Test 3 (Chapters 7, 9, 12) Flashcards
What part of nervous system do sedatives and hypnotics effect
Central nervous system (CNS) depressants are a diverse group of drugs that slow physical and mental activities, relieve anxiety, diminish awareness, and increase sleep. Sedatives and hypnotics are two types of CNS-depressant drugs.
What are sedatives and hypnotics and that are two popular classes
Sedatives are drugs that relieve anxiety, cause relaxation, and produce mild depression of the CNS. Hypnotics induce drowsiness and sleep (hypnos=Greek word for “sleep”). Two popular classes of sedative/hypnotics are barbiturates and benzodiazepines. Barbiturates are used mainly for an anesthesia and treatment of seizure disorders, while benzodiazepines (BZDs) are used mainly as muscle relaxants and to reduce anxiety.
What is valerian used for
Valerian root has been used for thousands of years as a remedy for insomnia.
First synthetic drug truly classified as hypnotic
Synthesized in 1832, chloral hydrate quickly induces a long, deep sleep. Today it is sometimes given to infants as a sedative prior to surgical or EEG procedures or to help people withdraw from opioid or alcohol addiction.
That schedules are sedatives and hypnotics in
• barbiturates: Schedule IV
• BZD: Schedule IV
• Quaalude: Schedule III
• GHB: Schedule I
Who synthesized barbiturates and how
In 1864, Adolf von Baeyer, a German scientist, synthesized barbituric acid by combining malonic acid from apples with urea, a waste product found in urine.
Most frequently prescribed benzodiazepines and what they were originally marketed for
The most frequently prescribed benzodiazepines in Canada include Valium (diazepam), Ativan (lorazepam), and Xanax (alprazolam), totalling over 26 million prescriptions in Canada in 2017. During their early days, benzodiazepines were predominantly marketed to women to help them deal with the stress of daily life.
How safe are benzodiazepines
At first, benzodiazepines were viewed as extremely safe and free from the problems of tolerance, dependence, and withdrawal. BZDs are relatively safe when used for short periods (and are much safer than barbiturates), but long-term use can cause tolerance, dependence, and withdrawal problems.
Prevalence of Sedative and Hypnotic Use
In 2017 CTADS reported that 11.7 per cent of the population used sedatives. Sedative/hypnotic use is higher in females (14.3 per cent) than males (9.1 per cent), and increases with age: about 5.1 per cent of 15–19-year-olds, 7.5 per cent of 20–24-year-olds, and 12.6 per cent of those age 25 and older report past-year use.
Different categories of barbiturates and what they are used for
Barbiturates are categorized as long-acting, intermediate-acting, short-acting, or ultra-short-acting, based on their duration and this decides their clinical use. Shorter-acting drugs are more lipid-soluble and take effect rapidly, because they quickly enter the bloodstream and easily cross the BBB and are cleared from system faster. These short-acting barbiturates are more likely to be abused.
Longer-acting drugs are best used as anticonvulsants in treatment of epilepsy or to reduce anxiety. Intermediate- and shorter-acting drugs are used to treat insomnia, for emergency management of seizures, and as a preanaesthetic sedative. Ultra-short-acting barbiturates can be used to rapidly anaesthetize a patient in emergency situations and to bring them out of anaesthesia quickly as well and they leave the patient with no memory of the experience.
What are drugs that reduce anxiety called
Anxiolytics
Routes of Administration of sedatives
Sedatives can be administered rectally or by injection, but they are most commonly administered orally. Some anaesthetic medications or drugs given to treat emergency seizures or status epilepticus (epileptic seizures following one another in which the sufferer remains unconscious) are administered intravenously.
Sedative and hypnotic absorption + difference between BZD absorption and barbiturate
Sedative/hypnotics are absorbed into the bloodstream after oral administration. Barbiturates are absorbed in the stomach, while benzodiazepines are absorbed in the small intestine; this means that BZDs are absorbed into the bloodstream more slowly than are barbiturates.
Distribution of sedatives in bloodstream is determined by what
Once in the blood, a sedative’s distribution is determined by its lipid solubility. Barbiturates are more fat-soluble than BZDs; as a result, barbiturates are better able to cross the blood brain barrier, leading to a faster onset of action. Shorter-acting barbiturates are especially lipid-soluble.
Barbiturates and fatty tissues in body
Barbiturates stored in fatty tissues of the body. From these body fat deposits, the barbiturate is released slowly into the blood. The amount of body fat a person has can influence their response to barbiturates and BZDs. Although the initial effects of a short-acting barbiturate may recede quickly, the drug may be released from body fat deposits and then circulate at low levels in the blood for a significant period of time.
How are sedatives metabolized + what happens when they enter bloodstream
Barbiturates and benzodiazepines are metabolized in the liver. When these drugs enter the bloodstream, some bind to plasma proteins. Only unbound molecules of the drug are free to bind to receptor sites and exert an action. As the unbound molecules of barbiturates are metabolized and excreted, the drug that was previously stored in fat or that was bound to plasma proteins becomes free and available for metabolism. The balance between the free and bound forms of the drug is responsible for the varying durations of action for different barbiturates.
Benzodiazepines undergo two major pathways of metabolism:
Oxidation= such as diazepam (Valium), chlordiazepoxide (Librium), and flurazepam (Dalmane), produce active metabolites, prolonging their duration of action until they are further detoxified by metabolism and then excreted.
Conjugation= metabolized to pharmacologically inactive, water-soluble products that are excreted in urine.
How does liver diseases/ weakness affect metabolism of sedatives
Metabolism is decreased. Half life becomes much longer, effects last very long
Sedatives Mechanism of Action on receptors
Sedative/hypnotics exert their effects by binding to GABA receptors. Barbiturates and BZDs both work on the receptor, but by slightly different mechanisms.
GABA receptors are _____ (what type)
ionotropic, meaning that the receptor itself is an ion channel
Benzodiazepines Interaction with the GABA-A Receptor
GABA-A receptors in brain (limbic system and cortex) have binding sites for benzodiazepines, When a BZD binds to a GABA receptor, the shape of the receptor changes, increasing the frequency of chloride channel openings and enhancing GABA’s inhibitory effects. The GABA receptors that control respiration and other vegetative processes do not have many BZD sites, so BZDs do not suppress respiration as much as barbiturates do. There are also GABA receptors with BZD binding sites in the peripheral nervous system, which modulate the immune system and are involved in the body’s response to injury.
Benzodiazepines effect on adenosine
BZDs slightly block the reuptake of the inhibitory neurotransmitter adenosine, which acts to increase adenosine’s activity at the synapse and is responsible for some of the anticonvulsant, anxiolytic, and muscle relaxant effects of BZDs.
Barbiturates’ Interaction with the GABA-A Receptor
Unlike benzodiazepines, barbiturates don’t act at a specific single site on the GABA-A receptor, they bind to multiple cavities on the surface of the receptor. Barbiturates have a more general effect that enhances the inhibitory activity of GABA.
Difference between effects of BZDs and barbiturates on chloride channels
Barbiturates increase duration of channel opening, even in the absence of GABA which is a reason why barbiturates are more dangerous than BZDs. BZDs can only open the chloride channel if GABA is present. Because barbiturates have a more general effect on GABA receptors, they have more widespread sedating effects than do the BZDs. Along with widespread CNS depression, barbiturates can suppress cognitive function, muscle activity, and respiration.
Physiological Effects of sedatives at Low and Moderate Doses
Barbiturates and BZDs are CNS depressants. They cause sedation, increase sleep, reduce anxiety, and relax muscles. Lower doses can lead to relaxation, decreased anxiety, and drowsiness. As the dose increases, the user may experience euphoria and disinhibition, as well as sedation, dizziness, staggering, and sleep.
Sedatives effect on sleep
Sedatives and hypnotics help people to fall asleep faster and increase a person’s total sleep time. But they decrease the time spent in REM sleep, as well as the time spent in deep sleep. Therefore, although most hypnotics increase total sleep time, the sleep they produce is not as restful and restorative as normal slumber.
Sedatives taken with alcohol
When taken with alcohol the drugs act synergistically, and a potentially fatal suppression of respiration can occur. (both are CNS depressants)
Behavioural and Psychological Effects of sedatives at Low and Moderate Doses
Sedatives and hypnotics produce mood changes that are similar to those caused by alcohol. They reduce anxiety and give a sense of relaxation and mellowness. People on sedatives may have difficulty thinking clearly and making rational judgments. Their learning and memory may be impaired. Disinhibition—the release of bizarre, uninhibited behaviours, or of hostility or rage—may occur, and users sometimes become emotionally unstable.
Sedative addiction and therapeutic index
Sedatives can be addictive. They bind to GABA receptors that modulate the firing of neurons in the addiction pathways of the brain. Abuse and dependence are more likely to occur with faster-acting agents than with those that have long-lasting effects.
Barbiturates have a narrow therapeutic index, a high potential for tolerance, dependence, and abuse and are lethal in overdose.
Side effects of barbiturates and bzd’s
• drowsiness
• lethargy
• dizziness
• confusion
• reduced libido
• diminished concentration
• incoordination and impairment of driving skills
Barbiturates may also lead to
• gastrointestinal distress
• joint pain
• skin rash
• impotence and menstrual irregularities
• impaired thinking
• anterograde amnesia
Adverse Psychotic Reactions to Halcion (sedative)
Halcion was widely prescribed in 80s. Complaints from others began to accumulate, however, reporting that Halcion led to amnesia, confusion, paranoia, hostility, and adverse psychiatric reactions. The drug was banned in five countries, but the US Food and Drug Administration concluded that its benefits outweighed its risks, and Halcion is still available today in Canada
Sedatives and cancer/death
A recent study found that sedative/hypnotic drugs were associated with an elevated risk of death and cancer. The researchers followed 10,529 patients who received hypnotic prescriptions and 23,676 matched controls for an average of 2.5 years. They discovered that patients prescribed any hypnotic were more likely to die when compared to those prescribed no hypnotics.
Rohypnol
Rohypnol (sedative) is a colourless, odourless, tasteless drug that is 5–10 times stronger than Valium. When slipped into an unsuspecting victim’s drink (especially an alcohol-containing drink), Rohypnol can lead to blackouts, unconsciousness, and complete memory loss. Rohypnol is not approved for use in Canada (or in the United States), but it is available in many countries, including much of Europe.
Sedatives effect on fetus
About 2 per cent of pregnant women use benzodiazepines. BZD use during pregnancy is known to increase the risk of spontaneous abortion by almost 2x. Possible increased risk for cleft palate, no other malformations. May sensitize GABA receptors in infants. Baby may have withdrawal. Taking antiepileptic drugs during pregnancy is thought to increase the risk of congenital malformations.
Sedatives drug interactions
Barbiturates and benzodiazepines have a synergistic effect with other depressants, in which the combined result is greater than the sum of the effects of each drug alone. That means that when users take these sedatives with other CNS depressants such as alcohol, opioids, or general anaesthetics, there is a chance they may stop breathing. Both barbiturates and BZDs are metabolized by the cytochrome P450 (CYP450) enzymes of the liver and, therefore, may interact with other substances that use the same enzyme system.
Sedative overdose symptoms
One of the reasons barbiturates are so dangerous is that their lethal dose is not significantly higher than their effective dose. The exact lethal dosage depends on one’s tolerance, age, size, and other drugs that have been taken. Symptoms of a barbiturate overdose include sluggishness, incoordination, confusion, slurred and slowed speech, sleepiness, staggering, and shallow breathing, leading to coma and death.
Medical and Therapeutic Uses of Sedatives and Hypnotics
Benzodiazepines and barbiturates have been used as anaesthetics and preanaesthetic medications and to treat many conditions, including
• insomnia
• anxiety disorders
• seizure disorders
• withdrawal from chronic alcohol use
Why have bzd’s replaced barbiturates
BZDs have for the most part replaced barbiturates because BZDs have more specific effects than barbiturates, fewer side effects, a much wider margin of safety, less potential for abuse or tolerance, less effect on REM sleep, and minimal effects on the respiratory centre of the brainstem.
Sleep stages
Sleep is divided into five stages—non-REM (NREM) stages 1, 2, 3, 4 and REM sleep—which are characterized by specific brain wave patterns and other physiological properties. One advances through these stages in cycles throughout the night. As one progresses from stage 1 to stage 4, sleep becomes progressively deeper and more restorative.
Different neurotransmitters and drugs affect our sleep/wake cycle:
Glutamate, norepinephrine, acetylcholine, and orexin all increase wakefulness. Non-REM sleep is increased by GABA, the main inhibitory neurotransmitter of the CNS. Adenosine also promotes sleep.
Insomnia can have widespread consequences:
Sleeplessness can increase the risk of memory and learning problems, inflammation, diabetes, weight gain, and mood disorders. Both depression and attention-deficit/hyperactivity disorder (ADHD) are associated with insufficient sleep (may not be causal).
Z drugs
Z drugs are not BZDs, but they bind to the same place on the GABA receptor, and their effects are primarily hypnotic rather than anxiolytic. Z drugs produce a sleep rhythm that more closely matches one’s natural sleep cycle.
Negatives of Z drugs
Z drugs are cross-tolerant (tolerance to one drug results in tolerance to another similar drug) with ethanol, overdose can occur if the Z drugs are combined with alcohol or other CNS depressants. Many ppl go to ER with z drug overdose
Chronic Effects of Sedatives and Hypnotics
Long-term use of sedatives, especially of barbiturates, is associated with daytime fatigue, accidents, and overall mortality. Use is especially problematic in the elderly, and is associated with increased risk of falls, traffic accidents, and cognitive decline. Except when they are used as anticonvulsants, barbiturates are typically recommended for only short-term use.
Tolerance to barbiturates
Tolerance to barbiturates develops at different rates. Those who take daily or near-daily barbiturates over a period of weeks or months will need ever-increasing doses to achieve the desired sedative or hypnotic effects. Tolerance does not develop for the anticonvulsant effects, even after years of use. Tolerance also fails to develop for respiratory depression, so the margin of safety decreases dangerously as the user becomes tolerant to the drugs’ sedative effects.
Cellular and metabolic tolerance to barbiturates
Cellular tolerance occurs when the neurons in the brain adapt to the presence of the drug and receptors downregulate. Metabolic tolerance occurs because barbiturates increase the activity of the liver’s CYP450 enzymes that metabolize barbiturates, the more drug used, the faster it is metabolized.
Bzd tolerance
Tolerance to BZDs is not as fast or complete. As with barbiturates, tolerance first develops to the sedative and hypnotic effects, tolerance to the anxiolytic effects develops slowly and to a limited extent. When the sedative effects wear off, the disinhibitory effects become more prominent. Unlike barbiturates, BZDs do not increase the activity of the liver enzymes that normally metabolize the drug, so they show no metabolic tolerance.
Sedative and Hypnotic Dependence and Addiction, when does it develop
When large quantities of barbiturates are taken for several weeks, physical dependence begins to develop. Benzodiazepines are not as strongly addictive. Most people who use BZDs as medically directed—even long term—do not become dependent. The risk of BZD dependence is higher in patients who are anxious or have sleep disorders, those who take large doses, individuals who abuse other drugs, and users who obtain the drug illegally simply to get high. Sedatives with a fast onset of action and a short half-life are typically more likely to be abused than slower-acting compounds.
Sedative and Hypnotic Withdrawal: when does it happen
Withdrawal from sedatives occurs when a person has a physical dependence to these drugs. Not all long-term users will experience withdrawal symptoms upon discontinuation, and when they do, the onset of symptoms may be delayed for days or even weeks.
Sedative withdrawal symptoms
• insomnia
• anxiety
• irritability
• tremor
They may also suffer from
• nausea and vomiting
• loss of appetite
• headache
• sweating
• muscle pain
• fever
• confusion
• memory problems
• difficulty concentrating
Sedative withdrawal treatment
Withdrawal should be medically supervised to monitor for fatal symptoms. Paper down drug use gradually. Therapy helps to deal with psychological symptoms underlying dependence.
_______ reduce anxiety and increase relaxation; _______ reduce anxiety and work as a muscle relaxant; _______ induce drowsiness and sleep; and _______ treat seizures and work as an anesthetic.
Sedatives; benzodiazepines; hypnotics; barbiturates
Why, given the sheer number of drugs in the sedative/hypnotic categories, is the search for CNS depressants that alleviate stress and anxiety still ongoing?
Drugs in these categories were all thought to be safe and non-addictive, however, they were later discovered to have significant dangers, and cause tolerance, dependence, and withdrawal.
What is the correct order in terms of best clinical uses of barbiturates from long-acting to intermediate/short-acting to ultra-short-acting?
epilepsy management → pre-anesthetic sedative → emergency (rapid) surgical anesthetic
Benzodiazepines can have a half-life ranging from
1–3 up to 200 hours
Barbiturates tend to work faster than benzodiazepines because
barbiturates are absorbed in the stomach, whereas benzodiazepines are absorbed in the small intestine
Sedatives: _______ work as GABA agonists, while _______ work at the GABA receptor but have a more specific mechanism of action involving GABAA
barbiturates and benzodiazepines
BZDs exert different primary effects depending on which subtype of GABA-A receptor they bind to. For instance, BZDs that bind to alpha1 subunits are effective _______, and those with a higher affinity for alpha2 or alpha3 subunits are better _______.
hypnotics; anxiolytics
One of the reasons that barbiturates are so dangerous is that
their lethal dose is not significantly higher than their effective dose.
BZDs are safer compounds than barbiturates, but they are not risk-free. In 2013, BZDs were involved in about ________ per cent of all fatal overdoses of prescription drugs in the United States.
30%
What is the link between the recent rise in BZD overdose mortality rates and opioids?
This rise occurred at the same time that opioid prescriptions were on the rise and opioids are involved in about three-quarters of the overdose deaths involving BZDs.
What is GHB and where does it naturally occur
Gamma-hydroxybutyric acid (GHB) is both a naturally occurring substance and a synthetic drug. GHB occurs naturally in beef, wine, and some fruits, and in the body from the breakdown of GABA; in fact, GHB is considered a neurotransmitter in its own right. GHB has both therapeutic and recreational uses.
History of GHB
Gamma-hydroxybutyric acid was first synthesized in 1960, when Dr Henri Laborit, a French researcher, investigated the drug’s properties as an anticonvulsant that could cross the blood brain barrier more easily than GABA. Later, GHB was used in a limited capacity as an anaesthetic. Although GHB does induce unconsciousness, it doesn’t prevent pain, which makes it less than ideal for surgical use. GHB gained popularity in the 1980s as a nutritional supplement for bodybuilders as it increases secretion of growth hormone
Pharmacokinetics of GHB
When given as a drug, GHB has effects similar to other CNS-depressant drugs. It is an odourless, colourless, salty-tasting liquid that is rapidly absorbed into the bloodstream and easily crosses the blood brain barrier. Effects are usually felt within 15 minutes and peak within 40 minutes.
Mechanism of action of GHB
GHB birds to excitatory GHB receptors and inhibitory GABA receptors which are metabotropic meaning it causes a cascade that open a separate ion channel, slower and more complex process than mechanism by which sedatives interact with GABA receptors.
Difference between low and high doses of GHB mechanism of action
At low doses, GHB binds almost exclusively to GHB receptors in brain. Binding to these receptors stimulates the release of excitatory glutamate. As the dose of GHB increases, more GHB binds to and activates GABAB receptors, producing sedation and sleepiness. GHB has a relatively low affinity for GABA receptors; a high dose is required for GHB to have an effect at these inhibitory receptors.
GHB also affects other neurotransmitters:
• GHB has a biphasic effect on dopamine—low doses of GHB inhibit the release of dopamine, while high levels of GHB increase it.
• GHB increases levels of acetylcholine and serotonin.
• GHB also mediates opioid effects in the brain. The opioid antagonist naloxone blocks some of GHB’s effects.
Acute effects of GHB for mild and higher dose
GHB can give the sensation of inebriation. A mild dose (1 gram or less) will cause relaxation, mild euphoria, a loss of inhibition, increased sociability, and short-term forgetfulness. The user may feel heightened sexual interest, although, like alcohol, GHB is actually associated with decreased sexual performance. A higher dose (2–3 grams) can cause lethargy, drowsiness, and sleep. Loss of muscle control, slurred speech, vomiting, dizziness, visual disturbances, and amnesia also may occur. Doses of 4–5 grams or more can lead to very deep sleep, depressed respiration, hypothermia, coma, and possibly death.
Medical and Therapeutic Uses of GHB
In Europe, GHB is approved for use as an anaesthetic, sleeping aid, and as a treatment for opioid addiction and alcohol withdrawal, because it has been found to help relieve withdrawal symptoms and to reduce cravings. In Canada, GHB’s only approved use is for the treatment of narcolepsy. Under the trade name Xyrem, GHB reduces the frequency of cataplexy and alleviates the excessive daytime sleepiness.
