CNS depressants Flashcards
SEDATIVE-HYPNOTICS
General Description
* Drugs which slow/reduce/depress nervous system
activity and behavior
* Collectively, most widely used class of psychoactive drugs
* Arbitrarily classified into four groups
SEDATIVE-HYPNOTICS
General Description Cont’d
* Similarities:
– Uses
– Sites of action
– Ability to induce various levels of behavioral
depression
- Differences
– Individual potency
– Chemical structures which affect Absorbed Distributed Metabolized Eliminated
SEDATIVE-HYPNOTICS
Sites and Mechanisms of Action
(1) Ascending Reticular Activating System
(2) Diffuse Thalamic Projection System
(3) GABA Receptor Complex System
(4) Cells
- increase and decrease matabolism in cells
(5) Norepinephrine synapses
- decrease activity in synapses
SEDATIVE-HYPNOTICS
- Effects are additive
- barbs + alc = more effects (combined) –> greater degree of sedation
- Potentiation can occur
- can be supra-additive ==> potentiation occurring and ca be unpredictable*** —> one benzo can potentiate effects of alc and vice versa (1 beer = 8 beer)
- physical state of person can play a role in that
- morale == DONT MIX
- Inhibitory synapses are depressed slightly before
excitatory synapses - that pepped up feeling from disinhibition occuring
- Dependency can develop
- more sevre is seen in people taking high doses of drug for 6 months (barb, benzo) –> this is for extreme withdrawals seen with these drugs
2 types of with
1. s-hyponotic withd type
- more severe withdrawal
- charactorized by tremors, delerium, hallucinations, cramps, convulsions
- can be fatal
- seen in people taking very high doses for 6 months , can be as short as 1 month
- starts within a few days
- peak and dissipate
- in a couple weeks, withd is over
- low dose type
- seen in benzo taking theraptic dse for longer than 6 months
- symptoms seen slower , not as severe, go up and down in terms of severity
- can still experience withd in 30 days
- no data in when withd stops in l-d ,
can see symptoms reemergence
- problems iht sleeping and anxiety can reeemerge wth people (getting withdrawal symptoms, inc HR, sensisty to light, bad attention, –> not feeling like themselves) all of this and THEN reeemergence of problem that they had (problem with sleep and anxiety)
- few mg of benzo can treat withd symptoms
- Tolerance can develop
- 3 tyeps
1. acute tol –> rapid to benzo and barbs - seen in single dose with benzo
2.chronic tol- more slolwy developing tolerance to benzo anticonvulsant action and drowsiness
- cross tolerance –> brbs , benzo, alc
- barb , stop and take benzo= will be tolerant to benzo
- or regular consumer of alc –> need more benzo or barb to get effect
ALCOHOL
Absorption
- Alcohol is completely and rapidly absorbed when
taken orally - some absorption in stomach, but majority in
intestines - Rate of absorption modified by a # of factors
ALCOHOL
Distribution
- Alcohol fully and evenly distributed through all body fluids and tissues
- BBB is 90% permeable to alcohol (not very perm to alc)
- Dissolves more readily in water than in fat, thus:
- higher Blood alcohol levels in women than men –> women have more body fat than men do = less body water (higher concentration of alcohol)
higher BA levels in older men than younger men (more fat in older men)
- Readily crosses placental barrier
- why women are advised not to consume alcohol during pregnancy
Fetal Alcohol Spectrum Disorders
- Prenatal exposure to alcohol is associated with a
range of congenital physical and behavioral
abnormalities categorized under the umbrella
term of Fetal Alcohol Spectrum Disorders - Distinction between conditions is the number
and/or severity of the symptoms - fetal alc syndrome vs fetal alcohol effects –> differ from physical and behvaioural symptoms you see
- partial FAS
- static encephalopathy
- alcohol related birth defects
- Symptoms include:
– Facial abnormalities - small eye opening
- short indentation in upper lip (smooth philtrm)
- short flat broad nose
- abnoraml creases in palm of hands
- webbingin hands
consistently seen across different species
7 drinks per week can cause FADS
3rd leading cause of birthdefects at birth
- only preventable one
Fetal Alcohol Spectrum Disorders
- Symptoms include:
– Facial abnormalities
– Heart defects
– Low intellectual functioning
– Growth retardation
– Learning disabilities - CDN Prevalence Estimates
– 9 /1000 births FASD
– 1-3/1000 births FAS - 4%in canada
FASD Cont’d
- Risk and extent of abnormalities believed to be dose- related (higehr alc consumption = higher likelihood of symptoms)
- Type of abnormality believed to be related to timing of alcohol use
- thin upper lips (1-3 drinks/day in 2nd half of 1st trimester
- small head (first trimester ingestion)
-first trimester –> abnormal brian dev and abnormal brain development
later in pregnancy –> (after 1st trim) fetal malnutrition (less food and less vitamin d )—> associated to growth retardation
– Feldman et at (2012)
ALCOHOL
Metabolization & Elimination
- 90-98% of alcohol ingested is metabolized is stomach (15-20%) and liver (80-85%) before excreted
- Excretion can occur thru breath, sweat, tears, urine,
and feces - some nonmetabolized through skin and breath
- Metabolization in liver occurs in two steps:
- 1st step (rate limiting step): slow step, determined by amount of alcohol dehydrogenase
- 2nd step ():
paper: ethanol + alco dehy –> acetaldehyde + (aldehyde dehydrogenase) –> acetyl coenzyme A + (citric acid cycle) –> energy, carbon dioxide, water
–> shows that alc has no nutritional value**
ALCOHOL
Metabolization & Elimination
- Rate of metabolization is linear with time (10-20mg/100 ml of blood per hour)
– 1 to 1.5 hours for
—–30 ml of whiskey (40%)
——120 ml of wine (11%)
—–360 ml of beer (5%) - Considerable variability between individuals in
elimination rates*** - Non-drinkers metabolize alcohol (12-14 mg/100ml blood) at slightly lower rates than light to moderate drinkers (15-17mg/100ml)
- 1 drink per hour –> will be metabolized so you wont be intoxicated (typically but there is variability)
alcohol dehydrogenase system
- acetyladehye will build up in system when you drink more (causes nausea) cuz it is toxic
- a treatment for alc abuse (Antabuse (trade name), disuflerame (generic name)) –> interfers with action of aldehyde dehydrogenase –> gets them sick from causing a build up of acetylaldehyde
Metabolization & Elimination
2nd system :
Microsomal Ethanol Oxidizing System (MEOS)
- metabolized to acetlyaldehyde –> metabolizses the alcohol
– Handles approximately 5 to 10% of alcohol metabolization, but activity will increase with higher Blood Alcohol Levels –> consuming a lot of alcohol, this system ups its action substantially
- Operation of this system believed to be responsible for tolerance seen with heavy drinking**–> along with alc dehydrogenase (metab 85%), MEOS increase with more alcohol –> goal = to increase more alcohol
- 30-50% increase in drinking with action of this system
- Operation of this system (MEOS) believed to be
responsible for cross tolerance to barbiturates
and benzodiazepines****
ALCOHOL
Mechanisms of Action
A lot of pharm actions**
Facilitates action at the GABAa receptor chloride
ionphore complex system
– Binds to an allosteric (causes change) site (located within cloride ion channel)
– This affects GABA binding at GABA receptor; opens up Cl- ion channel
- At high levels, alcohol can directly open up Cl- channel**
by facilitating GABA distributed very widely across NS (causes inhibition*****)—> Antagonist of glutamate at NMDA receptors blockign NMDA from getting to receptors== causes IPSPs
- depresses activity of thalamus (lowers peripheral vision), Brain stem (sedating effect) , cerebellum (loss of coordination),
- Impacts production and release of endorphins and
dynorphins; increases release of Dopamine in nucleus accumbens ==> responsible for euphoria from alcohol , and cravings for alcohol - Increase activity in mesolimbic dopamine
system/levels of DA in nucleus accumbens thru release
of inhibition - shows complexity of drugs effects:
frst 2 = pre-alcohol
–> GABAergic neurons (ALPHA) coming from NA activate GABAergic interneurons
–> GABAergic interneurons (BETA) inhibit DA neurons in VTA: this is the normal state
INTRODUCE ALCOHOL
GABAergic neurons coming from NA (the alphas) increase release of GABA onto the inhibitory GABAergic interneurons (BETAs) - which decrease the BETAs activity (cl- channels open up = IPSP)
DEcreased BETA activity = less inhibition of DA neurons ==> more DA released in NA
- receptor site determines effects*****
ALCOHOL
Physiological Effects
- Sleep disturbances
– Induces Slow Wave Sleep (reduces amount of time it takes to fall asleep) and prolongs SWS and depressed REM sleep - Affect on REM varies with dose** (low alc levels –> REM reduced at first sleep cycle but then return to normal levles, high alc levels –> REM depressed throught entire sleep cycle (asleep, wake with no dreams)
ex: a lot to drink sat, sun, mon (REM cycles will return to normal after 3 days (tolerance will develop to this effect**)
- then stop drinking –> REM rebound –> see greater periods in REM sleep (restless sleep, nightmares) –> induces drug cycle
- effect on REM and sleep can last for months (withdrawal symptom)
- Depressed Respiration (in high doses of alc)
- effect on medulla (can drink themselves to death)
- tolerance never develops to this effect
- Prevents Seizures
- Vasodilation
- leads to flushed faces
also, decrease sensitivity to taste and smell
ALCOHOL
Physiological Effects
- Diuretic Effect on Kidney –> increase secretion of water (pee) –> decrease output of ADH suppressant
–> seen when BAL start to remain steady or start to fall - Immunosuppression
–> not good to drink on a cold
ALCOHOL
Psychological Effects
- Relief from anxiety
- Disinhibition
- Euphoria
- 3 above are unpredictable –> determined by a persons personality, characteristics, expectations of alcohol consumption scenario, setting of alcohol
- Disrupted Memory Functioning
both encoding, storing and retrieval of information - due to reduced neurological alertness in Brainstem
- GABA receptors in hippo will disrupt Hippo functioning –> disrupt LT potentiation (which is how we form a memory)
- interferes in creating new neurons in hippocampus
- dysfunction of PreFC plays a large role in focusing attention (encoding of info) –> cant get a memory of something we didn’t pay attention to it)
-summary, hippo, LTP, PFC, attention, formation disrupted ====> blackout (unable to determine events that happened)
- can have fragmentory blakcouts (remeber bits and pieces)
ALCOHOL
Effects and BAL
BAL Effect
.01-.02 (1 drink in hour)—> Slight changes in feeling (well being, less anxiety)
.03-.05 (2 drink in hour)–> Overt feelings of relaxation, happiness, skin may flush, tingling
.05-.06 (2.5 drink/hour)–> More noticeable changes in emotion, slight increase in RT (slower), tingling more noticeable
.08-.09 (3 drink/hour)–> Moderate increase in RT, possible numbness in cheeks, lips, extremities, impaired judgment (PFC gets affected)
- cortex affected first in drunkness***
- frontal, parietal, temporal, down BS
.10 (4 drinks/hour)–> Coordination/balance impaired (cerebellum affectde)
ALCOHOL
Effects and BAL
BAL Effect
.20 (7 drinks/hour) Difficulty staying awake, standing,
walking without assistance; sensory functions impaired
.30 (10 drinks/hour) Confusion and stupor, not sure where or who they are, how they got there
.40 (14 drinks/hour) Typically unconscious, threshold of coma
.45-.60 (20-25 drinks/hour) Typically deep coma, LD50 in humans*** due to circulatory and respiratory depression
sed/hyps (4)
barbs
non barb hyps
benzo
misc compounds (alcohol)
similarily: uses (treats anxiety)
- alcohol can treat anxiety (all of this category treats this)
- induce a lot of behvaioural depression
- similar Sof A
-
differences:
ALCOHOL
Toxic Effects with Chronic Use
Liver Disease
1. Fatty Liver –> liver breask down alcohol in favour of fat –> build up of fatty tissue in liver , accumulation of fatty tissue compromises liver function (is reversible***) if not drinking:
- Alcoholic Hepatitis–> inflammation and scarring of liver tissue–> caused by build up fatty tissue (liver cells will breakdown (dead tissue debris) , see jaundice, fever, abdominal pain (reversible**_ liver functioning will mostly turn to normal with some scarring) if they continue:
- Alcoholic Cirrhosis: progression of scar tissue, chokes off BV in liver–> BV burst and death (not reversible )
- only treatment is a liver transplant
- wont automatically die from this but death rate si 75%
- most deaths in men40-60yo
- minimum amount is 5 drinks/day for 5 years straight
- takes a fair bt of drinking for AC to happen
Cardiovascular Problems
– Inflammation of Heart Muscle –> poor ciruculation to heart
– Irregular Heart Contractions
– Fatty accumulation in heart and arteries
– High Blood Pressure
ALCOHOL
Toxic Effects with Chronic Use
Cancer
– Esophagus, Pharynx, Larynx, Breast
Wernicke-Korsakoff Syndrome
- 2nd stage = korsakoff psychosis
– Permanent diffuse damage to hippocampus and
cerebral cortex
– Memory problems –> anterior brain amnesia (inability to from memories) similar to dementia
- memories back to childhood
- make things up* –> not truthful answer
– Primarily due to malnutrition, but other factors
may play a role
- vitamin B deficiency* –> needed by neurons for metab of glucose
–> there ca be improvemetns with a vitamin replacement therapy –> if too much, vitamin replacement doesnt work
- Fetal Alcohol Spectrum Disorders
increasing doses of the drug
normal –> relief from anx –> disinhibtion–> sedation –> hypnosis (sleep) –> general anesthesia (ultra short acting barbs will dothis) –> coma –> death
Tolerance
- Can develop with heavy use re: effects of mood
and behavior (maximum tolerance developing in 3 weeks with heavvy use) –> increase dose by 50% for fx to be realized - Minimal tolerance re: depressant actions of respiration
Mechanisms responsible for tolerance:
– Increased # of Cytochrome P450 enzymes
– Increased activity of alcohol dehydrogenase in liver and stomach (a lot of alc metabolized in both b4 getting to BS
– Increased activity of MEOS
– Down regulation of GABA receptors –> fewer GABA receptors availbale for GABAa to bind to
– Upregulation of NMDA receptors (from NMDA being blocked from alcohol) –> body responds by creating more receptros
Acute tolerance to alcohol: fx more pronounced when BAL are rising vs falling
– Behavioral compensation –> move slowly to compensate for loss of coordination
ALCOHOL
Dependence
to get physio dep: need t consume large amount for months to see withdrawal symptoms
psychological dep: primary (+ effects)
Psychological and physiological dependency can
develop
- Withdrawal can be life-threatening –> can get heart failure –> leads to death ,,,, can experience dysphoria = depression= suicide for some people
- Withdrawal symptoms begin in 6-48 hours after stopped consumption
- Two clusters of symptoms
