Psych Exam 2 CNS Depressants (Sartor)

what arethe 3 classes of CNS depressants

sedatives, hypnotics, and tranquilizers/anxiolytics

sedative CNS depressants

o reduces activity and excitement, calms the recipient

§ For hyper-excited/manic

hypnotic CNS depressants

o produce drowsiness and facilitates the onset and maintenance of sleep

tranquilizer/anxiolytic CNS depressants

o reduce anxiety without drowsiness

indications of CNS depressants

o Anxiety-related disorders

o Insomnia

o OCD

o Seizures/convulsions

o Alcohol withdrawal

GABA function

-inhibitory (breaks)

-causes hyperpolarization of neurons

glutamate function

-excitatory (gas)

- cuases depolarization of neurons

sedative hypnotic subclasses

-benzos

-barbiturates

- misc (busprione, chloral hydrate, z drugs, ramelteon)

barbiturates original uses

· as sedatives, hypnotics, anesthetics, and anticonvulsants

which barbiturate is still used as an anesthetic

phenobarbital

ultra-short barbiturates (onset + duration)

§ Onset <1 min; duration a few mins

which barbiturates are ultra-short acting

methohexital and thiopental

methohexital brand name

brevital

thiopental brand name

pentothal

short barbiturate duration

~2 hours

intermediate barbiturate duration

~3-6 hours

which barbiturates are intermediate-acting?

amobarbital and pentobarbital

amobarbital brand name

amytal

pentobarbital brand name

newbutal

long-acting barbiturate duration

~6 hours

which barbiturates are long-acting

phenobarbital (luminal)

phenobarbital brand name

luminal

effects of barbiturates on sleep

o Shorten sleep latency (fall asleep quicker)

o Increase in total sleep

o Often decrease in waking time during the night

o REM suppression

o Reduce neurogenic respiratory drive

barbiturate overdose

· : highly toxic in acute overdose

o Ten times the therapeutic dose may lead to fatal respiratory or CV depression

o Effect increased when combined with alcohol or other CNS depressants

o Coma and death from respiratory depression

o More common in elderly

misuse of barbiturates

o Relaxed contentment and euphoria- short/intermediate group generally preferred

o Can induce tolerance- need more drug to get effects the more you use it

o Physiological dependence

barbiturate withdrawal symptoms

insomnia, agitation, irritability, hyperthermia, risk of seizures

steps of lethal injection and what they do

o Barbital (thiopental or pentobarbital) causes sedation

o Followed by muscle relaxant (pancuronium bromide) which causes muscle paralysis and respiratory arrest

o Followed by KCl which stops the heart

barbiturates vs benzodiazepines

· At increasing doses, both can cause sedation, hypnosis

· At higher doses benzos peak in effect until they reach very very high doses

· On the other hand, higher doses of barbiturates can cause anesthesia and depression of medulla respiratory centers/coma

effect of barbirturates on GABA

· Enhance GABA receptor activity acting as a positive allosteric modulator (bind to BABA-A receptor which decreases the rate of dissociation of GABA and increases the duration of GABA Cl channel opening)

· The longer it’s open, the more hyperpolarizing occurs/ inhibition

· Can be GABA receptor agonist at high doses

what areas do barbiturates affect other than GABA?

o Potentiate glycine (inhibitory NT)

o Inhibit glutamate receptor (excitatory NT)

· May also have non-specific membrane effects

net result of barbiturates

reduction in neuronal activity

structure of GABA-A receptor

-5 subunits (2 alpha, 2 beta, 1 gamma)

-Cl- channel pore in the middle

-multiple allosteric binding sites

where does GABA bind on GABA-A receptor

binds between alpha and beta

where do barbiturates bind on GABA-A receptor

binds on alpha or beta

where do benzodiazepines bind on GABA-A receptor

bind between alpha and gamma

GABA receptor subunit subtypes

· Different assemblies of 16 subunits although there may be 1 million possible

· Alpha, beta, gamma, sigma, epsilon, pi, theta

role of GABA receptor's alpha subunit

critical for affinity of GABA and for benzodiazepine effects

role of alpha 1 subunit on GABA-R

important for hypnotic effects

may cause anticonvulsant effects

Z drug affinity on GABA-R

have higher affinity for alpha 1 subunit

role of alpha 2 subunit on GABA-R

highly expressed in the limbic system

important for anti-anxiety effects

what type of receptor is the GABA-B receptor?

is a Gi GPCR

2 subunits of GABA-B receptor

beta 1 and 2

MOA of GABA on GABA-B receptors

· GABA binds to B1 and the B2 binds to the subunit proteins

· Inhibits activity by opening K channels (more hyperpol) and closing Ca channels (stop depol)

chloral hydrate

o Sedative and hypnotic

o 1st CNS depressant develop for inducing sleep

o Not FDA approved

o Replaced by Z drugs

paraaldehyde

o Relatively safe hypnotic

o Used in psych wards and people with AUD until the 60's

o 30% of dose is excreted through the lungs which causes halitosis (bad breath)

o Anticonvulsant (doesn't suppress breathing at therapeutic doses)

bromides

o older sedative-hypnotic

o NaBr, KBr

o KBr still used in veterinary practice as anticonvulsant

o NaBr no longer used due to toxicity

o Bromides mimic the activity of Cl- but larger so hyperpolarizes for longer

methaqualone (Qualude)

o GABA receptor agonist

o Marketed as a safe, non addicting barbiturate substitute

o Became schedule I in 1984

o OD symptoms: delirium, coma, restlessness, hyperreflexia, convulsions, tachycardia, cardiac and respiratory depression

Z drug indication

for insomnia

Z drug vs BZDs

Z drugs aren't benzodiazepines and tend to have fewer side effects in comparison

which CNS depressants are antihistamines

diphenhydramine, doxylamine, pyrilamine

what type of drug are antihistamines (what do they do at which receptors?)

H1 receptor antagonist

antichoolinergic side effects of antihistamines

§ Cant see, pee, spit, or poop

§ Long-term associated with dementia

herbal/natural products that are CNS depressants

o Valerian

§ May decrease GABA metabolism and binds to GABA

o Passion flower

§ Tea may contain GABA

o Lemon balm/hops

o Tryptophan

propofol indication

injection for anesthesia

onset (IV) if propofol

~30 secs

-short half life of 3 mins so must be used as an infusion for longer sedative periods

what does propofol do at which receptor

GABA-A receptor enhancement

xyalazine (what does it do at which receptor?)

NE alpha-2 agonist ( decrease in NE releases)

xylazine use

o Not approved for humans

o Used to cut drugs of abuse which can cause many side effects

o "Tranq" is its nickname

gamma-hydroxy butyrate (GHB), what is it and what does it do at whcih receptor

o Endogenous NT, precursor to GABA, glutamate and glycine

o GHB receptor agonist, weak GABA-B agonist

effects of GHB on a patient

o Produces dreamy/euphoric effect, relaxation

§ Onset ~15 min, duration 3-4 hours

§ Rapidly metabolized (depleted in 12- 24 hours)

§ Can produce coma, respiratory failure

§ Also dance club drug, date rape drug, abuse by body builders (can acutely elevate GH)

sodium oxybate brand name

xyrem

sodium oxybate (Xyrem) indication

treat narcolepsy and excessive daytime sleepiness

what receptor does Xyrem interact with

GABA-B and GHB receptor action

functions of the limbic system

· controls emotion and emotional responses

o Fear + rage

o Mood

o Motivation

o Pain + pleasure

o Memory (especially with strong emotional component)

o Fight or flight (autonomic regulation)

hippocampus function

long-term memory, spatial navigation, contextual information

cingulate gyrus function

· autonomic functions as well as cognitive and attentional processing

amygdala function

· involved in aggression, fear, reward

o “salience” – significant information that stands out

fornix function

· white matter connection between hippocampus and hypothalamus

hypothalamus function

· homeostasis, link CNS to endocrine system, feeding, sleep, motivation

thalamus function

· relaying sensory info, consciousness, sleep, and alertness

fear

an emotional reaction to a specific, real danger

stress

caused by an external trigger, short-term

anxiety

persistent, excessive worries that don't go away even in the absence of a stressor

what is the main brain region for anxiety and fear

the amygdala

amygdala and anxiety

o Lesion of amygdala produces docile animals

o Coordinates autonomic threat response

o Integrates sensory info and prior learning (association of a queue with a stressor)

o May regulate hormonal response to threat

o Fast response but not necessarily accurate

cortex and anxiety

· recognition and cognitive appraisal of threat

Slow and thought out

amygdala other functions

· supports skills necessary for a complex social life

o Involved in interpersonal functions like interpreting facial expressions, reacting to visual threats and trusting strangers

o The larger social network a person has the larger their amygdala

general adaptation syndrome, what is it?

· Hans Selye proposed a paradox that physiologic symptoms activated by stress can not only protect and restore but also damage the body

stages of general adaptation syndrome

o Alarm: your body reacts to a stress, activates the hypothalamic pituitary adrenal axis (HPA)

o Resistance: parasympathetic branch of the ANS counteracts the changes that the stressful stimulus has produced, and attempts to restore a state of homeostasis

o Exhaustion: the body’s resources have been depleted

§ Chronic stress

· HTN

· MI

· Depression

· Sleep disturbances

· Decreased metabolism

· Migraines

· Decrease serotonin

steps of the stress response system

1. Hypothalamus releases CRH (corticotropin-releasing hormone)

2. CRH interacts with the pituitary gland which then releases ACTH (adrenocorticotropic hormone)

3. ACTH interacts with the adrenal gland to produce cortisol

4. The hypothalamus responds to the cortisol

working model of anxiety

· Prefrontal cortex uses reason and thought to process incoming info

· Limbic system (amygdala especially) registers threats and dangers and induces reflexive fear responses

· In anxiety, inhibitory inputs from cortex may be disrupted resulting in unchecked amygdala activity

anti-anxiety drugs

· Alcohol

· Barbiturates

· Benzos

· Buspirone

· SSRIs/SNRIs

· Antihistamines

· Beta-blockers

what action do BZDs have?

GABA-A receptor modulation

effects of low to moderate does of BZDs

· relaxation, relief from anxiety and tension, promote sleep, muscle relaxation, epilepsy

effects of high doses of BZDs

can cause respiratory depression

binding of benzos vs barbiturates

· Barbiturates at low concs- augment the affinity of the GABAA receptor for GABA and increase the mean channel opening time induced by GABA (similar to benzos)

· At high barb doses- barbiturates directly increase channel openings, even in the absence of GABA

· benzos have no direct effect on channel opening but only increase the affinity of the receptor for GABA and frequency of channel openings

· gamma subunit is not needed for barbiturate activity

neurosteroids, what action do they have for anxiety?

· endogenous positive allosteric modulators of GABA-A receptor

· changes in neurosteroid levels are associated with conditions like stress, depression, pregnancy, neural development , aging

· different GABA R subtypes have different sensitivity

natural products for anxiety

picamillon

diet

L-theanine

picamillon and anxiety

GABA bonded to niacin so it can travel across the BBB

diet and anxiety

complex carbs increase glutamine

L-theanine and anxiety

found in some herbal teas, may increase GABA synthesis

MOA of pregabalin

o MOA: selective inhibitor of voltage dependent Ca channel (VDCC)

§ Blocks Cl from coming through to lower depolarization

pregabalin is a GABA analog BUT...

o doesn’t act on GABA-A receptors or alter the uptake/metabolism of GABA

MOA of buspirone

o 5HT1A receptor agonist

o Also D2 antagonist

o NOT GABA- no anticonvulsant, muscle relaxant, or psychomotor impairment

o Less sedation, little interaction with alc

o Slow response

does busprione act on GABA?

no, it doesn't

serotonin and anxiety

· May have anxiolytic and anxiogenic effects depending on the rain region involved, receptor subtype and location on neuron

· Anxiogenic effects are mediated by HT2A stimulation

· Anxiolytic effects are from stimulation of HT1A receptors

5HT1A MOA in anxiety

· somatodendritic auto receptors, coupled to the Gi protein

o Mediate inhibitory neurotransmission

o Partial agonists are anxiolytic

o Is stimulatory

5HT2 MOA in anxiety

o Is inhibitory

o Pts ith anxiety have more sensitive 5HT2R’s

o SSRIs increase 5HT to desensitize 5HT2R

5HT2A and 5HT2C antagonists in anxiety

are anxiolytic

5HT2 agonists in anxiety

trigger panick attack and PTSD flashbacks