Sedative-Hypnotics (Benzos, Imidazos, Pyrrolos) Flashcards
What are 3 general clinical uses of the sedative hypnotic drugs?
Insomnia
Anxiety disorders
Alcohol withdrawal
Describe the dose dependent effects of sedative hypnotics
Increasing the dose increases the degree of sedation, which could eventually lead to coma and death
Benzodiazepines have a plateau or “tailing off” where they no longer produce sedative effects
Barbiturates are more dangerous and continually increase sedation with inc dose
What receptor do all the sedative hypnotic drugs work on?
GABA-A
Describe the GABA-A receptor. It is ___tropic. What activates it and what happens downstream?
Inotropic
Requires an alpha, beta, and gamma subtype to function
Activated by GABA> Leads to inc Cl- channel opening, leading to Cl- influx and an IPSP. Causes hyperpolarization and decreased neuron firing.
What determines the subtype of the GABA A receptor?
Alpha subunit
Describe the BZ1 subtype
a1B2y2
Can bind benzodiazepines, imidazopyridines, or pyrrolopyrazines
Describe the BZ2 subtype
a2B3y2 or (a3,a5)Bny2
Binds ONLY benzodiazepines
What part of the GABA-A receptor binds GABA?
Alpha-Beta interface
What part of the GABA-A receptor binds drugs (benzos, imidazos, pyrrolos)?
Alpha-Gamma interface
What part of the GABA-A receptor binds barbiturates?
Intracellular beta portion
Where does the benzodiazepine antagonist flumazenil bind the GABA A receptor?
Alpha-Gamma interface
What is the primary indication for flumazenil and what is one potential contraindication or drawback?
Benzodiazepine overdose, but may cause withdrawal symptoms in patients who have been on benzodiazepines for a long time
May also be used to reverse Benzodiazepine sedation after surgery
What is the MOA of Beta-Carbolines?
Inverse agonists –> negative allosteric modulators of GABA receptor function
Bind BZ1 or BZ2 sites and block benzo effects
Lead to decreased frequency of chloride channel opening
What are the basic MOAs of benzodiazepines, imidazopyridines, and pyrrolopyrazines?
Positive allosteric modulators of GABA-A receptor
They bind their sites, increase GABA’s affinity for the alpha-beta receptor site, increase frequency of Cl- channel opening, IPSP, decreased neuron firing
What is the basic MOA of barbiturates?
Increase DURATION of Cl- channel opening in the presence of GABA
Does NOT bind BZ1 or BZ2 sites
Benzodiazepines
Indications
Anxiety disorders Insomnia EtOH withdrawal Anticonvulsant effects Skeletal muscle relaxation
List the Benzodiazepines
Midazolam
Alprazolam
Tiazolam
Estazolam
Diazepam Lorazepam Oxazepam Temezepam Clonazepam
Chlordiazepoxide
Chlorazepate
Benzodiazepines
Metabolism
All undergo Phase I oxidation and Phase II conjugation, except…
LOT only go through Phase II glucoronidation (Lorazepam, Oxazepam, Temazepam)
Benzodiazepines
Solubility and Protein binding
Lipid soluble
Highly protein bound, so drug-drug interactions are likely
How does the half life of benzodiazepines contribute to potential toxicity and adverse effects?
Short half life – concentration remains pretty consistent day to day
Long half life– drug conc accumulates to a much higher concentration, which could lead to oversedation
What is diazepam’s active phase I metabolite? How long does it take after diazepam withdrawal for it to clear from your system?
Desmethyldiazepam is the primary metabolite
Takes 6-7 to clear from a patient’s system after stopping diazepam
How does hepatic function affect benzodiazepine blood levels?
Tend to stay elevated longer in elderly patients with decreased hepatic function
Benzodiazepines
Adverse Effects
Drowsiness
Ataxia
Amnesia
Confusion
Paradoxical excitement
Dizzy
Paradoxical rage
Allergic rxn
Benzodiazepines
Tolerance and Dependence
Physical dependence can occur in pts who take large doses for long periods of time
Can develop tolerance to sedative effects of benzodiazepines over time, but tolerance is NOT developed to their anxiolytic effects
Symptoms of Benzodiazepine Withdrawal
Anxiety Insomnia Loss of appetite HA Nausea Tremor Muscle aches Sweating Irritability
Rare: Confusion, Delirium, Psychosis, Seizures, Catatonia
How could each of these factors increase risk for tolerance and dependence?
- T 1/2
- Time to drug onset
- Potency
- Dose
- Time length drug taken
- Low T 1/2
- Short time to drug onset
- High Potency
- High Dose
- Long time length drug taken
List the imidazopyridines
Zolpidem
Zaleplon
What is the only Pyrrolopyrazine?
Eszopiclone
What drug can block effects of imidazopyridines and pyrrolopyrazines?
Flumazenil (benzodiazepine antagonist)
Imidazopyridines and Pyrrolopyrazine Dependence Risk
Lower than for benzodiazepines, but can still be habit forming
Imidazopyridines and Pyrrolopyrazine
Adverse Effects
HA Dizziness Somnolence Nausea Vomiting Diarrhea Anterograde amnesia Rebound insomnia
Sleep driving and sleep eating with no memory of event
Relative half lives of Imidazopyridines and Pyrrolopyrazine
Zolpidem- 1.5-3 hrs
Zaleplon- 1 hr
Eszopiclone- 6 hrs
List the Barbiturates
Phenobarbital
Methohexital
Thiopental
Barbiturates
MOA at low and high doses
Low doses – bind intracellular GABA-A Beta subunit; increase DURATION of Cl- channel openings
High doses- directly activate Cl- channel opening independent of GABA
Barbiturates
Adverse Effects
Low therapeutic index that is lethal at 10x the hypnotic dose
Potent resp depression, esp when combined with alcohol
Can cause physical dependence and withdrawal
Barbiturates
Metabolism
Stimulates CYP450 activity and induces hepatic microsomal oxidases
May increase metabolism of other drugs
Ramelteon
MOA
Melatonin receptor (MT1 and MT2) agonist
What is 1st, 2nd, and 3rd line therapy for insomnia?
1st: CBT and Sleep Hygeine
2nd: Work up for underlying cause of insomnia
3rd: Sedative Hypnotic Drugs
Which sedative hypnotic is most commonly prescribed for insomnia treatment?
Temazepam
Which sedative hypnotics should be used more in elderly people? Why?
LOT = Lorazepam, Oxazepam, Temazepam
Elderly ppl have lower liver function, so it is better to give them drugs that don’t require phase I oxidation via the liver
How are benzodiazepines dosed for insomnia treatment?
In general, you don’t want them to take the drug more than 3 nights per week so they don’t associate a good night’s sleep with the drug
Should be used short term (1-3 months)
What might happen after cessation of benzodiazepine for insomnia?
Rebound insomnia – original symptoms recur, or reoccur in greater intensity
Withdrawal
Herbal Preps
Valeriana officinalis
What is the active compound and its MOA?
Sesquiterpenes: mediate GABA release and inhibit GABA breakdown
Useful for 4 weeks insomnia
Herbal Preps
Chamomile
What is the active compound and its MOA?
Apigenin, a benzodiazepine agonist
What are the two currently available FDA-approved OTC sleep aids? Active compounds and general MOA?
Unisom – contains doxylamine (antihistamine)
ZzzQuil- contains diphenhydramine (antihistamine)
Buspirone
MOA
5HT 1A partial agonist
Buspirone
Drug Interactions
DO NOT use buspirone with a MAOI
-Need to clear system of either drug entirely before starting the other, or you risk Serotonin Syndrome
Buspirone
Indications
Anxiety disorder(with antidepressants)
Major depression (with antidepressants)
