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Depressants
CALAMBA, MICAH LOU C.
BSPh N36-A
The CNS Depressants
•Responsible for depressing or “slowing down” the
functions of the CNS
•Inhibition of Excitation
•Types of CNS depressants:
Anxiolytics
Sedative-hypnotics
Antipsychotics
Anxiolytic, Sedative & Hypnotic
Agents
•Note: these groups have several common
structural features and share at least one common
mode of action which is the positive modulation of
the action of the ϒ-aminobutyric acid (GABA) at
GABAA receptor complex
ϒ-aminobutyric acid (GABA)
•An inhibitory neurotransmitter
•Depressants increase the activity of the GABA, as
a result, the brain activity slows down
producing a calming sensation
•Two types of GABA receptors
Ionotropic GABAA and GABAC
Metabotropic GABAB
Anxiolytic, Sedative & Hypnotic
Agents
1. GABAA receptor modulators
Benzodiazepines
Non-benzodiazepine hypnotics
Barbiturates
2. Melatonin 1-receptor agonist
3. Atypical azaspirodecanediones
4. Miscellanous Drugs
5. Antipsychotics and Anticonvulsants
Anxiolytic, Sedative & Hypnotic
Agents
6. Antidepressants; SSRIs
7. Sedative H1 – antihistamine
8. Β-adrenoreceptor anatagonists
9. Sleep promoting agents
Adenosine-2A receptor
Linoleamide and 9,10-octadeconamide
Anandamide
Benzodiazepines
• Also known as “benzodiazepine receptor” (BzR),
“Benzodiazepine receptor agonists” (BzRAs)
•The are highly effective Anxiolytic and hypnotic agents
•They bind to the benzodiazepine recognition site on
the GABA receptor.
•It induces conformal (allosteric) changes in the GABA-
binding site, thereby increasing the affinity of the
GABA receptor.
Chlordiazepoxide HCl, USP
• This drug enhances activity of the inhibitory
transmitter GABA in different parts of CNS by
increasing neuronal-membrane permeability to
chloride ions resulting to hyperpolarization and
stabilization. It has some muscle relaxant and
anticonvulsant activity.
Diazepam, USP
• a long-acting benzodiazepine w/ anticonvulsant,
anxiolytic, sedative, muscle relaxant and amnestic
properties. It increases neuronal membrane
permeability to Cl ions by binding to stereospecific
benzodiazepine receptors on the postsynaptic GABA
neuron w/in the CNS and enhancing the GABA
inhibitory effects resulting in hyperpolarisation and
stabilisation.
Flurazepam Hydrochloride, USP
• Flurazepam is a long-acting benzodiazepine which
binds to stereospecific benzodiazepine receptors on
the postsynaptic GABA neuron w/in the CNS, including
the limbic system, reticular formation. It is notable for
treating insomnia for it has a side effect of excessive
sedation.
Clorazepate Dipotassium, USP
• Clorazepate binds to stereospecific benzodiazepine
receptors on the postsynaptic GABA neuron within the
central nervous system, limbic system, reticular
formation resulting to an increase in chloride ion
permeability which further leads to hyperpolarisation
and stabilisation.
Oxazepam, USP
• Oxazepam is a short-acting benzodiazepine. It
increases neuronal membrane permeability to Cl ions
by binding to stereospecific benzodiazepine receptors
on the postsynaptic GABA neuron w/in the CNS
(including the limbic system, reticular formation) and
enhancing the GABA inhibitory effects resulting in
hyperpolarisation and stabilisation.
Lorazepam, USP
• Lorazepam is a short acting benzodiazepine. It
increases neuronal membrane permeability to Cl ions
by binding to stereospecific benzodiazepine receptors
on the postsynaptic GABA neuron w/in the CNS
(including the limbic system, reticular formation) and
enhancing the GABA inhibitory effects resulting in
hyperpolarisation and stabilisation.
Prazepam, USP
Halazepam, USP
Quazepam
Temazepam, USP
Alprazolam, USP
• Alprazolam binds to stereospecific benzodiazepine
receptors on the postsynaptic GABA neuron at several
sites w/in the CNS, including the limbic system,
reticular formation. Enhancement of the inhibitory
effect of GABA on neuronal excitability results by
increased neuronal membrane permeability to Cl ions,
which results in hyperpolarisation (a less excitable
state) and stabilisation.
Triazolam, USP
• An ultra-short-acting hypnotic and is widely used in
elderly for it causes less daytime sedation because of
its very fast metabolism.
Midazolam
•This drug is used intravenously as a
short acting sedative-hypnotic and as an
induction synesthetic because of its
short half-life.
Zolpidem
• Zolpidem acts by binding to the benzodiazepine (BZD)
receptors of the GABA receptor complex resulting in
neuronal hyperpolarization, action potential inhibition,
increased in chloride conductance and decreased in
neuronal excitability. It has strong sedative action but
only minimal anxiolytic, myorelaxant and
anticonvulsant properties. Zolpidem has a rapid onset
but short duration of hypnotic action.
•Most commonly prescribed drug for insomia in 2000’s
Eszopiclone
• Eszopiclone may interact w/ γ-aminobutyric acid
(GABA) receptor complexes at binding domains
located close to or allosterically coupled to
benzodiazepine receptors.
• A “superagonist” at BzRs
Zaleplon
• It is shown to interact with GABA subtype A complex
by binding selectively to benzodiazepine type 1
receptor. It reduces sleep latency without affecting
sleep duration.
Ramelton
• Acts on the melatonin receptors, specifically MT1,
therefore it is more effective in initiating sleep.
•No addiction liability
•Recently approved tx for insomnia
Barbiturates
• Used extensively as sedative-hypnotic drugs
• Binds on an allosteric binding site in the GABAA
receptors that positively modulates the effect of
GABAA receptor---- GABA binding.
• Increase the duration of GABA-gated Cl- channel
openings
•Can increase Cl- flux w/o GABA attaching to the
receptor site; GABA mimetic effect.
Mephobarbital, USP
Phenobarbital, USP
Mephobarbital, USP
• Is metabolically N-methylated to phenobarbital, which
may consider to account for almost all of the activity
•Its principal use is an anticonvulsant
Phenobarbital, USP
• Is a long-acting sedative hypnotic
• Anticonvulsant, partial seizures
Amobarbital
Butabarbital
Pentobarbital
Secobarbital
Glutethimide, USP
• Is one of the most active nonbarbiturate hypnotics
that is structurally similar to barbiturates, especially
phenobarbital.
Ethclorvynol, USP
• Mild sedative-hypnotic, with a quick onset and short
duration of action
Meprobamate, USP
• Officially indicated as an antianxiety agent
•a sedative-hypnotic agent
•Centrally acting
Carisoprodol, USP
• Indicated in acute skeletomuscular conditions
characterized by pain, stiffness and spasm.
•Major side effect is drowsiness
Chlorphenesin Carbamate, USP
• P-chloro substitute and 1-carbamate derivative of the
lead compound in the development of Mephenesin
(a centrally acting muscle relaxant.)
Methocarbamol, USP
•More sustained effect than
mephenesin.
•its dihydric mother compound is
Guaifenesin
Chloral Hydrate, USP
•is an aldehyde hydrate stable enough to be isolated.
•Chloral hydrate is unstable in alkaline solutions,
undergoing the last step of the haloform reaction to
yield chloroform and formate ion.
•In hydroalcoholic solutions, it forms the hemiacetal with
ethanol.
•Easily converted to Trichloroethanol, in which where the
sedative-hypnotic effects were actually credited.
Chloral Hydrate, USP
Paraldehyde, USP
•It is a liquid with a strong
characteristic odor detectable in the
expired air and an unpleasant taste.
•In the past, when containers were
opened and air admitted and then
reclosed and allowed to stand,
fatalities occurred because of
oxidation of paraldehyde to glacial
acetic acid.
What is Psychosis?
•A very serious mental illness that makes you
behave strangely because of loss of contact with
reality.
•There are several psychotic disorders and these
include:
Schizophrenia*
Bipolar Disorder
Acute idiopathic psychotic illness etc.
What are Antipsychotic drugs?
•a.k.a. Neuroleptics (seizing hold of the nerves)
•They don’t cure psychosis rather, reduces and control
many symptoms such as
Delusions and hallucinations
Paranoia and hearing voices
Severe anxiety
Incoherent speech, confusion
Violent behavior
mania
How do Antipsychotics work?
•BLOCKING THE ACTION OF DOPAMINE. Most
mental illnesses are caused by the excessive
production of dopamine (a neurotransmitter).
Blocking the production of dopamine means
disrupting the transfer of stimuli or messages,
which are frequent in patients suffering from
psychoses.
Types of Antipsychotics
TYPICAL ATYPICAL
Causes
Less likely to
extrapyramidal
cause EPS
symptoms (EPS)
•Dystonia •Tremor
•Akathisia •Tardive
•Parkinsonism dyskinesia
•Bradykinesia
Chlorpromazine HCl, USP
•Was the first phenothiazine compound introduced into
therapy.
•It is still useful as an antipsychotic. Other uses are in
nausea, vomiting, and hiccough (hiccup).
•The drug has significant sedative and hypotensive
properties, possibly reflecting central histaminergic and
peripheral 1-noradrenergic blocking activity, respectively.
Effects of peripheral anticholinergic activity are common.
Promazine
•A dopamine inhibitor that is used to control restlessness
Perphenazine, USP
•Control sever nausea and vomiting
•Management of Schizophrenia
Fluphenazine Hydrochloride, USP
•long-acting preparations have use in treating psychotic
patients who do not take their medication or are subject
to frequent relapse.
Thiothixene, USP
•Decreases the abnormal excitement in the brain
•Used for the management of Schizophrenia
Loxapine
•an effective antipsychotic, blocks D2-type receptors
•It is also N-demethylated to yield amoxapine (an
antidepressant drug), which inhibits norepinephrine (NE)
neurotransporter to block neuronal NE reuptake.
Clozapine
•Used to treat severe Schizophrenia
•Reduce risk of suicidal behaviour
Olanzapine & Quetiapine
•is used to treat the symptoms of psychotic conditions
such as schizophrenia and bipolar disorder, also manic
depressions.
Haloperidol, USP
•chosen as the agent to terminate mania and often
used in therapy for Gilles de la Tourette syndrome.
Droperidol, USP
•may be used alone as a preanesthetic neuroleptic or as
an antiemetic. Because of its very shortacting and
highly sedating properties, its most frequent use is in
combination with the narcotic agent fentanyl
Risperidone
Ziprasidone
Aripiprazole
• The benzamides evolved from observations that the
gastroprokinetic and antiemetic agent, metoclopramide, has
antipsychotic activity related to D2 receptor block. It was
hoped that the group might yield compounds with diminished
EPS liability. This expectation appears to have been met. An H-
bond between the amido H and the unshared electrons of the
methoxyl group to generate a pseudo ring is considered
important for antipsychotic activity in these compounds.
Presumably, when the protonated amine is superimposed on
that of protonated DA, this pseudo ring would superimpose
on DA’s aromatic ring.34 These features can be seen in
sulpiride and remoxipride.
Lithium Salts