Unit 3 - Sedative-Hypnotic Drugs Flashcards
what does sedative mean?
calming, anxiolytic effect (ideally with little effect on motor or mental functions)
what does hypnotic mean?
induce sleep (more pronounced CNS depression than sedation; can be achieved with most sedative drugs simply by increasing dose)
what are the uses of sedative hypnotic drugs?
- acute treatment of anxiety disorders (anxiolytic)
- muscle relaxant (often diazepam)
- anticonvulsant
- pre-anesthetic
- recreation
what are the classes of sedative-hypnotic drugs?
- ethyl alcohol
- benzodiazepines (and pseudo-benzos)
- barbiturates
- antihistamines
- others, including non-sedating anxiolytics
what is the mechanism of sedative-hypnotic drugs?
bind to some site on GABA-A receptor complex to potentiate GABA-mediated inhibition
- opens Cl- channel –> hyperpolarize cell –> cell is inhibited
- receptor specificity is the key to selectivity of drug effects
what are the agents that allosterically enhance GABA binding to GABA-A receptor?
- benzodiazepines - binding site between a1 and gamma2 subunits
- barbiturates - bind to alpha or beta subunit
- ethanol - binds to alpha
where is the GABA binding site?
between a1 and B2 subunits
what does picrotoxin do?
from berries of east Indies shrub
-blocks GABA-A Cl- channel directly (non-competitive antagonist) that causes convulsions
what are the benzodiazepine/GABA-A receptor subtypes? what does this mean?
2 main families
- BDZ1 = omega 1
- BDZ2 = omega 2
- most clinically used benzos bind to BOTH subtypes
different receptor subunit compositions have different functions and different binding affinities for different benzodiazepines
-thus, some differences in pharmacological profiles of various benzos
what are properties of diazepam?
- sedation»_space; hypnosis (dose-related –> anti-anxiety and sleep)
- muscle relaxation
- anticonvulsant activity
- often anterograde amnesia
- very little cardiovascular or respiratory effects
degree of CNS depression in benzos VS barbiturates? if combined?
benzos = ceiling effect (limited depression)
- don’t produce respiratory depression, coma, or death at OD-levels
- augment action of GABA
barbs (and alcohol, general anesthetics) = full CNS depression –> coma and death at OD
-augment action of GABA, and at high doses can directly open Cl- channel
synergistic effects if benzo + alcohol, meaning less alcohol is needed to cause coma/death
what are the pharmacokinetic and pharmacodynamic differences between benzodiazepines?
- some have active metabolites, meaning some are longer acting than others
- differences in GABA-A subtype affinity and location
what are diazepam, chlorodiazepoxide, lorazepam, alprazolam, midazolam, and triazolam? which ones have active metabolites and what does this do?
benzodiazepines
-chlordiazepoxide, diazepam, and flurazepam have active metabolites, meaning their half lives are much higher than others (100 hrs VS 10 hrs)
what are pseudo-benzos?
sleeping pills that are BDZ (omega) 1 selective
- sedation and hypnosis without muscle relaxation or anticonvulsant activity
- short half-life (~2 hrs) so little hang-over for many users
- have largely replaced sleeping benzos
- all insomnia medicines (OTC or Rx) have a risk for next-morning impairment
what are zolpidem, eszopiclone, zaleplon, and zolpiclone?
BDZ (omega) 1 agonists; pseudo-benzos; sleeping pills
what is flumazenil?
synthetic benzodiazepine antagonist used to reverse benzo and pseudo-benzo OD
-no effect on GABA-A receptor function per se
explain barbiturate metabolism?
Phase I: oxidation at several different P450s (significant enzyme induction)
Phase II: subsequent glucuronide formation
what are phenobarbital and thiopental and how do they work?
both are barbiturates
PB: less lipid soluble, slower onset, slow elimination (t 1/2 = 4-5 days), so longer-acting
-used as anti-epileptic or anti-convulsant
TP: highly lipid-soluble, fast-on/off (due to tissue redistribution)
-used to induce anesthesia
between antidepressants and benzodiazepines, which are for long term VS short term?
AD for long-term treatment (esp. SSRIs) that takes effect in weeks
BD for short-term treatment (due to addictive potential)
what is used in:
- acute anxiety
- generalized anxiety disorder
- panic disorder
- OCD
- PTSD
AA: benzodiazepines GAD: SSRIs and/or benzos; buspirone relieves w/o sedation PD: SSRIs or benzodiazepines OCD: SSRIs PTSD: antidepressants
what is buspirone?
relieves anxiety without marked sedation
- euphoric, hypnotic, anticonvulsant, or muscle relaxant effects
- no interaction with GABA-A receptor complex
- may act as partial agonist at 5-HT1A receptors
what drugs are used for sedation?
short-acting benzos: alprazolam, lorazepam
what drugs are used for hypnosis?
triazolam (short-acting benzo) or zolpidem (pseudo-benzo)
what drugs are used for anesthesia?
- barbiturate thiopental for induction
- benzos for calming and anterograde amnesia (short acting midazolam
what drugs are used for anticonvulsion?
lorazepam, diazepam, phenobarbital
-these aren’t for chronic seizures, but if someone presents in ER with status epilepticus
what drugs are used for muscle relaxation?
diazepam
-inhibitory effects on polysynaptic reflexes and inter-neuron transmissions
what are general adverse effects of sedative-hypnotics?
- dose-related CNS depression (additive if >1 agent)
- drowsiness/hangover
- may cause falls especially in elderly
- produces confusion, sedation, and unsteadiness - tolerance (cross-tolerance, metabolic tolerance, or dynamic tolerance)
- psychologic and physiologic dependence
what is important to remember if withdrawing non-benzo sedative-hypnotics?
alcohol and barbiturates can have psychologic and physiologic dependence, so abrupt withdrawal is life-treatening
-must do tapered withdrawal
what is the difference between metabolic tolerance and dynamic tolerance?
MT: induces enzymes (notably with barbiturates and alcohol)
DT: decreased CNS responsiveness (receptor down-regulation)
what are adverse effects of benzodiazepines?
- daytime sedation and drowsiness
- additive or synergistic depression of CNS with other drugs (notably alcohol)
- significant dose-related anterograde amnesia
- psychologic and physiologic dependence with chronic use
- no significant effects on respiration or cardiovascular function with normal dosing
