PHAR 100 - Moddule 3
o Seductive-hypnotics
· In low doses can be used to treat anxiety disorders, increase sedation by relieving anxiety and moderate excitement and used to produce drowsiness and maintain sleep.
· In high doses, can be used to induce general anesthesia.
o Mechanism of action of seductive-hypnotics
· Without sedative-hypnotics
◊ Brain activity involve excitatory neurons
◊ Neurons release neurotransmitter glutamate
◊ Neurons “fire” when the excitory inputs exceed inhibitory input
· With sedative hypnotics
◊ Inhibitory signals from GABA neurons increase
◊ Decrease glutamate nerve firing
o GABA signalling
· GABAA receptors have subunit has four transmembrane-spanning regions.
· When there is nothing bound to the GABA binding site, the channel is closed.
· 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
o Drugs that bind to chloride channel
· Most sedative hypnotics modulate chloride ion channel in the brain and spinal cord
· Each bind is on different sites on the channel
· Enhancement of the inhibitory effect of GABA
o Benzodiazepines
· Route of administration
◊ Usually taken as a capsule or tablet
◊ 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
◊ Relaxation and calmness
◊ Can decrease aggression
◊ Can relief from anxiety
◊ Produce skeletal muscle relaxation
◊ Produce anticonvulsant effects
◊ Can be effective hypnotics
◊ Minimally supresses REM-type sleep
o Lethality of benzodiazepines
· Very high therapeutic index hence death from overdose is rare
· Death has occurred when ingesting multiple doses, rapid intravenous of large dose or when in combination with other CNS depressants
· Antidote is flumazenil
◊ Benzodiazepine receptor antagonist that blocks the effects of benzodiazepine
o Adverse effects of benzodiazepine use
· Short-term use
◊ CNS
s Drowsiness
s Lethargy
s Fatigue
s Impairment of thinking and memory
s Adverse effects depends on targeted therapeutic effect
◊ Breathing
s Respiratory depression
◊ Motor coordination
s Impair motor coordination and driving
· Long-term use
◊ Some people can take large amounts for long periods of time without any major evidence of intoxication
◊ Some people will have symptoms such as impaired thinking, poor memory and judgement, disorientation, incoordination and slurred speech
· Special populations
◊ Pregnant/breastfeeding
s Can cross the placenta and get to the fetus
s Can cause small but significant risks to fetal abnormalities
s Can be in the breastmilk in a therapeutic or toxic dose
◊ Older adults
s Can produce cognitive dysfunction
s Metabolized more slowly
o Benzodiazepines: potential for misuse and SUD
· Tolerance
◊ Can develop to the sedative effects and impairment of coordination, the relief of anxiety, euphoric effects
◊ High-degree of cross-tolerance since most CNS depressant modulate channel in the CNS
· Withdrawal
◊ Mild withdrawal can occur after therapeutic use
s Cause anxiety, headaches and insomnia
◊ More pronounced withdrawal after chronic use (1 year or more)
s Cause paranoia, agitation, seizure and delirium
· Addiction
◊ May develop in some individuals
◊ Depends on multiple factors
· Misuse potential
◊ Have weaker reinforcing properties than other drugs
◊ Inherent harmfulness is low (does not depress respiration at therapeutic dose)
o Barbiturates
· Older class of drug replaced by safer more effective sedative-hypnotics
· Route of administration
◊ Administered in different ways
◊ Can be orally or intravenous
· Mechanism of action
◊ Activation of barbiturate receptor increases the duration of the opening of chloride channel
· Therapeutic use
◊ Low doses results in tranquility and relaxation; can induce sleep
◊ Clinical uses are limited
◊ Can be ultra-short-acting (20 mins) to induce anesthesia, short-acting (3-8 hrs) to induce anesthesia and long-acting (1-2 days) to induce antiepileptics
· Lethality
◊ Low therapeutic index and potential for lethality
◊ Due to the respiration depression when combined with alcohol
◊ Lethal dose varies between individuals
◊ Has no antidote
◊ Death can occur during withdrawal
o Adverse effects of barbiturate use
· Suppress REM-type sleep
· Short-term use
◊ In low doses, Mild euphoria
◊ Reduce interest in ones surrounding
◊ Diziness
◊ Mild impairment of motor coordination
◊ Pleasurable state of intoxication
◊ Euphoria
◊ In high dose, depresses the cardiovascular system (slow HR and low BP)
· Long-term use (chronic inebriation)
◊ Impaired memory, judgement and thinking
◊ Cause hostility, mood swings and depression
o Barbiturates: potential for misuse and SUD
· Potential for misuse
◊ Should be avoided
◊ Equal or greater than alcohol
◊ Pleasurable effects give significant degree of reinforcement
◊ Sometimes injected to produce “rush effect”
◊ Inherant harmfulness is very high due to risk of death from respiratory depression or withdrawal
· Tolerance
◊ Can develop
◊ High-degree of cross-tolerance between CNS depression
· Withdrawal
◊ Occurs after discontinuation of chronic use
◊ Can cause tremors, anxiety, weakness, insomnia and postural hypotension (low BP)
◊ Can cause seizures, delirium, visual hallucinations and high body temperature
◊ Must be withdrawn slowly under medical supervision
· Addiction
◊ Results from regular use
◊ Craving of the drug
◊ Feeling of panic if cannot get supply
o Comparison: Barbiturates vs Benzodiazepine
o Zopiclone and the benzodiazepine-like drugs
· Zolpiclone and zolpidem are benzodiazepine-like drug that bind to subset of the GABA receptors and cause sedation
· Distrub REM-sleep less
· Have more sedative effects as compared to anxiolytic effects
o Buspirone
· Anxiolytic does not act on the GABA receptor
· Acts on the serotonin receptor
· No additive effects with other sedative-hypnotic drugs
· Can be given to individual that takes other CNS depressants
o Alcohol
· Most used non-medical drug
· CNS depressant
· Slows brain function and neural activity
· Ethanol is the only type of alcohol safe for consumption
o ADME of Alcohol
· Absorption
◊ Absorbed rapidly in the stomach (20%)
◊ Absorbed by upper small intestine (80%)
◊ Absorption rate depends on stomach-emptying time, time required for alcohol to reach the small intestine, ethanol concentration in the GI tract and presence of food in the GI tract
◊ Maximal blood alcohol concentration after last drink ranges from 30-90 mins
· Distribution
◊ Distributes throughout all the body water
◊ Accesses the brain
◊ Can transfer across the placenta and get to the fetus
· Metabolism
1. Alcohol dehydrogenase
◊ Ethanol converts to acetaldehyde by enzyme alcohol dehydrogenase
2. MEOS (Microsomal ethanol oxidizing system)
◊ Part of the cytochrome P450 system
◊ Contributes to metabolism of ethanol
◊ Breaks down ethanol to acetaldehyde
◊ Occurs when Alcohol dehydrogenase is used up and there is a high concentration of ethanol
3. Aldehyde dehydrogenase
◊ Acetaldehyde converts to acetate by the enzyme aldehyde dehydrogenase
4. Acetate
◊ Acetate gets metabolized into carbon dioxide and water by tissues
· Excretion
◊ 95% eliminated by biotransformation in the liver
◊ 5% eliminated by the breath urine and sweat
· Rate of metabolism occurs at a constant rate no matter the blood alcohol concentration
◊ Body rate of ethanol is 120 mg ethanol/kg body weight/ hour
◊ Rate-limiting for alcohol dehydrogenase is 20 mg ethanol/kg body weight/ hour
o Medical use of Ethanol
· Alcohol sponge to treat fevers
· Skin disinfectant
· Antidote in methanol poisoning (wood ethanol)
· Hand sanitizer
o CNS Effects of Ethanol
· Proportional to the blood alcohol concentration (BAC)
· Converting BAC in mg/dL to a BAC represented as % of weight volume by moving BAC in mg/dL to 3 decimal places
◊ Ex: 300 mg/dL = 0.3 g/100ml = 0.3%
o BAC and driving
· Risk for a car accident increase exponentially concerning BAC
o Mechanism of action of ethanol
· Alcohol affects large number of membrane proteins that participate in signalling pathways
· Binds to chloride ion channel and augments GABA-mediated neuronal inhibition
· Reinforcing of the drug is linked to interaction of alcohol with chloride channel on dopaminergic neurons in the reward areas of the brain
o Effects of short-term use of alcohol
· Besides the CNS
· Cardiovascular
◊ Low doses
s Vasodilation (widening of blood vessels)
s Result in feeling of warmth
◊ High doses
s Depress the cardiovascular system
s Results in alteration in normal rhythm
· Stomach
◊ Low doses
s Increases gastric secretion
◊ High doses
s Irritate the lining of the stomach
s Results in inflammation and erosion
s Results in vomiting and abdominal pain
s Results in ulcers aggravation
· Liver
◊ Low doses
s No significant effect
◊ High doses
s Inhibition of glucose production
s Hypoglycemia
o Adverse effects of short-term high-dose alcohol use
· Memory loss
◊ No memory of events while under the influence
· Psychiatric effects
◊ Depression, irritability and over-sedation
◊ Impaired judgment and impulsiveness
· Overdose
◊ Characterized by respiratory depression, coma, and death
o Adverse effects of chronic high-dose alcohol use
· CNS
◊ Alcohol 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
◊ Cardiomyopathy An increased incidence of hypertension and stroke is also apparent.
· Liver
◊ Alcoholic liver disease
◊ At early stages, this can be reversible with alcohol abstinence, but at later stages it is irreversible and liver function is severely impaired
o Effects of alcohol use during pregnancy
· Produces teratogenic effects in the embryo/fetus
· Teratogenic effects manifest after birth as Fetal Alcohol Spectrum Disorder (FASD)
o Alcohol and drug interactions
· Alcohol use during drug therapy
◊ Ingestion of ethanol and other CNS depressants leads to an additive effect of CNS depression
◊ Inhibition of metabolism of certain drugs
· Chronic alcohol use before drug therapy
◊ Only if no co existing ethanol-induced liver injury
◊ Increases the activity of metabolizing enzymes in the liver resulting in increased metabolism of certain drugs
o Alcohol: potential for misuse and SUD
· Potential for misuse
◊ Significant reinforcing properties
◊ Misuse potential is moderate
◊ Inherent harmfulness is moderate
◊ Death can occur from high-dose acute ethanol ingestion
· Tolerance
◊ To chronic consumption of ethanol
◊ Develop rapidly to the ethanol-induced impairment of performance
· Cross-tolerance
◊ Sedative-hypnotics
s Higher dose of the sedative is required for desired therapeutic effect
◊ General anesthetics
s Higher dose of the anesthetic agent is required for desired therapeutic effect
· Withdrawal
◊ Causes compensatory excitation of the CNS
◊ In severe cases, delirium tremens (convulsion, coma and death) can occur
◊ Treatment
s Maintain fluid, and electrolyte balance and prevent seizures
s Severe ones with benzodiazepine (diazepam)
· Addiction
◊ Compulsive desires to seek, obtain and drink ethanol
◊ Most powerful factor contributing to SUD
o Drugs used to treat alcohol Use Disorder
· Naltrexone
◊ Opioid antagonist
◊ Diminishes the craving for ethanol (reinforcement)
◊ Assist in the maintenance of abstinence
◊ Blocks activation of dopaminergic reward pathways
o Cannabis
· Refers to the drug-containing forms of the hemp plant (Cannabis sativa)
· Chemical compounds found in Cannabis sativa are called cannabinoids
· Most potent psychoactive agent of those compounds is THC
o History of Cannabis
· 2700 BCE – 1800 CE
◊ Used for manufacturing rope
◊ Used for mild intoxicating effects
· 1920s
◊ Use of cannabis was outlawed (considered narcotic)
· 1960s
◊ Use of cannabis increased
· 1978
◊ USA citizens were smoking cannabis containing herbicide called paraquat
· 1997
◊ 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. 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
◊ Recreational cannabis became legal in Canada
o Classification of cannabis
· Pharmacological
◊ Classified as CNS depressant, euphoriant and hallucinogen
· Legal
◊ Became legal in canada
o Administration of cannabis
· Typically smoked or inhaled
· Extracts containing concentrated amounts of cannabinoids, typically in oil, can be administered by vaping or through oral consumption.
o Mechanism of action of cannabis
· THC binds specifically to receptors located in the brain and spinal cord called type 1 cannabinoid receptors (CB1)
· Anandamide is an endogenous ligand for CB receptors involved in learning and memory processes.
· CB1 receptor, when activated by anandamide or THC, inhibits the release of excitatory neurotransmitters.
· Explains the reduction in cognitive function and CNS depressant effects seen
with THC
o Cannabinoid receptors
· CB1
◊ Large number in the brain
◊ THC is not a very effective agonist but because of large number of receptors it produces a response
◊ In the cerebral cortex, the receptor mediates the distortion of time, colour, sound and taste
s Also mediate the decrease in cognitive function and concentration
◊ In the hippocampus, the receptor may account for changes in memory and learning
◊ No present in the brainstem = no respiration depression
· CB2
◊ Found only on the outside of the CNS
◊ Involved in inflammation
◊ Can be found on lymphocytes and its binding to THC thought to be responsible for the immunosuppressive properties
o ADME of THC
· Absorption
◊ Inhaled
s Rapid absorption and onset
s Effects lasts 3-4 hrs
◊ Ingested
s Slow absorption and incomplete
s Onset of action is 30-60 mins
s Effect is less than smoking cannabis
· Distribution
◊ THC rapidly distributes throughout the body
◊ THC rapidly crosses the placenta
◊ THC is lipid soluble and over time stored in adipose tissue
· Metabolism
◊ Metabolized slowly
◊ Metabolites can be in the body for weeks
· Excretion
◊ Half-life of 30 hrs
◊ Elimination of THC from adipose tissue may take longer
o Effects of short-term use of cannabis
· CNS
◊ Relaxation and drowsiness
◊ Feeling of well-being and euphoria
◊ Impaired motor coordination
◊ Increased appetite
◊ Pseudo hallucination and impaired judgement and coordination (as dose )
· Cardiovascular system
◊ Increased HR
◊ Increased blood flow to the extremities
◊ Postural hypotension (low blood pressure when standing or sitting up)
· GI tract
◊ Increased appetite
◊ Dryness of mouth and throat
· Other
◊ Reduction of sex drive in males ( testosterone goes ¯)
◊ Disruption of the ovarian cycle
◊ Hangover when drug wears off
o Short-term effects of cannabis while driving
· Impairment of motor coordination, tracking, perception and vigilance
· Alcohol and THC used together will intensify the adverse effects of each drug
o Effects of long-term cannabis use
· Psychological
◊ Permanent effects
s associated with impairment of memory and learning
◊ High dose
s Significant psychological problems occur over time such as loss of short-term memory, lack of concentration, and loss of ability in abstract thinking.
s Amotivational syndrome is characterized by these psychological problems, as well as loss of ambition and emotional flatness.
· Cardiovascular
◊ Usually reversible
◊ Increased heart rate can be dangerous for those with heart problems
· Respiratory
◊ Symptoms include bronchitis, asthma, sore throat, and chronic irritation of and damage to respiratory tract membranes.
◊ 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.
◊ The incidence of lung cancer and chronic obstructive pulmonary disease (COPD) are both increased with long-term use of smoked cannabis.
· Fertility
◊ Males
s Long-term use can lead to decreased sperm count
◊ Females
s Long-term use can lead to a reduction of the FSH and LH hormones
◊ Pregnancy
s THC freely crosses the placenta and causes developmental delays
o Medical use of cannabis
· Still in creation and development phase
· Will bind to CB1 and CB2 receptors and cause beneficial effect (no pain) with no psychotropic effects
· Not approved for therapeutic use but medical professionals can authorize use for relief of symptoms that are not relieved with all other medications
o Cannabis: potential for misuse and SUD
· Potential for misuse
◊ Low to moderate misuse
◊ Euphoria and reinforcement are less compared to other drugs
◊ Inherent harmfulness of cannabis is low
· Tolerance
◊ Occurs to psychoactive properties of THC
◊ Occurs to effects on cardiovascular system
◊ Occurs to impairment of performance and cognitive function
· Withdrawal
◊ Mild withdrawal if was taken in a long-term dose use
◊ Sleep disturbances
◊ Irritability
◊ Loss of appetite
◊ Nervousness
◊ Mild agitation
◊ Upset stomach
◊ Sweating
· Addiction
◊ Develops as a persistent craving for the drug
◊ More evidence in those who use cannabis to control psychological stress
o Opioids
· Found within the opium poppy plant Papaver somniferum
· Morphine and codeine come from it
· An opioid is any natural or synthetic substance which exerts actions on the body through binding to the opioid receptors.
· Most are analgesics
· Has a high potential for misuse
o Classes of opioids
· Endogenous
◊ Not administered drugs, but are opioids made in the body that bind to opioid receptors and exert analgesic effects
◊ Three families of endogenous opioids are enkephalins, dynorphins, and beta-endorphins (also known as endorphins)
◊ Affect the perception of pain and the emotional response to pain
· Natural opioids
◊ not made by the human body but are derived from the opium poppy plant. They include morphine and codeine.
◊ Morphine
s binds directly to opioid receptors. It is used clinically to treat severe acute and chronic pain and can cause euphoria
◊ Codeine
s converted to morphine in the body by liver enzymes. Morphine is approximately 10 times more potent than codeine
· Semi-synthetic opioids
◊ are slightly altered versions of morphine that are chemically changed to obtain different pharmacological properties
◊ Hydromorphone
s clinically used for analgesia. It is five times more potent than morphine
◊ Diacetylmorphine (brand name heroin)
s used as part of injectable opioid agonist therapy to manage OUD.
s often synthesized for illicit use. It is two to five times more potent than morphine
· Synthetic opioids
◊ not derived from morphine but are chemically synthesized to bind to the opioid receptor.
◊ Fentanyl and Related Compounds
s 100 times more potent than morphine and was designed for treatment of severe acute and chronic pain.
◊ Loperamide
s is used to treat diarrhea.
s little enters and remains in the circulation, but instead stays in the intestine or is quickly metabolized.
◊ Methadone
s used for analgesia and can be used in the treatment of OUD.
s When used to treat OUD, it prevents withdrawal symptoms, however, does not cause euphoria in a stabilized patient.
o Opioid receptors
· located in both the central and peripheral nervous systems.
· These receptors are also located in the gastrointestinal tract and are responsible for the constipation caused by opioids
· Mu
◊ 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
· Kappa
◊ involved in analgesia, dysphoria, and miosis
· Delta
◊ involved in analgesia at the level of the spinal cord and brain.
◊ They may also modulate the emotional response to opioids
o Mechanism of action of opioid
· Morphine and other opioids will block pain pathways in the spinal cord
and brain
· Reduce Neurotransmitter Release
◊ prevent pain signals from travelling by reducing
neurotransmitter release
· Reduce Emotional Reaction
◊ reduce the emotional reaction to pain through modulation of
the limbic system
o Opioid use during pregnancy
· Increase chance of low birth weight
· 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
· Withdrawal may last weeks to months
o Treatment of OUD
· Buprenorphine/Naloxone
◊ long-acting synthetic opioid that binds to mu opioid receptors
◊ provides enough opioid agonist activity to prevent withdrawal symptoms
◊ decreased euphoria and sedation compared to another opioid agonist
· Methadone
◊ synthetic opioid that is effective following oral administration and has a long duration of action
◊ misuse potential of methadone is much lower than other opioids
◊ taken orally, it removes the potential risks of injections
◊ Oral administration also leads to slower onset of pharmacological effects, and therefore less euphoria
◊ is long-acting, it is also taken less often, which again leads to a lower misuse potential