mod 3 - cns depressants and opiods Flashcards
1
Q
what are sedative hyponotic agents
A
CNS depressants
2
Q
what are the magnitudes of CNS depressants
A
low to high dose:
1. anti-anxiety
2. sedation
3. hypnosis (sleep)
4. general anesthesia
3
Q
mechanism of action of sedative hypnotics
A
without s/h:
- more excitatory than inhibitory input causing neurons to fire
- excitatory input releases glutamate
with s/h:
- inhibitory signals from GABA neurons increase
- decreases glutamate nerve firing
4
Q
GABA signalling
A
GABA: primary inhibitory neurotrasnmitter
- modifies chloride channels and allow an influx of sodium ions
- causing it harder for the postsynaptic neuron to transmit incoming messages to other neurons
- depressing CNS signallling
5
Q
drugs that bind to the chloride channel
A
- benzodiazepines
- barbiturates
- benzodiazepine-like drugs
- alcohol
6
Q
benzodiazepines
A
- among most widely prescribed drugs in the world (5-10% Canadians)
7
Q
benzodiazepine route of administration
A
capsule or tablet
- some avail for intravenous or intranasal use
8
Q
benzodiazepines mechanism of action
A
- activating benzodiazepine receptor inc FREQUENCY of chloride channel openings
9
Q
benzodiazepines therapeutic effects
A
- relaxation, calmness, relief from anxiety or tension
- skeletal muscle relaxation
- anticonvulsant effects
- MINIMAL suppression of REM-type sleep (effective hypnotic)
10
Q
lethality of benzodiazepines
A
- one of the most commonly involved in overdose
- high therapeutic index – wide margin of safety, overdoses are rare
- ingestion of enormous dose, iv injection of large dose, or in combination with other sedating drugs = death
11
Q
antidote for benzodiazepines
A
flumazenil
12
Q
adverse effects of benzodiazepine use
A
short term
- CNS: drowsiness, lethargy, fatigue, impaired thinking and memory
- breathing: respiratory depression
- motor coordination: impair motor and driving
long term
- varies
13
Q
benzodiazepines in special populations
A
pregnant/breastfeeding:
- cross placenta and distribute into the fetus
- first trimester: small but significant risk for fetal abnormalities
- secreted into the milk, exposes nursing infants – may result in sedation or death
older adults:
- cognitive dysfunction
- metabolized slower often leading to over-sedation, falls, injury
14
Q
benzodiazepines potential for misuse and SUD
A
misuse: low
- weaker natural drug properties
- low inherent harm
tolereance: yes, develops to desired effects but not a clinical issue
- develops to sedative effects and impairment of coordination, anxiolytic effects (less common), euphoria (occasionally)
- cross tolerance: with other s-h drugs like barbiturates and alcohol
withdrawal: yes, less common
- mild
- anxiety, headache, insomnia
addiction: yes, in some
- sometimes
15
Q
barbiturates duration of action
A
- long acting (1-2 days)
- short acting (3-8 hours)
- untra short acting (20 minutes)
16
Q
barbiturates routes of administration
A
- varies
- epilepsy: orally
- anesthesia: intravenosuly
17
Q
barbiturates mechanism of action
A
- inc DURATION of opening of chloride channel
- demonstrate full spectrum of dose-dependent CNS depression (anti anxiety, sedation, hypnosis, anesthesia, death)
18
Q
barbiturates therapeutic uses
A
low dose: tranquility and relaxation, induce sleep
- limited clinical use
- ultra-short and short-acting induce anesthesia
- long-acting: antiepileptics
19
Q
barbiturates lethality
A
- most have been replaced for newer and safer drugs
- have a low therapeutic index
- no antidote
- withdrawal can cause death
20
Q
adverse effects of barbiturates
A
short term
- low dose: mild euphoria and reduced interest
- dizzy and impairment of motor coordination
- pleasurable state of intoxication and euphoria when dose increased
- high dose: depress cardio system, slow heart and lower bp
long term
- chronic inebriation
- memory, judment, thinking impairment
- hostility
- mood swings and depression
21
Q
barbiturates potential for misuse and SUD
A
misuse: equal or greater than alcohol (mod)
- significant pleasurable effects
- injected for a “rush effect”
- inherent harm is very high – can die from respiratory depression or withdrawal
tolerance: yes
- cross tolerance between other sedatives
withdrawal: yes
- tremors, anxiety, weakness, insomnia, postural hypotension (low bp, bp drops when sudden standing up)
- progress to seizures, delirium, visual hallucinations , high body temp
- withdrawal must occur slowly under medical supervision
addiction: yes
- large cravings irrespective of the dose
22
Q
benzodiazepine-like drugs
A
- zopiclone
- zolpidem
- treat anxiety and insomnia
- bind to a subset of GABA receptors and cause sedation
- disturb sleep patterns (REM sleep) even less than benzos
- more sedative than anxiolytic effects
- inc freq of chloride channel opening
23
Q
difference between benzo and barbit receptor binding
A
benzos: bind to GABA, inc frequency of chloride channel opening
barb: bind to GABAA, inc duration of chloride channel opening
24
Q
therapeutic uses of sedative-hypnotics
A
barbiturates: anit-epileptic
benzos: anti-anxiety
benzo-like-drugs: hypnotic
flumazenil: antidote for benzo
25
buspirone
- anxiolytic (reduce anxiety)
- acts on seratonin receptor
- treats general anxiety and advantages over other sedatives bc it doesn't have additive effects with other sh drugs (no drug-drug interactions)
26
ADME of alcohol
| when;s max, ratios
1. absorption
- rapid from stomach (20%)
- rapid from upper small intestine (80%)
- maximal blood alcohol conc happens from 30-90 mins within last drink
2. distribution
- throughout the total body water
- easy access to brain
- transfer across placenta to developing fetus
3. metabolism
- alcohol dehydrogenase
- MEOS
- aldehydyde dehydrogenase
- acetate
- water and carbon dioxide
4. excretion
- 95% eliminated by biotransformation in the liver
- 5% excreted in breath, urine, sweat
27
how is alcohol absorption rate affected
1. stomach emptying time -- time required to reach small intestine
2. ethanol concentration in gi tract and presence of food
28
metabolism of alcohol
1. alcohol dehydrogenase (ADH): converts ethanol to acetaldehyde (rate-limiting step; speed of this sets pace for the rest of metabolism)
2 (1b). MEOS: another pathway of ethanol conversion, MEOS is part of the P450 system; MEOS converts when there is high doses and alchol dehydrogenase is at full capcity
3. aldehyde dehydrogenase (ALDH): acetaldehyde converted to acetate
4. acetate: further metabolized into CO2 and water
29
genetic variability in alcohol metabolism
- genetic variants in ADH (some ppl convert rapidly, some ppl slow)
- rapid causes accumulation of acetaldehyde -- produces unpleasant side effects like flushed face (prevents alcoholism in some)
- genetic variability in ALDH also exists
30
rate of alcohol metabolism
- constant rate irrespective to blood alcohol concentration (BAC)
- bc ADH is rate-limiting
- rate of ethanol metabolism is about 120mg ethanol/ kg body weight/ hr
31
which is the rate limiting step in alcohol metabolism
ADH: alcohol dehydrogenase
32
medical uses of ethanol (alcohol)
few
- alcohol sponges applied topically to treat fever
- skin disinfectant
- antidote in methanol poisoning
- hand sanitizer
33
CNS effects of alcohol
- CNS depressant; effects proportional to blood alcohol conc (BAC)
34
how do you convert BAC in mg/dL to BAC as a percentage
move decimal places 3 places to the left
ex. 50-100mg/dL -> 0.05-1%
35
BAC and clinical effects
0.05-1%: sedation, slower reaction times
0.1-0.2%: impaired motor function, slurred speech, ataxia
0.2-0.3%: emesis, stupor
0.3-0.4%: coma
>0.4%: respiratory depression, death
36
what is the legal BAC driving
0.05%: provincial offence
0.08%: criminal
drivers under 22 in age:
- 0%; zero tolerance BAC
37
alcohol mechanism of action
- bind directly on the chloride channel and modifies GABA inhibition
38
short term effects of alcohol
| cardio, stomach, liver
cardio:
- low dose (1-3 drinks): vasodilation of vessls to skin (flushing), warmth
- high dose (>5): depress cardio system and alterations of heart rhythm
stomach:
- low dose: increased gastric secretion
- high dose: irritate stomach lining, inflammation and erosion, vomiting, ab pain, ulcers (can lead to gi bleed)
liver:
- low: no sig effects
- high: inhibit glucose prod, if fasting can lead to hypoglycemia (low blood sugar)
39
adverse effects of short term high dose alcohol
- memory loss
- psychiatric effects: depression, irritability, over sedation, self-harm, violence
- overdose: respiratory depression, coma, death
40
adverse effects of chronic high dose alcohol
| nervous, cardio, liver
CNS: mental disorders like alcoholic dementia, dec in cog function and memory, judgement, thinking; damages axons in the brain, fewer connections between neurons
Cardio: alcoholic cardiomyopathy -- destruction of or poor heart muscle
liver: alcoholic liver disease
41
effects of alcohol during pregnancy
- fetal alcohol spectrum disorder (FASD)
- FASD: 1 per 1000 live births
facial features
- short palpebral fissures
- flat idface
- indistinct philtrum
- short nose
- thin upper lip
42
alcohol and drug interactions
alcohol + drug:
- additive effect or synergistic effect of CNS depression
- inhibition of metabolism of certain drugs (ex. sedative hypnotics)
alcohol before drugs:
- only happens if no liver injury
- inc activity of liver metabolizing enzymes, inc metabolism of certain drugs (ex. sh)
43
alcohol potential for misuse and SUD
misuse: moderate
- easily available
- socially and legally accepted
- inherent harm: moderate, death occurs at high doses but less harmful overall than methanol
tolerance: yes
- can develop performance of tasks that are repeatedly done under the influence
- cross tolerance: yes with s-h and general anesthetics
withdrawal: yes
- in severe withdeawal delirium tremens may occur -- incl convulsions, coma, possible death
addiction: yes
44
treatment of alcohol withdrawal
- maintain fluid and electrolyte balance
- prevent seizures
- severe cases: oral administration of diazepam (benzo)
45
drugs used to treat alcohol use disorder
- naltrezone: diminishes craving blocks activation of dopaminergic reward brain pathway
46
when was cannabis considered a narcotic
1920s
47
administration of cannabis
- smoked or inhaled
- oils can be smoked
48
cannabis mechanism of action
- bind to CB1 (in brain and spinal cord)
- when anandamide of THC activates CB1, inhibits the release of excitatory neurotransmitters = CNS depressant
49
anandamide
endongenous cannabinoid
- retrograde transmitter released from postsynpatic neuron and influences the presynaptic neuron (opposite)
- binds to CB1 and inhibits release of excitatory neurotransmitters such as glutamate into the synaptic cleft = CNS depression
50
CB1
- cannabinoid receptor
- in the brain more than any other receptor = produces response due to large amount
- cerebral cortex cb1: distorts time, colour, sound, taste, dec in cog function and concentration
- hippocampus cb1: changes memory and learning
- no cb1 in brain stem, do not depress respiration = non lethal
51
CB2
- outside CNS
- not involved in psychoactive effects
- involved in inflammation
- when on lymphocutes it is responsible for the immunosuppressive proerties of thc
52
ADME of THC
1. absorption:
- inhaled or ingested
- inhaled: rapid, last 3-4 hours
- ingested: slow and incomplete: delayed onset of 30-60 mins; weaker than smoking
2. distribution:
- inhalation: rapid distribution throughout body, esp tissues with high blood perfusion like lung, heart, brain, liver
- rapidly crosses placenta
- oral: slower
- lipid soluble and will be stored in adipose tissues
3. metabolism
- slow, thus metabolites can be detected in drug tests even after weeks of stopping
4. excretion:
- half life of approx 30 hours
- elmiination from adipose tissues take longer
53
effects of short term cannabis use
CNS
- relaxation and drowsiness
- euphoria
- impaired motor coordination
- inc appetite
- higher dose = pseudo hallucinations
cardio
- inc hr
- inc blood flow to the extremities
- postural hypotension
gi tract
- inc appetite
- dryness of mouth and throat
other
- reduction of sex drive in males (red testosterone)
- disrupt ovarian cycle in females
- hangover
54
effects of long term cannabis use
psychological
- low dose: no rlly harmful effects
- high doses: loss of short term memory, lack of concentration, loss in abstract thinking, amotivational syndrome, loss of ambition and emotional numbness
permanent effects
- unknown
- possible impairment of memory and learning
cardio
- change in bp
- inc in hr
respiratory
- bronchitis, asthma, sore throat, chronic irritation of and damage to membranes of respiratory tract
- higher conc of tars and carcinogens in cannabis smoke compared to tobacco and inhaled deeper to get more thc and cannabinoids
fertility
- males: dec sperm
- females: follicle stimulating and lutenizing hormone reduced, no ovulation
- pregnancy: thc freely crosses placenta and can cause developmental delays - cognitive deficits, impulsiveness, inattention, hyperactivity
55
vaping lung injury
e-cig or vaping associated lung injury (EVALI)
56
medical use of cannabis
- prevention of nausea and comiting associated with anticancer drugs
- synthetic thc derivatives more selective than cannabis in treating nausea
57
cannabis potential for misuse and SUD
misuse: low - moderate
- euphoria and reinforcement is less compared to other drugs
- inherent harm is low
tolernace: yes
occurs to
- psychoactive properties
- effects on cardio sys
- impairment of performance and cog function
withdrawal: can occur mildly to high doses
- sleep disturbance
- irritability
- nervousness
- mild agitation
- upset stomach
- sweating
addiction: can occur
- moreso in those who take it for stress
58
OUD
opiod use disorder
59
classes of opiods
1. endogenous
2. natural
3. semi-synthetic
60
analgesic effects
asbence of pain
61
endogenous opiods
- produced by the body
- exert analgesic effects (perception of pain and emotional response to pain)
- associated with reward pathways in the brain
includes:
1. enkephalins
2. dynorphins
3. beta endorphins
62
natural opiods
- from opium poppy plant
includes:
1. morphine - treat pain, cause euphoria
2. codeine - converted to morphine by liver enzymes; morphine is 10x more potent than codeine
63
prescription drug that contains codeine
Tylenol 3
- combination of codeine, acetaminophen and caffeine
64
semi-synthetic opiods
- derived from morphine
- chemically synthesized to bind to opiod receptors
- designed to elicit similar responses to morphine (analgesia, euphoria)
includes:
1. fentanyl and related compounds
2. loperamide
3. methadone
65
fentanyl
100x more potent than morphine, treats severe acute and chronic pain
66
loperamide
treat diarrhea, chemical structure allows little amount to enter and remain in circulation, but stays in intestine, or metabolized quickly -- prevents illicit use, no really analgesia or euphoria
67
methadone
analgesia, treats OUD -- prevents withdrawal symptoms and no euphoria
68
opiod receptors
1. mu
2. kappa
3. delta
69
mu receptors
- brain and spinal cord
- mediate analgesia
- responsible for morphine-mediated depression of respiration in the brain stem
- responsible for both effects, hard to find a drug that separates them
70
kappa receptors
- analgesia
- dysphoria: state of dissatisfaction or unease
- miosis: pinpoint pupils
71
delta receptors
- analgesia at spinal cord and brain
- emotional response to opiods
72
mechanism of action of opiods
- block pain pathways in spinal cord and brain (primarily through mu opiod receptors)
73
how do opiods inhibit pain impulses
1. reduce neurotransmitter release
- prevent pain signals from travelling by reducing release of neurotransmitters by presynaptic and reduces effect on postsynaptic neuron
2. reduce emotional reaction
- through modulation of the limbic system
74
morphine administrations
- oral: tablet
- iv
- smoked
- sniffed
75
short term effects of opiods
analgesia
- reduce pain
- limiting factor: respiratory depression
sedation and hypnosis
- not as intense as CNS depressants
- aroused but also drowsy, dreamy
- all opiods
suppression of cough center (medulla)
- relief or prevention of cough
repisratory depression
- suppress respiratory center in brain stem
- response to co2 is stunted
- mu and delta receptors
- usual cause of death in overdose
endocrine
- reduce the hormone responsible for regulating sex hormones from hypothalamus
- reduction in testosterone, estrogen, progresterone
- dec in libido in men
miosis
- constriction of pupils of the eyes (miosis) -- pinpoint pupils happen with opiods that gain access to CNS
heart rate and thermoregulation
- hr is irregular
- body temp is low
- skin is cold and clammy
decreased intestinal motility
- constipation
76
therapeutic uses of opiods
mostly morphine*
1. pain relief (severe pain)
2. treatment of diarrhea (loperamide, doesn't produce withdrawal)
3. cough suppression
77
opiod potential for misuse
large misuse risk (powerful euphoric effects)
inherent harmfulness:
- low-med doses: not high for morphine
- high doses: life threatening
risks of injections
- higher risk
- infection
- contaminated needles
overdose
- profound respiratory depression -> death
- treatment: opiod antagonists and respiration support
78
opiod antagonist
naloxone -- treat opiod overdose
naltrexone -- treat alcohol use disorder
79
risk of OUD
tolerance: occurs to most effects
- occurs to most effects except miosis and constipation
- slow develop to respiratory depression than to analgesic effects
- reverses
- cross tolerance between all opiods
withdrawal: not life threatening
- not life threatening
- restless, anxiety, sweating, inc resp rate, cramp, vomit, diarrhea
- specific symptoms depending on the opiod
addiction: very common
- euphoric action is additive
80
opiods during pregnancy
- inc risk of premature delivery
- low birth weight infant
- at birth, fetus goes through withdrawal lasting weeks to months
81
treatment of oud
1. counselling, etc...
2. buprenorphine/naloxone
3. methadone
82
buprenorphine/naloxone treating oud
buprenorphine:
- bind to mu receptors
- provides enough opiod agonist to prevent withdrawal symptoms
- dec euphoria and sedation
naloxone: blocks opiod receptors -- causes withdrawal
- if taken orally, will be broken down before reaching blood circulation and has no sig effects
*usually taken in combination
83
methadone in treating oud
- oral administration (remove risk of injection, leads to slower onset of pharmacological effects so less euphoria)
- long duration of action
- misuse is much lower
- long acting, taken less often, lower misuse potential
