Sedatives Flashcards
What are the three types of sedative hypnotics?
- Benzodiazepines
- Benzodiazepine like drugs
- Gamma- hydroxybutyrate (and precursors)
What are the general effects of sedatives?
Increases the effects of GABA in the CNS and generally depress neuronal activity. Used to help fall asleep
Between which subunits do benzos bind to and what do they do?
Between the alpha and the gamma subunit (separate from the GABA binding site).
They increase the affinity of the receptor for GABA and increase the frequency of the channel opening
What is the allosteric effect?
increasing the frequency by which a channel opens
Do benzos exert their effects directly onto the receptor?
No, they cannot be directly activated. GABA needs to bind to the receptor as well as the benzos to activate it.
True or false: the neuronal membrane depolarizes in the presence of benzos
False, the membrane becomes hyperpolarized, the channel for GABA stays open for longer –> inhibitory response
Where are the receptors for benzos most abundant?
- Cerebral cortex
- Striatum
- Cerebellum
What are benzos clinically used for, and at what doses?
Low dose: anxiolysis, reduce anxiety by decreasing overall neuronal excitability
Low - medium: Muscle relaxant properties
High dose: sedation/hypnosis, induce sleep. To treat seizures in emergency situations
Explain the effects of benzos on memory:
Can have severe effects on memory; can cause complete loss of recent events, short term memory isn’t stored into long term memory
Which receptors mediate the effects of memory when taking benzos?
Alpha 1 Subunit of the GABA-a receptor
Can benzos cross the placenta? If so, what are the effects in the womb?
Yes they can, it results in ‘floppy baby syndrome’. Sedatives are highly lipophilic and can cross into the placenta easily, because the baby’s liver can’t metabolize the drug efficiently, there is a significant accumulation in the fetus (twice the amount found in the mother)
What are the effects of “floppy baby syndrome” when the fetus is born?
In the womb, there was loss of muscle tone (due to the sedatives effects– muscle relaxant), so when the baby is born, they are unable to nurse so they become malnourished
What is the abuse potential of benzodiazepines and benzodiazepine-like drugs compared to cocaine or alfentanil (opioid with same receptor as morphine)?
A study using break points looked at how many times an animal would press a lever before receiving the reward (drug). They found that benzos and benzo like drugs aren’t as reinforcing as cocaine and alfentanil. Benzos break point was only about 300-500 times, while cocaine and alfentanil were both over 1000 times
Explain how benzodiazepines affect the reward pathway/VTA circuit
Normally GABA and glutamate are both firing on the VTA and there is a balance. When benzos bind to GABA-a receptors, it inhibits GABA from firing on the VTA (disinhibition), even though no more glutamate is being released, there is nothing regulating it, so the VTA increases its activity to the NA resulting in high dopamine doses–> High reward
Explain the general structure of benzos
7 membered main ring with nitrogens in positions 1 and 4 with a pendant phenyl group
What extra chemical group is added when looking at a short acting benzo?
Triazole group, two nitrogens are added for them to be rapidly metabolized. These shorting lasting benzos have a short half life
What is added to the chemical group to increase the metabolism of a drug?
Hydroxyl groups are added to increase the metabolism rate of the drug. Drug companies started to add OH to their compounds to the effects would occur quicker
Do benzos produce tolerance?
Yes, tolerance can develop quite rapidly and need increasing doses to achieve the same effects. Chronic use has been linked to depression and violence.
Can withdrawal of benzos be severe or even fatal? What are the differences between short acting and long acting benzos?
Yes, benzos depress the CNZ which causes an up regulation of glutamate receptors. When you stop taking benzos the brain becomes hyper excitable due to the tolerance. Withdrawal of short acting produces the worst symptoms but they are short lasting. Withdrawal from long acting produces older symptoms but can last for much longer.
What is the best way to stop taking benzos?
Tapering off use. Switch from short acting to long acting to avoid mini withdrawals.
When someone is overdosing on benzos, what should you give them?
Flumazenil, it is a GABA-a receptor site antagonist
What does GBH (gamma-hydrozybutyrate) produce?
Can produce euphoria, at low doses its lowers inhibitions, produces a strong sedative effect
Which receptor does GBH work through?
GABA-b receptors at either pre or post synaptically
What happens to the presynaptic receptor when activated by GHB?
It tends to inhibit NT release. It works by hyper polarizing cells by opening K+ channels and reducing Ca2+ channels
How do y-butyrolactone and 1,4 butanediol compare to GHB?
- y-butyrolactone is more lipophilic than GHB and enters the brain quicker. It is also shorter lasting than GHB but has a higher potency
- 1,4 butanediol is less lipophilic than GHB and it has longer effects, but lower potency
What is the therapeutic index of benzodiazepines?
About 2, so there is a very fine line between a good dose and a dangerous dose
