Module 3 - Central nervous system depressants and opioids Flashcards
sedative-hypnotic agents
sedative-hypnotic agents are CNS depressants
used for:
1. anti-anxiety
2. sedation
3. hypnosis
4. general anesthsia
Mechanism of action for sedative hypnotics
- 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
GABA signalling
- 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
Drugs that bind to the chloride channel
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
Benzodiazepines
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
Lethality of benzos
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
Adverse effects of short term benzos
- 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
Adverse effects of long term benzos
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
Benzos on special populations
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
Benzos on special populations
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
Benzos potential for misuse
- 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
Benzos potential for SUD
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
Barbiturates
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
Adverse effects of barbiturates
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
Barbiturate potential for misuse
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
Barbiturates potential for SUD
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
Zopiclone and the Benzodiazepines-like drugs
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
Buspirone
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
ADME of alcohol
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
- MEOS
- the MEOs contribute to the metabolism of ethanol, breaking it down to acetaldehyde - aldehyde dehydrogenase
- acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase - 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
Medical use for ethanil
- 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
CNS effects of ethanol
- ethanol is a general CNS depressant
- effects are proportional to the blood alcohol concentration (BAC)
Mechanism of action of alcohol
It is thought that alcohol works through one main mechanism - by binding to the chloride ion channel and augmenting GABA mediated neuronal inhibition
Effects of short-term use of alcohol
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)
Adverse effects of short term high dose alcohol use
- memory loss
- psychiatric effects
- overdose
Adverse effects of chronic high doses of alcohol
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
Effects of alcohol use during pregnancy
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
Alcohol and drug interactions
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
Alcohol potential for misuse
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
Alcohol potential for SUD
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
Drugs used to treat alcohol disorder
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
Cannabis
- 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)
Classification of cananbis
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
Administration of cannabis
cannabis is a dried flowering plant that is typically smoked or inhaled
Mechanism of action of Cannabis
- 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
Cannabinoid receptors
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
ADME of THC
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
Effects of long-term cannabis use
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
Effects of short-term cannabis use
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
Medical use of Cannabis
analgesia:
- a loss of sensation of pain due to an interruption of nervous system pathways between sense organs and the brain
Cannabis potential for misuse
- 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
Cannabis potential for SUD
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
Opioids
- 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
Classes of opioids
- endogenous opioids (enkephalins, dynorphins, and bet-endorphins)
- natural opioids (morphine and codeine)
- semi-synthetic opioids (hydromorphone and diacetylmorphine)
- synthetic opioids (fentanyl, loperamide, methadone)
Opioid receptors
- 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
Mechanism of action of opioids
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
Short term effects of opioids
- analgesia
- sedation and hypnosis
- suppression of cough centre
- respiratory depression
- endocrine effects
- miosis
- heart rate and thermoregulation
- decreased intestinal motility
Therapeutic use of opioids
- 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
Opioid potential for misuse
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
Opioid risk of injection
- 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
opioid overdose
- 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
Risk of OUD
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
Opioids during pregnancy
- 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
Treatment of OUD
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
