PHAR 100 - Unit 3

INTRODUCTION TO SEDATIVE-HYPNOTIC AGENTS

• Sedative-hypnotic agents are CNS depressants

• The magnitude of CNS depression produced by a drug at a particular dose determines what effect the agent produces

• Magnitudes of CNS depression from low dose to high dose:

  • Anti-anxiety: used to treat anxiety disorders, such as generalized anxiety disorder and obsessive compulsive disorder

  • Sedation: used to relieve anxiety, decrease activity, moderate excitement, and generally calm the individual

  • Hypnosis (sleep): used to produce drowsiness and aid in the onset and maintenance of sleep

  • General anesthesia: used to induce general anesthesia, which is a state of unconsciousness with an absence of pain sensation

MECHANISMS OF ACTION OF SEDATIVE-HYPNOTICS

• Recall: 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, by decreasing glutamate-induced nerve firing. This can be accomplished by increasing inhibitory signaling in the brain

• Most of the sedative-hypnotic drug classes work in this manner

• How CNS excitation is controlled by comparing neuronal activity with and without sedative-hypnotics:

  • Without sedative-hypnotics: most brain activity involves excitatory neurons. These excitatory neurons release the neurotransmitter glutamate. Neurons “fire” when the excitatory inputs exceed inhibitory inputs

  • With sedative-hypnotics: inhibitory signals from GABA neurons increase with most sedative-hypnotics, resulting in decreased glutamate nerve firing

GABA SIGNALLING

• Recall: GABA is the primary inhibitory neurotransmitter in the CNS

  • It causes inhibition by binding to and selectively opening chloride channels

  • 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

  • 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 postsynaptic neuron to transmit incoming messages to other neurons, thereby depressing CNS neuronal signalling

DRUGS THAT BIND TO THE CHLORIDE CHANNEL

• Most sedative-hypnotics modulate the chloride ion channel in the brain and spinal cord, but each bind to a different site on the chloride channel

• The result is an increase in synaptic inhibition and, thus, a dampening of neuronal responses. In essence, they enhance the inhibitory effect of GABA

BENZODIAZEPINES

• Are among the most widely prescribed drugs in the world, with 5-10% of Canadians being prescribed this class of drugs

• Characteristics of benzodiazepines:

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

  • Mechanism of Action: activation of the benzodiazepine receptor increases the frequency of the opening of the chloride channel

  • Therapeutic Effects: the desired effects are relxation, calmness, and a relief from anxiety or tension. They also produce skeletal muscle relaxation and have anticonvulsant effects

LETHALITY OF BENZODIAZEPINES

• Are among the drugs most commonly involved in overdose, however deaths from overdose are very rare

• Death has occured with enormous doses, rapid intravenous injecition of a large dose, or when taken in combination with other sedating drugs (i.e alcohol)

  • Antidote for benzodiazepines:

    • An antidote exists to reverse its effects in the event of an overdose

    • The antidote is called flumazenil, a benzodiazepine receptor antagonist that blocks the effects of benzodiazepines

    • When benzodiazepines are taken in overdose, flumazenil can be administered as an antidote

ADVERSE EFFECTS OF BENZODIAZEPINE USE

• Short term use: affects the CNS, lungs, and motor coordination

  • CNS: adverse effects may include drowsiness, lethargy, fatigue, and impairment of thinking and memory

    • For CNS depression, what is considered an adverse effect depends on the targeted therapeutic effect

      • Ex. 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: respiratory depression has been observed following rapid intravenous administraion of benzodiazepines

  • Motor Coordination: moderate doses of all benzodiazepines can impair motor coordination and driving

    • Patients taking these drugs during the day should refrain from driving or operating dangerous machinery

    • These responses are exaggerated as the dose is increased

• Long Term use: effects vary between individuls

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

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

• Use in special populations: benzodiazepine use should be particularly considered for pregnant people and older adults

  • Pregnant/chestfeeding: 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, exposing nursing infacts to therapeutic or toxic doses of the drug, and can resuolt in sedation or death

  • Older adults: benzodiazepines can produce cognitive dysfunction in older adults

    • As a result, they should be used with caution, if at all, in this age group

    • They are metabolized more slowly in older adults than in young adults, often leading to over-sedation, falls, and injury

BENZODIAZEPINES: POTENTIAL FOR MISUSE AND SUD

• Benzodiazepine use can result in tolerance, withdrawal, and addiction

• Misuse for recreation purposes does occur, typically in combination with alchol to enhance the CNS depression effects of both

  • Misuse Potential: 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

  • Tolerance: tolerance can develop to the sedative effects and impairment of coordination, the anxiolytic effect (less common) or the euphoric effects.

    • The magnitude of tolerance that develops to benzodiazepines does not produce clinical concerns

    • A high degree of cross-tolerance occurs emong benzodiazepines and other sedative-hypnotic drugs, such as barbiturates and alcohol

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

    • Following chronic use (one year or more), sudden discontinuation may lead to more pronounced withdrawal symptoms, such as agitation, paranoia, seizures, and delirium. These extreme symptoms ocur much less frequently than with barbiturates

  • Addiction: may develop in some individuals, but not all, and depends on a multitude of factors including genetics and the environment

BARBITURATES

• Another class of sedative-hypnotics

• These drugs are classified according to their durration of action, and can be long-acting (1-2 days), short-acting (3-8 hours), and ultra-short acting (20 minutes)

• Are an older class of drugs that have generally been replace by safer, more effective sedative-hypnotics

• Properties of barbiturates include:

  • Routes of Administration: are adminstered in different ways depending on what they are being used to treat

    • Ex. For epilepsy, they are administered orally

    • Ex. For anesthesia, they are administered intravenously

  • Mechanism of Action: activation of barbiturate receptor increases the duration of the opening of the chloride channel

    • They demonstrate the full spectrum of dose-dependent CNS depression that you learned about earlier in this section:

      • Anti-anxiety — Sedation — Hypnosis — General Anesthesia — Death

  • Therapeutic Use: in low doses they usually result in the beneficial effects of transquility and relaxation. They will also induce sleep if the dose is sufficient

    • Clinical uses are limited. Ultra-short acting and short-acting barbiturates can be used to induce anesthesia. Some long-acting agents can be used as antiepileptics

  • Lethality: barbiturates have been replaced for the most part of 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

    • A specific antidote for barbiturate poisoning does not exist. Death can occur during barbiturate withdrawal

ADVERSE EFFECTS OF BARBITURATE USE

• Barbiturates also have numerous adverse effects, in general, they suppress REM-type sleep

  • Short-term use:

    • In low doses, usually result in mild euphoria and reduced interest in one’s surroundings

    • 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: the term best used to describe long term use is chronic inebriation. Memory, judgement, and thinking are all impaired

    • Individuals often exhibit hostility and mood swings, including depression

BARBITURATES: POTENTIAL FOR MISUSE AND SUD

• Are prescribed much less frequently now than they were 40 years ago, but illicit use continues to be a problem. They are also sometimes combined with other drugs such as opioids, amphetamines, and alcohol

• Potential for misuse and SUD in barbiturates:

  • Potential for misuse: barbiturates should be avoided, as the potential for misuse is equal or greater than alcohol

    • The pleeasurable effects of some barbiturates gives a significant degree of reinforcement

    • 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: can develop. A high degree of cross-tolerance occurs between barbiturates and other sedatives

  • Withdrawal: occurs after discontinuation of chronic use. Symptoms initially appear as tremors, anxiety, weakness and insomnia, as well as postural hypotension

    • These symptoms may progress to include seizures, delirium, visual hallucinations, and a high body temperature

  • Addiction: can result 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. Craving often persists long after use has stopped

COMPARISON: BENZODIAZEPINES VS. BARBITURATES

• Are two classes of sedative-hynotics with similarities and some key differences

ZOPICLONE AND THE 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 similarily to the benzodiazepines, however, has an advantage 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

BUSPIRONE

• Is an interesting anxiolytic as it does not act on the GABA receptor, but rather at the serotonin receptor

• It is 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-like drug when the individual is already taking other CNS depressant drugs and there is a concern of additive effects

END OF SECTION 01 PRACTICE QUIZ

• Which one of the statements listed correctly applies to sedative-hypnotics

  • Zopiclone, a benzodiazepine like drug, is a GABA receptor agonist which has minimal effects on sleep patterns

• Which one of the options listed is a pharmacological property of the benzodiazepines

  • Tolerance occurs to the sedative and hypnotic effects of the benzodiazepines

SECTION 02 - ALCOHOL

INTRODUCTION TO ALCOHOL

• Alcohol (ethanol) is one of the three most used non-medical drugs in Canada, alonside caffeine and nicotine

• While alcohol consumption has decreased, 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

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 - these terms will be used interchangeably throughout this section

• The pharmacokinetics of ethanol include:

  • Absorption: 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:

    • Stomach-emptying time, or the time required for the alcohol to reach the small intestine

    • Ethanol concentration in the 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: ethanol distributes throughout the total body water and readily gains access to the brain. Ethanol can also readily transfrer across the placenta and distribute throughout a developing fetus

  • Metabolism: has four main steps

    • Alcohol dehydrogenase: ethanol is converted to acetaldehyde by the enzyme alcohol dehyrdogenase. This is the rate-limiting step in alcohol metabolism, meaning the speed of this conversion typically sets the pace for the rest of the metabolism

    • Meos: a second step is the microsomal ethanol oxidizing system, which is part of the cytochrom P450 system. Contributes to the metabolism of ethanol, breaking it down to acetaldehyde, especially at high doses when alcohol dehydrogenase is running at full capactiy

    • 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

      • Genetic Variablity in ethanol metabolism: genetic variants in the gene that codes for alcohol dehydrogenase exist

        • Some individuals rapidly convert alcohol to acetaldehyde, causing an accumulation of acetaldehyde in the body. 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, 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

        • This is because alcohol dehyrogenase becomes rate-limiting, or saturated. Therefore, the body rate of ethanol metabolism is about 120 mg ehtanol/kg body weight/hour

  • Excreation: 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 USES OF ETHANOL

• Very few medical uses for ethanol exist. Some of the current uses are:

  • As an alcohol sponge applied topically to treat fever

  • As a skin disinfectant

  • As an antidote in the treatment of methanol poisoning

  • As a hand sanetizer, particularly since the SARS epidemic. More recently, hand sanetizers 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 depessant

• The CNS effects of ethanol are proportional to the blood alcohol concentration

• 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

BAC AND DRIVING

• The risk for a driver getting in an accident increases exponentially in relation to their BAC

• 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 offence, and having a BAC of 0.08% is a criminal offence

MECHANISM OF ACTION OF ALCOHOL

• Alcohol affects a large number of membrane proteins that participate in signalling pathways. However, it is thought that alcohol works through one main mechanism- by binding to the chloride ion channel and agumenting 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

• Besides the CNS, alcohol also affects other systems and organs in the body such as the cardiovascular system, the stomach, and the liver

ADVERSE EFFECTS OF SHORT-TERM HIGH DOSE ALCOHOL USE

• Short-term high dose drinking, otherwise known as binge-drinking, has several additional adverse effects to the ones you just explored

• Some effects of short-term high-dose alcohol consumption are:

  • Memory loss: this is the phenomenon where the individual does not remember events while under the influence of alcohol. This can be very frightening and may result in the individual seeking help

  • Psychiatric effects: heavy drinking often leads to depression, irritability, and over-sedation. The negative mood states, in concert with impaired judgement and impulsiveness, may lead to self-harm or acts of violence

  • Overdose: excessive short-term alcohol consumption can also result in overdose, which is characterized by respiratory depression, coma, and death. A number of comatose drinkers die each year after aspirating their own vomit

ADVERSE EFFECTS OF CHRONIC HIGH DOSE ALCOHOL USE

• Chronic high dose use of alcohol has a number of detrimental effects on the body

• Some effects of chronic high dose use are:

  • CNS: a number of neurological and mental disorders are associated with chronic alcohol misuse. One such disorder is alcoholic dementia, which is a decrease in cognitive functioning affecting memory, judgement, and thinking. Alcohol damages axons of neurons within the brain, resulting in fewer connections between neurons

  • Cardiovascular: high chronic doses of alcohol can lead to alcoholic cardiomyopathy. An increased incidence of hypertension and stroke is also apparent

  • Liver: chronic high doses of alcohol leads to alcoholic liver disease, a major cause of hospitalization and deaths in North America. At early stages, this can be reversible with alcohol abstinence, but at later stages it is irriversible 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)

• The incidence of FASD in Canada is 1 per 1000 live birth

• A safe dose of ethanol in pregnancy has not been established. 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

• There are two types of drug-drug interactions:

  • Alcohol use during drug therapy: the effects of having a drug and ethanol in the body at the same time include:

    • Ingestion of ethanol and other CNS depressants lead to an additive or synergistic effect of CNS depression

    • Inhibition of metabolism of certain drugs (e.x. sedative-hypnotics)

  • Chronic alcohol use before drug therapy: the effects of chronically drinking alcohol but abstaining during drug therapy

    • Only ocurs if there is no co-existing ethanol-induced liver injury

    • Increases the activity of metabolizing enzymes in the liver, resulting in increased metabolism of certain drugs (ex. 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

• The potential for misuse and SUD with alcohol are:

  • 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 ethanol’s misuse potential

    • 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: is 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 ethanol and:

    • Sedative-hypnotics: a higher dose of a sedative-hypnotic drug is required for the desired therapeutic effect

    • General Anesthetis: a higher dose of anesthetic agent is required for surgical anesthesia in someone who has developed tolerance to alcohol

  • Withdrawal: from ethanol produces compensatory excitation of the CNS (ex. arousal, stimulation). In sever cases of ethanol withdrawal, delirium tremens (DTs) may occur, which can involve convulsions coma, and possibly death

  • Addiction: a compulsive desire to seek, obtain, and drink ethanol exists. Addiction could be the most powerful factor in chronic use of ethanol, contributing to SUD

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

• An example of a drug is:

  • Naltrexone (an opioid antagonist) - is effective in the treatment of alcohol addiction. It diminishes the craving for ethanol, and assists in the maintenance of abstinence. It 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:

  • Rapidly absorbed from the stomach and intestine

• Which step of alcohol metabolism is considered rate-limiting

  • Conversion of alcohol to acetaldehyde by alcohol dehydrogenase

SECTION 03: CANNABIS

INTRODUCTION TO CANNABIS

• The term cannabis refers to the drug-containing forms of the hemp plant

• Sixty chemical compounds are found only in Cannabis sativa, and these compounds are referred to as cannabinoids (CB)

• Of these compounds, I-trans-delta-9-terahydrocannabinol (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 - cannabis plants were used for manufacturing rope. Cannabis was used for its mild intoxicating effects

• 1920s - public concern was raised in north america over the effects of cannabis on individuals and society. Legislation was enacted to outlaw the use of cannabis, which was considered a narcotic

• 1960s - Throughout the 60s, use of cannabis increased. This is purported to be driven by the cold war and the changing political and cultural climate

• 1978 - A USA sponsered project using the herbicade pareaquat was initiated in an attempt to destroy cannabis crops in Mexico. It failed. USA citizens were smoking cannabis products containing paraquat, which can produce lungg-toxicity

• 1997 - 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

  • Canada changed the law to allow the cultivation of some varieties of cannabiis that contain very small amounts of THC for use in the manufacture of rope, clothing, and other hemp products. Farmers must obtain a special license to grow hemp

• 2005 - Health Canada supported trials on the medical use of cannabis

• 2012 - Recreational use of cannabis was legalized in Washington

• 2018 - In the fall of 2018, recreational cannabis became legal in Canada

CLASSIFICATION OF CANNABIS

• Cannabis can be classified pharmacologically and legally

  • Pharmacological: cannabis is classified as a CNS depressant, auphoriant, and hallucinogen (although the hallucinogenic properties only occur at high doses)

  • Legal: 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

CANNABINOID RECEPTORS

• Two types of cannabinoid receptors exist and they are found in specific locations in the body

  • CB1 receptors: a large number are in the brain, more than any other receptor. 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 timem 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

    • 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: are 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 are lynphocytes is thought to be responsible for the immunosuppressive properties of THC

ADME OF THC

• THC is the primary component in cannabis cuasing psychoactive effects

  1. Absoroption: THC is commonly inhaled or ingested. The method of administration influences its absorption:

     1. 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

     2. Ingested: When THC is absorbed after oral administration, the absorption occurs slowly and is incomplete. The onset of action is delayed 30 to 60 minutes. The effect is less than that from smoking cannabis

  2. Distribution: Following inhalation, THC rapidly distributes throughout the body, especially to tissues with high blood perfusion such as the lung, heart, brain, and liver. THC also rapidly crosses the placenta. These processses are much slower following oral ingestion given the slow absorption of this route of administration

     1. THC is highly lipid soluble and over time will be stored in adipose tissues

  3. Metabolism: THC is metabolized slowly. 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

  4. Excretion: THC has a half-life of approximately 30 hours. However, the elimination of THC from adipose tissue may take longer

EFFECTS OF SHORT-TERM CANNABIS USE

• The short-term effects of cannabis are primarily observed in the CNS, the cardiovasular system, and the GI tract

  • CNS: early effects of cannabis on the CNS will be seen as

    • Relaxation and drowsiness

    • A feeling of well-being and euphoria

    • Impaired motor coordination

    • Increased appetite

      • As the dose is increased, a person may experience pseudo-hallucinations, a running together of sense, and impaired judgement and coordination. In some cases, a toxic psychotic reaction may occur

  • Cardiovascular System: short-term effects of cannabis use on the cardiovascular system include:

    • Increased heart rate

    • Increased blood flow to the extremities

    • Postural hypotension (may occur)

  • GI tract: short-term effects of cannabis use on the GI tract include:

    • Increased appetite

    • Dryness of the mouth and throat

  • Other: include:

    • Reduction of sex drive in males, as THC may reduce testosterone levels

    • Disruption of the ovarian cycle by THC in females

    • A hangover, similar to that with alcohol, when the drug wears off

EFFECTS OF LONG-TERM CANNABIS USE

• Long-term effects of cannabis involve multiple body systems and range from easily reversible to serious

  • Psychological:

    • Occasional Low-Dose: does not appear to be associated with harmful psychological effects

    • High Doses: significant psychological problems occur over time such as loss of short-term memory, lack of concentration, and loss of ability in absract thinking. Amotivational syndrome is characterized by these psychological problems, as well as loss of ambition and emotional flatness. This syndrom usually disappears upon cessation of drug use, suggesting that it represents chronic intoxication

    • 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: effects of cannabis are usually reversible. 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: a number of respiratory symptoms are associated with smoking cannabis. 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

    • 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

    • The incidence of lung cancer and chronic obstructive pulmonary disease (COPD) are both increased with long-term use of smoked cannabis

  • Fertility: long-term cannabis use can also have effects on fertility and pregnancy:

    • Males: long-term cannbis use can lead to decreased sperm count

    • 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)

    • 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

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 (ex. analgesia) from the psychotropic effects

CANNABIS: POTENTIAL FOR MISUSE AND SUD

• The misuse potential of cannabis products is low to moderate, as euphoria and reinforcement are less compared to some other drugs. The inherent harmfulness of cannabis is also low, especially with infrequent use

• The greatest concerns may be automobile accidents, accidental exposure of cannabis to children, and the lung effects associated with smoking and vaping

  • Tolerance: occurs to:

    • The psychoactive properties of THC

    • The effects on the cardiovascular system

    • The impairment of performance and cognitive function

  • Withdrawal: upon termination of long-term high dose use, a mild withdrawal syndrome occurs. Withdrawal is characterized by:

    • Sleep disturbances

    • Irritablity

    • Loss of appetite

    • Nervousness

    • Mild agitation

    • Upset stomach

    • Sweating

  • Addiction: develops as a persistent craving for the drug. The risk of addiction is more evident in those who use cannabis to control psychological stress

SUMMARY: CANNABIS

• Cannabis is a CNS depressant, euphoriant, and hallucinogen. Research is still underways to determine its specific mechanism of action and identify all of its long-term effects

  • Mechanism of action:

  		Receptor Location Function
  CB1	Found in high concentrations in the brain	Responsible for cognitive alterations
  CB2	Found in the periphery	Responsible for immunosuppressive qualities

  • Effects:

  		CNS Effects Fertility Respiratory Effects
  Euphoria, relaxation, distortions of time, colour, sound, taste, decrease in cognitive function and concentration, impaired motor coordination	Potential adverse effects in males and females, should be avoided in pregnancy	Potential serious adverse effects if smoked (ex. COPD, lung cancer)

  • Misuse:

  			Misuse Tolerance Withdrawal Addiction
  Low, car accidents may be greatest risk	Yes, occurs to most effects	Can occur with long-term high dose use	Can occur, particularly if using drug to deal with stress

END OF SECTION 03 PRACTICE QUIZ

• The mechanism of action of cannabis is best described as?

  • Cannabis binds to CB1 receptors on presynaptic neuronal membranes in the brain

• Which receptor does THC bind to

  • Cannabinoid

SECTION 04: OPIOIDS

INTRODUCTION TO OPIOIDS

• Opioids are a class of drugs naturally found within the opium poppy plant

• Drugs obtained from poppys have been used of 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. 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. Many different types of opioids exist. Most opioids are analgesics and have high potential for misuse and OUD

  • Endogenous Opioids: are not adminstered drugs, but are opioids made in the body that bind to opioid receptors and exert analgesic effects

    • The three families of endogenous opioids are enkephalins, dynorphins, and beta-endorphins

    • Endogenous opioids affect the perception of pain and the emotional response to pain. They may also influence mood and are associated with the reward pathways in the brain

  • Natural Opioids: are not made by the human body, but are derived from the opium poppy plant. They may include morphine and codeine

    • Morphine: binds directly to opioid receptors. It is used clinically to treat severe acute and chronic pain, and can cause euphoria

    • Codeine: is converted to morphine in the body by liver enzymes. Morphine is approximately 10 times more potent than codeine. 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: are slightly altered versions of morphine that are chemically changed to obtain different pharmacological properties (ex. potency, duration of action, distribution), but typically maintain a very similar effect profile

    • Hydromorphone: is clinically used for analgesia. It is five times more potent than morphine

    • Diacetylmorphine: is used as part of injectable opioid agonist theraphy to manage OUD. There are limited other clinical uses of diacetylmorphine, therefore, it is most often synthesized for illicit use. It is two to five times more potent than morphine

  • Synthetic Opioids: are not derived from morphine, but are chemically synthesized to bind to the opioid receptor. These drugs may be designed to elicit imilar pharmacological responses to morphine or be used for other clinical purposes that are related to the other functions of opioid receptors

    • Fentanyl and Related Compounds: fentanyl is approximately 100 times more potent than morphine and was designed for treatment of severe acute chronic pain. Illicit synthesis and use of fentanyl, and other new, related, and more potent compounds contribute to the OUD crisis

    • Loperamide: is an over the counter drug that leverafes a common side effect of opioids, constipation, and is used to treat diarrhea. 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. This prevents illicit use as it does not cause substantial analgesia or euphoria

    • Methadone: is used for analgesia and can be used in the treatment of OUD. When used to treat OUD, it prevents withdrawal symptoms, however, does not cause euphoria in a stabilized patient

OPIOID RECEPTORS

• Opioid receptors are located in both the central and peripheral nervous systems. These receptors are located in the GI tract and are responsible for the constipation caused by opioids

  • MU: receptors are present in all structures of the brain and spinal cord

    • They mdeiate 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

  • Kappa: receptors are involved in analgesia, dysphoria and miosis

  • Delta: receptors are involved in analgesia at the level of the spinal cord and brain

    • They may also modulate the emotional response to opioids

SHORT-TERM EFFECTS OF OPIOIDS

• Morphine may be taken orally in tablet form, adminstered intravenously, smoked, or sniffed to produce its effects

  • Analgesia: opioids, including morphine, produce analgesia and indifference to pain, reducing the intensity of pain and the perception or reaction to pain. There is no ceiling to the intensity of pain which can be relieved. Respiratory depression is the limiting factor

  • Sedation and hypnosis: opioids produce sedation and hynosis, but not as intense as that produced by the CNS depressants. Usually, the patient can be aroused but may experience a drowsy, dreamy, mild dozing state. All opioid analgesics produce sedation

  • Suppression of Cough Centre: relief of prevention of cough occurs through suppression of the cough centre in the mdeulla

  • Respiratory Depression: opioids suppress the respiratory entre in the brain stem. In particular, the response to respiratory drive by carbon dioxide is blunted. The receptores that mediate this effect are mu and delta opioid receptors. Depression of respiration is the single most important side effect of the opioids, and is usually the cause of death in overdose

  • Endocrine Effects: opioids reduce the release of the hormone that is responsible for regulating the release of sex hormones from the hypothalamus. This results in a reduction in the production of testosterone, estrogens, and progesterone. The overall result is a drop in libido in men

  • Miosis: opioids cause constriction of the pupils of the eyes, or miosis. All opioids that gain access to the CNS will cause pinpoint pupils. This can indicate someone has an opioid in their system

  • Heart rate and thermoregulation: with high doses of opioids, the heart rate is irregular, body temperature is low, and the skine is cold and clammy

  • Decreased intestinal motility: all individuals taking opioids will experience constipation as an adverse effect

THERAPEUTIC USES OF OPIOIDS

• Opioids have three main therapeutic uses. These three therapeutic uses apply to morphine and most of the other opioids

  • Relief of Severe pain: analgesia is the major use of opioids. For example, opioids may be used to mitigate post-surgival pain and pain experienced by some terminally ill patients

  • Cough suppression: all opioids are effective cough suppressants, however, better alternatives with lower misuse potential are available

  • Treatment of diarrhea: loperamide is an over-the-counter opioid that is not an analgesic and does not produce withdrawal, but it is useful in controlling diarrhea

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. The misuse potential described on this slide is for opioids alone

  • 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 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: individuals who administer drugs by injection are at higher risk of developing abscesses at the site of administration as well as other infections. If contaminated needles are used, there is also the risk of spreading pathogens

  • Overdose: 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

    • 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: occurs to most pharmacological effects of opioids, except the constriction of the pupils and the contstipating effect. It develops more slowly to respiratory depression than to the analgesic effects of the opiates. Tolerance reverses in a few days after the opioid is discontinued

    • Cross-tolerance between all opioid analgesics occur, 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: a pronounced withdrawal syndrome can occur after opioid discontinuation. Opioid withdrawal is not life threatening and manifests as:

    • Restlessness, anxiety, insomnia

    • Sweating, fever, chills

    • Increased respiratory rate

    • Cramping, retching and vomiting

    • Diarrhea

  • Addiction: pronounced craving and compulsion for opioids can develop. The basis for addiction is the euphoric action of the opioids, resulting in very powerful reinforcement

    • Use of opioids with other psychoactive drugs can occur in an attempt to achieve an even greater euphoria

OPIOID 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

• Psychosocial supports, counselling, and treatment of concurrent physical and mental health issues should also be considered to optimize recovery

  • Buprenorphine/Naloxone: 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

    • 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

  • Methadone: is a synthetic opioid that is effective follwoing oral administration and has a long duration of action. The misuse potential of methadone is much lower than other opioids such as morphine, due to a number of factors

    • 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

    • 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?

  • It transfers individuals with OUD to an opioid that is long-acting and doesn’t cause euphoria in stabilized patients

• Which one of the options listed is an adverse effect of opioids

  • Respiratory Depressio