Sedative Hypnotic Drugs
What Are Sedative Hypnotic Drugs?
Definition:-
“Sedative Hypnotic Drugs are chemically heterogeneous class of drugs which produce dose dependent CNS depressant effects.”
These drugs are divided into sub-groups as;
- Benzodiazepines
- Short Acting → Triazolam
- Intermediate Acting → Alprazolam
- Long Acting → Flurazepam
- Barbiturates
- Ultra Short Acting → Thiopental
- Short Acting → Secobarbital
- Long Acting → Phenobarbital
- Miscellaneous Drugs
- Buspirone
- Zaleplon
- Zlopidem
- Ramelteon
- Eszopiclone
- Chloral Hydrate
What Is Pharmacokinetics Of Sedative Hypnotic Drugs?
(What the body does with the drugs!)
Absorption, Distribution, Metabolism, Excretion
Absorption
Most of these drugs are well absorbed from GIT due to lipid solubility so administered entrally.
Distribution
Because of lipid solubility, these drugs have good distribution to the brain.
♦ Lipid solubility indicates the ability to cross lipids barriers so such drugs are well distributed to brain with lipid barrier (Blood Brain Barrier)
Thiopental → ↑ (highest) lipid solubility → enters CNS rapidly → used as induction agent in anesthesia
Eszopiclone, zaleplon & zolpidem with higher lipid solubility also have rapid onset of action on CNS.
The CNS effects of these lipid soluble drugs are terminated by redistribution to other highly perfused organs or tissue like skeletal muscles.
Metabolism
Hepatic enzymes are responsible for metabolism of sedative hypnotics drugs in most cases except;
- Lorazepam
- Oxazepam
These two drugs undergo extra-hepatic conjugation & don’t form active metabolites.
- Benzodiazepines are converted into active metabolites by metabolism so often leads to excessive sedation.
- Barbiturates (except phenobarbital which is excreted partly unchanged in the urine) are extensively metabolized.
- Chloral hydrate is oxidized into trichloroethanol (active metabolite).
- Zolpidem is rapidly metabolized by hepatic enzymes (inactive metabolites so have short duration of action but longer plasma half life).
- Zaleplon is more rapidly metabolized by hepatic aldehyde oxidase & cytochrome P450.
- Eszopiclone is metabolized by cytochrome P450 (half life 6h).
The duration of action of these drugs ranges from few hrs (zolpidem,triazolam,eszopiclone & chloral hydrate) to >30 hrs (diazepam, phenobarbital & chlordiazepoxide)
Excretion
These drugs are excreted via urinary track after converting into their metabolites or partly unchanged (phenobarbital is excreted partly unchanged in the urine).
Mechanism of Action Of Sedative Hypnotics
Sedative Hypnotic Drugs act in a different ways depending upon its sub-groups;
What Is The Mechanism of Action Of Benzodiazepines?
Style:- facilitates neural membrane inhibition.
Location:- Benzodiazepines receptors (BZ receptors) are present in brain regions like;
thalamus, limbic system & cerebral cortex.
Structure:- BZ receptors form the part of GABAA receptor chloride ion channel macromolecular complex (a pentameric structure assembled from five subunits each with 4 transmembrane domains). An isoform of GABAA receptor comprises 2 α1, 2β2 & 1 γ2 subunits. In this isoform, the binding region for benzodiazepines are b/w α & γ subunits.
Elaboration:- Binding of benzodiazepines causes increase Chloride ion conductance which facilitates the inhibitory action of GABA. These drugs also increases the frequency of chloride ion channel opening.
Antagonists:-
- Flumazenil reverses the CNS effects of benzodiazepines (antagonist at BZ receptors).
- β carbolines binds with BZ receptors with high affinity & exert anxiogenic & convulsant effects (inverse agonists)
What Is The Mechanism of Action Of Barbiturates?
Style:- depress the neural membrane activity in mid-brain reticular formation.
Location:- Barbiturates receptors are present in brain regions like;
thalamus, limbic system & cerebral cortex.
Structure:- Barbiturates receptors also form the part of GABAA receptor chloride ion channel macromolecular complex but at the different sites from those with which benzodiazepines interact.
Elaboration:- Binding of barbiturates causes increase in GABA mediated chloride ion channel opening which facilitates the inhibitory action of GABA. These drugs may also block glutamic acid (excitatory transmitter) & sodium channels (at higher concentration).
Antagonists:- These aren’t antagonized by flumazenil.
continue…
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