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Chapter
5
DRUGS ACTING ON CENTRAL
NERVOUS SYSTEM
STRUCTURE
5.1 Anaesthetics
5.2 Sedatives and Hypnotics
5.3 Antipsychotics
5.4 Anticonvulsants
5.5 Anti-depressants
5.6 Exercise
OBJECTIVES
Drugs Acting on Central Nervous System:
➢ Anaesthetics: Thiopental Sodium, Ketamine Hydrochloride, Propofol
➢ Sedatives and Hypnotics: Diazepam, Alprazolam, Nitrazepam, Phenobarbital
➢ Antipsychotics: Chlorpromazine Hydrochloride, Haloperidol, Risperidone, Sulpiride,
Olanzapine, Quetiapine, Lurasidone
➢ Anticonvulsants: Phenytoin, Carbamazepine, Clonazepam, Valproic Acid, Gabapentin,
Topiramate, Vigabatrin, Lamotrigine
➢ Anti-depressants: Amitriptyline Hydrochloride, Imipramine Hydrochloride, Fluoxetine,
Venlafaxine, Duloxetine, Sertraline, Citalopram, Escitalopram, Fluvoxamine, Paroxetine.
5.1 ANAESTHETICS
The term “anaesthesia” refers to the loss of sensation. Anaesthetics are drugs that cause
anaesthesia. Anaesthetics are used to numb sensation in certain areas of the body during testing
and surgical operations to prevent pain and discomfort, allowing a wide range of medical
treatments to be performed. Anaesthetics are divided into two categories: local anaesthetics and
general anaesthetics.
138 Text Book of Pharmaceutical Chemistry
1. Local anesthetics: Local anesthetics are the agents used to induce loss of sensation in a
small part of the body. Generally, local anaesthetics are used in case of minor surgery and
does not require general or regional anesthesia. Common examples of surgery using local
anesthetic are having teeth removed and some common operations on the eye.
2. General anesthetics: General anesthetics are the agents that exert their effect mainly on
the central nervous system (CNS). Anesthesia can be induced and maintained either by
inhalation or by intravenously with a variety of compounds. A general anaesthetic is
required for a very wide range of operations. This includes most major operations on the
heart, lungs or in the abdomen, and many operations on the brain or the major arteries.
Stages of general anesthesia are:
➢ Stage 1: Analgesia or Disorientation: This phase happens between the
administration of the drug and the loss of consciousness.
➢ Stage 2: Excitement or Delirium: The period after a loss of consciousness,
characterized by excited and delirious activity. Breathing and heart rate becomes
irregular, and nausea, pupil dilation, and breath-holding might occur.
➢ Stage 3: Surgical Anesthesia: Muscles relax, vomiting stops, and breathing is
depressed. Eye movements slow and then end. The patient is ready to be operated on.
➢ Stage 4: Overdose: Excessive medication has been administered, leading to the brain
stem or medullary suppression. This results in respiratory and cardiovascular
collapse.
Classification:
General anesthetics are administered by inhalation or by intravenous injection. Variety of
drugs is given to induce unconsciousness, amnesia and analgesia.
A. Inhalation
1. Gas: Nitrous Oxide
2. Volatile liquids: Ether, Halothane, Enflurane, Isoflurane, Desflurane, Sevoflurane
B. Intravenous
The intravenous anesthetics can be classified according to their chemical structure and
include:
1. Barbiturates: Thiopental, Methohexital
2. Benzodiazepines: Midazolam, Diazepam, Lorazepam
3. Phenols: Propofol
4. Imidazoles: Etomidate
5. Phencyclidines: Ketamine
Drugs Acting on Central Nervous System 139
5.1.1 Thiopental Sodium
Brand Name: Pentothal
Thiopental sodium is systemic anesthetics result in a rapid onset of anesthesia after a single
dose, because of their high solubility in lipids. It induce deep unconsciousness in about 10-20
seconds.
Thiopental sodium is an organic sodium salt, the structure is 2-thiobarbituric acid substituted
at C-5 by ethyl and sec-pentyl groups. The structure of Thiopental sodium is:
IUPAC Names: Sodium; 5-ethyl-4, 6-dioxo-5-pentan-2-yl-1H-pyrimidine-2-thiolate
Properties: Thiopental sodium is a yellowish-white crystalline powder or a pale greenish
hygroscopic powder with an alliaceous, garlic-like odor. It is partially soluble in alcohol and is
practically insoluble in ether, benzene, and petroleum ether. Thiopental melts at 158°C-160°C.
Uses: Thiopental sodium is used for the induction of general anaesthesia as well as it is also used
as an adjunct to provide hypnosis during balanced anaesthesia with other anaesthetic agents,
including analgesics and muscle relaxants. It can be used in surgery for pregnant mothers with no
effect on the fetus. It has been a useful tool in psychiatry as a “truth serum”, which has also given
it notoriety in fiction and film.
Storage/Stability: Thiopental remains stable at 22°C and sterile for 6 days and well beyond
7 days at 3°C. When stored in the dry form, thiopental sodium is stable indefinitely. Solutions are
stable for 3 days at room temperature and for 7 days if refrigerated. However, as no preservative
is present, it is recommended to use it within 24 hours after reconstitution. After 48 hours, the
solution has been reported to attack the glass bottles it is stored in.
Officials:
➢ Thiopental Sodium, I.P.
➢ Thiopental Sodium Injection, I.P.
5.1.2 Ketamine Hydrochloride
Brand Name: Ketalar (Parkdale)
Ketamine is a member of the class of cyclohexanones in which one of the hydrogens at
position 2 is substituted by a 2-chlorophenyl group, while the other is substituted by a
methylamino group. It is a rapid-acting general anaesthetic administered as the hydrochloride by
intravenous or intramuscular injection and producing dissociative anaesthesia characterized by
profound analgesia, amnesia, and a trance-like state. The (S)-enantiomer is 3-4 times more potent
than the (R)-enantiomer.
140 Text Book of Pharmaceutical Chemistry
IUPAC Names: 2-(2-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride
Properties: Ketamine hydrochloride is a white crystalline powder, soluble in water. Its free base,
ketamine, has lipid solubility 10 times that of thiopentone. The commercially available
pharmaceutical form is an aqueous solution for injection of the racemic mixture of the
hydrochloride salt.
Uses:
➢ Ketalar is indicated as the sole anesthetic agent for diagnostic and surgical procedures
that do not require skeletal muscle relaxation.
➢ It is indicated for the induction of anesthesia prior to the administration of other general
anesthetic agents.
Stability: The stability of ketamine hydrochloride (10 mg/mL) in water for injection stored in
polypropylene syringes has been studied at 25°C.
Officials:
➢ Ketamine Hydrochloride, I.P.
➢ Ketamine Hydrochloride Injection, I.P.
5.1.3 Propofol
Brand Names: Diprivan, Propoven
Propofol is a simple phenol substituted with two isopropyl groups in each of the positions
adjacent to the hydroxyl group, the ortho positions. It is an intravenous anesthesia which works
by increasing GABA-mediated inhibitory tone in the CNS. Propofol decreases the rate of
dissociation of the GABA from the receptor, thereby increasing the duration of the GABA-
activated opening of the chloride channel with resulting hyperpolarization of cell membranes. At
supraclinical concentrations, it may directly activate the receptor’s chloride channel. The
structural formula of Propofol is:
IUPAC Name: 2,6-di(propan-2-yl)phenol
Properties: Propofol is very slightly soluble in water, miscible with hexane and with methanol.
Melting point is 18°C.
Uses:
➢ Propofol is used to put you to sleep and keep you asleep during general anesthesia for
surgery or other medical procedures.
➢ It is used for initiation and maintenance of monitored anesthesia care (MAC) sedation.
➢ It is used to sedate a patient who is under critical care and needs a mechanical ventilator.
Drugs Acting on Central Nervous System 141
Dosage Form: Propofol 10 mg/mL Emulsion for injection/infusion.
Storage: It should be store at 2°C to 8°C.
5.2 SEDATIVES AND HYPNOTICS
Sedatives or tranquillizers are different group of drugs synthesized for the purpose to relax
the central nervous system. These classes of drugs are used to induce sedation by reducing
irritability
or excitement, used to promote sleep, in conditions like injury, illness and some other
factors. Sedatives are commonly used in surgical procedures such as dentistry, endoscopy and
vasectomy, and in some cosmetic surgeries.
Hypnotics are the class of psychoactive drugs used to induce sleep by depressing the CNS.
These drugs are used for the treatment of insomnia (sleeplessness) which is characterized by
difficulties with falling asleep or maintaining sleep.
The most commonly used hypnotics include benzodiazepine receptor agonists (BzRAs), anti-
depressants, antipsychotics, antihistamines, and melatonin (or melatonin receptor agonists).
Ideal Characteristics of Hypnotics:
➢ Maintain a “natural sleep” similar to a non-drug-induced.
➢ Immediately induces sleep after administration of the drug.
➢ Avoid accumulation in the body during the course of treatment.
➢ Does not cause addiction, tolerance or dependence.
➢ Does not interact with other drugs or alcohols.
Fig. 5.1: Classification of Sedative and Hypnotics
142 Text Book of Pharmaceutical Chemistry
5.2.1 Diazepam
Brand Names: Diastat, Valium
Diazepam belongs to a class of drugs called anti-anxiety agents. It is a 1,4-benzodiazepinone,
that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one substituted by a chloro group at position 7,
a methyl group at position 1 and a phenyl group at position 5. The structural formula is as
follows:
IUPAC Names: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin2-one.
Diazepam produces its effects by facilitating the activity of gamma-aminobutyric acid
(GABA) at various sites. It binds at an allosteric site at the interface between the alpha and
gamma subunits on GABA-A receptor chloride ion channels. After binding, these drugs allow
them to allosterically modulate and enhance the activity of GABA. This results into increased
frequency of Cl
–
ion channel opening (hyperpolarization), at the target neurons, thus inhibits the
formation of action potential.
Properties: It occurs as a colorless to light yellow crystalline compound with a melting point of
131.5°C to 134.5°C. It is odorless and has a slightly bitter taste. It is very slightly soluble in
water, soluble in alcohol, and freely soluble in chloroform.
Uses: Diazepam is commonly used for the treatment of various conditions, including:
➢ Insomnia
➢ Anxiety
➢ Muscle spasms
➢ Seizures
➢ Alcohol withdrawal syndrome
➢ Benzodiazepine withdrawal syndrome
➢ Memory loss during certain medical procedures.
Storage and Stability: The stability of diazepam injectable is evaluated at three storage
conditions: 4°C to 10°C (refrigerated); 15°C to 30°C and 37°C (oven-heated) and these injections
were stored for 210 days in clear glass syringes. The syringes were stored in light-resistant bags
on their sides so that the solution was in contact with the rubber stoppers on both ends.
Drugs Acting on Central Nervous System 143
Dosage Forms:
➢ Tablets: 2 mg, 5 mg, 10 mg
➢ Oral solution: 1 mg/1 ml, 5 mg/mL
➢ Rectal gel: 2.5 mg, 10 mg, 20 mg
Officials:
➢ Diazepam, I.P.
➢ Diazepam Injection, I.P.
➢ Diazepam Capsulles, I.P.
➢ Diazepam Tablet, I.P.
Marketed Preparations:
➢ Vallium (Diazepam 5mg Tablet), manufactured by Abboott
➢ Calmpose 10 mg Injection (Diazepam 10 mg Injection) manufactured by Sun
Pharmaceutical Industries Limited
➢ Calmpose 5 mg Tablet by Sun Pharmaceutical Industries Limited
5.2.2 Alprazolam
Brand Names: Alprax, Alzam, Alzolam, Zolam, Zopax, Niravam, Xanax, Xanax XR
Alprazolam is a drug of the class triazolobenzodiazepines that is 4H-[1,2,4]triazolo
[4,3-a][1,4]benzodiazepine carrying methyl, phenyl and chloro substituents at positions 1, 6 and 8
respectively. The structural formula is represented as:
IUPAC Names: 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Mechanism of Action: Alprazolam binds to a specific site distinct from the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA) binding site on the benzodiazepine-GABA-
A-chloride ionophore receptor complex in the CNS. Binding leads to an allosteric modification of
the receptor and enhances the affinity of GABA to the receptor leading to an increase in the
frequency of chloride-channel opening events. This results in an increase in chloride
ion conductance, neuronal hyperpolarization, inhibition of the action potential and leads to a
decrease in neuronal excitability.
144 Text Book of Pharmaceutical Chemistry
Properties: It occurs as a white or almost white to pale yellow crystalline powder. It is sparingly
soluble in water and soluble in methanol or ethanol.
Uses: Alprazolam is used to treat:
➢ Anxiety disorders specifically panic disorder and anxiety associated with depression.
➢ Generalized anxiety disorder (GAD).
➢ Chemotherapy-induced nausea.
Dosage Forms:
➢ Oral concentrate (1 mg/mL)
➢ Oral tablet (0.25 mg, 0.5 mg, 1 mg and 2 mg)
➢ Oral tablet, disintegrating (0.25 mg, 0.5 mg, 1 mg and 2 mg)
➢ Oral tablet, extended release (0.5 mg, 1 mg, 2 mg and 3 mg)
Storage and Stability: Store at 20 to 25°C. Commercially available alprazolam tablets should be
stored in tight, light-resistant containers at 15-30°C. Keep container tightly closed in a dry and
well-ventilated place.
Marketed Preparations: Alprazolam Tablet I.P.: 1.0 mg, 0.5 mg, 0.25 mg tablet by Excel Labs,
Sun Pharmaceutical Industries Limited and Cipla Limited
5.2.3 Nitrazepam
Brand Names: Alodorm, Apodorm, Arem, Mogadon, Nitrados, Nitrazadon, Nitrosun, Nitravet
Nitrazepam is categorized as a nitrobenzodiazepine family of drugs. It is a 1,4-
benzodiazepinone that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one which is substituted at
positions 5 and 7 by phenyl and nitro groups, respectively.
Chemical Names: 7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one
The main pharmacological effects of nitrazepam are the enhancement of GABA at the
GABA
A
receptor. GABA is a major inhibitory neurotransmitter in the brain, involved in inducing
sleepiness, muscular relaxation and control of anxiety and fits, and slows down the central
nervous system.
Properties: Nitrazepam occurs as yellow, crystalline, and odorless powder. It is soluble in
alcohol, acetone, chloroform and ethylacetate; and insoluble in water, ether, benzene and hexane.
Drugs Acting on Central Nervous System 145
Uses:
➢ Nitrazepam has sedative hypnotic and motor-impairing properties.
➢ It is used to treat short-term sleeping problems (insomnia).
➢ It is used as anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant.
➢ It is used to treat anxiety disorders.
➢ It is used in myoclonic seizures.
Storage and Stability: The drug is stored in a cool and dry place at room temperature between
59°F and 86°F (15°C and 30°C) away from heat and light.
Officials:
➢ Nitrazepam, I.P.
➢ Nitrazepam Tablet, I.P.
Marketed Preparations:
➢ Nitrosun (Nitrazepam 10 mg tablet) by Sun Limited, India
➢ Nitravet (Nitrazepam 10 mg tablets) by Anglo-French Drugs & Industries Limited
5.2.4 Phenobarbital
Brand Names: Donnatal, Luminal, Phenobarb, Phenohytro, Solfoton
Phenobarbital, also known as phenobarbitone, is a member of the class of barbiturates, the
structure of which is that of barbituric acid substituted at C-5 by ethyl and phenyl groups.
Chemical Name: 5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione
Properties: Barbiturates are usually white crystal or crystalline powder having a slight bitter
taste. It is slightly soluble in water and freely soluble in ethanol. It can be dissolved in ether,
acetone and other organic solvents. Sodium salt is easy to dissolve in water and difficult to
dissolve in organic solvent. It forms water-soluble compounds with alkali hydroxides, carbonates
and ammonia. Its melting point is 174°C.
Uses: Phenobarbital exhibits sedative, hypnotic, anticonvulsant and antiepileptic activities. It is
widely used in treating:
146 Text Book of Pharmaceutical Chemistry
➢ It is effective for the treatment of all forms of epilepsy (except typical absence seizures)
and in the treatment of status epilepticus.
➢ It is widely used in treating chorea and spastic paralysis.
➢ It is used as a component of a large number of combined drugs, valocordin and corvalol
in particular.
➢ It also enhances the role of antipyretic analgesics, and can induce liver microsomal
glucuronosyl transferase activity, promote bilirubin and glucuronic acid binding, reduce
plasma bilirubin concentration, and treat neonatal cerebral nucleus jaundice.
Storage and Stability: Storage temperature for phenobarbital is 2°C to 8°C, stable in the air. It is
combustible incompatible with strong oxidizing agents. Phenobarbital sodium is hygroscopic in
nature, stored in well closed airtight container.
Officials:
➢ Phenobarbital Sodium, I.P.
➢ Phenobarbital Sodium Tablet, I.P.
➢ Phenobarbital Tablet, I.P.
➢ Phenobarbital Sodium Injection, I.P.
5.3 ANTIPSYCHOTICS
Psychosis is an abnormal mental condition in which it is difficult to differentiate between
what is real and what is not real. A psychotic episode occurs when someone becomes ill in this
way.
During the period of psychosis, person experiences false sensations. These include delusions
(false beliefs) and hallucinations (tactile sensations of things that are not real, auditory, visual,
and feelings that something strange is going on.)
Antipsychotics are class of medications primarily used to treat psychosis such as delusions
(hearing voices), hallucinations, paranoia, or confused thoughts, mainly in the schizophrenia
bipolar disorder, senile psychoses, psychotic depression, and in drug-induced psychoses.
Chemical Classification of Antipsychotic Drugs:
1. First-generation (Typical) Antipsychotics
(a) Phenothiazine:
➢ Aliphatic side chain – Chlorpromazine, Triflupromazine.
➢ Piperidine side chain – Thioridazine.
➢ Piperazine side chain – Trifluoperazine, Fluphenazine.
(b) Butyrophenone: Haloperidol, Droperidol, Trifluperidol, Penfluridol.
(c) Thioxanthene: Flupentixol, Clorprotixene, Thiothixene.