Sedative-Hypnotics Flashcards
Clinical uses of sedative hypnotics
Insomnia Anxiety disorders Alcohol Withdrawal Anticonvulsants (some) Adjunct to anesthesia (some)
Classes of Sedative Hypnotic Drugs
GABAa receptor: Benzodiazepines Non-benzodiazepines (Imidazopyridines, pyrrolopyrazine) Barbituates Alcohol
Others:
Melatonin receptor agonists
Anti-histamines
Herbal preparations
GABAa receptors
Ionotropic receptors Activated by GABA Increase Cl channel opening Inhibit post-synaptic potential Hyperpolarization Decreased neuron firing
Which type of GABA receptors do sedative-hypnotic drugs modulate?
Only GABAa, no not interact with GABAb
GABAb receptors
Metabotropic G-protein linked receptors
At presynaptic terminals, regulate the release of GABA (homoreceptors), or other neurotransmitters (heteroreceptors)
At postsynaptic membranes, activation produces hyperpolarization
Polypeptide classes and isoforms of GABAa receptor complex
7 polypeptide classes • α 1 2 3 4 5 6 • β 1 2 3 • γ 1 2 3 • δ • ε • π • ρ 1 2 3
How many transmembrane domains does each polypetide subunit of GABAa have?
4
How many subunits assemble to form the GABAa hetero-pentameric receptor ?
5
Which isoforms are required for a functional GABAa receptor
α, β, γ
What are the most common GABAa receptor subtypes?
two (2) α subunits
two (2) β subunits
one (1) γ subunit
Which subunit isoform determines the GABAa subtype and its ability to be modulated by certain drugs?
α subunit
What are the majority of GABAa subtypes?
BZ1 (α1β2γ2) -60%
Which drugs can bind the BZ1 subtype?
Benzodiazepines
Imidazopyridines
Pyrrolopyrazines
What isoforms form BZ2?
~15-20% (α2β3γ2)
10-15% ([α3,α5]βnγ2)
Which drug can bind BZ2?
Benzodiazepines
What percentage of GABAa receptors respond to benzos?
85-95%
What percentage of GABAa receptors respond to BZ-1 selective drugs (imidazopyridine, pyrrolopyrazine)
60%
α/β interface
- # of sites?
- what does is bind?
- 2 sites
- binds GABA
α/γ interface
- # of sites?
- what does is bind?
- what does it require?
- 1 site
- allosteric modulatory site
- Binds benzodiazepines, Imidazopyridines, pyrrolopyrazines
- needs GABA bound at α/β site
Which α-isoforms are found at BZ1 site?
α1
Which α-isoforms are found at BZ2 site?
α2, α3, α5
Which sites do benzodiazepines bind?
BZ1 and BZ2
Which site(s) do imidazopyridine bind?
BZ1
Which site(s) do pyrrolopyrazine bind?
BZ2
Which sites do Flumazenil bind?
BZ1 and BZ2
Benzodiazepines
Bind to BZ1 and BZ2
Positive allosteric modulators of GABAa receptor
GABA required for GABAa receptor to open Cl channels
Non-benzodiazepine selective agonists
Selectively bind BZ1 Imidazopyridine: zolpidem, Zaleplon Pyrrolopyrazine: eszopiclose Positive allosteric modulators of GABAa receptor GABA required
Mechanism for BZ1 and BZ2 positive allosteric modulation:
Benzo/ selective BZ1 bind >
Increased GABA affinity for GABAa receptor >
Increased FREQUENCY of Cl channels opening >
Inhibitory post synaptic potential >
Hyperpolarization >
Decreased neuron firing
Inverse “agonists” (β-Carbolines)
Require GABA’s presence
Negative allosteric modulators of GABA receptor (decrease binding at the receptor and decrease frequency of Cl channel opening)
Binds to BZ1 or BZ2 site
Produce anxiety, seizures, block benzo effects
Antagonist
Flumazenil
High affinity competitive antagonist
No effect alone, blocks effects of drugs binding to BZ1/BZ2
NOTE: will NOT antagonize (GABA agonists, barbituates, meprobamate, ethanol)
Clinical uses of flumazenil
Treat BZ overdose
Can precipitate withdrawal in patients dependent on benzos
Reverse BZ-induced sedation
Barbituates
Bind to GABAa receptor at site distinct from BZ binding sites
No specificity for isoform
Increases DURATION of Cl channel opening
At high concentrations can directly open Cl channels (no GABA needed)
Effects can be potentiated by alcohol, other drugs that increase GABAa receptor function
Why are barbituates more dangerous than benzos?
no specificity for isoform, work on all isoforms
Barbituates do not GABA
Flumazanil does not counteract effect
Neuroactive steroids
Affects regions of GABAa receptors distinct from BZ1/BZ2
Affects GABAa receptor isoforms (not containing BZ1/BZ2)
Facilitates GABAergic transmission
At high concentrations can directly produce Cl channel opening
Ethanol
Known site of action
Thought to alter GABAa neurotransmission
Effect similar to BZs
Can potentiate the effects of other GABAa receptor modulators
Treatment of alcohol withdrawal
Benzodiazepine
Benzodiazepine drugs
Midazolam Triazolam Alprazolam Estazolam Lorazepam Oxazepam Temazepam Clonazepam Diazepam *Chlordiazepoxide *Chlorazepate (*active metabolite = desmethldiazepam) "If its AM, PAM, LAM, likely a benzodiazepine"
What are the five most prescribed benzodiazepines
Alprazolam Lorazepam Clonazepam Diazepam Temazepam
Clinical use for Benzodiazepines
ANXIETY DISORDERS SLEEP DISORDERS Anticonvulsant effects (some) EtOH withdrawal treatment Relaxation of skeletal muscles (some) Adjuncts for anesthesia (some)
When do fatality concerns come into play with benzos?
Patient has significant pulmonary illness
Patient has taken multiple meds that have CNS depression effects
Pharmacokinetics of Benzos
All lipid soluble
Very good bioavailability
Highly protein bound
Metabolism of Benzos
Most metabolized by Phase I and Phase II
3 benzos go directly through Phase II only! : LOT
Which 3 benzos only go through Phase II metabolism?
Lorazepam
Oxazepam
Temazepam
Abuse of benzos- methadone
Diazepam and alprazolam used w/ methadone to increase euphoric effect
Abuse of benzos- cocaine
Use benzos to relieve side effects (irritability and agitation)
Abuse of benzos- alcohol
augment its effect and take the edge off withdrawal states
Which benzos have short half lives?
Alprazolam
Triazolam
Also “LOT”
Which benzos have long half lives?
Diazepam, prazepam, clorazepate, chlordiazepoxide, Flurazepam
(chlordiazepoxide has additional Phase I intermediate with long half life)
Which benzos are preferred for geriatric patients or patients with impaired hepatic function?
LOT!
Lorazepam, Oxazepam, Temazepam
Side effects of benzos
Frequent: Drowsiness, ataxia, amnesia
Occasional: confusion, paradoxical excitement, dizziness
Rare: paradoxical rage, allergic rxn
Tolerance to benzos
Tolerance to sedating effects
NO tolerance to anxiolytic or muscle relaxant effects
Cross tolerance can occur with ethanol
Physical dependence and Benzos
Drug removal produces unpleasant symptoms , occur when abruptly stop benzo or rapidly decrease the dose
Symptoms of Benzo withdrawal
Common: anxiety, insomnia, loss of appetite, headache, muscle aches, nausea, tremor, sweating, irritability
Rare: confusion, delirium, psychosis, seizures, catatonia
Taping benzo dosage
Most you decrease dose is 50% at one time, wait at least a week before lowering dose again
Drug duration effect on tolerance/dependence
Shorter half-life = increased risk for dependence/tolerance
Amount of time to drug onset effect on tolerance/dependence
Decreased time = increased risk for dependence/tolerance
*route of administration
Drug’s potency effect on tolerance/dependence
Increased potency = increased risk for dependence/tolerance
Dose of drug taken effect on tolerance/dependence
Increased dose = increased risk for dependence/tolerance
Time length drug taken effect on tolerance/dependence
Increased time length = increased risk for dependence/tolerance
BZ1 site selective Non-benzo Drugs
Imidazopyridines: Zolpidem, Zaleplon
Pyrrolopyrazine: Eszopiclone
BZ1 site selective Non-benzo Drugs MOA
Binds BZ1 selectively Positive modulator of GABAa receptor Decreased risk of dependence than benzos Overdose does NOT produce dangeous CNS depression Flumazenil can block effects
BZ1 site selective Non-benzo Drugs Side Effects
Headache, dizziness, somnolence, anterograde amnesia, rebound insomnia, sleep driving, sleep eating
Which BZ1 site selective drug has the longest half life?
Eszopiclone
What are the benefits of BZ1 site selective drugs over benzos?
Less morning hangover effect
Not restricted for short term use
No effect on stages of sleep
Barbiturate Drugs
Phenobarbital
Methohexital
Thiopental
“AL” the barbiturates
Barbiturate MOA
Binds to ionotropic GABAa receptors at regions distinct from BZ1/BZ2
Likely binds intramembrane lipophillic portions of β subunits
No specificity for isoform subtype
Low doses: increases DURATION of Cl channel opening (needs GABA)
High doses: Can directly activity Cl channel opening (no GABA)
Short acting Barbituates
t1/2= hours
Thiopental, Mexihexital
Rapid onset, induce anesthesia
Intermediate acting Barbiturates
t1/2=18-48 hours
Amobarbital, Secobarbital, Pentobarbital
Now replaced by benzos
Long acting Barbiturates
t1/2 = 4-5 days
Phenobarbital
Used for epilepsy
Barbiturates Side Effects
Low therapeutic index
Lethal
Ramelteon MOA
Melatonin agonist
Selectively binds MT1 & MT2 melatonin receptors
No affinity for BZ1/BZ2
Ramelteon Pharmacokinetics
Rapid absorption Moderate protein bidning Large volume distribution Extensive 1st pass metabolism Short half life
Ramelteon Side effects
Comparable to placebo
(headache, somnolence, fatigue, dizziness, nausea, worsened insomnia)
Well tolerated even if taken for long period
No physical dependence or abuse potential!
