M3s1 Sedtive-Hypnotics Flashcards
What are sedative-hypnotic agents
CNS depressants
Magnitude of Sedative-hypnotic agents
-magnitude of CNS depression produced by a drug at a particular dose determines the effect the agent produces
Low dose
Anti-anxiety - treats anxiety disorders like 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 (compared to without)
-major excitatory neurotransmitter in brain is glutamate
-when a person is anxious or having difficulty sleeping, some therapies aim to depress the overall brain activity, by decreasing gluamate-induced nerve firing
-this accomplished by increasing the inhibitory signalling in the brain
MOST SEDATIVE-HYPNNOTIC DRUG CLASSES WORK IN THIS MANNER
Without sedative-hypnotics
-most brain activity involves excitatory neurons
-excitatory neurons release 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
*refer to goodnotes for image
Drug classes
A class of drugs is a group of drugs that have the same mechanism of action and similar pharmacological properties
Ex. Thiopental, secobarbital, and phenobarbital are all drugs that fall under the barbiturate class of drug
GABA signalling
-GABA is primarily inhibitory neurotransmitter
-causes the inhibitation by binding to and selectively opening chloride channels
-chloride channels are built of multiple subunits that span the neuronal cell membrane, allowing chloride ions to flow into the cell when signalling to open
-when GABA binds to and opens the chloride channel, chloride ions flow into the postsynaptic neuron
-influx of chloride ions makes it harder for the postsynaptic neuron to transmit incoming messages to other neurons, thereby depressing CNS neuronal signalling
-each GABA receptor subunit has four tramsmebrane-spanning regions. The receptor itself is a pentamer, with two alpha subunits, two beta subunits and one gamma subunit. 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
*refer to goodnotes for image
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
-result is an increase in synaptic inhibition and thus, a dampening of neuronal responses
-in essence, they enhance the inhibitory effect of GABA
*REFER TO GOODNOTES
How popular are benzodiazepines
-among most widely prescribed drugs in world
-just over 3% of Canadians use a benzodiazepines at least once a year for medical reasons
Routes of administration of benzodiazepines
-usually taken as capsule or tablet, but some are available for intravenous or intranasal use
Mechanism of action for benzodiazepines
-activation of the benzodiazepines increases the frequency of the opening of the chloride channel
Therapeutic effects of benzodiazepines
-benzodiazepines have minimal suppression of REM-type sleep, which is the type of sleep that allows you to feel rested when you wake
Lethality of benzodiazepines (and antidote for benzodiazepines)
-most commonly involved drug in overdose
-fortunately, high therapeutic index and therefore a wide margin do safety so deaths from overdose rare
-death has occurred following ingestion of enormous doses, rapid intravenous injection of a large dose, or when taken in combination with other sedating drug (ex. Alcohol)
Antidote for benzodiazepines:
-allows for reverse effects in event of overdose
-for this drug, called flumazenil, a benzodiazepine receptor antagonist that blocks the effect of benzodiazepine
Adverse effects of benzodiazepine use
Short-term use
CNS:
- adverse effects like drowsiness, lethargy, fatigue, 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, but considered therapeutic effect if goal is sedation
Breathing:
-respiratory depression has been observed following rapid intravenous administration of benzodiazepines
Motor coordination:
-moderate doses of all benzodiazepines can impair motor coordination and driving
-patients should refrain from driving or operating dangerous machinery
-responses exaggerated as dose is increased
Long-term
-varies per individual
-some individuals take large amounts of benzodiazepines for long periods of time with no major evidence of intoxication while others demonstrate symptoms of chromic sedative-hypnotic intoxication like impaired thinking, poor memory or judgement, disorientation, in coordination and slurred speech
Special populations
Pregnant/chestfeeding:
-benzodiazepines crosses placenta and distribute into the fetus
-if administrated into first trimester, they result in a small but significant risk for fetal abnormalities
-benzodiazepines secreted into milk, exposing nursing infants to therapeutic or toxic doses of the drug can result in sedation or death
Older adults:
-can produce cognitive dysfunction in older adults
-should be used in caution, if not at all ages, this age
-metabolized more slowly in older adults, which can lead to over-sedation, falls and injury
Benzodiazepines potential for misuse and SUD
-misuse for recreation purpose does occur, typically in combination with alcohol to enhance the CNS depression effects of both
Misuse potential:
-weaker reinforcing properties than other drugs like barbiturates, alcohol, opioids, stimulants
-inherent harmfulness is also low, as does not depress respiration at therapeutic doses and does not lead to death on own
Tolerance:
-can develop to the sedative effects and impairment of coordination, the anxiolytic effect (less common) or the euphoric effects (occasionally)
-magnitude don’t produce clinical concern though
-higher degree of cross-tolerance occurs among benzodiazepines and other sedative-hypnotic drugs, like barbiturates or alcohol, as modulate the chloride channels in CNS
Withdrawal:
-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 occur much less with barbiturates
Addiction:
-may develop in some individuals, but not all, and depends on a multitude of factors including genetic and environment
How do benzodiazepines reduce an athlete’s anxiety
-increase CNS depression in a dose-dependent manner
-therefore, at low dose act as anti-anxiety agents
Class of sedative-hypnotics - barbiturates
-classified according to their duration of action, and can be long-acting (1-2 days), short-acting (3-8 hours), and ultra-short acting (20 minutes)
-older type and have generally been replaced by safer drugs
-barbituric acid, the basic structure of all barbiturates
Routes of administration for barbiturates
-administrated depending on what they are being used to treat
For epilepsy, barbiturates are administered orally
For anesthesia, administrated intravenously
Mechanism of action for barbiturates
Activation of barbiturate receptor increases the duration of the opening of the chloride channel
-demonstrate the full spectrum of dose-dependent CNS depression (anti-anxiety -> sedation -> hypnosis -> general anesthesia -> death)
Therapeutic use of barbiturates
-in low dose, usually result in the beneficial effects of tranquility and relaxation
-will induce sleep if dose is sufficient
-clinical use of barbiturates are limited
-ultra-short acting and short-acting barbiturates can be used to induce anesthesia
-some long-acting agents can be used as antiepileptics
Lethality of barbiturates
-low therapeutic index
-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 individual
-specific antidote for barbiturate poisoning does not exist
-death can also occur during barbiturate withdrawal
adverse effects of barbiturate use
In general, they suppress REM-type sleep
-REM sleep is essential so that one does not wake up with the feeling of “not having slept” or feeling of a hangover
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 (especially find motor dexterity)
-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:
-chronic inebriation. Memory, judgement and thinking all impaired
-individuals often exhibit hostility and mood swings, including depression
Barbiturates potential for misuse and SUD
-prescribed much less frequently than they were 40 years ago, but illicit use continues to be problem
-sometimes combined with other drugs like opioids, amphetamines and alcohol
Potential for misuse:
-should be avoided, as potential for misuse greater than alcohol
-pleasurable effects give significant degree of reinforcement
-sometimes injected to obtain a “rush effect”
-the inherent harmfulness is very high due to risk of death from respiratory depression or from withdrawal
Tolerance:
-can develop
-high degree of cross-tolerance occurs between barbiturates and other sedatives (benzodiazepines)
Withdrawal:
-occurs after discontinuation of chronic use
-symptoms initially appear as tremors, anxiety, weakness and insomnia, as well as postural hypotension (a form of low blood pressure in which a persons blood pressure falls when suddenly standing up or stretching)
-symptoms may progress to include seziures, delirium, visual hallucinations and high body temperatures
-barbiturates must be withdrawal slowly under medical supervision
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 adequate supply
-craving often persists long after use has stopped
Comparison of benzodiazepines and barbiturates
*refer to goodnote images
Zopiclone and the benzodiazepine-Like drugs
-another class of sedative-hypnotics used to treat problems like anxiety or difficulty sleeping
-benzodiazepine-like drugs such as zopiclone and zoplidem bind to a subset of the GABA receptors and cause sedation
-this class of drugs act similarly to 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
-as with benzodiazepines, these drugs should be used with caution in order adults
Drugs that bind to the chloride channel
*Refer to goodnotes
Therapeutic use of sedative - hypnotics
Barbiturates - anti-anxiety
Benzodiazepines - anti-epileptic
Benzodiazepine-like drugs - hypnotic
Flumazenil - antidote for benzodiazepine overdose
Buspirone
-sold under brand name Buspar
-interesting anxiolytic as it does not act on the GABA receptor, but rather serotonin receptor
-used in generalized anxiety states and may have an advantage over the other sedatives in that it does not appear to have additive effects with other sedative-hypnotic drugs
-as such, this drug may be prescribed instead of a benzodiazepine or benzodiazepine-like drug when the individuals already taking other CNS depressant drugs and there is a concern of addictive effects
