors or opening the associate Cl- ion channels .
→able to to potentiate the GABAergic inhibition by increasing the frequency of Cl- ion channels open!

Question 13

BZD receptor ligands

Answer 13

•Agonist:
   →positive allosteric modulators
   →e.g DIAZEPAM
   →cause : an allosteric change in the structure of GABA receptor-Cl channel complex that promote the GABA binding at its own receptor-->increase the frequency of chloride channels that remains open.
  →Anxiolytic  effect
  →Sedative effect
  →Hypnotic effect

•Antagonist:
→neutral allosteric modulator
→e.g FLUMAZENIL
→occupies the BZD receptor and inhibits the agonist to bind to it

•Inverse agonist:
→ e.g β-CARBOLINES
→negative allosteric modulators –>inhibit GABA binding at its own receptor
cause: seizures , anxiety

Question 14

Pharmacological actions of BZD

Answer 14

(we have different kind of BZD (receptor agonists) are more or less the same but may have different pharmacokinetics)
•anxiolytic
•hypnotic : able to increase the non-rapid-eye-movement 2(nREM2) and decrease REM , nREM3, nREM4
•no complete general anesthesia
•anterograde amnesia
→temporary impairment of memory
→impair ability to learn and form new memories
•antiepileptics
•sk. muscle relaxants(centrally mediated)
•anticonvulsant

Question 15

anxiolytics (sedatives)

Answer 15

• CHLORDIAZEPOXIDE
• OXAZEPAM
• CLONAZEPAM
• ALPRAZOLAM
• MEDAZEPAM
• CLORAZEPATE
• HALAZEPAM
• PRAZEPAM
• LORAZEPAM

Question 16

Hypnotics

Answer 16

• NITRAZEPAM
• FLUNITRAZEPAM
• MIDAZOLAM
• FLURAZEPAM
• TRIAZOLAM
• BROTIZOLAM
• ESTAZOLAM
• LORAZEPAM
• QUAZEPAM
• TEMAZEPAM
• LORMETAZEPAM

Question 17

panic attacks and mental depression

Answer 17

• ALPRAZOLAM

* CLONAZEPAM

Question 18

Centrally acting skeletal muscle relaxants

Answer 18

•DIAZEPAM

Question 19

Antiepileptics

Answer 19

• DIAZEPAM
• LORAZEPAM(status epilepticus)
• CLONAZEPAM(absence seizures)

Question 20

premedication before general anaesthesia

Answer 20

•DIAZEPAM

Question 21

for induction of general anaesthesia , part TIVA (=total intravenous anaesthesia)

Answer 21

•MIDAZOLAM