CENTRAL NERVOUS SYSTEM

DEPRESSANTS
ALICIA JANE V. TAMETA
Central nervous system (CNS) depressants are drugs that
can be used to slow down or “depress” the functions of
the CNS.
CNS in a dose-dependent manner, progressively
producing calming or drowsiness (sedation), sleep,
unconsciousness, surgical anesthesia, coma, and
eventually death from respiratory and cardiovascular
depression.
• GABA system (deficiency of GABA activity in CNS) is important
in the pathophysiology of anxiety and insomnia.
• GABA is the most common and major inhibitory
neurotransmitter (NT) in the brain and it exerts its rapid
inhibitory action mostly through GABA receptors.
• Two types of receptors:
the ionotropic GABAa and GABAC receptors
metabotropic the GABAB receptor
There are six isoforms of the α-polypeptide (α1–α6), four of the
β with two splice variants, and three of the with two variants
. The most common pentomeric GABA receptor combination
includes two α 1, two β 2, and one γ2 subunit.
BENZODIAZEPINES
Benzodiazepines are highly effective anxiolytic and hypnotic agents.
 are lipophilic, in the nonionized form and thus well absorbed from the GI tract
They tend to be highly bound to plasma proteins
Are also very effectively distributed to the brain.
Chlordiazepoxide Hydrochloride (Librium)
7- chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide
monohydrochloride
is well absorbed after oral administration, reaches peak plasma levels in 2 to 4
hours
Diazepam (Valium) 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-benzodiazepine-2-one
 is prototypical and was the first member of the benzodiazepine-2-one group to be
introduced.
 It is very lipophilic and is thus rapidly and completely absorbed after oral administration with
a maximum peak blood concentration occurs in 2 hours and elimination is slow, with a half-
life of about 46 hours.
 Diazepam clearance is decreased in the elderly and in patients with hepatic insufficiency, a
dosage reduction may be warranted.
 It is widely used for several anxiety states and has an additional wide range of uses (e.g., as
an anticonvulsant, a premedication in anesthesiology, and in various spastic disorders).
Prazepam (Verstran)
 7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one
 has a long overall half-life. Extensive N-dealkylation occurs to yield active nordazepam.
Halazepam (Paxipam)
 7-chloro-1,3-dihydro-5- phenyl-1(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepine-2-one
 is marketed as an anxiolytic and well absorbed.
 is active and present in plasma, but much of its activity is caused by the major active
metabolites nordazepam and oxazepam.
Flurazepam Hydrochloride (Dalmane)
 7-chloro-1-[2-(diethylamino)ethyl]-5-(2- fluorophenyl)-1, 3-dihydro-2H-1, 4-
benzodiazepine-2-one dihydrochloride
 is notable as a benzodiazepine marketed almost exclusively for use in
insomnia
 has a very long half-life
 it produces cumulative clinical effects and side effects (e.g., excessive
sedation) and residual pharmacologic activity, even after discontinuation.

Quazepam (Doral)
 has an absorption half-life of 0.4 hours with a peak in plasma levels
after 1.75 hours.
 It is eliminated both renally and through feces.
Clorazepate dipotassium (Tranxene)
 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid dipotassium
salt monohydrate
 it has a quick onset, overall long half-life, and shares similar clinical and pharmacokinetic
properties to chlordiazepoxide and diazepam.
Oxazepam (Serax)
 7-chloro-1,3-dihydro-3- hydroxy-5-phenyl-2H-1,4-benzodiazpin-2-one
 half-life of oxazepam is about 4 to 8 hours
 it is marketed as a short-acting anxiolytic
Lorazepam (Ativan)
 7-chloro-5-(2-chlorophenyl)-3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one
 has short half-life (2–6 hours)
Temazepam (Restoril)
 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl -2H-1,4-benzodiazepine-2-one
 it is intermediate acting and marketed as a hypnotic said to have little or no residual effect
Alprazolam (Xanax)
 8-chloro-1-methyl-6- phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
TRIAZOLOBENZODIAZEPINES
 is rapidly absorbed from the GI tract.
 the drug's elimination half-life for a healthy adult ranges between 6.3 and 26.9 hours,
with an average of about 11.2 hours
 consequently, the duration of action is short.
 It is a highly potent anxiolytic on a milligram basis.

Triazolam (Halcion)
 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine
 has all of the characteristic benzodiazepine pharmacological actions.
 It is an ultra–short-acting hypnotic because it is rapidly -hydroxylated to the 1-methyl
alcohol, which is then rapidly conjugated and excreted.
Midazolam (Dormicum)

 This drug is used intravenously as a short acting sedative–hypnotic and as an

induction anesthetic because of its short half-life for the same reason.
NONBENZODIAZEPINE
ZOLPIDEM (AMBIEN, AN IMIDAZOPYRIDINE) AND ESZOPICLONE (LUNESTA, A
CYCLOPYRROLONE)

are non benzodiazepines and have been introduced as short- and

moderate-acting hypnotics, respectively
has a rapid onset of action of 1.6 hours and good bioavailability (72%),
mainly because it is lipophilic and has no ionizable groups at physiological
pH.
Food can prolong the time to peak concentration without affecting the
half-life probably for the same reason.
has short elimination half-life
Its half-life in the elderly or the patients with liver disease is increased
It was the most commonly prescribed drug for insomnia in 2001.
Zaleplon (Sonata, a pyrazolopyrimidine)

is another short-acting nonbenzodiazepine hypnotic

is similar to zolpidem; both are hypnotic agents with short halflives
 is well absorbed following oral administration with an absolute
bioavailability of approximately 30% because of significant
presystemic metabolism.
It exhibits a mean half-life of approximately 1 hour, with less than
1% of the dose excreted unchanged in urine.
It may have a more rapid onset (about 1 hour) and termination of
action than zolpidem, and therefore, it is good to initiate sleep
instead of keeping sleep.
Ramelteon (Rozerem)

it has recently been approved for the treatment of insomnia

It appears to be distinctly more efficacious than melatonin but less
efficacious than benzodiazepines as a hypnotic
The half-life of circulating ramelteon is in the range of 1-2 h,
depending on the dose, which is considerably longer than that of
melatonin.
it is promoted commercially as a sleep aid by the food supplement
industry
it is a poor hypnotic drug because of its poor potency, poor
absorption, poor oral bioavailability, rapid metabolism, and
nonselective effects.
 BARBITURATES
The barbiturates were used extensively as sedative–hypnotic drugs. Except for a
few specialized uses, they have been replaced largely by the much safer
benzodiazepine.
Barbiturates act throughout the CNS.
The barbiturates are 5,5-disubstituted barbituric acids.
Sodium salts of the barbiturates are readily prepared and are water soluble.
Sodium salts of barbiturates in aqueous solution decompose at varying rates by
base
catalyzed hydrolysis, generating ring-opened salts of carboxylic acids
Barbiturates with an intermediate duration of action are used principally as
sedative–hypnotics.
BARBITURATES WITH A LONG DURATION OF ACTION (MORE
THAN 6 HOURS)
Mephobarbital (Metharbital)
3-methyl-5- ethyl-5-phenylbarbituric acid
is (metabolically N-demethylated to phenobarbital, which many
consider to account for almost all of the activity.
Its principal use is as an anticonvulsant.
Phenobarbital, 5-ethyl-5-phenylbarbituric acid (Luminal)
 is a long-acting sedative and hypnotic.
 is also a valuable anticonvulsant, especially in generalized tonic–
clonic and partial seizures
AMIDES AND IMIDES
Glutethimide, 2-ethyl-2-phenylglutarimide (Doriden)
 is one of the most active nonbarbiturate hypnotics that is structurally similar
to the barbiturates, especially phenobarbital.
 its dissolution and absorption from the GI track is somewhat erratic.
 Consistent with its high lipophilicity, it undergoes extensive oxidative
metabolism in the liver with a half-life of approximately 10 hours.
 The drug is an enzyme inducer.
 In the therapeutic dosage range, adverse effects tend to be infrequent.
 Toxic effects in overdose are as severe as, and possibly more troublesome
than, those of the barbiturates.
ALCOHOLS AND THEIR CARBAMATE DERIVATIVES

• The very simple alcohol ethanol has a long history of use as a sedative
and hypnotic.
• It is widely used in self-medication as a sedative–hypnotic. Because this
use has so many hazards, it is seldom a preferred agent medically.
• Most of the alcohols and carbamates have been superseded as
sedative–hypnotics.
• Several difunctional compounds (e.g., diol carbamates) have
depressant action on the cord in addition to the brain and are retained
principally for their skeletal muscle relaxant properties.
Ethchlorvynol, 1-chloro-3-ethyl-1- penten-4-yn-3-ol (Placidyl)
 is a mild sedative–hypnotic with a quick onset and short duration of action (t1/2 5.6
hours).
 It reportedly induces microsomal hepatic enzymes.
 Acute overdose shares several features with barbiturate overdose.

Meprobamate, 2-methyl-2- propyltrimethylene dicarbamate, 2-methyl-2-propyl-1,3-

propanediol dicarbamate (Equanil, Miltown)
 is officially indicated as an antianxiety agent. It is also a sedative– hypnotic agent.
 The mechanism of action underlying anxiolytic effects is unknown but may involve effects
on conductivity in specific brain areas
 The drug is effective against absence seizures and may worsen generalized tonic–clonic
seizures.
 is also a centrally acting skeletal muscle relaxant.
 Also, the general CNS depressant properties they possess may contribute to, or be mainly
responsible for, the skeletal muscle relaxant activity.
Carisoprodol, N-isopropyl-2- methyl-2-propyl-1,3-propanediol dicarbamate, 2-methyl-2-
propyl-1,3-propanediol carbamate isopropylcarbamate (Soma)
 It is indicated in acute skeletomuscular conditions characterized by pain, stiffness, and
spasm.
 As can be expected, a major side effect of the drug is drowsiness
Chlorphenesin carbamate, 3-(p-chlorophenoxy)-1,2-propanediol 1-carbamate (Maolate)
 is the p-chloro substituted and 1-carbamate derivative of the lead compound in the
development of this group of agents, mephenesin.
 Mephenesin is weakly active and shortlived because of facile metabolism of the primary
hydroxyl group
 Metabolism, still fairly rapid
 The biological half-life in humans is 3.5 hours.
Methocarbamol, 3-(o-methoxyphenoxy)-1,2-propanediol 1-carbamate (Robaxin)
 is said to be more sustained in effect than mephenesin
 The dihydric parent compound, guaifenesin, is used as an expectorant.
 ALDEHYDES AND THEIR DERIVATIVES

Chloral hydrate, trichloroacetaldehyde monohydrate, CCl3CH(OH)2 (Noctec)

 is an aldehyde hydrate stable enough to be isolated.
this compound is the basis for the notorious and potentially lethal effect of the
combination of ethanol and chloral hydrate (the “Mickey Finn”) is controversial.
GI upset commonly occurs for the drug if undiluted or taken on an empty stomach
Although an old drug, it still finds use as a sedative in nonoperating room
procedures for the pediatric patient
Paraldehyde, 2,4,6-trimethyl-strioxane, paracetaldehyde
is recognizable as the cyclic trimer of acetaldehyde
It is a liquid with a strong characteristic odor detectable in the expired air and an
unpleasant taste.
These properties limit its use almost exclusively to an institutional setting (e.g., in
the treatment of delirium tremens)
 ANTIPSYCHOTICS

The psychoses affect approximately 1% of the population in all cultures.

 They are psychogenic mental disorders involving a loss of contact with
reality.
The psychotic disorders include schizophrenia, the manic phase of bipolar
(manic–depressive) illness, acute idiopathic psychotic illness, and other
conditions marked by severe agitation. The most common is
schizophrenia, in which perception, thinking, communication, social
functioning, and attention are altered
PHENOTHIAZINES
 Several dozen phenothiazine antipsychotic drugs are chemically related agents used
worldwide. Other phenothiazines are marketed primarily for their antiemetic, antihistaminic,
or anticholinergic effects.
Chlorpromazine hydrochloride, 2-chloro-10-[3-(dimethylamino)propyl]phenothiazine
monohydrochloride (Thorazine)
 was the first phenothiazine compound introduced into therapy.
 It is still useful as an antipsychotic. Other uses are in nausea, vomiting, and hiccups.
 Alterations of GI motility also may contribute
 The drug has significant sedative and hypotensive properties, possibly reflecting central
histaminergic and peripheral 1-noradrenergic blocking activity, respectively
 Chlorpromazine was introduced in the U.S. in 1954, gaining rapid and widespread acceptance
for its use as an anti-emetic, for the mental and emotional disorders.
 Side-effects included dry mouth, dizziness, blurred vision, hypotension and tachycardia.
Promazine, 10-[3-(dimethylamino) propyl- (phenothiazine monohydrochloride (Sparine)
• was introduced into antipsychotic therapy after its 2-chloro-substituted relative.
• Tendency to EPS (Extrapyramidal symptoms) is also lessened, which may be significant, especially if it is
decreased less than antipsychotic potency.
Prochlorperazine maleate, 2-chloro-10-[3-(4-methyl-1-
piperazinyl)propyl]phenothiazine maleate (Compazine)
• is in the piperazine subgroup of the phenothiazines, characterized by high-
milligram antipsychotic potency, a high prevalence of EPS, and low sedative and
autonomic effects.
• it is used mainly for its antiemetic effect, not for its antipsychotic effect.
Perphenazine, 4-[3-(2-chlorophenothiazine-10-yl)propyl]piperazineethanol; 2-
chloro-10-piperazinyl]propyl]phenothiazine (Trilafon)
• is an effective antipsychotic and antiemetic.
Fluphenazine hydrochloride (Permitil, Prolixin)
• use in treating psychotic patients who do not take their medication or are subject
to frequent relapse.
Thiothixene (Navane)
• displays properties similar to those of the piperazine subgroup of the
phenothiazines.
 RING ANALOGS OF PHENOTHIAZINES: BENZAZEPINES,
DIBENZOXAZEPINES, AND DIBENZODIAZEPINES
Loxapine
A dibenzoxazepine derivative in use is loxapine succinate, 2-chloro-11-(4-methyl-1-
piperazinyl)dibenz[b, f][1,4]oxazepine succinate (Daxolin)
• an effective antipsychotic, blocks D2-type receptors and has side effects similar to those
reported for the phenothiazines
Clozapine
• The dibenzodiazepine derivative is clozapine (Clozaril).
• has proved effective even in chronically ill patients who respond poorly to standard neuroleptics
• Elimination half-life averages about 12 hours
Olanzapine and Quetiapine. Clozapine analogs, olanzapine (Zyprexa) and quetiapine (Seroquel)
• The drugs are atypical antipsychotics
• Plasma concentrations of olanzapine peak at about 6 hours after oral administration, and its
elimination half-life ranges from 20 to 54 hours
 FLUOROBUTYROPHENONES
Haloperidol, 4[4-(p-chlorophenyl)- 4-hydroxypiperidone]-4-n-fluorobutyrophenone (Haldol)
• Is a potent antipsychotic useful in schizophrenia and in psychoses associated with brain
damage.
• It is frequently chosen as the agent to terminate mania and often used in therapy for Gilles
de la Tourette syndrome.
Droperidol, 1-{1-[3-(p-fluorobenzoyl)propyl]-1,2, 3,6-tetrahydro-4-pyridyl}-2-
benzimidazolinone (Inapsine)
• may be used alone as a preanesthetic neuroleptic or as an antiemetic.
• It is very short acting and highly sedating properties, its most frequent use is in combination
(Innovar) with the narcotic agent fentanyl (Sublimaze) pre anesthetically.
Risperidone (Risperdal, a benzisoxazole)
• Its superior side effects profile (compared with haloperidol) at dosage of 6 mg/d or less and
the lower risk of tardive dyskinesia have contributed to its very widespread use.
• It benefited refractory psychotic patients, with parkinsonism controlled at one tenth the
dose of antiparkinsonian drugs used with haloperidol
Ziprasidone (Geodon, a benzisothiazolpiprazinylindolone derivative)
• An anti-psychotic and a trazodone-like antidepressant
Aripiprazole (Abilify)
• Bioavailability of aripiprazole is around 87%, with peak plasma concentration attained
at 3 to 5 hours after dosing.

Molindone hydrochloride, 3-ethyl-6,7-dihydro-2-methyl-5-

morpholinomethyl)indole4(5H)-one monohydrochloride (Moban)
• is about as potent an antipsychotic as trifluoperazine. Overall, side effects resemble
those of the phenothiazines.
BENZAMIDES
Remoxipride (Roxiam)
• The drug is classed as an atypical antipsychotic. Life-threatening aplastic anemia was
reported with its use, which prompted its withdrawal from the market.
 ANTIMANIC AGENTS
LITHIUM SALTS
 The lithium salts used in the United States are the carbonate (tetrahydrate) and the citrate.
 Lithium chloride is not used because of its hygroscopic nature and because it is more
irritating than the carbonate or citrate to the GI tract.
 The indications for lithium salts are acute mania (often with a potent neuroleptic agent for
immediate control, because lithium is slow to take effect) and as a prophylactic to prevent
occurrence of the mania of bipolar manic–depressive illness.
 Lithium salts are also used in severe recurrent unipolar depression.
 One effect of the drug that might be pertinent is an increase in the synthesis of presynaptic
serotonin.

Lithium Carbonate, USP, and Lithium Citrate. Lithium carbonate (Eskalith, Lithane) and
lithium citrate (Cibalith-S)
 are the salts commercially available in the United States.
REFERENCE:

• Wilson, C. O., Gisvold, O., & Doerge, R. F. (1982). Wilson and Gisvold's
Textbook of organic medicinal and pharmaceutical chemistry. Philadelphia:
Lippincott.