Applied Pharmacology of the Nervous and Endocrine System CNS Depressants

Learning Objectives for CNS Depressants

• Identify the different pharmacological strategies that enhance GABAergic synaptic transmission and therefore neuronal inhibition.
• Name drugs that modulate these different aspects of GABAergic synaptic transmission, and describe in detail their mechanisms of action.
• Identify the appropriate clinical indications for these different drugs.

Drugs Targeting GABA Synapses

• Drugs targeting the GABA synapses
• GABAA receptor allosteric modulation
• Benzodiazepines
• Non-benzodiazepine allosteric modulators
• GABAA receptor agonism
• GABAB receptor agonism
• GABA transporter inhibition
• GABA transaminase inhibition

B2 Y2 GABA site BDZ site CI pore 0.1 0.1 GABA site B2 Fig. 20.1 The GABAA receptor. The GABAA receptor is a ligand-gated chloride ion channel and consists of five transmembrane subunits configured from the 19 possible subunits that have been identified; thus many configurations of the GABA receptor exist, which vary in their sensitivity to benzodiazepines. A common configuration comprises two a1, two B2, and one y2 subunit. Binding of GABA to the receptor at the interfaces of the @1 and 2 subunits mediates opening of the CI" channel and an influx of CI" ions, resulting in hyperpolarisation of the cell. This action is enhanced by drugs stimulating allosteric regulatory sites on the GABA receptor, distinct from the GABA-binding site. Diazepam, lorazepam and other 'classic' benzodiazepines (BDZ) bind at the interface of the @1 and Y2 subunits. Compounds such as zolpidem bind with high affinity for the 01-subunits and also enhance CI- ion influx. The intravenous anaesthetics propofol and etomidate bind to ß2- and ß3-subunits (see Chapter 17).

Functions of GABA Neurotransmitter

• GABA functions as an inhibitory neurotransmitter
• ~ 20% of neurons are GABAergic
• Most are short interneurons
• Some long GABAergic tracts (e.g. striatum to substantia nigra and globus pallidus)
• Hyperpolarization of neurons
• Making the membrane potential more negative
• Less likely to fire action potential

GABAergic neuron -presynaptic terminal Glutamine < Glutaminase Glutamate GAD65/67 GABA GABAAR VGAT GABABR Ca2+ channel Glutamine GAT . GAT 1 Glutamate 1 GABABR GABAAR K+ channel CI GABA-T7 Astrocyte Postsynaptic neuron

GABA Receptors Overview

GABAA Receptors

• Ligand-gated ion channel (ionotropic)
• Selectively permeable to CI- ions
• CI- enter the cells: hyperpolarization
• Reduce the neuronal excitability

GABAB Receptors

• G protein-coupled receptors (metabotropic)
• inhibit adenylyl cyclase via Gi/Go
• Reduced production of cAMP
• Open the potassium channel: reduce postsynaptic excitability

b 01 6 -B1-3 8 B GABA Y1-3 Y or 8 δ. ε. θ. π BZs CI- GABA GABAB1 GABAB2 K+ Ca2+ Y Gaijo + B Adhesion molecules Trafficking proteins Inhibition of adenylyl cyclase Interacting proteins B-filamin Actin microfilament

GABAA Receptors Details

• Primarily located postsynaptically
• Fast and tonic postsynaptic inhibition
• Pentamer made up of different subunits
• 19 known subunits now
• α1-6; β1-3; γ1-3; δ; ε; θ; π; ρ1-3
• But you need 5 proteins to form one GABAA receptors
• In general, two a, two ß, one y in a sequence a-B-a-B-Y
• GABA bind at a/ß interface
• Benzodiazepines bind at a/y interface (subunit determine drug sensitivity)

B2 Y2 GABA site BDZ site CI pore 0.1 GABA site B2 b ₾1-6 -₿1-3 B GABA B Y y1-3 or 8 δ. ε. θ. π BZs CI-a5 a1

Pharmacological Effects and Distribution of GABAA Receptor Alpha Subunits

Alpha 1 Beta Gamma 2 Subunit Effects

• Sensorimotor gating
• Cognitive impairment
• Myorelaxation
• Anterograde amnesia
• Anticonvulsant activity
• Premature cortical plasticity
• Sedation
• Addiction

Alpha 2 Beta Gamma 2 Subunit Effects

• Sensorimotor gating
• Anxiolysis
• Decrease thalamic oscillations
• Antihyperalgesia

Alpha 3 Beta Gamma 2 Subunit Effects

• Myorelaxation
• Antidepression
• Antihyperalgesia

Alpha 5 Beta Gamma 2 Subunit Effects

• Cognition in SZ [AU: pls define]
• Myorelaxation

Pharmacological effects and distribution of GABAA receptor a subunits in the mouse brain 7

GABAB Receptors Details

• Located pre- and postsynaptically
• Require second messenger: cAMP
• Dimer: B1 and B2 are seven-transmembrane subunit
• Held together by a coil/coil interaction at C- terminals
• B1: binds to GABA (Venus fly trap)
• B2: interact and activate G protein

GABA GABABR-GABAB2R G protein GABA GABAB1 GABAB2 K+ Ca2+ Go i/o Y B Adhesion molecules Trafficking proteins Transcription factors Inhibition of adenylyl cyclase Interacting proteins B-filamin Actin microfilament

Benzodiazepines (BZDs) Mechanism

• Bind at a/y interface (subunit determine drug sensitivity)
• BZDs have NO agonist activity
• NO direct action on ion flow
• BZDs are positive allosteric modulators
• Binding of BZDs to a/y interface induces a conformational change of GABAA receptors
• Enhance its affinity to GABA

cr GABA GABA Benzodiazepines Flumazenil Extracellular Zolpidem T- Barbiturates Intracellular lon channel 9

Benzodiazepines (BZDs) Subunit Sensitivity and Effects

• Only a1, a2, a3 and a5 are sensitive to BZDs
• a1 and a5 induce sedation and hypnosis (at higher doses) to increase relaxation for improved focus and concentration
• a2 and a3 induce anxiolytic/calming and muscle-relaxant effects
• a1, a2, a3 and a5 subunits exhibit anticonvulsant activity (suppress the excessive rapid firing of neurons during seizures)
• NO subunit-specific BDZs: unwanted side effects
• a4 and a6 are insensitive to BDZs

cr GABA GABA Benzodiazepines Flumazenil Extracellular Zolpidem T- Barbiturates Intracellular lon channel 10

Subunit Selectivity of Various BDZs

Table 45.2 GABAA-receptor a-subunit selectivity of some therapeutically used benzodiazepines Drug Subunit selectivity Diazepam α1, 2, 3, 4, α5, α6 Flunitrazepam α1, 2, 5 Midazolam α1, 2, 3, 4, α5, α6 Zolpidem α1 Flumazenil Antagonist at x1, x2, x3, a4, a5, a6 (Adapted from Tan, K.R., Rudolph, U., Lüscher, C., 2011. Hooked on benzodiazepines: GABAA-receptor subtypes and addiction. Trends Neurosci. 34, 188-197.) 11

BZD - Diazepam

• Fast-acting (quick absorption and redistribution), long- lasting (long half-life) BZDs
• Used to treat:
• Muscle spasm (sudden, involuntary movement in muscles)
• Convulsions (status epilepticus/acute recurrent seizures, febrile seizures caused by fever in child, convulsions due to poisoning)
• Anxiety (severe acute anxiety, control of acute panic attacks)
• Symptomatic relief of alcohol withdrawal (agitation, tremor, alcoholic hallucinosis, and acute delirium tremens)

Diazepam Tablets B.P. 10mg 50 x 10 Tablets Diazepam Tablets B.P. 10mg 12

BZD - Lorazepam

• Fast-acting (1-3 min), short-lived BZDs
• Used to treat:
• Short-term (4 months) relief of anxiety symptoms
• Short-term use for anxiety-associated insomnia
• Anaesthesia premedication in adults to relieve anxiety or to produce sedation
• Convulsions (status epilepticus, febrile seizures, convulsions due to poisoning)

SPO-LORAZEPAM 85946 REFILLS:3 ATO 1 TABLETS AILY AS NEEDED 8654 13

BZD - Midazolam

• Fast-acting (water soluble), ultrashort-lived BZDs
• Used to treat:
• Convulsions (status epilepticus, febrile seizures, convulsions in palliative care)
• Sedation (conscious sedation for procedures, sedative in combined anaesthesia, sedation of patient receiving intensive care)
• Adjunct to antipsychotic for confusion and restlessness in palliative care

Midazolam 1 mg/ml Solution for Injection 5 mg in 5 ml 5 mg in 5 ml ON 10 m Each 5 ml ampoule contains 5 mg of midazolam For intravenous, intramuscular and rectal use CON HOURS EXP: hameln 14

BZD - Clonazepam

• Fast-acting, long-lived BZDs
• Used to treat:
• broad spectrum of epilepsy (acute management of epilepsy and acute treatment of non- convulsive status epilepticus)
• Short-term management of panic disorders
• Acute treatment of panic attacks

Rivotril 2 mg Tabletten 0 Clonazepam 2 mg Rivotril® 2 mg Tabletten Clonazepam 2 mg 000 100 Tabletten 100 Tabletten N2 Roche 15

BZD - Alprazolam

• Fast-acting, medium-lived BZDs
• Used to treat:
• Short-term use for treating anxiety
• Panic disorders with or without agoraphobia (a fear of being in situations where escape might be difficult)

Lifecare Neuro Psychiatric PRAZIL-0.5 NR Alprazolam Tablets I.P. 0.5 mg PRAZIL-0.5 प्राज़िल-0.5 Lifecare 5 X 6 X 10 Tablets 16SITYOF 1OUTH

Characteristics of Benzodiazepines in Humans

Table 45.1 Characteristics of benzodiazepines in humans Drug(s) Half-life of parent compound (h) Active metabolite Half-life of metabolite (h) Overall duration of action Main use(s) Midazolamª 2-4 Hydroxylated derivative 2 Ultrashort (<6 h) Hypnotic Midazolam used as intravenous anaesthetic and anticonvulsant Zolpidemb 2 No - Ultrashort (~4 h) Hypnotic Lorazepam, oxazepam, temazepam, 8-12 No - Short (12-18 h) Anxiolytic, hypnotic. Lorazepam used as anticonvulsant lormetazepam Alprazolam 6-12 Hydroxylated derivative 6 Medium (24 h) Anxiolytic, antidepressant Nitrazepam 16-40 No - Medium Anxiolytic, hypnotic® Diazepam, chlordiazepoxide 20-40 Nordazepam 60 Long (24-48 h) Diazepam used as anticonvulsant Flurazepam 1 Desmethyl- flurazepam 60 Long Anxiolytic, hypnotic® Clonazepam 50 No Long Anticonvulsant, anxiolytic (especially mania) ªAnother short-acting benzodiazepine, triazolam, has been withdrawn from use in the United Kingdom on account of side effects. "Zolpidem is not a benzodiazepine but acts in a similar manner. Zopiclone and zaleplon are similar. "Due to their long half-life, drowsiness is common on waking. 17 Anxiolytic, muscle relaxant

Side Effects of BZDs (Short-Term)

• Drowsiness - avoid driving or operating machinery
• Confusion, especially in the elderly
• Amnesia - memory impairment
• Ataxia and muscle weakness
• Potentiation of sedative effects of other CNS depressants - severe depression of respiratory and cardiovascular centres in the brainstem (fatal)
• Paradoxical increase in aggression - suppress cortical inhibition of limbic areas of the brain that normally modulate social behaviour or conventions