B3-4: Benzodiazepines + Non-Benzo Anxiolytics, Hypnotics Flashcards
How is GABA synthesized?
How is its action terminated?
Synthesis: Glu -> GABA via Glutamic Acid Decarboxylase
Termination: (re)uptake into nerve terminal/glia or degraded by GABA transaminase
What are the types of GABA receptors?
GABA-A: Ionotropic, allows Cl- influx to hyperpolarize the cell (decreases excitability). Faster synaptic inhibition than GABA-B. Most sedatives act on GABA-A.
GABA-B: Metabotropic, Gi GPCR -> K+ efflux -> hyperpolarization. Exist on both presynaptic and postsynaptic terminals. Only GABA-B agonist to know is Baclofen.
[GABA-C: not so important, primarily in the eye]
What are the subunits of the GABA-A receptor?
Which anxiolytic/hypnotic drugs bind to which subunits?
Has 2 α, 2 β, 1 γ subunits. Drugs allosterically modify these subunits to alter Cl- permeability.
α subunit = GABA binding site. Normally requires 2 molecules of GABA to open the channel.
γ subunit = benzodiazepine, flumazenil, zolpidem binding site
β subunit = barbiturate binding site (barbs maybe also bind α according to lecture slide)
What are 2 toxins / chemicals not used pharmacologically that act on GABA-A receptors?
[prob not important for exam but was on lecture slide]
Muscimol: probably the more important toxin inside Amanita muscaria mushroom (the other being Muscarin). GABA binding site agonist
Bicuculline: GABA binding site antagonist
Picrotoxin: channel blocker (non-competitive antagonist)
How are CNS effects changed with an increasing dose of drugs that increase GABA transmission?
- Anxiolytic-Sedation: low dose. May be anti-convulsant too.
- Hypnotic action: moderate dose
- General anesthesia: higher dose
- Medullary depression, Coma, Death: very high dose. Occurs more easily in barbiturates or alcohol, but less so in benzos (unless combined with other sedatives / “synergism”)
What are the long-acting barbiturates, medium and short-acting barbiturates, and ultra short-acting barbiturates
Long-acting (1-2 days): Phenobarbital
Medium and short-acting (3-8 hours): Cyclobarbital, amobarbital, pentobarbital
Ultra short-acting (20 minutes): Thiopental, methohexital, hexobarbital
What are the uses for the different barbiturates?
both historically and currently
Historically, short-acting to long-acting ones used as hypnotics/sedatives. Phenobarbital still used as anti-epileptic.
Ultra-short acting: IV anesthesia (rarely used). Have ultra-short action bc they quickly redistribute from brain into other tissues.
What are the disadvantages of barbiturates as sedative-hypnotic drugs?
- Low safety margin, easier to overdose to the point of fatal respiratory depression
- No antagonist / antidote
- Psychological dependence, tolerance
- CYP450 induction, contraindicated in porphyria
- Drug interaction (esp. other depressants like alcohol)
What sedative drug was famous for causing for severe teratogenic effects?
Thalidomide (used in West Germany 1957-1961).
Now used in multiple myeloma
What barbiturate-like sedative drug, originally developed as potential malaria treatment, became a popular drug of abuse from the 1950s-1980s until they became less prescribed as benzodiazepines became the preferred drug?
[Prob not important for exam, but TMYK]
Methaqualone: called Quaalude (“ludes”) in the US or Mandrax in other countries.
Important for understanding drug references in old movies, maybe David Bowie or Rolling Stones lyrics. Bill Cosby used them as a date rape drug :(
What are the two types of benzodiazepine receptors?
How do benzodiazepines work on these receptors?
BDZ-1: on α1 subunit of GABA-A receptor. Sedative, hypnotic effect.
BDZ-2: on α2 subunit of GABA-A. Anxiolytic effect.
Benzos are agonists of both BDZ-1 and BDZ-2, and enhance the CNS inhibitory effect of GABA binding to its own receptor (potentiation / positive allosteric modulation). Increased frequency of Cl- channel opening.
Why are benzodiazepines more commonly used than barbiturates for sedation?
As the dose increases, Benzodiazepines do not tend to cause severe respiratory depression, coma, or death. They’re much safer than barbiturates, and are only really dangerous when combined with other drugs or alcohol. Benzos also have an antidote in case of overdose (Flumazenil)
Barbiturates can also cause irreversible damage to neurons (inhibit complex I of electron transport chain)
What drug is an antagonist of BDZ receptors?
What drugs are inverse agonists of BDZ receptors?
Antagonist (neutral allosteric modulator): Flumazenil. Used IV for benzodiazepine overdose. May cause withdrawal symptoms/seizures if person is addicted to benzos.
Inverse agonist: β-carbolines. Cause anxiety, possibly improve memory. [extra: β-carbolines are also MAOIs, used in ayahuasca]
What are the main pharmacological actions of benzodiazepines?
- Sedation (anxiolytic)
- Hypnotic (nREM2 ↑, REM and nREM3,4 ↓) - help sleep
- Antiepileptic
- Centrally-acting skeletal muscle relexant
- Creates anterograde amnesia (BDZ-1 effect)
What are some commonly-used benzodiazepines for anxiety and as muscle relaxants?
- Anti-anxiety: Alprazolam, Clonazepam, Lorazepam, Diazepam (all have long half-lives)
- Muscle relaxant: Diazepam, Tetrazepam, Lorazepam
[Extra: Brand names you may already know include Diazepam = Valium; Alprazolam = Xanax; Clonazepam = Klonopin; Lorazepam = Ativan]
