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112 Pharmaceutical Chemistry
5.1.2.2 Antipsychotic Drugs
Antipsychotic drugs (also called antischizophrenic drugs, neuroleptic drugs or
tranquilizers) are used mainly to treat schizophrenia, psychotic states; such as manic states
and delirium (confusion). Schizophrenia is one of the most important forms of psychiatric
illness, which often affects people during adolescence and tends to be a chronic and
disabling disorder. Patients with schizophrenia have delusions (paranoid in nature),
hallucinations (often in the form of voices) and abnormal thoughts. The pathogenesis of
schizophrenia is not clear but the disease has a strong genetic component including
fundamental biochemical abnormality, possibly an increased dopamine activity of the
mesolimbic system. Examples:
1. Phenothiazine derivatives: Chlorpromazine and Promethazine.
2. Butyrophenone derivatives: Haloperidol and Droperidol.
3. Newer antipsychotics: Risperidone and Clozapine.
5.1.2.3 Antidepressant Drugs
The most common psychiatric disorder is depression, characterized by intense feelings of
sadness, hopelessness, despair and inability to cope with ordinary life events. There are
two types of depression: unipolar and bipolar. Unipolar depression is more common and
affects old patients who are subjected to certain circumstances associated with anxiety.
The patients are usually inert. Bipolar depression develops early in life and a hereditary
factor may be involved. Bipolar depression has some features common with schizophrenia,
and patients oscillate between depression and mania. Monoamine theory of depression
suggests that depression results from deficient monoamine (norepinephrine or/and
serotonin (NE)) transmission in the CNS. Reserpine, a drug that causes depletion of NE
and 5-HT (5-hydroxytryptamine receptors) can cause depression while drugs which
elevate the levels of these key neurotransmitters in the CNS can be used in the treatment
of depression. Antidepressant drugs can be categorized as:
(i) Tricyclic antidepressants (TCAs): They closely resemble the amitriptyline,
imipramine (Tofranil) and phenothiazines, the prototype drugs of this class. TCAs
block the amine (NE and 5-HT) reuptake pumps, though they have several other
properties.
(ii) Heterocyclic antidepressants: They are also known as second- and third-generation
drugs that act similar to TCAs but may exhibit slightly different pharmacokinetics,
e.g., Maprotiline.
(iii) Selective serotonin reuptake inhibitors (SSRIs): They are antidepressant drugs
that include unique character which specifically inhibit serotonin reuptake, e.g.,
Fluoxetine (Prozac).
(iv) Monoamine oxidase (MAO) inhibitors: These drugs bind and inhibit the actions
of MAO, a mitochondrial enzyme responsible for the degradation of catecholamines,
particularly NE and serotonin, e.g., Tranylcypromine.
Central Nervous System Agents 113
(v) Lithium salts: Lithium is a mood stabilizing agent as it is used to prevent mood
swings in patients with bipolar affective disorders.
5.1.2.4 CNS Stimulants
Stimulation of CNS can be produced in men and animals by a large number of natural and
synthetic substances. As a group, the CNS stimulants have a few clinical uses, but some
are important as drugs of abuse. Drugs which cause CNS stimulation fall into three broad
categories:
1. Convulsants and respiratory stimulants (e.g., Nikethamide (couramine), doxapram
and strychnine).
2. Psychomotor stimulants (e.g., Methylxanthines, amphetamines, and cocaine).
3. Psychotomimetic drugs (hallucinogens) (e.g., Phencyclidine, lysergic acid
diethylamide (LSD) and cannabis. LSD may precipitate schizophrenia in susceptible
people).
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stimulants.
5.1.3 Anti-epileptic Drugs and Drugs Used in Anaesthesia
5.1.3.1 Anti-epileptic Drugs
Epilepsy is a recurrent, sudden, transient, excessive discharge of cerebral neurons without
any immediate provoking cause resulting in abnormal movements and/or sensory
perceptions (seizure). In partial (localized) epilepsy, the discharge starts in a localized area
of the brain and may remain localized or spread to affect the whole brain (secondary
generalization).
The epileptic seizure probably arises from a local imbalance between excitatory
neurotransmission, principally glutamate, and inhibitory neurotransmission, mediated by
GABA, which leads to neuronal instability. Most antiepileptic drugs act either by blocking
of depolarizing ion channels, or by enhancing the inhibitory actions of GABA. Example:
Carbamazepine (structurally related to the tricyclic anti-depressants), Phenytoin
(Diphenylhydantoin), Lamotrigine, Sodium valproate, Ethosuximide, Phenobarbital
Primidone, and Benzodiazepines (e.g., Clonazepam and Diazepam).
5.1.3.2 General Anaesthetics
General anaesthesia is a state of:
(a) loss of sensation,
(b) controllable reversible loss of consciousness, and
(c) skeletal muscle relaxation.
Four stages of anaesthesia are known:
6WDJH,DQDOJHVLDLoss of sensation but patient is still alert and speaking.
114 Pharmaceutical Chemistry
6WDJH ,, H[FLWHPHQW Increase in CNS excitation, irregular blood pressure,
increase in respiratory rate, and release of subconscious emotions.
6WDJH,,,VXUJLFDODQDHVWKHVLD Regular respiration, relaxed skeletal muscles,
and progressive decrease in eye reflexes till eye movement stops and the pupil
is fixed.
6WDJH,9PHGXOODU\SDUDO\VLVFatal depression of respiratory centre (RC) and
vasomotor centre (VMC).
5.1.3.2.1 Classification of General Anaesthetic Agents
(a) Inhaled volatile agents: They are suitable for maintaining the anaesthetic state as
long as the surgical procedure is going on. In the past, anaesthesia was induced and
maintained by inhalation of a volatile agent alone. If this method is used, the patient
passes through the previously mentioned stages (I-III) during induction and
recovery of which, the excitation stage (stage II), is undesirable. Nowadays, this is
overcome by using a ball of intravenous anaesthetic for induction, followed by an
inhalation anaesthetic for maintenance. In children, this is less problematic and
anaesthesia is often both induced and maintained with an inhalational anaesthetic
agent.
(b) IV anaesthetic drugs: General intravenous anaesthesia can be used for short
surgical procedures. For longer procedures, IV anaesthetic agent is used for rapid
induction followed by an inhalational agent.
Common symptoms of insomnia are sleeplessness, stress and various medical disorders,
however transient insomnia is a common type which is due to acute situational factors.
The psychiatric disorders are mostly responsible for chronic insomnia. Many drugs have
been identified which are responsible to elevate insomnia: viz., nicotine, caffeine, alcohol,
thyroid hormones, oral contraceptives, phenyltoin, antineoplastics, corticosteroids,
antihypertensives, selective serotonin reuptake inhibitors, E-blockers, protriptyline and
stimulants theophylline, etc. Hypnosis is CNS depression almost similar to natural sleep
while sedation is an intermediate degree of CNS depression and both are primarily known
as CNS depressants. Sedatives are CNS depressant drugs that reduce excitement and
tension, and produce calmness and relaxation. Hypnotics are drugs that produce sleep
similar to that of natural sleep. Both sedative and hypnotic actions may reside in the same
drug; a small dose may act as a sedative, whereas a large dose of the same may act as a
hypnotic.
A number of barbiturate and benzodiazepine classes of compounds can be used as
tranquilizers and to treat anxiety. These drugs share other therapeutic indications such as
sedation and induction of sleep. Some common benzodiazepine derivatives are diazepam,
halazepam alprazolam, clorazepate, chlordiazepoxide, oxazepam, prazepam, lorazepam,
etc. The benzodiazepine derivatives (clonazepam, diazepam and clorazepate) are
anticonvulsants and used to elevate seizure threshold. Benzodiazepines with barbiturates
Central Nervous System Agents 115
are used to block EEG (electroencephalographic) arousal from stimulation of the brainstem
reticular formation. Basically, benzodiazepines with barbiturates can cause centraldepressant actions on spinal reflexes which are actually mediated by the brainstem reticular
system. The action of chlordiazepoxide is similar to meprobamate and barbiturates which
depress the duration of electrical imbalance after discharge in the limbic system, including
hypothalamus, amygdale, septal region, and the hippocampus.
Benzodiazepines also have effects on neurotransmission found in the forebrain which
are mediated by GABA. Inhibition of neurotransmission in the brain is mostly mediated
–
by Cl
ion channels and GABAA receptors which are responsible for generating protein
macromolecular complex as a binding site. The binding of benzodiazepines are actually
modulated by Cl
–
ion channels and GABAA receptors. Numerous imidazole-benzodiazepine
derivatives are competitive inhibitors of benzodiazepines, and can act as benzodiazepine
antagonists (viz., flumazenil/Ro-15-1788), and inverse agonists carboline derivatives [viz.,
ethyl-E-carboline- 3-carboxylate (E-CCE) and its 6,7-dimethoxy congener (DMCM)].
Benzodiazepine derivatives also reduce the neurons’ excitability without involving or
altering Cl
–
ion channels and GABAA receptors. Generally, benzodiazepines have minimal
pharmacokinetic interactions with other drugs, however their oxidative metabolism may
be inhibited by ioniazid, disulfiram, rifampin and cimetidine.
5.2 DRUGS ACTING ON CNS AND PERIPHERAL NERVOUS SYSTEM (PNS)
These drugs act on CNS of the human body which consists of the brain and the spinal cord,
and controls and regulates the special functions like circulation, digestion and respiration.
It also modifies the psychic reactions such as feeling, attitude logical thinking, to remember
past experiences, communication—the unique qualities of man which can be attributed to
the development of highly specialized CNS. The drugs which can affect the CNS can either
stimulate or depress it. The CNS drugs can be subdivided into the following groups:
(a) Non-selective central nervous system depressants: These depressants are
non-specific in action, for example, general anaesthetics, hypnotics and sedatives,
narcotic analgesics, antipyretics, antirheumatic analgesics, etc.
(b) Selective modifiers of CNS: These drugs are specific or restricted to certain areas
within the CNS. The action of a specific CNS depressant may also be modified by
the internal environment. Certain examples of these types of drugs are
psychotherapeutic agents, anticonvulsants, antitussives, and central intraneural
blocking agents, etc.
(c) Central nervous system stimulants: In therapeutic doses the stimulant action is
usually confined to specific areas of the CNS; however, in toxic doses convulsions
may be observed. Stimulants acting directly on the CNS are Xanthine alkaloids,
CO
, nicotine, pipradrol, etc. Other types of stimulants that act on the CNS reflex
2
are Veratrum and lobeline, etc.
116 Pharmaceutical Chemistry
(d) Drugs acting on PNS: PNS (peripheral nervous system) consists of somatic and
autonomic nerve fibres. Drugs act on peripheral nervous system by either stimulating
or blocking it. These have the following classes of drugs:
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cholinomimetic alkaloids.
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diaryl-carbinylethers, dimenhydrinate, etc.
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biosynthesis and metabolism, viz., Adrenaline, isoperanaline, etc.
5.2.1 Classification of Sedatives and Hypnotics
These drugs are classified in Table 5.1, 5.2 & 5.3 as follows.
1. Barbiturates
Table 5.1: Duration-based classification of barbiturates and their examples
(i) Long duration of action (more than 6 hours)
RR
O
R
N
O
HN
O
Phenobarbital H Et Ph
R
1
Mephobarbital CH
R
2
Metharbital CH
3
3
1
Et Ph
Et Et
R
2
(ii) Intermediate duration of action (3-6 hours)
Butabarbital H -Et CH3CH2CH(CH3)-
Amobarbital H -Et (CH3)2CHCH2CH2-
Aprobarbital H -CH2CH=CH
Talbutal H -CH2CH=CH
Butalbital H -CH
Hexobarbital CH
3
CH=CH
2
CH
3
2
2
2
(CH3)2CH-
CH3CH2CH(CH3)-
(CH3)2CHCH2-
(iii) Short duration of action (less than three hours)
Pentobarbital H Et CH
Secobarbital H CH
=CHCH2-CH
2
3CH2CH2
3CH2CH2
CH(CH3)-
CH(CH3)-
2. Benzodiazepines (Table 5.2 & 5.3)
(i) 1,4-benzodiazepines
Table 5.2: Derivatives of 1,4-benzodiazepines
Diazepam CH
Oxazepam H =O OH Cl H
Clorazepate H =O COOH Cl H
R
1
N
R
4
R
5
N
Prazepam
R
2
Lorazepam H =O OH Cl Cl
R
3
Halozepam CH
Temazepam CH
Flurazepam CH2CH2NEt
Clonazepam H =O H Cl NO
Nitrazepam H =O H NO
Quazepam CH2CF
Doxefazepam CH
(ii) Triazolobenzodiazepines
Table 5.3: Derivatives of triazolobenzodiazepines
R
N
N
N
Cl
R
1
N
Alprazolam CH
Triazolam CH
Estazolam H H
Central Nervous System Agents 117
R
1
3
H2C
2CF3
3
2
3
OH =O OH Cl F
2
R
2
R
3
R
4
=O H Cl H
=O H Cl H
=O H Cl H
=O OH Cl H
=O H Cl F
=S H Cl F
RR
3
3
R
5
2
2
H
1
H
Cl
(iii) Imidazobenzodiazepines: Midazolam and loprazolam
(iv) Miscellaneous: Bromozepam, chlordiazepoxide and brotizolam
3. Miscellaneous: Ethchlorvynol, ethinamate, glutethimide, meprobamate, zolpidem,
zopiclone and zaleplon.
5.2.2 Anticonvulsants and Their Mechanisms
Anticonvulsant drugs, also known as antiepileptic drugs (Fig. 5.1), have some specific
properties, viz., well tolerated, non-sedative and potently active against various seizure
types, and their functions. In addition, their action should be rapid in the onset of acute
parenteral injection for the control of status epilepticus and of long duration after oral
administration for the prevention of recurrent seizures. The search of anticonvulsants was
facilitated by an experimental method of assay introduced by Putnam and Merritt in 1937,
118 Pharmaceutical Chemistry
and the modification of the molecular structure of barbiturates, hydantoins, and
oxazolidinediones proved the most profitable source of new compounds with potential
antiepileptic activity.
O
H
Ph
N
O
HN
Diphenylhydantoin
(Dilantin)
Ph
O
HN
O O
Phenobarbital
Fig. 5.1: Antiepileptic drugs
Ph
Ph
N
H
O
Me
Trimethadione
(Tridione)
Me
O
Me
N
O
In general, compounds with hydantoin and barbiturate structures are particularly
effective against tonic electroshock seizures and clinical grand mal, the oxazolidinediones
and succinimides control clonic pentylenetetrazol seizures and petit mal, and
phenylacetylureas and sulfonamide-carbonic anhydrase inhibitors have activity against
most types of clinical seizure patterns. This specificity is not invariable, however, and
some seizure disorders are resistant to all conventional anticonvulsants. The need for new
and improved antiepileptic therapies has led to the development of a battery of laboratory
tests for the preliminary evaluation of experimental compounds.
5.3 BARBITURATES
Barbituric acid was first synthesized in 1864 by Adolf Van Baeyer (German researcher).
Barbituric acid itself does not have any effect on the CNS while it has been derivatized over
2500 compounds for their possible pharmacological effects. Barbiturates usually act as
depressants of the CNS, and thus produce a wide spectrum of pharmacological effects
from mild sedation to anaesthesia, hypnotics, anticonvulsants, anxiolytics and analgesic
effects.
Barbiturates have been widely used in the treatment of epilepsy and anaesthesia
however the use of barbiturates as sedative/hypnotics is superseded by the benzodiazepine
group in recent times. The barbiturates are used as sedative-hypnotics and thus known as
non-selective CNS depressants however, they are used as anticonvulsants when
administered as sub-hypnotic dose.
Barbiturates are used for controlling insomnia, tension, nervousness, pre- and postoperational sedation during anxiety, severe convulsive conditions and treating various
forms of epilepsy, etc. Barbiturates are hydrogenated pyrimidine rings containing two
substituents on C5 that exhibit CNS depressant action.
Barbiturate derivatives are mostly known as CNS depressants which produce mild
sedation to anaesthetic effects. They may be classified as ultra-short-, short-, intermediate-,
and long-acting barbiturates on the basis of their action and prolonged effects (Table 5.1).
Central Nervous System Agents 119
Phenobarbital (5-phenyl substituent) is a selective anticonvulsant agent and useful in
epilepsy. Barbiturates generally act by elevating the action of GABA through binding to a
site on the Cl
–
ion channels and GABAA receptors. These drugs have adverse effects on
overdose.
Adverse side effects include headache, sedation, confusion, drowsiness, gastrointestinal
disturbances, memory impairment, and respiratory depression. Overdose of these drugs
includes coma, confusion, hypotension, incoordination, renal failure, slurred speech and
respiratory and cardiovascular depression.
5.3.1 Mechanism of Action
Barbiturates bind to the allosteric site of GABAA receptor and modulate the transmission
of ions through the following actions:
Ion channel structures are altered making it easier to open.
Receptors are altered and thus increase the affinity of GABA for its receptor, so that
GABA binds easily.
Ion channel remains open (by a magnitude of 4/5-folds) for a prolonged period of
time.
In the absence of GABA and high dose of barbiturates can open Cl
GABA
receptor activation increases the membrane permeability to chloride ions that
A
produces hyper polarization in the cell body. This, in turn, inhibits neuronal activities.
–
channels.
5.3.2 General Method for Preparation of 5,5-disubstituted Barbiturates
This method is applicable for the synthesis of all barbiturates except Phenobarbital and
Hexobarbital. Diethyl malonate reacts with sodium ethoxide to form mono-sodium salt of
diethyl malonate, which, in turn, reacts with the first alkyl halides to form mono alkyl
diethyl malonate. This further reacts with the second alkyl halides in the presence of
sodium ethoxide and gives dialkyl diethyl malonate. Dialkyl diethyl malonate on
condensation with urea undergoes cyclization to form an appropriate barbiturate.
O
COOEt
H
H
Diethyl
malonate
COOEt
RX
EtONa
X = Halogen
COOEt
R
COOEt
H
Momoalkyl
diethyl malonate
X
R
1
EtONa
COOEt
R
COOEt
R
1
Dialkyl
diethyl malonate
Urea
EtONa
HN
O
HN
O
Substituted
Phenobarbital
R
R
1
5.3.3 Structural Activity Relationship of Barbiturates
Hypnotic and sedative activity increases with lipid solubility until the total number
of C-atoms for R
of the C-atoms decreases activity in spite of further increase in lipid solubility,
indicating that lipid solubility must remain within certain limits.
and R5’ at C-5 is between C-6 and C-10. Further increase in the sum
5
120 Pharmaceutical Chemistry
Greater lipid solubility, activity and shorter duration of action was observed when
R
and R
5
were branched chain isomers while lower with when R5 and R
5’
straight chain isomers.
R5 and R
hexobarbital (cycloalkenyl) derivatives are more active than the
corresponding saturated analogues containing the same number of
C-atoms.
Aromatic or alicyclic variants at C-5 are more potent than the
aliphatic substituents containing the same number of C-atoms.
specified agent talbutal (allyl), methohexial (alkynyl) and
5’
O
6
1
R
1
N
5
2
3
N
O O
H
Phenobarbital
Methylation of 5,5-disubstituted barbituric acid into 1,5,5-trisubstituted barbituric
acid does not change activity at all.
Lipid solubility and potency were reduced when polar substituents (viz., NH
COOH, OH and SO
H) were introduced in aromatic group at C-5.
3
2
Replacement of the oxygen at C-2 by S-atom increases on quick onset and shortens
the duration of action, but replacement of additional carbonyl oxygen by S-atom
decreases the activity again, indicating that lipid solubility cannot be increased
beyond limits.
5.3.4 Phenobarbital
were
5’
R
5
R
5'
4
, RNH,
Substituted pyrimidine derivative phenobarbital is one of the most
widely used drugs and was synthesized in 1911. They act as depressants
of the CNS. Bromide was introduced for the treatment of epilepsy by
Locock in 1857 and Samuel Wilks in 1859 but has been largely replaced
by phenobarbital and diphenylhydation. The first parent barbituric acid
O
O
HN
HN
Phenobarbital
Et
O
was synthesized in 1864, however the pharmacological studies started
after 1890s and first introduced as a medicine in 1904. The CNS activity may be improved
by substituting aryl, alkyl or alkenyl groups at C
position of pyrimidine ring. There are
5
approximately >2500 derivatives that have been synthesized; however only about 100
have ever been used medically.
Phenobarbital was first introduced as a sedative, and hypnotic in 1912 and in the same
year was shown by Hauptmann to be superior to bromide in the treatment of epilepsy. It
remains the initial therapy of choice in the majority of seizure disorders, and the principal
limitation of its use is the sedative side effect. Until the development of diphenylhydantoin,
sedation was considered a requisite for anticonvulsant action, and this concept tended to
impede the progress in the search for more potent and specific drugs.
Phenobarbital is the oldest and safest antiseizure drug presently in use which also has
lesser sedative effects, however barbiturates consider seizures only in case of infants. Some
barbituric acid derivatives are clinically useful as antiseizure drugs, viz., primidone,
phenobarbital, metharbital and mephobarbital (Fig. 5.2). The pKa ranges between 7.3-7.9
for weak acids primidone, phenobarbital and mephobarbital. Thus, the minor acid base
Central Nervous System Agents 121
changes cause significant fluctuation particularly in the ratio of the ionized to the un-ionized
species. This minor change in phenobarbital is very important whose pKa is almost similar
to the plasma pH of 7.4. Phenobarbital and N-methylphenobarbital derivatives possess a
phenyl ring and are active against partial seizures due to the similar three-dimensional
conformations as phenytoin dose. Primidone drug generates phenobarbital and PEMA as
active metabolites (Fig. 5.2).
Et
CONH
2
CONH
2
Phenylethylmalonamide
(PEMA)
O
Et
NH
O
N
H
Primidone
Fig. 5.2: Primidone and its active metabolites
O
Phenobarbital
O
Et
NH
N
O
H
It is the most commonly used drug for convulsive disorders and is the drug of choice
for infants and young children. Drowsiness is the most common side effect.
Phenobarbital increases the minimal electroshock seizure threshold and protects animals
against pentylenetetrazol- and fever-induced convulsions, thus it is superior anticonvulsant
than the other barbiturates. Phenobarbital is effective against the clonic seizure pattern
whichever method of seizure induction is used, whereas diphenyl-hydantoin is particularly
effective against the tonic seizure pattern. Clinically, phenobarbital is of value against
grand mal and focal seizures of the tonic or clonic type and sometimes against petit mal,
but has no effect on psychomotor or temporal lobe seizures.
5.3.4.1 Specification
Name : 5-Ethyl-5-phenyl barbituric acid
Molecular formula : C
12H12N2O3
Molecular weight : 232.3 g/mol
Melting point : 174.33°C
Physical State : White crystalline powder, odourless
Solubility : Partially water soluble, soluble in ether, alcohol, and in solutions of
fixed alkali hydroxides and carbonates.
5.3.4.2 Synthesis of Phenobarbital
Benzyl chloride on reaction with potassium cyanide affords benzyl cyanide which on
esterification gives phenyl acetic acid ethyl ester. The methylene group in ester undergoes
acylation with diethyloxalate that results in diethyl ester of phenyloxo-butandioic acid
which further eliminates CO
under heating giving phenylmalonic ester. The alkylation of
2
the phenylmalonic ester using ethylbromide in the presence of NaOEt leads to the formation
of D-phenyl-D-ethylmalonic ester, which on condensation with urea results in phenobarbital.