sleep, GABA, Benzos

Ion Gradients and excitability

Net excitation/ inhibition determined by receptor characteristics

Ion conductance directly influences cell excitability

- Cation permeability increases probability of cell firing > more excitable

- Anion permeability decreases probability of cell firing characteristics > less excitable

Brain Excitation/Inhibition Balance (GABA)

Controlled balance between excitation and inhibition

Too much net excitation = anxiety, hyperexcitability, epilepsy, convulsions (death)

Too much net inhibition = sedation, depression, anaesthesia, coma (death)

Ion Gradients and excitability

Net excitation/ inhibition determined by receptor characteristics

Ion conductance directly influences cell excitability

- Cation permeability increases probability of cell firing > more excitable

- Anion permeability decreases probability of cell firing characteristics > less excitable

Brain Excitation/Inhibition Balance (GABA)

Controlled balance between excitation and inhibition

Too much net excitation = anxiety, hyperexcitability, epilepsy, convulsions (death)

Too much net inhibition = sedation, depression, anaesthesia, coma (death)

Major brain neurotransmitters (2)

Glutamic acid (glutamate): excitatory

GABA (gamma- amino butyric acid): inhibitory

Synaptic Transmission

Electrochemical

1) Na+ entry through VGSC increases membrane potential from resting (-70mV) to threshold potential - generates action potential

2) Spatial and temporal summation leads to terminal depolarisation (-55mV)

GABA Features

Non-protein amino acid, high concentration in mammalian CNS

All CNS neurons have GABA receptors, 40% CNS neutrons release GABA

GABA Transmission

Important for: memory, sleep, mood, stress responses, analgesia, CV function, neuroendocrine function, control of food intake

Disrupted in:

- Epilepsy, schizophrenia, mood disorders, anxiety, migraines, memory disorders, sleep disorders, stress responses

GABAergic Drug Use

Anticonvulsants, anxiolytics, muscle relaxants, sedatives, hypnotics, analgesics, general anaesthetics

GABA Storage

1. Active transport intosynaptic terminals in vesicles(~1.1M) via vesicular GABA transporters (VGAT)

2. VGAT store GABA into the terminals and stored as bound complex with ATP, protein Ca2+, Mg2+ to prevent GABA leakage from vesicles into the cytoplasm

- Active process driven by H+ and electrical gradient across vesicular membrane

No known selective inhibitor of GABA storage in vesicles.

GABA Synthesis

From glutamate by decarboxylation catalysed by Glutamate decarboxylate (GAD).

GAD inhibitors:3- mercaptopropionic acid, allylglycine (examples only not used therapeutically because they are convulsants). If taken would reduce GABA levels.

Multiple pathways because GABA very important:

1. In neuronal and glial cells:

(Glucose -> pyruvate -> acetyl-coA -> citric acid) kerb cycle

-> alpha-ketoglutarate -> glutamate -> GABA

- Essentially, kerb cycle produces citric acid, GABA shunt can occur here, to make alpha-ketoglutarate, then glutamate and GABA

2. In neuronal cells only:

glutamine -> glutamate -> GABA

GABA also found to have metabolic function (isoforms 67 not found at nerve terminals but instead in the body, making the GABA shunt), not just CNS function (iso form 65 found at nerve terminals to rapidly make GABA and release into the synapses)

Drugs that can block GABA release

TETANUS TOXIN

- convulsant

- blocks GABA release from presynaptic terminals following depolarisation.

- Also blocks glycine release (important transmitter in spinal cord)

- causes spastic paralysis

GABA Receptors (3)

GABAa/c: ligand gated ion channels/ ionotropic, conduct ions

- inhibitory

GABAb: metabotropic/ G-protein coupled receptors

- inhibitory

- gate K efflux, reducing excitability

- inhibit Ca influx

- down stream effects

Ionotropic GABA receptors (a and c)

GABAa and GABAc

Class:

- Ligand gated ion channels (LGIC)

- Cys loop or nicotinicoid superfamily LGICs (also includes nAChR, 5-HT3, glycine receptors)

The conducting (gating) of anions or cations dependent on amino acid residues lining the channel pore

Actions

GABA binds to 2 allosteric sites > conformation change > allows Cl- through ion channel > reduces membrane excitability

Structure:

Subunits arranged around central pore (ion channel)

GABAa: Heterooligomeric, 15 subunits

- Mostly made of 2⍺, 2β, 1 Ɣ subunits

- Fast onset, rapid densensitisation

GABAc: Homooligomeric, subunits

- 3 subunits, most receptors made of 1 subunit type

- Slow onset, little densensitisation

- More potent (lower EC50)

Agonists

- GABAa: GABA muscimol

- GABAc: GABA, CACA muscimol. CACA is what differs GABAc from GABAa

Antagonists

GABAa: Bicuculline, SR-95531

GABAc: TPMPA

Metabotropic GABA receptors (GABAb)

Class:

G protein coupled 2nd messengers

- Gi: Activate K+ efflux channels (postsynaptic inhibition)

- G0: Inhibit Ca2+ influx (presynaptic inhibition)

Actions

Overall reduces membrane excitability

Can modulate release of glutamate and NA in CNS

Structure:

Heterooligomeric: Heterodimer, 2 subunits:

- GABAB1 and GABAB2

- Hetero-oligomeric, formed from subunit dimers

Agonists: Baclofen (tx for spinal spasticity)

Antagonists: Phaclofen

- The structure that determines agonism vs antagonism lies in the COOH group (GABA lec 49:30)

GABA Reuptake

Active transport into neurons via high affinity Na+ dependent membrane transporter protein

Main mechanism for terminating GABA synaptic action

↓ GABA uptake = ↑ GABA-mediated inhibition

e.g. Nipecotic acid (anticonvulsant development), arecaidine (in Betel nut)

GABA Metabolism

Converted to succinate via GABA-T and SD in mitochondria

- broken down to succinic acid

- multiple mechanisms to breakdown GABA

- Too long pls refer to Eve's notes not important imo

GABA shunt: Metabolic pathway α-ketoglutarate - glutamate - GABA - succinate

- Bypasses part of normal TCA (Krebs) cycle in brain

- 30% of TCA cycle turnover in brain is via GABA shunt

GABA metabolism inhibitor - ↑ brain GABA up to 10-fold, anticonvulsants

e.g. sodium valproate inhibits succinic semialdehyde dehydrogenase, vigabatrin inhibits GABA-T

What is the role of Orexin (OR/hypocretin) in sleep and wakefulness?

Regulates wakefulness, arousal, and appetite.

What are the wake promoting neurochemical systems?

AcCh, NE, Hist, 5-HT, DA, OR.

What are the sleep promoting neurochemical systems?

GABA, Galanin, Adenosine, PGD2, Cytokines.

What is the sleep-wake model proposed by Von Economo?

A flip-flop switch regulating sleep-wake, with mutual inhibition of sleep and wake promoting regions.

Mutual inhibition of sleep and wake promoting regions - when one region becomes active, it simultaneously inhibits the other, ensuring that only one state predominates at any given time.

What are the treatments to enhance sleep?

1) Enhance VLPO activity

2) Suppress activity of ascending arousal system

3) Enhance circadian drive to sleep

4) Work on endocannabinoid system.

BDZ (AE, interactions, problems, precautions/safety)

AE:

- Headache, dizziness, dry mouth, tiredness, leg cramps, weakness, amnesia, excitation, blurred vision, malaise, weakness, disorientation

- Tolerance, Dependence

- Hangover sedation

- Fall/fracture risk: higher when used with interacting drug, dose and duration of treatment dependent

INTERACTIONS: CYP3A4, alcohol

PROBLEMS:

- Dependence: Prolonged use > cravings, tolerance, physical withdrawal on abrupt stopping (insomnia, anxiety, convulsions)

- Amnesia

- Somnambulance (sleep walking)

- Bizarre sleep behaviours

- Concurrent use with ethanol or opioids > dangerous or lethal

- In old people, due to cause of dizziness, change the gait in people, making them sway more than they would, additionally to hangover sedation -> fall risk

PRECAUTIONS/SAFETY

- Myasthenia gravis

- Memory impairment

- Dose reduction in elderly, renal/hepatic impairment (highly protein bound)

- Ensure pt has opportunity to sleep through the night for 7-8 hours

Addiction/ tolerance of BDZ

GABA work on alpha 1 -> increase GABA levels -> DA release regulated

BDZ potentiates inhibitory action -> inhibit action of GABA (inhibiting the inhibitor)-> no regulation of DA -> more DA release

Z drugs for sleep

Zolpidem and Zopiclone (AUS), Zaleplon, Eszopiclone, Indiplon

Non-Benzodiazepine BDZ receptor modulators that work through GABAa receptors.

MOA: bind to receptors containing α1 subunit and have a potent effect when bound to α2,α3 receptors.

Use as prn, same effect on sleep architecture + AE profile as BDZ. Limit use to 4 wks max under medical supervision

AE: headache, dizziness, nausea, diarrhoea, anxiety, amnesia, parasthesia, nightmares

Safety: no alcohol, caution with other CNS depression drugs

TGA for zolpidem

Requirement to place boxed warning at start of approved CMI/PI

Gender affects in dose (zolpidem)

Pack sizes limited to 14 (10 mg)

May be associated with potentially dangerous complex sleep-related behaviours which may include sleep walking, sleep driving and other bizarre behaviours.

What are some other GABAergic drugs used off-label for sleep?

Tiagabine (GABA reuptake inhibitor)

- Increases sleep continuity and slow-wave sleep (SWS) in older people and cocaine users.

- 8 mg dose best

Gabapentin, and Pregabalin (structural GABA analogs)

- target and reduce transmission of Substance P, NE, 5HT, DA. Useful in pain related sleep loss

- 450 mg d (tid) best

What are the sleep and wake promoting effects of 5-HT?

Wake promoting:

- 5HT-1a,b

- 5HT-2a,c

- agonists enhances ACh and DA release, increasing wakefulness.

- blockage of these enhances sleep

Sleep promoting:

- 5-HT2 b agonist

- blockage inhibits sleep

If looking for sedation, 5-HT1a,b antagonist, 5-HT2a,c antagonist and 5-HT2b agonist

Role of antidepressants in sleep

Important to treat comorbid sleep disorders and depression: address both conditions and improve overall well-being.

SSRI: cause fragmented sleep, suppressed REM sleep, insomnia in 10-20% of patients. Hence take mane to avoid side effects

TCA:

-Inhibit NA and 5-HT presynaptic reuptake, block various receptors.

- Doxepin approved in US for insomnia: 3-6mg

- Cardiotoxic effects in the elderly and others, anticholinergic effects, t-wave changes, sedative effects may decrease.

MAOIs:

- Increase DA, NA, 5HT -> insomnia risk

Mirtazapine:

- Blocks postsynaptic 5HT2 and 5HT3 receptors, inhibits central a2-adrenergic autoreceptors.

- AE: Orthostatic hypotension, seizures, mania, suicidal thoughts, nightmares.

Off label use for sleep:

- Amitriptyline, doxepin, and mirtazapine, agomelatine

- Quetiapine (use of this for sleep in frowned upon in Antipsychotic lecture)

Antihistamine for sleep

examples: doxylamine, promethazine, diphenhydramine, trimeprazine

MOA: block histamine (mediates wakefulness) -> mediate sleep

Clinical use:

- Extremely poor evidence

- Tolerance develops very quickly, even in 3-4 days (e.g. for diphenhydramine) - <10 days

>2 years old (SIDS)

AE: anticholinergic, daytime sedation, psychomotor impairment

Caution in elderly people, epilepsy (some lower seizure threshold)

Dual Orexin receptor antagonists (DORA) for sleep

Suvorexant, lemborexant, almorexant (discontinued because of SE)

MOA: Dual orexin receptor antagonist (OX1 and OX2) (DORA) - blocks action of orexin

↓ SOL, ↑REM, ↑TST, ↓WASO

TGA approved for insomnia, non-pbs so expensive

Dose:

- Assess after 7-10 days and re-evlaute use in 3 months

- Lower dose in elderly (15 mg suvorexant/5 mg lemborexant)

- Take on empty stomach for quicker effect (7h before planed waking), avoid driving 9h after

AE:

- Sleepiness (next day), headache

- Rarer: abnormal dreams, fatigue, dizziness, sleep paralysis, hallucinations during sleep (hypnogogic/hypnopompic), suicidal ideation

Safety:

- DDI CYP3A4 inhibitors, alcohol

- Avoid in severe hepatic impairment

What are the functions regulated by orexin receptors?

Appetite, stress response, respiratory effects, addiction, analgesia, food intake regulation, glucose metabolism regulation, energy balance regulation

What are the melatonergic drugs?

Melatonin, CBD, Ramelteon, Agomelatine

What are MT1, MT2, and MT3 receptors of the melatoninergic system?

Receptors involved in the modulation of GABA receptors.

Melatonin for sleep

MOA: MT1 and MT2 receptor agonist

↓ SOL, subjective ↑ sleep quality

Attenuates wake-promoting drive through circadian system, promoting sleep .

Low melatonin drive in elderly, CRDs, β-Bs, NSAIDs

Dose: 2mg 1-2h bb for 13 wks

2-18: slenyto 2mg n 30-60mins bb for 3 wks, increase prn to 5mg, max 10mg

- May be more impactful in > 55 yrs

Good AE profile

It is a better chronobiotic than a sedative.

What drugs can affect sleep?

Beta blockers, opioids, short and long-acting beta agonists, inhaled/oral corticosteroids, SSRIs, ACE inhibitors, statins.

What are some herbal treatments for sleep?

Valerian, passionflower extract, chamomile tea.

Sedation

Reduced excitement, vigilance, and physiological arousal

Hypnosis

ability to induce drowsiness and sleep

Sedatives and hypnotics (drugs)

Reduces time taken to get to sleep

Increases duration of sleep

BDZ, Barbiturates, Melatonin agonists, Sedative antihistamines

Anxiolysis

Reduced anxiety - measured by:

• Elevated Plus Maze and other paradigms

• Physiological responses

• Psychological measurements

Anxiolytics (drugs)

BDZs

Antidepressants

5-HT1A partial agonists

Benzodiazepines MOA

Positive allosteric modulators of GABAA receptors > ↑ inhibitory effects of GABA on neurons = neurons less excitable = ↓ neuronal activity

Selectively binds to GABAA receptors containing γ2L + α1/α2/α3/α5

↑ Cl- ion channel opening = ↑ Cl- conductance = neuron hyperpolarization = less likely to generate APs = ↓ neuronal excitability

α1 > sedative/hypnotic, anticonvulsant

α2, a3 - anxiolytic

α3, a5 - myorelaxant

α5 - myorelaxant, learning/memory

Occupancy vs Rate Mechanisms of Action

Occupancy mechanism (barbiturate, ethanol) = ↑ opening time of channel

Rate mechanism (BDZ) = ↑ rate of channel opening

BDZ Discontinuation

Gradual taper vs abrupt withdrawal, taper alone, taper + CBT

Reduce slowly by 25-50% of daily dose each week-month

Adjust according to response

- Conversion to long-acting not required if patient taking short-acting

- No withdrawal symptoms - continue to wean and stop

o Consider slower weaning (12.5%) when reducing to final lowest dose

o End tx 2 weeks after administering lowest dose

o Consider alternate day dosing if dosage forms are limited

If recurrent/withdrawal sx: revert to previous tolerated lowest dose, recommedce 5-12.5% weaning each month then stop

BDZ for anxiety vs sleep

INSOMNIA: nitrazepam, temazepam, diazepam Drugs of choice

- Drugs with 6-12h t1/2 is preferred (temazepam, oxazepam), but not too short to avoid rebound (<6h)

- Short term use, max 1 month including tapering off

ANXIETY

- as short as possible

- no longer than 2-3 months including tapering off

Non-Sedative and Non-Hypnotic Anxiolytics

Buspirone - 5-HT1A partial agonist

o No memory impairment or dependence

o Delayed therapeutic effect

o Not for panic or severe anxiety

Antidepressants - eg: SSRIs

o Long term maintenance, eg: GAD, PTSD, OCD, social phobia

o No memory impairment or dependence

o Some patients "treatment resistant"