Sedative-Hypnotics and Barbiturates

Module Overview

• The module covers the mechanism of action, therapeutic effects, and adverse effects of central nervous systems depressants.
• Sedative-hypnotics, alcohol, cannabis, and opioids are included in the module.
• For each drug it examines the potential for misuse and substance use disorders.
• It emphasizes tolerance, withdrawal, and addiction.
• The Module links basic pharmacology principles to substance use disorder framework.
• It uses central nervous system depressants as examples.
• The goal is to empower individuals with pharmacology knowledge and apply it to news regarding drugs.
• By the end of the module, students should be able to compare sedative-hypnotics and describe short-term and long-term effects of alcohol and cannabis, and summarize issues of CNS depressants.

Sedative-Hypnotics

• Sedative-hypnotic agents are central nervous system depressants where the magnitude of central nervous system depression determines the effect.
• Ranges from anti-anxiety to general anesthesia, depending on the dose.
• Clinically important and dangerous interactions may occur between sedative-hypnotics and other CNS depressants like alcohol or some antihistamines.
• Primary excitatory neurotransmitter in the brain is glutamate.
• Therapies aim to decrease glutamate-induced nerve firing and increase inhibitory signalling in the brain to reduce overall brain activity for patients with anxiety or difficulty sleeping.
• Most sedative-hypnotic drug classes function by increasing inhibitory signals from GABA neurons, reducing glutamate-induced nerve firing.
• GABA is the primary inhibitory neurotransmitter in the central nervous system which causes inhibition by binding to and selectively opening chloride channels.
• When GABA binds and opens chloride channels, chloride ions flow into the postsynaptic neuron.
• An influx of chloride makes it harder for the neuron to transmit, depressing CNS neuronal signalling.
• Sedative-hypnotics modulate the chloride ion channel, each binding to a different site and enhancing GABA's inhibitory effect.
• Benzodiazepines are among the most widely prescribed drugs in the world, with 5-10% of Canadians being prescribed them.
• Activation of the benzodiazepine receptor increases the frequency of the opening of the chloride channel leading to relaxation, calmness, skeletal muscle relaxation, and anticonvulsant effects.
• Benzodiazepines have minimal suppression of REM-type sleep.
• Benzodiazepines have a high therapeutic index, and deaths from overdose are rare, however, overdose deaths have happened with enormous doses, rapid intravenous injection, or when combined with other sedating drugs, like alcohol.
• Flumazenil is a benzodiazepine receptor antagonist which reverses the effects of an overdose.
• Short-term adverse effects of benzodiazepines include drowsiness, lethargy, fatigue, impairment of thinking and memory, and respiratory depression is possible after rapid intravenous administration.
• Moderate doses of all benzodiazepines can impair motor coordination and driving.
• Long-term use of benzodiazepines can cause chronic sedative-hypnotic intoxication with impaired thinking, poor memory, disorientation, incoordination, and slurred speech which has prompted concerns for use during pregnancy and for older people.
• Use of benzodiazepines during the first trimester carries the risk of foetal abnormalities.
• Benzodiazepines are secreted into milk, exposing nursing infants to therapeutic or toxic doses and possible sedation or death.
• Misuse of benzodiazepines for recreation occurs, often combined with alcohol to enhance the effects.
• Tolerance can develop to sedative effects and impairment of coordination, and withdrawal includes anxiety, headache, and insomnia.
• Barbiturates are another class of sedative-hypnotics classified by duration of action (long, short, ultra-short).
• Barbiturates have been generally replaced by safer, more effective drugs.
• Activation of the barbiturate receptor increases the length of time the chloride channel is open, resulting in Anti-Anxiety → Sedation → Hypnosis → General Anesthesia → Death.
• Clinical uses of barbiturates are limited, but clinical use includes ultra-short and short-acting to induce anesthesia and some long-acting agents used as antiepileptics.
• Barbiturates have lower therapeutic index and potential for lethality.
• Overdoses can occur, especially when combined with alcohol, and death can also occur during barbiturate withdrawal.
• Long-term use of barbiturates can result in chronic inebriation, as well as impaired memory, judgment, and thinking.
• Abruptly ceasing barbiturates leads to tremors, anxiety, weakness, and insomnia, postural hypotension and can progress to seizures, delirium, visual hallucinations, and fever.
• Zopiclone and benzodiazepine-like drugs bind to a subset of GABA receptors to cause sedation.
• Benzodiazepine-like drugs disturb sleep patterns (REM sleep) even less than benzodiazepines.
• The video presented in this section demonstrated that Barbiturates have separate and distinct binding sites on the chloride channel from benzodiazepines.
• Buspirone is an unusual anxiolytic that acts on the serotonin receptor, not on GABA receptor
• It is prescribed instead of benzodiazepines when the individual is already taking other CNS depressant drugs amid concerns of additive effects.

Alcohol

• Alcohol (ethanol) is one of the three most used non-medical drugs in Canada.
• Alcohol consumption produces more health problems and deaths than all illicit drugs combined.
• It is a CNS depressant that works slowing brain functioning and neural activity.
• Absorption of ethanol is rapid within the stomach and upper small intestine influenced by stomach-emptying time, ethanol concentration, and the presence of food.
• Ethanol distributes and gains access throughout the total body water, to the brain, into the placenta, distributing throughout a developing fetus.
• The rate-limiting step in alcohol metabolism, meaning the pace, is ethanol being converted to acetaldehyde by the enzyme alcohol dehydrogenase (ADH).
• A second pathway, microsomal ethanol oxidizing system (MEOS), is important at high doses when ADH is saturated.
• Acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase (ALDH).
• Acetate is further metabolized into carbon dioxide and water.
• Acetaldehyde build-up causes unpleasant reactions such as facial flashing, nausea, vomiting, etc..
• Genetic variants in the gene that code for alcohol dehydrogenase (ADH) cause rapid alcohol to acetaldehyde conversions, resulting in a flushed face and is considered protective against alcoholism.
• The metabolism of alcohol occurs at a constant rate determined by how saturated ADH is, which is approximately 120 mg ethanol/kg of body weight/hour.
• The breath, urine, and sweat excrete about 5% and biotransformation accounts for the other 95%.
• Levels of intoxication are measured via breathalyzers.
• The minor pathway for ethanol metabolism is the microsomal ethanol oxidizing system (MEOS) which doesn't contribute to ethanol metabolism at low doses.
• Very few medical uses for ethanol exist like alcohol sponges for fever, skin disinfectant, an antidote for 'wood alcohol' poisoning, and hand sanitizer.
• To convert blood alcohol concentration in mg/dL to a percentage of weight/volume, move the decimal three places to the left.
• The risk of a accident exponentially increases with BAC.
• Alcohol works by binding to the chloride ion channel and augmenting GABA-mediated neuronal inhibition, causing disinhibition, vasodilation, and gastric secretion at low doses.
• Gastritis occurs at high doses of alcohol as does glucose production production at high doses.
• Short-term high dose drinking has additional adverse effects like:
  • Memory Loss; where the individual can’t remember
  • Psychiatric Effects (including potential self-harm)
  • Overdose (coma, respiratory depression, and death)
• Neurological disorders and mental disorders are associated with chronic alcohol misuse that causes a decrease in cognitive functioning.
• A safe amount has not been established for ethanol use during pregnancy.
• Drug interactions with alcohol can happen at the same or at different times.
• The ingestion of other central nervous system depressants with ethanol has additive or synergistic effect.
• If there is no co-existing ethanol-induced liver injury, then chronic alcohol use increases the activity of metabolizing enzymes in the liver.
• The addiction of ethanol contributes to the substance use disorder.
• The ease of availability and social and legal acceptance contributes to misuse potential.
• Death occurs from acute or chronic high dose, however, ethanol is less inherently harmful than methanol.
• Tolerance to impairments from ethanol consumption can develop.
• A higher dose of a sedative-hypnotic drug and anaesthetic agent is required for the desired therapeutic effect amid alcohol cross-tolerance.
• Initial alcohol withdrawal symptoms cause compensatory excitation of the central nervous system and can lead to agitation, paranoia and potentially, delirium.
• Withdrawal can lead to convulsions, coma, and death.
• The alcohol withdrawal syndrome can be suppressed by benzodiazepines.
• Naltrexone, an opioid antagonist, is also effective decreasing craving for alcohol.

Cannabis

• Cannabis refers to drug-containing forms of the hemp plant, Cannabis sativa.
• 60 chemical compounds are found in Cannabis sativa, and referred to as cannabinoids (CB), but I-trans-A9-tetrahydrocannabinol (THC) is the most potent psychoactive agent.
• The Public became concerned on affects to individuals and outlawed it, however, during the 1960s, use of cannabis increased.
• Canada changed its laws for the cultivation of cannabis.
• As of October 17, 2018, cannabis became legal in Canada.
• It can be classified as a CNS depressant, euphoriant, and hallucinogen and is legal as of October 17, 2018.
• Cannabis is typically smoked/inhaled, but cannabinoid extracts can be administered by vaping/oral consumption.
• The body's endogenous CB receptors ligand responsible for learning and memory is Anandamide.
• Type 1 Cannabinoid receptors (CB1), when activated, inhibits excitatory neurotransmitters for cognitive function of THC.
• The mechanism of action of cannabis is considered a 'retrograde transmitter' since it's released postsynapticly but functions presynapticly.
• The distortions of time, color, sound, and taste are mediated by C B1 receptors are found in the cerebral cortex.
• No C B1 Receptors exist in the stems of the brain making THC use non-lethal.
• The immunosuppressive properties of THC are through C B2 receptors on lymphocytes.
• The method of administration of THC affects absorption:
  • Inhaled: absorption is rapid and effects are immediate for three to four hours.
  • Ingested: absorption is slow and incomplete through oral administration with effects that are longer lasting.
• THC is metabolized slowly by the body so that the metabolites will be measured by urine and blood tests.
• Short-term effects of cannabis are primarily in the central nervous, cardiovascular, and GI systems: -CNS exhibits relaxation and drowsiness with some loss of motor control. -Cardiovascular exhibits increase to heart rate and blood flow. -GI displays increase to appetite and throat dryness.
• Significant psychological problems with short-term memory and abstract thinking comes with high doses as can Amotivational syndrome.
• Respiratory symptoms come with cannabis with high concentrations of tars and carcinogens, leading to the increase for lung tissues and cancer.
• Long-term cannabis use may lead to reduce fertility for males as does TH C to pregnant individuals.
• High does and overexposure can lead to accidents for children and auto collisions.
• As more is learned on synthetic cannabinoids, the challenge is separating pain analgesia from the psychotropic effects.
• There is a lower euphoria in cannabis and THC unlike other CNS depressants making potential misuse and addiction lower of a concern.
• Long-term misuse may not be a concern as cannabis might not cause psychological deterioration; however, driving should never be under the influence as is illegal.
• Doses to the effects of TH C can vary in different regions to the body; in receptors in the brain may cause cognitive alterations, receptors on periphery might cause immunosuppressive qualities.
• While some show the potential for some serious long-term and short-term effects, the high dose can cause certain levels of impairment.

Opioids

• Opioids are naturally found within the poppy plant whose substances are used for a variety of reasons for many years.
• One of the most useful drugs known to pharmacologists from this plant, morphine, is known for becoming and causing opioid use disorder (OUD).
• The opioid is any substance that exerts actions through the body that binds to it from natural/synthetic reactions.
• Pain relief from opioid analgesics and high potential for use and disorder.
• The body's own way of fighting to binding opioid receptors for analgesic effects is known as endogenous opioids, including endorphins.
• These naturally occuring opioids provide affects the emotional and physical connection to pain.
• Opioids are derived from the poppy plant and are referred to as "Natural Opioids" with natural and clinical uses.
• Morphine is a direct binder that handles severe or critical cases for pain relief.
• The liver is where the conversion between codeine and morphine is used as codeine is about 10X less powerful.
• Semisynthetic are similar to the same effects while containing an altered version of the drug.
• Clinical analgesic Hydromorphone is 5x more potent and Diacetylmorphine, or Heroin, is known to be 2x more potent in illicit use, especially if made synthetically.
• The receptor for opioids are found all over the body in the peripheral and nervous system.
• Mµ receptors are present everywhere and are often found to assist for pain relief and is the main responder for morphine.
• K receptors are where the pain receptors are found related to analgesia, dysphoria, and miosis.
• A loss of this system due to analgesia is through any interruption to other sense organs and the brain.
• Delta (8) receptors are involved in analgesia at the level of the spinal cord and brain and may also control the emotional response to drug.
• As the body already carries its' own pain killing methods and receptors to send impulses, there must be a method to inhibit and supress the emotions and physical stimuli.
• This can be done by reducing the release of "pleasure signals" being sent everywhere else in the body. The short-term effects are analgesia, sedation, and/or hypnosis, with a suppression for cough, potential respiratory suppression, and a decrease to hormones.
• This can be done most importantly by reducing the release of the hormones that the body releases from the hypothalamus.
• Opioods can suppress breathing can be found in many overdose victims. The two main thereapeutic uses of opioid are for pain relief and treatment for direhea.
• Loperamide is an over-the-counter opioid that is not an analgesic and does not produce withdrawal, but it is useful in controlling diarrhea
• As opium has the potential for misuse it becomes vital to find ways to prevent the chance of overdose by supporting their vital functions. -Opioids such as morphine have a potential for misuse; low-to-moderate doses are not a concern; however, it becomes life-threatening at high does.
• To properly wean someone from high doses, a professional has to watch and monitor the patient.
• There, however, can be no guarantee of stopping a relapse with a good plan.
• Overdosing leads to the most damaging risk.
• Naloxone works as an emergency medical agent through the blocking of other agonists to prevent any function to breathing and respiratory functionality.
• While most of the points are found to not be dangerous to all patients, some risks are still worth taking as it helps the patient with discomfort in the moment.
• Tolerance reverses in days which is something to have in focus in particular.

Explore the effects, risks, and uses of sedative-hypnotics and barbiturates. Review the dangers of combining these agents with alcohol and their impact on the central nervous and cardiovascular systems. Learn why barbiturates are prescribed less frequently today.