Module 3 - Central nervous system depressants and opioids

Question 1

sedative-hypnotic agents

Answer 1

sedative-hypnotic agents are CNS depressants

used for:
1. anti-anxiety
2. sedation
3. hypnosis
4. general anesthsia

Question 2

Mechanism of action for sedative hypnotics

Answer 2

• the major excitatory neurotransmitter in the brain is glutamate
  
  • when a person is anxious or having difficulty sleeping, some therapies aim to depress overall brain activity
  • decreasing glutamate-induced nerve firing → accomplished by increasing inhibitory signalling in the brain
    
    • most sedative-hypnotic drug classes work in this manner

Question 3

GABA signalling

Answer 3

• causes inhibition by binding to and selectively opening chloride channels
• chloride channels are built of multiple subunits that span the neuronal cell membrane, allowing chloride ions to flow into the cell when signalled to open
• when GABA binds to and opens the chloride channel, chloride ions flow into the postsynaptic neuron
• the influx of chloride ions makes it harder for the post synaptic neuron to transmit incoming messages to other neurons, thereby depressing CNS neuronal signalling

Question 4

Drugs that bind to the chloride channel

Answer 4

most sedative-hypnotic modulate the chloride ion channel in the brain and spinal cord, but each binds to a different site on the chloride channel

Question 5

Benzodiazepines

Answer 5

Routes of administration:
- usually taken as a capsule or tablet, but some are available for intravenous or intranasal use

Mechanism of action:
- activation of the benzodiazepine increases the frequency of the opening of the chloride channel

Therapeutic effects:
- relaxation, calmness, and relief from anxiety or tension
- they also produce skeletal muscle relaxation and have anticonvulsant effects
- some are effective hypnotics
- have minimal suppression of REM-type sleep, which is the type of sleep that allows you to feel rested when you wake

Question 6

Lethality of benzos

Answer 6

they have a very high therapeutic index, therefore a wide margin of safety which means that deaths from overdose are very rare

Antidote for benzodiazepines:
- in the event of an overdose, the antidote is called flumazenil, a benzodiazepines receptor antagonist that blocks the effects of benzodiazepines

Question 7

Adverse effects of short term benzos

Answer 7

• CNS:
  
  • drowsiness, lethargy, fatigue, and impairment of thinking and memory
  • what is considered an adverse effect depends on the targetted therapeutic effect
• Breathing:
  
  • respiratory depression has been observed following rapid intravenous administration of benzodiazepines
• Motor coordination:
  
  • a moderate dose can impair motor coordination and driving
  • these responses are exaggerated as the dose is increased

Question 8

Adverse effects of long term benzos

Answer 8

Some can take large amounts for long periods of time without any major evidence of intoxication

Others will demonstrate the symptoms of chronic sedative-hypnotic intoxication, such as impaired thinking, poor memory and judgement, disorientation, incoordination, and slurred speech

Question 9

Benzos on special populations

Answer 9

pregnant/breastfeeding
- Benzodiazepines cross the placenta and distribute into the fetus
- if they are administered in the first trimester, they result in a small but significant risk for fetal abnormalities
- Benzodiazepines are secreted into the milk, and exposing nursing infants to therapeutic or toxic doses of the drug, can result in sedation or death

Older Adults:
- can produce cognitive dysfunction in older adults
- Benzodiazepines are metabolized more slowly in older adults than in young adults, often leading to over-sedation, falls, and injury

Question 10

Benzos on special populations

Answer 10

pregnant/breastfeeding
- Benzodiazepines cross the placenta and distribute into the fetus
- if they are administered in the first trimester, they result in a small but significant risk for fetal abnormalities
- Benzodiazepines are secreted into the milk, and exposing nursing infants to therapeutic or toxic doses of the drug, can result in sedation or death

Older Adults:
- can produce cognitive dysfunction in older adults
- Benzodiazepines are metabolized more slowly in older adults than in young adults, often leading to over-sedation, falls, and injury

Question 11

Benzos potential for misuse

Answer 11

• Benzodiazepines have weaker reinforcing properties than other drugs
• the inherent harmfulness is also low, as it does not depress respiration at therapeutic doses and does not often lead to death on its own

Question 12

Benzos potential for SUD

Answer 12

tolerance: occurs, and a high degree of cross-tolerance occurs among other sedative-hypnotics

withdrawal: a mild but distinct withdrawal can occur after therapeutic use, exhibiting anxiety, headaches and insomnia

addiction: may develop in some individuals, but not all and depends on a magnitude of factors including genetics, and environment

Question 13

Barbiturates

Answer 13

classified according to their duration of action and can be long lasting
1. long-acting = 1-2 days
2. short acting = 3-8 hours
3. ultra short-acting = 20 minutes

route of administration:
- administered in different ways depending on what they are being used to treat

mechanism of action:
- activation of the barbiturate receptor increases the duration of the opening of the chloride channel

therapeutic use:
- in low doses, barbiturates usually result in the beneficial effects of tranquillity and relaxation
- clinical use is limited

lethality:
- while respiratory depression is dose-dependent, the lethal dose of barbiturates varies between individuals
- a specific antidote for barbiturate poisoning does not exist
- death can also occur during barbiturate withdrawal

Question 14

Adverse effects of barbiturates

Answer 14

they suppress REM-type sleep

Short term use:
- in low doses, mild euphoria and reduced interest in ones surrounding
- may cause dizziness and mild impairment of motor coordination
- may cause a pleasurable state of intoxication and euphoria as the dose of drug is increased
- in high doses, depress the cardiovascular system, slowing the heart and lowering blood pressure

Long term use:
- chronic inebriation
- memory, judgement, and thinking they are all impaired
- individuals often exhibit hostility and mood swings including depression

Question 15

Barbiturate potential for misuse

Answer 15

should be avoided, as the potential for misuse is equal or greater to alcohol

the pleasurable effects of some barbiturates give a significant degree or reinforcement

sometimes injected to obtain and ‘rush effect’

the inherent harmfulness is very high due to the risk of death from respiratory depression or from withdrawal

Question 16

Barbiturates potential for SUD

Answer 16

Tolerance: occurs, high degree of cross tolerance between other sedatives

Withdrawal: occurs after discontinuation of chronic us

Addiction: can occur from regular use, irrespective of the dose, those with addiction will crave the drug and a feeling of panic may occur if they cannot get an adequate supply

Question 17

Zopiclone and the Benzodiazepines-like drugs

Answer 17

Benzodiazepines-like drugs are another class of sedative-hypnotic used to treat problems like anxiety or difficulty sleeping

Benzodiazepines-like drugs like zopiclone and zolpidem bind to a subset of the GABA receptors and cause sedation

disturb REM sleep less than benzos

appear to have more sedative effects

Question 18

Buspirone

Answer 18

Benzo like drug

does not act on the GABA receptor

used in generalized anxiety states and may have an advantage over other sedatives in that it does not appear to have additive effects with other sedative-hypnotic drugs

Question 19

ADME of alcohol

Answer 19

absoprtion: stomach (20%) and upper small intestine (80%)

distribution: throughout the total body water and readily gains access to the brain, can also readily transfer across the placenta and distribute throughout a developing fetus

Metablolism: 4 steps
1. alcohol dehydrogenase
- ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase

2. MEOS
   - the MEOs contribute to the metabolism of ethanol, breaking it down to acetaldehyde
3. aldehyde dehydrogenase
   - acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase
4. acetate
   - acetate is further metabolized by a number of tissues into carbon dioxide and water

Excretion: over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver, the remaining 5% is excreted in the breath, urine, and sweat

Question 20

Medical use for ethanil

Answer 20

• as an alcohol sponge applied topically to treat fever
• a skin disinfectant
• as an antidote in the treatment of methanol (wood alcohol) poisoning
• as a hand sanitizer, particularly since the SARS and COVID epidemic and pandemics

Question 21

CNS effects of ethanol

Answer 21

• ethanol is a general CNS depressant
• effects are proportional to the blood alcohol concentration (BAC)

Question 22

Mechanism of action of alcohol

Answer 22

It is thought that alcohol works through one main mechanism - by binding to the chloride ion channel and augmenting GABA mediated neuronal inhibition

Question 23

Effects of short-term use of alcohol

Answer 23

Cardiovascular:
- low dose = create vasodilation (flushing) of the vessels to the skin, resulting in a feeling of warmth
- high dose = depress the cardiovascular system, which can lead to alterations in the normal rhythm of the heart

Stomach:
- low dose = increased gastric secretion
- high dose = irritate the lining of the stomach, causing inflammation and erosion(gastritis)

Liver:
low dose = occasional use of low dose of alcohol does not appear to have significant adverse effects on the liver
high dose = acute high dose of alcohol (alcohol binge) will inhibit glucose production and in association with fasting, can lead to hypoglycemia (low blood sugar)

Question 24

Adverse effects of short term high dose alcohol use

Answer 24

1. memory loss
2. psychiatric effects
3. overdose

Question 25

Adverse effects of chronic high doses of alcohol

Answer 25

CNS: a number of neurological and mental disorders are associated with chronic alcohol misuse

Cardiovascular: high chronic doses of alcohol can lead to alcoholic cardiomyopathy (destruction of poor heart muscle)

Liver: high dose can lead to chronic alcoholic liver disease

Question 26

Effects of alcohol use during pregnancy

Answer 26

chronic use of high-dose ethanol throughout pregnancy can produce teratogenic effects in the embryo/fetus, which can manifest postnatally as fetal alcohol spectrum, disorder

Question 27

Alcohol and drug interactions

Answer 27

alcohol during drug therapy:
- ingestion of ethanol and other CNS depressants lead to an additive or synergistic effect of the CNS depression
- inhibition of the metabolism of certain drugs

chronic use before drug therapy:
- only occurs if there is no co-existing ethanol-induces liver injury
- increases the activity of metabolizing in the liver, resulting in increased metabolism of certain drugs

Question 28

Alcohol potential for misuse

Answer 28

potential for misuse
- ethanol has significant reinforcing properties, and as a result, the misuse potential is moderate
- the ease of availability and social and legal acceptance contributes to ethanols misuse potential

the inherent harmfulness of alcohol is moderate
- death can occur from a high dose of acute ethanol ingestion and chronic ingestion can have long-term effects on health

Question 29

Alcohol potential for SUD

Answer 29

tolerance:
- tolerance to chronic consumption of ethanol does occur
- individuals can develop tolerance more rapidly to the ethanol-induced impairment of performance of a task when they perform that task repeatedly under the influence of ethanol
- cross-tolerance occurs between alcohol and sedative-hypnotics and alcohol and general anesthetics

withdrawal:
- occurs, withdrawal produces compensatory excitation of the CNS
- in severe cases, delirium tremens may occur

Addiction:
- occurs, compulsive desire to seek, obtain and drink ethanol exists

Question 30

Drugs used to treat alcohol disorder

Answer 30

naltrexone:
- an opioid antagonist
- diminishes the craving of ethanol, and assists in the maintenance of abstinence
- it blocks the activation of dopaminergic reward pathways in the brain

Question 31

Cannabis

Answer 31

• cannabis = drug containing forms of the hemp plant
• cannabis sativa is an herbaceous annual
• 60 chemical compounds are found only in cannabis sativa and these compounds are referred to as cannabinoids (CB)

Question 32

Classification of cananbis

Answer 32

pharmacological:
- classified as a CNS depressant, euphoriant, or hallucinogen (these properties only occur at high doses)

legal:
- On October 17, 2018, cannabis became legal in Canada

Question 33

Administration of cannabis

Answer 33

cannabis is a dried flowering plant that is typically smoked or inhaled

Question 34

Mechanism of action of Cannabis

Answer 34

• anandamide is released from the postsynaptic neuron, diffuses across the synaptic cleft, and binds to the type 1 cannabinoid or CB1 for short receptors
• activating the CB1 receptors inhibits the release of excitatory neurotransmitters, such as glutamate, into the synaptic cleft

Question 35

Cannabinoid receptors

Answer 35

CB1 receptors:
- in the cerebral cortex mediate the distortions of time, colour, sound, and taste
- CB1 receptors in the hippocampus may account for the changes in memory and learning

CB2 receptors:
- only found outside the CNS
- they do not appear to be involved in the psychoactive effects of THC, but they may be involved in inflammation
- the binding of THC to CB2 receptors on lymphocytes (type of white blood cell) is thought to be responsible for the immunosuppressive properties of THC

Question 36

ADME of THC

Answer 36

Absorption: commonly inhaled or ingested - the method influences the absorption

Distribution: THC is rapidly distributed throughout the body, especially to tissues with high blood perfusion such as the lung, heart, brain, and liver, crosses the placenta

metabolism: THC is metabolized slowly

Excretion: half-life approx 30 hours, elimination of THC from adipose tissue may take longer

Question 37

Effects of long-term cannabis use

Answer 37

Psychological:
- low dose = does not appear to be associated with harmful psychological effects
- high dose = psychological problems occur over time such as short-term memory loss, lack of concentration, and loss of ability in abstract thinking

Cardiovascular:
- effects are usually reversible

Respiratory:
- bronchitis, asthma, sore throat, chronic irritation of and damage to membranes of the respiratory tract
- can be damaging long term due to the tars and carcinogens present in cannabis smoke

Fertility:
- males:
- long term cannabis can lead to decreased sperm count
- females:
- can cause follicle-stimulating hormone and luteinizing hormone to be reduced, and cycles can potentially occur without ovulation
- pregnancy:
- THC crosses the placenta and can cause developmental delays leading to cognitive deficits, impulsiveness and inattention, and hyperactivity

Question 37

Effects of short-term cannabis use

Answer 37

CNS:
- relaxation and drowsiness
- a feeling of well being and euphoria
- impaired motor coordination
- increased appetite
- as the dose increases, a person may experience pseudo-hallucinations (person knows its a hallucination), a running together of sense and impaired judgement and coordination

Cardiovascular system:
- increased heart rate
- increased blood flow to the extremities
- postural hypotension (may occur)

GI tract:
- increased appetite
- dryness of mouth or throat

Other:
- reduction of sex drive in males
- reduces testosterone levels
- disruption of the ovarian cycle in females
- a hangover, similar to alcohol, when the drug wears off

Question 38

Medical use of Cannabis

Answer 38

analgesia:
- a loss of sensation of pain due to an interruption of nervous system pathways between sense organs and the brain

Question 39

Cannabis potential for misuse

Answer 39

• misuse potential is low to moderate
  
  • as euphoria and reinforcement are less compared to come other drugs
• the inherent harmfulness is low especially with infrequent use

Question 40

Cannabis potential for SUD

Answer 40

tolerance: occurs to:
- the psychoactive properties of THC
- the effects of the cardio-vascular system
- the impairment of performance and cognitive function

Withdrawal: upon termination of long term high dose use, a mild withdrawal syndrome occurs:
- sleep disturbances
- irritability
- loss of appetite
- nervousness
- mild agitation
- upset stomach
- sweating

Addiction: addiction develops as a persistent craving for the drug

Question 41

Opioids

Answer 41

• class of drug naturally found in opium poppy plant ‘papaver somniferum’
• initially, it was used as a crude extract but has now been used as a purified substance producing clinically used drugs such as morphine and codeine

Question 42

Classes of opioids

Answer 42

1. endogenous opioids (enkephalins, dynorphins, and bet-endorphins)
2. natural opioids (morphine and codeine)
3. semi-synthetic opioids (hydromorphone and diacetylmorphine)
4. synthetic opioids (fentanyl, loperamide, methadone)

Question 43

Opioid receptors

Answer 43

• mu receptors
  
  • are present in all structures of the brain and spinal cord
  • they mediate analgesia and are responsible for morphine-mediated depression of respiration in the brain stem
  • because the same receptors is responsible for both effects, it is difficult to obtain drugs with a separation between 2 responses
  • are also involved in the compulsive misuse of opioids
• KAPPA
  
  • involved in analgesia, dysphoria (state of dissatisfaction or unease) and miosis (pinpoint pupils)
• Delta
  
  • receptors are involved in analgesia at the level of the spinal cord and brain
  • may also modulate the emotional response to opioids

Question 44

Mechanism of action of opioids

Answer 44

will block pain pathways in the spinal cord and brain
- this effect is primarily exerted through activation of mu receptors

reduce neurotransmitter release:
- prevent pain signals from travelling by reducing neurotransmitter release from presynaptic neurons and reducing the effect on post-synaptic neurons

reduce emotional reaction:
- reduce emotional reaction to pain through modulation of the limbic system

Question 45

Short term effects of opioids

Answer 45

• analgesia
• sedation and hypnosis
• suppression of cough centre
• respiratory depression
• endocrine effects
• miosis
• heart rate and thermoregulation
• decreased intestinal motility

Question 46

Therapeutic use of opioids

Answer 46

• relief of severe pain:
  
  • analgesia is the major use of opioids
  • For example: post-surgical pain
• treatment of diarrhea
  
  • loperamide is used to treat this
• cough suppression
  
  • effective but alternatives with lower misuse potential are available

Question 47

Opioid potential for misuse

Answer 47

misuse potential:
- most opioids have powerful euphoric effects, which means there’s a large risk for misuse

inherent harmfulness:
- low-moderate doses: not very high for morphine
- high dose: life-threatening since the individual is not always sure the actual dose of the opioid, and a lethal dose can be administered inadvertently

Question 48

Opioid risk of injection

Answer 48

• individuals who administer drugs by injection are at a higher risk of developing abscesses at the side of administration as well as other infection
• if contaminated needles are used there is also a risk of spreading diseases

Question 49

opioid overdose

Answer 49

• overdose of all opioids can produce profound respiratory depression, which can cause death
• treatment consists of opioid antagonists and support for respiration and other vital functions
• the opioid antagonist naloxone is primarily used to treat opioid overdose
  • naltrexone is another antagonist used to treat alcohol disorder

Question 50

Risk of OUD

Answer 50

tolerance: occurs except for the constriction of the pupils and the constipating effect, reverses a few days after the drug is discontinued, cross-tolerance between all opioid analgesic occur, providing they act on the same receptor

Withdrawal:
- restlessness, anxiety, insomnia
- sweating, fever, chills
- increased respiratory rate
- cramping, retching, and vomiting
- diarrhea

Addiction:
- craving and compulsion of opioids can develop
- the basis for addiction is the euphoric action of the opioids → powerful reinforcement
- the use of other psychoactive drugs can occur in an attempt to achieve an even greater euphoria

Question 51

Opioids during pregnancy

Answer 51

• a mother dependent on opioids while pregnant faces an increased risk of premature delivery and a low birth weight infant
• at birth, the infant undergoes an abrupt termination of opioid exposure, resulting in withdrawal reaction including irritability, sleep disturbances, poor feeding, and occasionally seizures → may last weeks or months

Question 52

Treatment of OUD

Answer 52

burprenophrine/naxolone:
- long-acting synthetic opioid that binds to mu receptors
- provides enough opioid agonist activity to prevent withdrawal symptoms, while having decreased euphoria and sedation compared to other agonist
- usually combines with naloxone

Methandone:
- synthetic opioid effective if orally administered and has a long duration of action
- misuse potential is much lower
- when taken orally, it removed the potential risks of injections
- however, it leads to a slower onset of pharmacological effects and less euphoria
- long-acting and taken less often → lower risk of misuse