Define sedative
Decreases activity Moderates Excitement Calms -Doesn't put you to sleep though
Define hypnotic
Produces drowsiness
Facilitates onset and maintenance of sleep that resembles natural sleep
Easily aroused sleep
GABA is
Major inhibitory NT
GABA(A)
Ligand operated
Permeable for Cl- which leads to hyperpolarization
GABA(B)
Metabotropic receptor
Inhibits adenylate cyclase, reduces NT release
Mostly in SPINE
Not helpful for anxiety
More Cl =
More inhibition = less anxiety
**Benzodiazepines MOA
Potentiate the action of GABA which increases the flux of chloride which makes more pronounced hyperpolarization and less excitable neurons
DOES NOT DIRECTLY ACTIVATE GABA(A) RECEPTOR
Flunitrazepam (BZ), pentobarbital and ethanol all
Cause sedation, CNS depression, anxiolysis and euphoria
GABA(A) has
different subunits
BZ are activators of which receptors
alpha 1/2/3/5 (not 4/6
Alpha 6 involved in
motor and balance coordination
Alpha 1 responsible for
Hypnotic/sedative
Anticonvulsant
Antergrade Amnesia
Alpha 2 responsible for
Anxiolysis
Pi pi stacking
Week form of bonding between groups when aligned parallel
Weak but multiple can be strong
Benzodiazepines are strictly :
allosteric modulators of the GABA(A) receptor
DO NOT directly open the receptor
What combination can be lethal?
Benzo and Alcohol
Antidote of Benzodiazepines
Flumazenil
Flumazenil MOA
Binds to GABA(A) receptor and competitively antagonizes BDZ
Overall Effects of BDZ
Reduction of anxiety and aggression Sedation (little suppression of REM) Anti-convulsant effect Anterograde amnesia Paradoxical effect (excitation)
PK of BDZ
Lipophilic
Liver
Active metabolites
No enzymes
Dizepam –>
Temazepam –> Oxazepam
Dexomoxepam –>
Diazepam
Prazepam –>
Diazepam
Short half life BZs
Triazolam
Oxazepam
Intermediate half life of BZ
Estazolam
Temazepam
Lorazepam
Alprazolam
Long half life of BZ
Flurazepam Diazepam Quazepam Nitrazepam Clonazepam
Rapid onset BZ
Triazolam Estazolam Flurazepam Diazepam Quazepam Nitrazepam Clonazepam
Slow onset BZ
Oxazepam
Temazepam
Intermediate onset of BZ
Lorazepam
Alprazolam
Overall side effects BZ
Daytime sedation Reduction of reaction time Ataxia, falls COGNITIVE DEFICITS Addictive!!!
BZ Approved for Insomnia
Flurazepam and Quazepam (long half life)
Triazolam (short)
Estazolam and temazepam (int)
Problem with ultra-long half-life
Sleep through the night and then sleep through the day
Then you take another and it keeps increasing until its toxic
Problem with ultra-short half-life
Fall off around 3-4 hours so then you wake up
Problem with moderate half-life
Stay during the day and you have a hangover effect
Zolpidem is what?
Non-BZ hypnotic (Z drugs)
Selective for alpha 1 subunit (which is great)
Zolpidem effects
Pronounced sedative
Onset: 15 minutes and last for 2-3 ours
Other Z drugs
Zaleplon (1 hr) and Eszopiclone (6 hr)
Thiopental
Pentothal
Induction of anesthesia
Pentobarbital
Nembutal
Secobarbital
Seconal
Pre-OP sedation
Insomnia
Phenobarbital (luminal)
Anti-consulvant
Barbiturates PD PK
High doses: open the channel directly (overdose)
Strong induction of P450s so drugdrug interactions
Acute effects of barbiturates
Strong sedation Some anticonvulsants No anxiety Suppresses REM Repiratory and CV depression at high doses Paradoxical excitement
BZ as drug of choice… But why?
High therapeutic index Few peripheral effects Low tolerance Low dependence Few drug interaction No respiratory depression (death)
Ramelteon is a
Melatonin MT1/2 receptor agonist
Extensive first pass
Cyp1A2 which is induced in smokers
MEEEEHHHH
Belsomra
Suvorexant Orexin antagonist (NT protein that regulate arousal and wakefulness)
Belsomra AE
Daytime somnolence
Suicidal thinking
COPD
Sleep paralysis, hallucinations
Belsomra Interactions
Digoxin
CYP3A