3.3 - Module 3 Central Nervous System Depressants and Opioids
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Fall 2023
10/11/2023
PHAR 100
Module 3: CNS Depressants & Opioids
Section 01: sedative-hypnotics
Introduction to Sedative-Hypnotic Agents
Sedative-hypnotic agents:
o
CNS depressants. o
The magnitude of CNS depression produced by a drug at a particular dose determines what effect
the agent produces.
Low dose to high dose (different magnitudes of CNS depression):
o
Anti-anxiety:
Used to treat anxiety disorders, such as generalized anxiety disorder and obsessive compulsive disorder. o
Sedation:
Used to relieve anxiety, decrease activity, moderate excitement, and generally calm the individual. o
Hypnosis (sleep):
Used to produce drowsiness and aid in the onset and maintenance of sleep. o
General anesthesia:
Used to induce general anesthesia, which is a state of unconsciousness with an absence of pain sensation.
The interaction between sedative-hypnotic agents with other CNS depressants (e.g., alcohol, some antihistamines) are clinically important and can be dangerous.
Mechanism of Action of Sedative-Hypnotics
The major excitatory neurotransmitter in the brain is glutamate. o
When a person is anxious or having difficulty sleeping, some therapies aim to depress overall brain activity, by decreasing glutamate-induced nerve firing.
This can be accomplished by increasing inhibitory signaling in the brain. o
Most of the sedative-hypnotic drug classes work in this manner.
Drug class:
A class of drugs is a group of drugs that have the same mechanism of action and similar pharmacological properties.
For example, thiopental, secobarbital, and phenobarbital are all drugs that fall under the barbiturate class of drugs.
Without sedative-hypnotics:
o
Most brain activity involves excitatory neurons. o
These excitatory neurons release the neurotransmitter glutamate. o
Neurons “fire” when the excitatory inputs exceed inhibitory inputs. 1
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With sedative-hypnotics o
Inhibitory signals from GABA neurons increase with most sedative-hypnotics, resulting in decreased glutamate nerve firing. Video: GABA Signaling
GABA is the primary inhibitory neurotransmitter in the CNS. o
It causes inhibition by binding to and selectively opening chloride channels. o
These 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. o
When GABA binds to and opens the chloride channel, chloride ions flow into the postsynaptic neuron. o
The influx of chloride ions makes it harder for the postsynaptic neuron to transmit incoming messages to other neurons, thereby depressing CNS neuronal signaling.
Each GABA
A
receptor subunit has four transmembrane-spanning regions. o
The receptor itself is a pentamer, with two alpha subunits, two beta subunits, and one gamma subunit. o
When there is nothing bound to the GABA binding site, the channel is closed. o
When a drug (such as a sedative-hypnotic) binds to the GABA binding site, the channel opens and
allows an influx of chloride ions into the neuron.
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Drugs that Bind to the Chloride Channel
Most sedative-hypnotics modulate the chloride ion channel in the brain and spinal cord, but each binds to a different site on the chloride channel, as indicated in the diagram.
The result is an increase in synaptic inhibition and, thus, a dampening of neuronal responses. o
In essence, they enhance the inhibitory effect of GABA. Benzodiazepines
The benzodiazepines are among the most widely prescribed drugs in the world. o
Just over 3% of Canadians use a benzodiazepine at least once a year for medical reasons.
Many different types of benzodiazepines exist, and their therapeutic effects and duration of action differ, however, their mechanism of action is the same.
Characteristics:
o
Routes of administration:
Benzodiazepines are usually taken as a capsule or tablet, but some are available for intravenous or intranasal use.
o
Mechanism of action:
Activation of the benzodiazepine receptor increases the frequency of the opening of the chloride channel.
o
Therapeutic effects:
The therapeutic or desirable effects of benzodiazepines are relaxation, calmness (i.e., they can decrease aggression), and relief from anxiety or tension.
They also produce skeletal muscle relaxation and have anticonvulsant effects.
Some benzodiazepines are effective hypnotics.
Benzodiazepines also have minimal suppression of REM-type sleep, which is the type of sleep that allows you to feel rested when you wake.
Lethality of Benzodiazepines
The benzodiazepines are among the drugs most commonly involved in overdose. o
Fortunately, they have a very high therapeutic index and, therefore, a wide margin of safety which means that deaths from overdose are very rare.
Death has occurred following ingestion of enormous doses, rapid intravenous injection of a large dose, or when taken in combination with other sedating drugs (e.g., alcohol).
A key benefit of the benzodiazepines is that an antidote exists to reverse its effects in the event of an overdose. 3
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o
The antidote is called flumazenil, a benzodiazepine receptor antagonist that blocks the effects of benzodiazepines.
o
When benzodiazepines are taken in overdose, flumazenil can be administered as an antidote.
Adverse Effects of Benzodiazepine Use
Benzodiazepines are associated with adverse effects.
Adverse Effects of Short-Term Benzodiazepine Use
CNS:
o
Adverse effects may include drowsiness, lethargy, fatigue, and impairment of thinking and memory. o
For CNS depression, what is considered an adverse effect depends on the targeted therapeutic effect.
For example, if the therapeutic goal is anti-anxiety, drowsiness may be an adverse effect,
however, it would be considered a therapeutic effect if the goal is sedation.
Breathing:
o
Respiratory depression has been observed following rapid intravenous administration of benzodiazepines.
Motor coordination:
o
Moderate doses of all benzodiazepines can impair motor coordination and driving. o
Patients taking these drugs during the day should refrain from driving or operating dangerous machinery. o
These responses are exaggerated as the dose is increased.
Adverse Effects of Long-Term Benzodiazepine Use
The effects of long-term use vary between individuals. o
Some individuals can take large amounts of benzodiazepines 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.
Benzodiazepine Use in Special Populations
Pregnant/chestfeeding:
o
Benzodiazepines cross the placenta and distribute into the fetus. o
If they are administered in the first trimester, they result in a small but significant risk for fetal abnormalities.
o
Benzodiazepines are secreted into the milk, exposing nursing infants to therapeutic or toxic doses
of the drug, and can result in sedation or death.
Older adults:
o
Benzodiazepines can produce cognitive dysfunction in older adults and, as a result, should be used with caution, if at all, in this age group. o
Benzodiazepines are metabolized more slowly in older adults than in young adults, often leading to over-sedation, falls, and injury.
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Benzodiazepines: Potential for Misuse and SUD
Benzodiazepine use can result in tolerance, withdrawal, and addiction.
Misuse of benzodiazepines for recreational purposes does occur, typically in combination with alcohol to enhance the CNS depression effects of both.
Misuse potential:
o
Benzodiazepines have weaker reinforcing properties than other drugs, including barbiturates, alcohol, opioids, and stimulants. o
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.
Tolerance:
o
Tolerance can develop to the sedative effects and impairment of coordination, the anxiolytic effect (less common) or the euphoric effects (occasionally).
Anxiolytic:
A drug, medication, or other intervention that reduces anxiety.
o
However, the magnitude of tolerance that develops to benzodiazepines does not produce clinical concerns. o
A high degree of cross-tolerance occurs among the benzodiazepines and other sedative-hypnotic drugs, such as barbiturates and alcohol, as they all modulate the chloride channel in the CNS.
Withdrawal:
o
A mild but distinct withdrawal can occur after therapeutic use, exhibiting anxiety, headache, and insomnia. o
Following chronic use (i.e., one year or more) sudden discontinuation may lead to more pronounced withdrawal symptoms, such as agitation, paranoia, seizures, and delirium. o
These extreme symptoms occur much less frequently than with barbiturates.
Addiction:
o
Addiction may develop in some individuals, but not all, and depends on a multitude of factors including genetics and the environment.
Benzodiazepine in Sports
How do benzodiazepines reduce an athlete’s anxiety?
o
Benzodiazepines increase CNS depression in a dose-dependent manner. o
Therefore, at low doses, they act as anti-anxiety agents.
Barbiturates
Classification based on duration of action:
o
Long-acting (1-2 days)
o
Short-acting (3-8 hours)
o
Ultra-short acting (20 minutes)
Barbiturates are an older class of drugs that have generally been replaced by safer, more effective sedative-hypnotics.
Properties:
o
Routes of administration:
Barbiturates are administered in different ways depending on what they are being used to treat. 5
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For epilepsy, barbiturates are administered orally.
For anesthesia, they are administered intravenously.
o
Mechanism of action:
Activation of the barbiturate receptor increases the duration of the opening of the chloride channel.
They demonstrate the full spectrum of dose-dependent CNS depression:
Anti-Anxiety → Sedation → Hypnosis → General Anesthesia → Death
o
Therapeutic uses:
In low doses, barbiturates usually result in the beneficial effects of tranquility and relaxation.
They will also induce sleep if the dose is sufficient.
Clinical uses of barbiturates are limited.
Ultra-short acting and short-acting barbiturates can be used to induce anesthesia.
Some long-acting agents can be used as antiepileptics.
o
Lethality:
Barbiturates have been replaced for the most part by newer and safer drugs because of their low therapeutic index and potential for lethality.
Lethality due to depression of respiration is common, especially when combined with alcohol.
While respiratory depression is dose-dependent, the lethal dose of barbiturates varies between individuals.
In addition, a specific antidote for barbiturate poisoning does not exist.
Death can also occur during barbiturate withdrawal.
Adverse Effects of Barbiturate Use
Unfortunately, barbiturates also have numerous adverse effects. o
In general, they suppress REM-type sleep.
REM sleep is essential so that one does not wake up with the feeling of "not having slept" or the feeling of a hangover.
Short-term use:
o
In low doses, usually result in mild euphoria and reduced interest in one’s surroundings. o
May cause dizziness and mild impairment of motor coordination (especially fine motor dexterity).
o
May cause a pleasurable state of intoxication and euphoria as the dose of drug is increased. o
In high doses, depress the cardiovascular system, slowing the heart and lowering blood pressure.
Long-term use:
o
Chronic inebriation. o
Memory, judgement, and thinking are all impaired. o
Individuals often exhibits hostility and mood swings, including depression.
Barbiturates: Potential for Misuse and SUD
Barbiturates are prescribed much less frequently now than they were 40 years ago, but illicit use continues
to be a problem. o
They are also sometimes combined with other drugs such as opioids, amphetamines, and alcohol.
Potential for misuse:
6
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o
Barbiturates should be avoided, as the potential for misuse is equal to or greater than alcohol.
The pleasurable effects of some of barbiturates give significant degree of reinforcement.
o
Barbiturates are sometimes injected to obtain a “rush effect”.
The inherent harmfulness is very high due to the risk of death from respiratory depression or from withdrawal.
Tolerance:
o
Tolerance to barbiturates can develop. o
A high degree of cross-tolerance occurs between barbiturates and other sedatives (e.g., benzodiazepines).
Withdrawal:
o
Withdrawal occurs after discontinuation of chronic use. o
Symptoms initially appear as tremors, anxiety, weakness, and insomnia, as well as postural hypotension.
Postural hypotension:
A form of low blood pressure in which a person's blood pressure falls when suddenly standing up or stretching.
o
These symptoms may progress to include seizures, delirium, visual hallucinations, and a high body temperature.
o
Barbiturates must be withdrawn slowly under medical supervision.
Addiction:
o
Addiction can result from regular use, irrespective of the dose. o
Those with addiction will crave the drug and a feeling of panic may occur if they cannot get an adequate supply. o
Craving often persists long after use has stopped.
Comparison: Benzodiazepines vs Barbiturates
Zopiclone and the Benzodiazepine-Like Drugs
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Benzodiazepine-like drugs are another class of sedative-hypnotics used to treat problems like anxiety or difficulty sleeping.
Benzodiazepine-like drugs, such as zopiclone and zolpidem, bind to a subset of the GABA receptors and cause sedation.
This class of drugs acts similarly to the benzodiazepines, however, has an advantages over the benzodiazepines as a hypnotic, as they disturb sleep patterns (REM sleep) even less than the benzodiazepines.
Benzodiazepine-like drugs appear to have more sedative effects as compared to anxiolytic effects.
As with benzodiazepines, these drugs should be used with caution in older adults.
Video: Drugs that Bind to the Chloride Channel
GABA receptor:
o
Chloride ion channel, with its several subunits. o
The chloride channel, depending on location in the body, may be comprised of different subunits,
which may in turn give different drug responses. o
When GABA binds to the GABA
A
receptor, it opens the chloride channel, chloride moves inward, and there is inhibition of the neuronal activity.
Benzodiazepines:
o
By binding to benzodiazepine receptors, they facilitate the actions of GABA and increase CNS inhibition.
o
They enhance GABA receptor mediated opening of the chloride channel causing increased inhibition.
Flumazenil:
o
Benzodiazepine receptor antagonist. o
It will block the enhanced GABA responses produced by the benzodiazepines.
Benzodiazepine-like drugs:
o
Zopiclone:
Binds to the chloride ion channel in a similar location to the benzodiazepines.
Like the benzodiazepines, it drug increases chloride channel opening induced by GABA.
o
Zolpidem:
Has a discrete binding site on the chloride channel.
Like the benzodiazepines, it increases chloride channel opening induced by GABA.
Barbiturates:
o
They have separate and distinct binding sites on the chloride channel from the benzodiazepines. o
Unlike the benzodiazepines, the barbiturates do not act by enhancing GABA but rather bind to the GABA receptor directly opening the chloride channel, resulting in increased CNS inhibition.
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Activity: Therapeutic Uses of Sedative-Hypnotics
Buspirone
Does not act on the GABA receptor, but rather at the serotonin 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.
As such, this drug may be prescribed instead of a benzodiazepine or benzodiazepine-like drug when the individual is already taking other CNS depressant drugs and there is a concern of additive effects.
Buspirone is sold under the brand name Buspar.
End of Section 01 Practice Quiz
Which one of the statements listed correctly applies to sedative-hypnotics?
o
Flumazenil is a GABA receptor agonist. o
Zopiclone, a benzodiazepine-like drug, which has minimal effects on sleep patterns.
Zopiclone and the other benzodiazepine-like drugs have been shown to disturb sleep patterns even less than the benzodiazepines.
o
Benzodiazepines act on serotonin receptors. o
Barbiturates are rarely, if ever, associated with lethality.
Which one of the options listed is a pharmacological property of the benzodiazepines?
o
The benzodiazepines often causes lethality. o
The benzodiazepines do not exhibit cross-tolerance with barbiturates. o
Tolerance occurs to the sedative and hypnotic effects of the benzodiazepines.
Tolerance does not appear to be a problem for the clinical use of benzodiazepines, however, it can develop to the sedative effects and impairment of coordination, the anxiolytic effects, or the euphoric effects.
o
Addiction does not develop to the benzodiazepines. 9
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Section 02: alcohol
Introduction to Alcohol
Alcohol (ethanol) is one of the three most used non-medical drugs in Canada, alongside caffeine and nicotine.
While alcohol consumption has decreased in the past decade, alcohol still produces more health problems
and deaths than all illicit drugs combined, resulting in enormous healthcare and social costs.
The major reason for the extensive use and misuse of alcohol is its ready availability and the permissive attitudes of society. o
However, societal attitudes to the misuse of alcohol, at least to drinking and driving, have undergone substantive changes since 1970.
ADME of Alcohol
Alcohol is a CNS depressant that works by slowing down brain functioning and neural activity.
Ethanol is the only type of alcohol that can be safely consumed.
Absorption of Ethanol
Ethanol is absorbed rapidly from the stomach (where 20% is absorbed) and the upper small intestine (where 80% is absorbed).
The overall absorption rate for a given dose of ethanol is affected by: o
Stomach-emptying time, or the time required for the alcohol to reach the small intestine. o
Ethanol concentration in the gastrointestinal (GI) tract and the presence of food.
The time from the last drink to the maximal blood alcohol concentration ranges from 30 to 90 minutes.
Distribution of Ethanol
Ethanol distributes throughout the total body water and readily gains access to the brain.
Ethanol can also readily transfer across the placenta and distribute throughout a developing fetus.
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Metabolism of Ethanol
Genetic Variability in Ethanol Metabolism
Genetic variants in the gene that codes for alcohol dehydrogenase (ADH) exist. o
Some individuals rapidly convert alcohol to acetaldehyde, causing an accumulation of acetaldehyde in the body. o
This is considered protective against alcoholism since accumulated acetaldehyde produces unpleasant side effects, such as a flushed face.
The second enzyme in the pathway, aldehyde dehydrogenase (ALDH), also exhibits genetic variability in a population.
Rate of Ethanol Metabolism
The metabolism of alcohol is unusual, in that it occurs at a constant rate, irrespective of the blood alcohol concentration (BAC).
o
Constant rate:
In other words, a constant amount of alcohol is metabolized each hour.
This is because alcohol dehydrogenase (ADH) becomes rate-limiting, or saturated, at 20 mg of alcohol per 100 mL of blood. 11
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o
Therefore, the body rate of ethanol metabolism is about 120 mg ethanol/kg body weight/hour.
That is, a 70 kg person metabolizes one drink per hour.
Excretion of Ethanol
Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver. o
The remaining 5% is excreted in the breath, urine, and sweat.
Breathalyzers are used to measure the level of intoxication via excretion of ethanol in the breath.
Video: Summary of Metabolism of Ethanol
Alcohol, or ethanol, is primarily metabolized by the enzyme alcohol dehydrogenase into acetaldehyde. o
Alcohol dehydrogenase is located mainly in the liver, but there is also some in the stomach.
Predominantly, alcohol is metabolized in the liver. o
However, in men, some alcohol metabolism also occurs in the stomach, but less alcohol metabolism occurs in the stomachs of women.
Alcohol converted to acetaldehyde by alcohol dehydrogenase is the primary mechanism of alcohol metabolism. o
However, once the blood alcohol concentration reaches 100mg/dL, which is equivalent to a 0.1% blood alcohol concentration, then the liver runs out of the cofactor NAD+, inhibiting this reaction from occurring.
To compensate for this, the body has an alternative method to metabolize alcohol, which involves the microsomal ethanol oxidizing system (MEOS), which consists of some enzymes from the cytochrome P450 family. o
So, during chronic alcohol consumption, or when the blood alcohol concentration is 0.1% or greater, the microsomal ethanol oxidizing system is induced, converting alcohol to acetaldehyde.
Acetaldehyde is then oxidized in the liver to acetate by the enzyme aldehyde dehydrogenase.
Acetate can be further metabolized into carbon dioxide and water, or acetate can be used to form acetyl-
CoA.
Interestingly, it is the buildup of acetaldehyde in your body that causes the unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache that you experience during a hangover.
Activity: Metabolism of Ethanol
The rate limiting step in ethanol metabolism is the first step in which alcohol dehydrogenase converts ethanol to acetaldehyde.
Additionally, the MEOS pathway contributes to ethanol metabolism when there are high levels of ethanol in the body and alcohol dehydrogenase is saturated.
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Medical Uses of Ethanol
Alcohol sponges applied topically to treat fever.
As a skin disinfectant.
As an antidote in the treatment of methanol (wood alcohol) poisoning.
As a hand sanitizer, particularly since the SARS epidemic. o
More recently, hand sanitizers have been widely used to reduce the risk of infection during the COVID-19 pandemic. CNS Effects of Ethanol
Ethanol is classified as a general CNS depressant.
o
The CNS effects of ethanol are proportional to the blood alcohol concentration (BAC), shown in the table. o
To convert BAC in mg/dL to a BAC represented as a percentage of weight/volume, you simply move the decimal place three places to the left.
For example, a BAC of 100 mg/dL is equal to 0.1 g per 100 mL of blood or 0.1% (weight/volume)
BAC and Driving
The risk for a driver getting in an accident increases exponentially in relation to their BAC, as shown in the graph on this slide.
In 2014, approximately 29% of all fatal car accidents in Canada were associated with alcohol, or alcohol and drugs combined.
In Canada, for new drivers and drivers under the age of 22, a zero tolerance BAC applies.
For all other drivers, having a BAC of 0.05% is a provincial offense, and having a BAC of 0.08% is a criminal offense.
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Mechanism of Action of Alcohol
Alcohol affects a large number of membrane proteins that participate in signaling pathways. o
However, it is thought that alcohol works through one main mechanism by binding to the chloride ion channel and augmenting GABA-mediated neuronal inhibition.
The binding site for alcohol is different from the other GABA agonists.
The interaction of alcohol with the chloride ion channels on dopaminergic neurons in the reward areas of the brain may explain the reinforcing effects of the drug.
Effects of Short-Term Use of Alcohol
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Adverse Effects of Short-Term High Dose Alcohol Use (Binge-Drinking)
Memory loss:
o
This is the phenomenon where the individual does not remember events while under the influence of alcohol. o
This can be very frightening and may result in the individual seeking help.
Psychiatric effects:
o
Heavy drinking often leads to depression, irritability, and over-sedation. o
The negative mood states, in concert with impaired judgement and impulsiveness, may lead to self-harm or acts of violence.
Overdose:
o
Excessive short-term alcohol consumption can also result in overdose, which is characterized by respiratory depression, coma, and death. o
A number of comatose drinkers die each year after aspirating their own vomit.
Adverse Effects of Chronic High Dose Alcohol Use
CNS:
o
A number of neurological and mental disorders are associated with chronic alcohol misuse. o
One such disorder is alcoholic dementia, which is a decrease in cognitive functioning affecting memory, judgement, and thinking. o
Alcohol damages axons of neurons within the brain, resulting in fewer connections between neurons.
Cardiovascular:
o
High chronic doses of alcohol can lead to alcoholic cardiomyopathy.
Cardiomyopathy:
The destruction of, or poor heart muscle.
o
An increased incidence of hypertension and stroke is also apparent.
Liver:
o
Chronic high doses of alcohol leads to alcoholic liver disease, a major cause of hospitalization and deaths in North America. 15
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o
At early stages, this can be reversible with alcohol abstinence, but at later stages it is irreversible and liver function is severely impaired.
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 (FASD).
o
Fetal Alcohol Spectrum Disorder (FASD):
A group of conditions that can occur in a person whose mother drank alcohol during pregnancy, including fetal alcohol syndrome (FAS).
o
The incidence of FASD is about 9 per 1000 live births.
A safe dose of ethanol in pregnancy has not been established. o
Therefore, alcohol abstinence during pregnancy is recommended.
Alcohol and Drug Interactions
Drug-drug interactions with alcohol can occur in two ways depending on whether the drug and alcohol are
in the body at the same time or not.
Alcohol use during drug therapy:
o
Ingestion of ethanol and other CNS depressants leads to an additive or synergistic effect of CNS depression. o
Inhibition of metabolism of certain drugs (e.g., sedative-hypnotics).
Chronic alcohol use before drug therapy:
o
Only occurs if there is no co-existing ethanol-induced liver injury. o
Increases the activity of metabolizing enzymes in the liver, resulting in increased metabolism of certain drugs (e.g., sedative-hypnotics). Alcohol: Potential for Misuse and SUD
Alcohol produces both reinforcing and sedating effects in the CNS, which contributes to its potential for misuse and SUD.
Potential for misuse:
o
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 ethanol’s misuse potential. 16
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o
The inherent harmfulness of alcohol is moderate.
Death can occur from high dose acute ethanol ingestion and chronic ingestion can have long-term effects on health.
Ethanol is less inherently harmful than methanol.
Tolerance:
o
Tolerance to chronic consumption of ethanol does occur. o
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:
o
Sedative-Hypnotics:
A higher dose of a sedative-hypnotic drug is required for the desired therapeutic effect. o
General Anesthetics:
A higher dose of anesthetic agent is required for surgical anesthesia in someone who has
developed tolerance to alcohol.
Withdrawal:
o
Withdrawal from ethanol produces compensatory excitation of the CNS (e.g., arousal, stimulation). o
In severe cases of ethanol withdrawal, delirium tremens (DTs) may occur, which can involve convulsions, coma, and possibly death.
Addiction:
o
A compulsive desire to seek, obtain, and drink ethanol exists. o
Addiction could be the most powerful factor in chronic use of ethanol, contributing to SUD.
Treatment of Alcohol Withdrawal
Initial therapy of alcohol withdrawal syndrome is to maintain fluid and electrolyte balance, and to prevent seizures.
More severe alcohol withdrawal can be treated effectively by oral administration of diazepam, a benzodiazepine.
What do you think is the pharmacological basis for using benzodiazepines to treat alcohol withdrawal symptoms?
o
The withdrawal syndrome following cessation of use of a particular drug is suppressed by administration of a second drug of similar mechanism of action. o
Following successful withdrawal of the patient from ethanol, the dose of diazepam is decreased gradually over the course of several days to weeks.
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Drugs Used to Treat Alcohol Use Disorder
A number of drugs can be used to treat alcohol use disorder.
These drugs are used as pharmacological adjuncts to psychotherapy or group therapy and are referred to as alcohol-deterrent or alcohol-sensitizing drugs.
Naltrexone:
o
Opioid antagonist.
o
Effective in the treatment of alcohol addiction. o
Diminishes the craving for ethanol and assists in the maintenance of abstinence. o
Blocks the activation of dopaminergic reward pathways in the brain.
Summary: Alcohol
End of Section 02 Practice Quiz
One pharmacological property of alcohol is that it is:
o
Classified as a C N S stimulant. o
Transferred across the placenta with some difficulty. o
Rapidly absorbed from the stomach and intestine.
Alcohol is rapidly absorbed from the stomach (20%) and intestine (80%).
o
Able to produce tolerance but not withdrawal.
Which step of alcohol metabolism is considered rate-limiting?
o
Conversion of alcohol to acetaldehyde by alcohol dehydrogenase.
Alcohol dehydrogenase is the rate-limiting step in alcohol metabolism. o
Conversion of alcohol to acetaldehyde by the MEOS. o
Conversion of acetaldehyde to acetate by aldehyde dehydrogenase. 18
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Conversion of acetate to carbon dioxide and water by a number of tissues. Section 03: cannabis
Introduction to Cannabis
The term cannabis refers to the drug-containing forms of the hemp plant, Cannabis sativa
, which is an herbaceous annual.
60 chemical compounds are found only in Cannabis sativa
, and these compounds are referred to as cannabinoids (CB). o
Of these compounds, l-trans-Δ9-tetrahydrocannabinol (THC), is the most potent psychoactive agent in cannabis and accounts for most, but not all, of the psychoactive effects.
History of Cannabis
2700 BCE-1800 CE: o
Cannabis plants were used for manufacturing rope. Cannabis was used for its mild intoxicating effects.
1920s: o
Public concern was raised over the effects of cannabis on individuals and society. o
Legislation was enacted to outlaw the use of cannabis, which was considered a narcotic.
Narcotic:
A drug that affects behaviour or mood consumed for non-medical reasons.
1960s:
o
Throughout the 1960s, use of cannabis increased. o
This is purported to be driven by the cold war and the changing political and cultural climate.
1978: o
A USA-sponsored project using the herbicide paraquat was initiated in an attempt to destroy cannabis crops in Mexico.
It failed. o
USA citizens were smoking cannabis products containing paraquat, which can produce lung toxicity.
1997: o
An Ontario court dismissed charges related to possession and cultivation of cannabis on the basis that the individual was using it to control epilepsy that was not controlled by conventional drug therapy. o
Canada changed the law to allow the cultivation of some varieties of cannabis that contain very small amounts of THC for use in the manufacture of rope, clothing, and other hemp products. o
Farmers must obtain a special license to grow hemp.
2005: o
Health Canada supported trials on the medical use of cannabis.
2012: o
Recreational use of cannabis was legalized in Washington.
2018:
o
In the fall of 2018, recreational cannabis became legal in Canada.
19
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PHAR 100
Classification of Cannabis
Pharmacological:
o
Cannabis is classified as a CNS depressant, euphoriant, and hallucinogen (although the hallucinogenic properties only occur at high doses).
Legal: o
As of October 17, 2018, cannabis became legal in Canada.
Administration of Cannabis
Cannabis is a dried flowering plant that is typically smoked or inhaled.
Extracts containing concentrated amounts of cannabinoids, typically in oil, can be administered by vaping or through oral consumption.
o
Vaping:
Inhalation of aerosolized extracts, usually containing other chemicals, that have been heated via an electronic device (i.e., e-cigarette).
Video: Mechanism of Action of Cannabis
The mechanism of action of cannabis is not fully understood.
Type 1 cannabinoid receptors (CB1):
o
Receptors located in the brain and spinal cord.
o
THC binds specifically to these receptors.
o
When activated by anandamide or THC, CB1 inhibits the release of excitatory neurotransmitters.
This explains the reduction in cognitive function and CNS depressant effects seen with THC.
Anandamide:
o
Endogenous ligand for CB receptors involved in learning and memory processes. o
Considered a retrograde transmitter, meaning that it is released from the postsynaptic neuron and influences the presynaptic neuron, which is opposite to the way most transmitters work.
Remember, most transmitters are released from the presynaptic neuron and bind to receptors on the postsynaptic
neuron. o
Anandamide is released from the
postsynaptic neuron, diffuses across the
synaptic cleft, and binds to the type 1
cannabinoid, or CB1 for short, receptors. o
Activating the CB1 receptors inhibits the
release of excitatory neurotransmitters,
such as glutamate, into the synaptic cleft.
Cannabis:
o
Binds to CB1 receptors on the presynaptic
neuron, and thereby inhibiting the release
of excitatory neurotransmitters. o
The overall effect is depression of the
central nervous system.
20
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PHAR 100
Cannabinoid Receptors
CB1 receptors:
o
A large number of CB1 receptors are in the brain, more than any other receptor. o
THC is not a very effective agonist, but as a large number of receptors exist, it does produce a response.
CB1 receptors in the cerebral cortex mediate the distortions of time, colour, sound, and taste.
They also mediate the decrease in cognitive function and concentration.
CB1 receptors in the hippocampus may account for changes in memory and learning. o
No CB1 receptors are present in the brain stem, thus, cannabinoids do not depress respiration, explaining the relative non-lethality of the drug.
CB2 receptors:
o
Only found outside the CNS. o
They do not appear to be involved in the psychoactive effects of THC, but they may be involved in
inflammation. o
The binding of THC to CB2 receptors on lymphocytes is thought to be responsible for the immunosuppressive properties of THC.
Lymphocyte:
A type of white blood cell.
ADME of THC
Absorption:
o
THC is commonly inhaled or ingested. o
The method of administration influences its absorption:
Inhaled:
The absorption of THC from cannabis smoke is rapid and the onset of action is almost immediate.
The effect lasts three to four hours.
Ingested:
When THC is absorbed after oral administration, the absorption occurs slowly and is incomplete.
The onset of action will be is delayed 30 to 60 minutes.
The effect is less than that from smoking cannabis.
Distribution:
o
Following inhalation, THC rapidly distributes throughout the body, especially to tissues with high blood perfusion such as the lung, heart, brain, and liver. o
THC also rapidly crosses the placenta. 21
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o
These processes are much slower following oral ingestion given the slow absorption of this route of administration. o
THC is highly lipid soluble and over time will be stored in adipose tissues.
Metabolism:
o
THC is metabolized slowly. o
The metabolites of THC can be measured in drug tests, so those consuming cannabis chronically may test positive for the metabolites weeks after use has stopped.
Excretion: o
THC has a half-life of approximately 30 hours. o
However, the elimination of THC from adipose tissue may take longer.
Effects of Short-Term Cannabis Use
CNS:
o
Relaxation and drowsiness. o
A feeling of well-being and euphoria. o
Impaired motor coordination. o
Increased appetite. o
As the dose is increased, a person may experience pseudo-hallucinations, a running together of senses, and impaired judgement and coordination.
In some cases, a toxic psychotic reaction may occur.
Pseudo-hallucinations:
The person knows that it is a hallucination.
Cardiovascular system:
o
Increased heart rate. o
Increased blood flow to the extremities. o
Postural hypotension
(may occur).
GI tract: o
Increased appetite. o
Dryness of the mouth and throat.
Other:
o
Reduction of sex drive in males, as THC may reduce testosterone levels. o
Disruption of the ovarian cycle by THC in females. o
A hangover, similar to that with alcohol, when the drug wears off. Question: Short-Term Effects of Cannabis on Driving
What short-term effects of THC on the body would interfere with driving a vehicle?
o
Motor coordination, tracking, perception, and vigilance are all impaired under the influence of THC and interfere with the safe functioning of a vehicle.
o
Driving while impaired is illegal and dangerous.
Performance on the road is impaired when driving under the influence of THC and the degree of disruption is dose-dependent.
Alcohol and THC, used simultaneously, will intensify the adverse effects of each other on driving performance.
22
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Effects of Long-Term Cannabis Use
Psychological:
o
Occasional low dose:
Does not appear to be associated with harmful psychological effects.
o
High doses:
Significant psychological problems occur over time such as loss of short-term memory, lack of concentration, and loss of ability in abstract thinking.
Amotivational syndrome is characterized by these psychological problems, as well as loss
of ambition and emotional flatness.
This syndrome usually disappears upon cessation of drug use, suggesting that it represents chronic intoxication.
o
Permanent effects:
The permanent effects of long-term cannabis use are currently unknown.
Some data suggests that structural changes do occur in the brain that may be associated with impairment of memory and learning.
Cardiovascular:
o
Cardiovascular effects of cannabis are usually reversible.
o
Changes in blood pressure do not appear to be serious, but an increase in heart rate can be a potential problem for those with heart disease.
Respiratory:
o
A number of respiratory symptoms are associated with smoking cannabis. o
Symptoms include bronchitis, asthma, sore throat, and chronic irritation of and damage to membranes of the respiratory tract.
These symptoms are additive with the simultaneous use of tobacco and cannabis. o
Smoking cannabis can be damaging in the long-term because of the higher concentrations of tars and carcinogens present in cannabis smoke compared to tobacco smoke.
Cannabis is typically inhaled deeply and held in the lungs in order to maximize the absorption of THC and other cannabinoids.
This also enhances the amount of tars and carcinogens absorbed. o
The incidence of lung cancer and chronic obstructive pulmonary disease (COPD) are both increased with long-term use of smoked cannabis.
These are the most serious effects of long-term use.
Fertility: o
Males:
Long-term cannabis use can lead to decreased sperm count. o
Females:
Long-term cannabis use can cause follicle stimulating hormone and luteinizing hormone to be reduced, and cycles can potentially occur without ovulation (i.e., no release of an egg from the ovary). o
Pregnancy:
THC freely crosses the placenta and can cause developmental delays leading to cognitive
deficits, impulsiveness and inattention, and hyperactivity.
It is difficult to distinguish the effects of THC from those of concurrent drug use, diet, and overall poor prenatal care.
The drug should be avoided in pregnancy. 23
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PHAR 100
Question: What About Vaping?
Do you think vaping is a safe way to consume cannabis without risking damage to your respiratory system?
o
No, vaping is associated with respiratory risks as well.
Electronic cigarette (e-cigarette) use and vaping have significantly increased in recent years.
In 2019, e-cigarette or vaping product use-associated lung injury (EVALI) was recognized as a unique disease entity. o
The rapid rise of individuals with EVALI has resulted in it being labeled a public health crisis, with over 2800 cases of hospitalizations and 68 deaths as of March 2020.
Medical Uses of Cannabis
As more information is obtained on the functions of anandamide and its receptors, it is likely that drugs that bind to the CB1 and CB2 receptors will be developed that are more effective and less toxic than THC.
The challenge for pharmacological use is to separate the beneficial effects (e.g., analgesia) from the psychotropic effects.
o
Analgesia:
A loss of sensation of pain due to an interruption of nervous system pathways between sense organs and the brain.
Cannabis is not a Health Canada approved therapeutic product. o
However, healthcare practitioners may authorize the use of cannabis for the relief of a number of symptoms which have not responded to conventional medical treatments.
o
For example, medical marijuana can be prescribed for the prevention of nausea and vomiting associated with anticancer drugs.
That being said, synthetic THC derivatives are generally more selective than cannabis in treating nausea.
Therefore, these, and other more effective anti-nausea medications, are generally used instead of cannabis.
Cannabis: Potential for Misuse and SUD
The misuse potential of cannabis products is low to moderate, as euphoria and reinforcement is less compared to some other drugs (e.g., cocaine). o
The inherent harmfulness of cannabis is also low, especially with infrequent use.
o
The greatest concerns may be automobile accidents, accidental exposure to children, and the lung effects associated with smoking.
Tolerance:
o
Occurs to:
The psychoactive properties of THC.
The effects on the cardiovascular system.
The impairment of performance and cognitive function.
Withdrawal:
o
Upon termination of long-term high dose use, a mild withdrawal syndrome occurs. o
Withdrawal is characterized by:
Sleep disturbances
24
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Irritability
Loss of appetite
Nervousness
Mild agitation
Upset stomach
Sweating
Addiction:
o
Develops as a persistent craving for the drug. o
The risk of addiction is more evident in those who use cannabis to control psychological stress.
Summary: Cannabis
Mechanism of action:
Effects:
Misuse:
End of Section 03 Practice Quiz
The mechanism of action of cannabis is best described as? o
Cannabis binds to CB2 receptors on postsynaptic neuronal membranes in the brain. o
Cannabis binds to CB1 receptors on postsynaptic neuronal membranes in the periphery. 25
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o
Cannabis binds to CB1 receptors on presynaptic neuronal membranes in the brain.
The mechanism of action of cannabis involves CB1 receptors on presynaptic neuronal membranes.
o
Cannabis binds to CB2 receptors on presynaptic neuronal membranes in the brainstem.
Which receptor does THC bind to? o
Dopamine o
Cannabinoid
THC binds to cannabinoid receptors.
o
Alpha o
Beta Section 04: opioids
Introduction to Opioids
Opioids are a class of drugs naturally found within the opium poppy plant, Papaver somniferum
.
Drugs obtained from Papaver somniferum
have been used for millennia.
Initially, opium was used as a crude extract, but for the last 200 years it has been used as purified substances, producing clinically used drugs such as morphine and codeine.
Morphine is one of the most useful drugs known to pharmacologists. o
Unfortunately, it is renowned for causing opioid use disorder (OUD).
Classes of Opioids
An opioid is any natural or synthetic substance which exerts actions on the body through binding to the opioid receptors.
Classes:
o
Endogenous opioids
o
Natural opioids
o
Semi-synthetic opioids
o
Synthetic opioids
Endogenous Opioids
Endogenous opioids are not administered drugs, but are opioids made in the body that bind to opioid receptors and exert analgesic effects.
Three families of endogenous opioids:
o
Enkephalins
o
Dynorphins
o
Beta-endorphins (also known as endorphins)
Endogenous opioids affect the perception of pain and the emotional response to pain. o
They may also influence mood and are associated with the reward pathways in the brain.
Natural Opioids
Natural opioids are not made by the human body but are derived from the opium poppy plant.
Morphine:
26
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o
Binds directly to opioid receptors. o
Used clinically to treat severe acute and chronic pain and can cause euphoria.
Codeine: o
Converted to morphine in the body by liver enzymes. o
Morphine is approximately 10 times more potent than codeine. o
A commonly prescribed drug you may be familiar with that contains codeine is Tylenol 3®, a combination of codeine, acetaminophen, and caffeine.
Semi-Synthetic Opioids
Semi-synthetic opioids are slightly altered versions of morphine that are chemically changed to obtain different pharmacological properties (e.g., potency, duration of action, distribution), but typically maintain a very similar effect profile.
Hydromorphone:
o
Clinically used for analgesia. o
Five times more potent than morphine.
Diacetylmorphine:
o
Diacetylmorphine (brand name heroin) is used as part of injectable opioid agonist therapy (iOAT) to manage OUD. o
There are limited other clinical uses of diacetylmorphine, therefore, it is most often synthesized for illicit use. o
Two to five times more potent than morphine.
Synthetic Opioids
Synthetic opioids are not derived from morphine but are chemically synthesized to bind to the opioid receptor.
These drugs may be designed to elicit similar pharmacological responses to morphine (i.e., analgesia, euphoria), or be used for other clinical purposes that are related to the other functions of opioid receptors.
Fentanyl and related compounds:
o
Approximately 100 times more potent than morphine and was designed for treatment of severe acute and chronic pain. o
Illicit synthesis and use of fentanyl, and other new, related, and more potent compounds (i.e., carfentanyl, furafentanyl) contribute to the OUD crisis.
Loperamide: o
Over the counter drug that leverages a common side effect of opioids, constipation, and is used to treat diarrhea. o
The chemical structure of the drug is such that very little enters and remains in the circulation, but instead stays in the intestine or is quickly metabolized. o
This prevents illicit use as it does not cause substantial analgesia or euphoria.
Methadone:
o
Used for analgesia and can be used in the treatment of OUD. o
When used to treat OUD, it prevents withdrawal symptoms, however, does not cause euphoria in a stabilized patient. 27
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Opioid Receptors
Opioid receptors are located in both the central and peripheral nervous systems. o
These receptors are also located in the gastrointestinal tract and are responsible for the constipation caused by opioids.
Three types:
o
Mu:
Mu (μ) 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 receptor is responsible for both effects, it is difficult to obtain drugs with a separation between the two responses.
These receptors are also involved in the compulsive misuse of opioids. o
Kappa:
Kappa (κ) receptors are involved in analgesia, dysphoria, and miosis.
Dysphoria:
o
A state of dissatisfaction or unease.
Miosis:
o
Pinpoint pupils.
o
Delta:
Delta (δ) receptors are involved in analgesia at the level of the spinal cord and brain.
They may also modulate the emotional response to opioids.
Mechanism of Action of Opioids
Morphine and other opioids will block pain pathways in the spinal cord and brain. o
This effect is primarily exerted through activation of mu opioid receptors.
Reduced neurotransmitter release:
o
Opioids prevent pain signals from travelling by reducing neurotransmitter release from presynaptic neurons and reducing the effect on postsynaptic neurons.
Reduced emotional reaction:
o
Opioids reduce the emotional reaction to pain through modulation of the limbic system.
28
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Short-Term Effects of Opioids
Morphine may be taken orally in tablet form, administered intravenously, smoked, or sniffed to produce its
effects.
Analgesia:
o
Opioids, including morphine, produce analgesia and indifference to pain, reducing the intensity of
pain and the perception or reaction to pain. o
There is no ceiling to the intensity of pain which can be relieved. o
Respiratory depression is the limiting factor.
Sedation and hypnosis:
o
Opioids produce sedation and hypnosis, but not as intense as that produced by the CNS depressants. o
Usually, the patient can be aroused but may experience a drowsy, dreamy, mild dozing state. o
All opioid analgesics produce sedation.
Suppression of cough centre:
o
Relief or prevention of cough occurs through suppression of the cough centre in the medulla.
Respiratory depression:
o
Opioids suppress the respiratory centre in the brain stem. o
In particular, the response to respiratory drive by carbon dioxide is blunted. o
The receptors that mediate this effect are mu and delta opioid receptors. o
Depression of respiration is the single most important side effect of the opioids and is usually the cause of death in overdose.
Endocrine effects:
o
Opioids reduce the release of the hormone that is responsible for regulating the release of sex hormones from the hypothalamus. o
This results in a reduction in the production of testosterone, estrogens, and progesterone. o
The overall result is a drop in libido in men.
Miosis:
o
Opioids cause constriction of the pupils of the eyes, or miosis. o
All opioids that gain access to the CNS will cause pinpoint pupils. o
This can indicate that someone has an opioid in their system.
Heart rate and thermoregulation:
o
With high doses of opioids, the heart rate is irregular, body temperature is low, and the skin is cold and clammy.
Decreased intestinal motility:
o
All individuals taking opioids will experience constipation as an adverse effect.
Long-term use: o
Marked physiological deterioration or psychological impairment does not seem to occur with long-term use of opioids.
Therapeutic Uses of Opioids
Relief of severe pain: o
Analgesia is the major use of the opioids. o
For example, opioids may be used to mitigate post-surgical pain and pain experienced by some terminally ill patients. 29
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Treatment of diarrhea:
o
Loperamide is an over-the-counter opioid that is not an analgesic and does not produce withdrawal, but it is useful in controlling diarrhea.
Cough suppression:
o
All opioids are effective cough suppressants, however, better alternatives with lower misuse potential are available.
Opioids: Potential for Misuse
Opioids, such as morphine, are usually taken alone but may be found in combination with other drugs such as cocaine and methamphetamine. o
The misuse potential described on this slide is for opioids alone.
Misuse potential:
o
Most opioids have powerful euphoric effects, which means there’s a large risk for misuse. o
Inherent harmfulness:
Low-moderate doses:
Not very high for morphine.
High doses:
Life threatening.
Those taking illicit opioids are at higher risk as they are not always sure of the actual dose of opioid, and a lethal dose can be administered inadvertently.
Risks of injections: o
Individuals who administer drugs by injection are at higher risk of developing abscesses at the site of administration as well as other infections (e.g., infected heart valves). o
If contaminated needles are used, there is also the risk of spreading pathogens (e.g., hepatitis, HIV).
Overdose:
o
Opioid overdose is a medical emergency.
Overdose of all opioids can produce profound respiratory depression, which can cause death.
Treatment consists of opioid antagonists and support of respiration and other vital functions. o
The opioid antagonist naloxone is primarily used to treat opioid overdose.
Interestingly, naltrexone, another opioid antagonist, is used to treat alcohol use disorder.
Risk of OUD
OUD is a specific type of SUD and can occur after both clinical and non-clinical use of opioids.
Tolerance:
o
Tolerance occurs to most pharmacological effects of opioids, except the constriction of the pupils and the constipating effect. o
It develops more slowly to respiratory depression than to the analgesic effects of the opiates. o
Tolerance reverses in a few days after the opioid is discontinued. o
Cross-tolerance between all opioid analgesics occurs, providing they act on the same receptor.
Therefore, those with a tolerance to morphine will also have tolerance to methadone, as
both drugs bind to opioid receptors.
Withdrawal:
30
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o
A pronounced withdrawal syndrome can occur after opioid discontinuation. o
Opioid withdrawal is not life threatening and manifests as:
Restlessness, anxiety, insomnia
Sweating, fever, chills
Increased respiratory rate
Cramping, retching, and vomiting
Diarrhea o
The specific symptoms, as well as their severity and duration of withdrawal, are determined by the particular drug, chronicity and pattern of use, typical daily dose, route of administration, and whether there is concurrent use of other drugs.
Addiction:
o
Pronounced craving and compulsion for opioids can develop. o
The basis for addiction is the euphoric action of the opioids, resulting in very powerful reinforcement. o
Use of opioids with other psychoactive drugs (e.g., cocaine) can occur in an attempt to achieve an
even greater euphoria.
Opioid Use During Pregnancy
A mother dependent on opioids during pregnancy 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 a specific withdrawal reaction including irritability, sleep disturbances, poor feeding, and occasionally seizures.
The withdrawal may last weeks to months.
Treatment of OUD
In Canada, a few options for treating OUD exist. o
Psychosocial supports, counselling, and treatment of concurrent physical and mental health issues should also be considered to optimize recovery.
Buprenorphine/Naloxone:
o
Buprenorphine is a long-acting synthetic opioid that binds to mu opioid receptors.
Buprenorphine provides enough opioid agonist activity to prevent withdrawal symptoms, while having decreased euphoria and sedation compared to other opioid agonists.
o
In Canada, buprenorphine is combined with the antagonist naloxone.
If injected, the naloxone blocks the opioid receptors, which causes withdrawal symptoms.
When taken sublingually/orally, however, naloxone is mainly broken down before getting
into the circulation and therefore has no significant effects on the individual.
31
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Methadone:
o
Methadone is a synthetic opioid that is effective following oral administration and has a long duration of action. o
The misuse potential of methadone is much lower than other opioids such as morphine, due to a number of factors.
o
As methadone is taken orally, it removes the potential risks of injections.
Oral administration also leads to slower onset of pharmacological effects, and therefore less euphoria.
o
Since methadone is long-acting, it is also taken less often, which again leads to a lower misuse potential.
Summary: Opioids
End of Section 04 Practice Quiz
Why is methadone used in the treatment of OUD? o
In combination with naloxone, it prevents the binding of opioids to the opioid receptor. o
It is more effective than illicit opioids in relieving pain, thus deterring illicit opioid use. o
It blocks mu opioid receptors in the case of overdose, preventing respiratory depression. o
It transfers individuals with OUD to an opioid that is long-acting and doesn’t cause euphoria in stabilized patients.
Methadone is used to treat OUDs because it doesn’t cause euphoria.
Which one of the options listed is an adverse effect of opioids? o
Mydriasis (dilation of pupil) o
Respiratory depression o
Diarrhea o
High body temperature 32
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