Medical University of Sofia, Faculty of Medicine

Department of Pharmacology and Toxicology

Neuroleptics
Anxiolytics
(Abstract)

Assoc. Prof. Ivan Lambev

e-mail: itlambev@mail.bg
Psychotropic drugs
influence on the psyche (mentality)
and behaviour of patients.
• Neuroleptics (antipsychotics)
• Anxiolytics
• Mood stabilizers
• Antidepressants
• Psychostimulants
• Nootropics
(cognition enhancers), etc.
 NEUROLEPTICS
(Antipsychotics,
Antischizophrenic drugs)
I. Typical antipsychotics
(with extrapyramidal motor symptoms)
• Phenothiazines
• Thioxanthenes
• Butyrophenones, etc.
II. Atypical antipsychotics
(lack of extrapyramidal motor symptoms in rats)
Schizophrenia is a particular kind of psychosis
(mental disorder) characterized mainly by a clear
sensorium but a marked thinking disturbance.
Key symptoms include hallucinations, delusions,
and abnormal experiences, such as the perception
of loss of control of one’s thoughts.
Patients lose empathy with others, become withdrawn,
and demonstrate inappropriate or blunted mood.
Schizophrenic symptoms:
Positive: can be regarded as an abnormality
(incoherent speech, agitation).
Negative: indicate a loss or decrease
in function, such as poverty of speech or
blunted affect. Negative signs are more chronic
and persistent and less responsive to treatment.
The dopamine (DA) hypothesis for schizophrenia
is the basis for rational drug therapy. Several lines
of circumstantial evidence suggest that excessive
DA-ergic activity plays a role in this psychosis:

(1) many antipsychotic drugs strongly block post-

synaptic D2-receptors in the CNS, especially
in the mesolimbic-frontal system;

(2) drugs that increase DA-ergic activity, such as

levodopa (a precursor), amphetamines (releasers
of DA), and apomorphine (a direct DA-ergic agonist),
either aggravate schizophrenia or produce psychosis
de novo in some patients;
(3) DA receptor density has been found postmortem
to be increased in the brains of schizophrenics who
have not been treated with antipsychotic drugs;

(4) positron emission tomography (PET) has shown

increased DA receptor density in both treated and
untreated schizophrenics when compared with such
scans of nonschizophrenic persons;

(5) successful treatment of schizophrenic patients

has been reported to increase the amount of homo-
vanillic acid (HVA), a metabolite of DA, in the
cerebrospinal fluid, plasma, and urine.
Neuroleptics – mechanism of action
Several important DA-ergic systems or
pathways are now recognized in the brain:

(1) The first pathway (the one most closely related

to behavior) is the mesocortical tract,
which projects from cell bodies near the
substantia nigra to the limbic system and neocortex.

(2) The second system (the nigrostriatal tract)

consists of neurons that project from the substantia
nigra to the caudate and putamen; it is involved in
the coordination of voluntary movement.
3) The third pathway (the tuberoinfundibular
tract) connects arcuate nuclei and periventricular
neurons to the hypothalamus and posterior pituitary.
DA released by these neurons physiologically
inhibits prolactin secretion.
Five DA receptors have been described, consisting
of two separate families – the D1- and D2-like groups:
(1) The D1-receptor is coded by a gene on chromo-
some 5, increases cAMP by activation of adenylyl
cyclase, and is located mainly in the putamen,
nucleus accumbens, and olfactory tubercle.
The second member of this family is D5. It is coded
by a gene on chromosome 4, also increases cAMP,
and is found in the hippocampus and hypothalamus.

The therapeutic potency of the most

antipsychotic drugs correlates strongly
with their D2-affinity.
(2) The D2-receptor family includes D2, D3 and D4-
receptors. D2-receptors is coded on chromosome 11,
decreases cAMP (by inhibition of
adenylyl cyclase), and inhibits calcium channels
but opens potassium channels. It is found both
pre- and postsynaptically on neurons in the caudate-
putamen, nucleus accumbens, and olfactory tubercle.
A second member of this family, the D3-receptor,
also coded by a gene on chromosome 11, is
thought to decrease cAMP and is located in the
frontal cortex, medulla, and midbrain.
The D4-receptor also decreases cAMP.
 Distribution and characteristics of DA
receptors in the central nervous system
Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)
The key steps in the synthesis and degradation of DA
and the sites of action of various psychoactive substances
at the dopaminergic synapse
It has not been convincingly demonstrated that
antagonism of any DA receptors (especially D4)
plays a role in the action of “atypical”
antipsychotic drugs.
Most of the newer “atypical” antipsychotics and
some of the traditional ones have significant
affinity for the 5-HT2A receptor, suggesting
an important role for the serotonin system.
Participation of glutamate, GABA, and ACh
receptors in the pathophysiology of schizophrenia
has also been proposed.
 (NE) (5-HT)

Schizophrenia
(DA)

The effects of DA, 5-HT and NE on the brain functions

Main effects
(1) CNS. In normal individuals antipsychotics produce
neuroleptic syndrome – indifference to surroundings,
paucity of thought, psychomotor slowing, emotional
quietening, reduction in initiative.
In psychotic patients neuroleptics reduce
irrational behaviour, agitation and aggresiveness.
They control psychotic symptomatology. Disturbed
thought and behaviour are gradually normalized,
anxiety is relieved. Hyperactivity, hallucinations,
and delusions are suppressed.
The psychosedative effect is produced immediately
while the antipsychotic effect takes a week to develop.
Tolerance develops only to the psychosedative effect.
In animal antipsychotic agents produce
a state of rigidity and immobility (catalepsy).
The thermoregulatory centre is turned off,
rendering the patient poikilothermic (body tem-
perature falls if surroundings are cold and the contrary).
The medullary, respiratory and other vital centres
are not affected, except of very high doses. It is very
difficult to produce coma with neuroleptics.
Antiemetic effect is exerted through the CTZ.
Almost all neuroleptics, except thioridazine, have this
effect. However, they are ineffective in motor sickness.
(2) ANS. Neuroleptics have varying degrees of alpha-
adrenergic blocking activity and produce
hypotension (primarily postural). The hypotensive
effect is more marked after parenteral administration.
Anticholinergic property of neuroleptics is weak.
The phenothiazines have weak H1-antihistaminic and
anti-5-HT actions as well. Promethazine has strong
sedative, and H1-antihistaminic action.
(3) Endocrine system. Neuroleptics consistently
increase prolactin release by blocking the inhibitory
action of DA on pituitary gland. This may result
in galactorrhea and gynecomastia. They reduce
gonadotrophins, ACTH, GH and ADH secretion.
I. Typical Neuroleptics (D2-blockers)

Phenothiazines

Type 1 (aliphatic side chain)

Chlorpromazine, Promazine,
Levomepromazine, Promethazine
Type 2 (piperidine side chain): Thioridazine
Type 3 (piperazine side chain)
Trifluoperazine,
Prochlorperazine, Fluphenazine
 Thioxanthenes

R
This is a three-ring compound structurally related
to phenothiazine but having the nitrogen atom at
position 10 replaced by a carbon atom with a
double bond. Thioxanthenes have nearly
equivalent potency with phenothiazines.
•Chlorprothixene
•Flupenthixol
•Zuclopenthixol
 Butyrophenones
•Droperidol
•Benperidol
•Haloperidol:

The butyrophenones are structurally

similar to GABA. They offer greater potency
and fewer autonomic side effects.
II. Atypical Neuroleptics
(They block mainly 5-HT2- and D4-receptors)

•Clozapine
They cause
•Olanzapine
•Quetiapine little extrapyramidal toxicity.
•Risperidone The risperidone is
•Ziprasidone representative of many of the
•Amisulpiride newer agents in having a better
•Zotepine side effect profile.
•Sertindole
Psychiatric indications of neuroleptics

Schizophrenia is the primary

indication for neuroleptics.
Unfortunately, many patients
show little response.

Antipsychotics are also indicated for schizoaffective

disorders, which share characteristics of both
schizophrenia and affective disorders.
The psychotic aspects of the illness require treatment
with antipsychotic drugs, which may be used with other
drugs such as antidepressants, lithium, or valproates.
Whilst a typical antipsychotics should
provide adequate treatment of positive symptoms
including hallucinations and delusions in at least
60% of cases, patients are often left with
unresolved negative symptoms such as
apathy, flattening of affect, and alogia. Evidence
suggests that clozapine and the newer atypicals
have a significant advantage over typical drugs
against negative symptoms.
The manic phase in bipolar affective disorder often
requires treatment with neuroleptics (chlorpromazine,
haloperidol), though lithium or valproic acid
supplemented with high-potency benzodiazepines
(e.g. lorazepam or clonazepam) may suffice
in milder cases.

Recent controlled trials support the efficacy of

monotherapy with atypical antipsychotics in the
acute phase (up to 4 weeks) of mania, and
olanzapine has been approved for this indication.
Nonmanic excited states may also be managed
by antipsychotics, often in combination with
benzodiazepines.
Other indications for the use of antipsychotics
include disturbed behavior in patients with
Alzheimer's disease, and, with antidepressants,
psychotic depression.
Antipsychotics are not indicated for the treatment
of various withdrawal syndromes, e.g. opioid
withdrawal. In small doses antipsychotics have
been promoted (wrongly) for the relief of anxiety
associated with minor emotional disorders, but
the anxiolytic agents are preferred.
Nonpsychiatric indications
Most older antipsychotics, with the exception of
thioridazine, have a strong antiemetic effect.
This action is due to D2-receptor blockade,
both centrally (in the chemoreceptor trigger zone
of the medulla) and peripherally (on receptors in
the stomach). Some drugs, such as prochlorperazine
are promoted only as antiemetics.
Phenothiazines with shorter side chains have consi-
derable H1-receptor-blocking action and used for
relief of pruritus or, in the case of promethazine,
as preoperative sedatives. The butyrophenone
droperidol is used in combination with an opioid,
fentanyl, in neurolept-anaesthesia (-analgesia).
Adverse reactions – behavioral effects:
The older typical antipsychotic drugs are unpleasant
to take. Many patients stop taking these drugs
because of the adverse effects, which may be
mitigated by giving small doses during the day and
the major portion at bedtime. A “pseudodepression”
that may be due to drug-induced akinesia usually
responds to treatment with antiparkinsonian drugs.
Other pseudodepressions may be due to higher
doses; the decreasing the dose may relieve the
symptoms. Toxic-confusional states may occur
with very high doses of drugs that have
prominent antimuscarinic actions.
Neurologic effects:
Extrapyramidal reactions occurring early during
treatment with older agents include typical
Parkinson's syndrome, akathisia (uncontrollable
restlessness), and acute dystonic reactions
(spastic retrocollis or torticollis). Parkinsonism can
be treated, with conventional antiparkinsonian
drugs of the antimuscarinic type or, in rare cases,
with amantadine. Parkinsonism may be self-limiting,
so that an attempt to withdraw antiparkinsonian
drugs should be made every 3–4 months.
Akathisia and dystonic reactions also respond to
such treatment, but many prefer to use a sedative
antihistamine with anticholinergic properties,
e.g. diphenhydramine.
Tardive dyskinesia
- persistent involuntary
movements of mouth,
tongue or face.

Autonomic nervous system effects

Antimuscarinic (atropine-like) adverse effects:
urinary retention, dry mouth, midriasis.
Alpha-blockade: Orthostatic hypotension or impaired
ejaculation should be managed by switching to drugs
with less marked adrenoceptor-blocking actions.
Ocular complications
Deposits in the anterior portions of the eye
(cornea and lens) are a common complication of
Chlorpromazine therapy. They may accentuate
the normal processes of aging of the lens.
Thioridazine is the only antipsychotic
drug that causes retinal deposits,
which in advanced cases may resemble retinitis
pigmentosa. The deposits are usually associated
with “browning” of vision. The maximum daily
dose of thioridazine has been limited to 800 mg
to reduce the possibility of this complication.
Metabolic and endocrine side effects
Weight gain is very common, especially with
clozapine and olanzapine, and requires monitoring
of food intake, especially carbohydrates.
Hyperglycemia may develop.
Hyperprolactinemia in women results in the
amenorrhea – galactorrhea syndrome and infertility;
in men loss of libido, impotence, and infertility
may result.
Toxic or allergic reactions
Agranulocytosis, cholestatic jaundice, and skin
eruptions occur rarely with the high-potency
antipsychotic drugs currently used.
Neuroleptic malignant syndrome
This life-threatening ADR occurs in patients who
are extremely sensitive to the extrapyramidal effects
of antipsychotics. The initial symptom is marked
muscle rigidity. If sweating is impaired, as it often
is during treatment with anticholinergic drugs,
fever may ensue, often reaching dangerous levels.
The stress leukocytosis and high fever associated
with this syndrome suggest an infectious process.
Autonomic instability, with altered blood pressure
and pulse rate, is often present. Creatine kinase
isoenzymes are usually elevated, reflecting
muscle damage.
This syndrome is believed to result from an excessively
rapid blockade of postsynaptic DA receptors. A severe
form of extrapyramidal syndrome follows. Early in
the course, vigorous treatment of the extrapyramidal
syndrome with antiparkinsonian drugs is worthwhile.
Muscle relaxants, particularly diazepam, are often
useful. Other muscle relaxants, such as dantrolene,
or DA agonists, such as bromocriptine, have been
reported to be helpful. If fever is present, cooling
by physical measures should be tried.
 ANXIOLYTICS
(antianxiety drugs)

•Benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
•Azapirones (buspirone)
•Benzoxazines (etifoxine)
•Sedative H1-blockers
(hydroxyzine)
•Nonselective
beta-blockers
•SSRIs
Gamma aminobutyric acid (GABA) is probably
the most important inhibitory transmitter in
the CNS. GABA-ergic neurones are distributed
widely in the CNS. GABA controls the state of
excitability in all brain areas and the balance
between excitatory inputs (mostly glutamatergic)
and the inhibitory GABA-ergic activity. If the balance
swings in favour of GABA, then sedation, amnesia,
muscle relaxation and ataxia appear and nervous-
ness and anxiety are reduced. The mildest reduction
of GABA-ergic activity elicits arousal, anxiety, rest-
lessness, insomnia and exaggerated reactivity.
Most drugs used in insomnia act as agonists
at the GABAA-receptor
and have effects other than their direct
sedating action, including muscle relaxation,
memory impairment, and ataxia, which can impair
performance of skills such as driving. Clearly those
drugs with onset and duration of action confined to
the night period will be most effective in insomnia
and less prone to unwanted effects during the day.
Those with longer duration of action are likely to
affect psychomotor performance, memory and
concentration; they will also have enduring
anxiolytic and muscle-relaxing effects.
Benzodiazepines

Bromazepam (t1/2 20 h)
•Chlordiazepoxide
•Cinolazepam
•Clorazepate
•Diazepam (t1/2 40 h)
•Flurazepam
•Flunitrazepam
•Lorazepam
•Nitrazepam: tab. 5 mg
•Medazepam
•Midazolam (t1/2 2 h)
•Triazolam (t1/2 3 h)
•Tetrazepam etc.
When GABA binds with
the GABAA-receptor, the
permeability of the central
pore of the receptor to
chloride ions increases
(hyperpolarization) and
decreasis excitability.
Benzodiazepines (BDZs) enhance the effectiveness
of GABA by increasing the frequency of the opening
of the chloride ions. BDZs are agonists at the receptor
and the flumazenil (antagonist) prevents agonists
from binding at the receptor site.
A model of the GABAA
receptor-chloride ion
channel macromole-
cular complex
Basic & Clinical
Pharmacology –
10th Ed. (2007)
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
BDZs enhance GABA-ergic inhibition.
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Advantages of BDZs
BDZs have a high therapeutic index. In hypnotic doses
they do not affect respiration and cardiovascuar
functions. Only in i.v. injection the blood pressure
may fall. BDZs cause less distortion of sleep
architecture. They do not alter disposition of other
drugs by microsomal enzyme induction.
They have lower abuse liability: tolerance is
mild, psycholgical and physical dependence and
withdrawal syndrome are less marked.
A selectve BDZs antagonist flumazenil
(partial agonist of benzodiazepinic receptor)
can be used in case of poisoning.
Chlordiazepoxide Flumazenil
CNS action and classification of BDZs
The action of all BDZs is qualitatively similar, but there
are prominent differences in selectivity and time
course of effect: different members of BDZs are
used for different therapeutic purposes. In contrast
to barbiturates BDZs exert relatively selective
anxiolytic (antianxiety), hypnotic (euhypnotic), muscle
relaxant, and anticonvulsant (antiepileptic) effects.
Anxiolytic effect have all BDZs:
Alprazolam, Bromazepam (Lexotan – tab. 3 mg),
Chlordiazepoxide, Diazepam, Lorazepam,
Мedazepam (daily tranquillisant), Nordiazepam, etc.
Hypnotic (euhypnotic) effect:
Bromazepam, Flurazepam, Flunitrazepam
Nitrazepam, Midazolam, Triazolam, etc.
Anticonvulsive (antiepileptic) BDZs:
Clonazepam, Clorazepate, Diazepam,
Lorazepam, Nitrazepam
Central muscle relaxants:
Diazepam, Tetrazepam
Pharmacokinetics

BDZs are effective after administration

by mouth but enter the circulation at very different
rates that are reflected in the speed of onset of
action, e.g. alprazolam is rapid, oxazepam is slow.
The liver metabolizes them, usually to inactive
metabolites, but some compounds produce
active metabolites with long t1/2 which greatly
extends drug action, e.g. chlordiazepoxide,
clorazepate, and diazepam.
 Clorazepate

Biotransformation of benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Uses
•Benzodiazepines are used for: insomnia;
anxiety; alcohol withdrawal states; muscle spasm
(tetrazepam, diazepam) due to a variety of causes,
including tetanus and cerebral spasticity;
epilepsy (clonazepam, lorazepam, diazepam);
anaesthesia and sedation (diazepam, midazolam,
triazolam) for endoscopies and cardioversion.
•Potent BDZs alprazolam and lorazepam injected
i.m. have an adjuvant role in the management of
acutely psychotic and manic patients.
•The choice of drug as hypnotic and anxiolytic
is determined by their pharmacokinetic properties.
Adverse effects of BDZs
•Common reactions:
Fatigue, drowsiness, ataxia.

•Infrequently reactions:
Constipation, incontinence,
•urinary retention,
•dysarthria, blurred vision,
•diplopia, hypotension,
•nausea, dry mouth, skin rash, tremor.
Tolerance to the anxiolytic effects does
not seem to be a problem.
Studies of subjective sleep quality show
enduring efficacy but about half of
the objective (EEG) studies indicate
decreased effects after 4–8 weeks,
implying that some tolerance develops.
The necessity for dose escalation in sleep
disorders is rare.
Withdrawal of BDZs should be gradual after
as little as 3 weeks’ use but for long-term users
it should be very slow, e.g. about 6–12 weeks. With-
drawal should be slowed if marked symptoms occur
and it may be useful to substitute a long t1/2 drug (e.g.
diazepam) to minimize rapid fluctuations in plasma
concentrations. In difficult cases withdrawal may be
assisted by concomitant use of an antidepressant.
Commonly there is a kind of psychological depend-
ence based on the fact that the treatment works to
reduce patients’ anxiety or sleep disturbance and
therefore they are unwilling to stop. If they do stop,
there can be relapse, where original symptoms return.
BDZs can affect memory
and balance.Hazards with
car driving or operating
any machinery can arise from
amnesia and impaired psychomotor function,
in addition to sleepiness (warn the patient).
Amnesia for events subsequent to administration
occurs with i.v. high doses, for endoscopy, dental
surgery (with local anaesthetic), cardioversion, and
in these situations it can be regarded as a blessing.
Women (1 in 200), may experience sexual fantasies,
including sexual assault, after large doses of BDZs
as used in some dental surgery, and have brought
charges in lawsuits against male staff.
Plainly a court of law has, in the absence of a witness,
great difficulty in deciding whom to believe.
Paradoxical behavior effects and perceptual disorders,
e.g. hallucinations, can occur.
Headache, giddiness, GI upset, skin rashes and
reduced libido can occur too.

The PRC of BDZs is D. BDZs cross the placenta and

can cause fetal cardiac arrhythmia and muscular
hypotonia, suckling hypothermia and respiratory
depression in the newborn.
Interactions
All BDZs potentiate the effects of alcohol
and other central depressants, and all are likely
to exacerbate breathing difficulties where this is
already compromised, e.g. in obstructive sleep
apnoea. BDZs potentiate the action of analgetics too.
The fluoroquinolones block GABAA-receptors and
decrease the action of BDZs.

Overdose. Flumazenil (Anexate®) selectively

reverses benzodiazepine effects and is useful in
diagnosis and in treatment of intoxication with them.
Flumazenil is a competitive partial agonist.
Fluoroquinolones

Adapted from Bennett and Brown (2003)

Azapirones
Buspirone is a selective partial agonsist of presynaptic
5-HT1A-receptors. By stimulating these receptors it
reduces activity of dorsal raphe 5-HT-ergic neurons.
Buspirone relieves mild to moderate generalized
anxiety, but is ineffective in severe cases (panic
reactions and obsessive compulsive disorder).

Sedative H1-blockers
Hydroxyzine is an H1-blocker
with sedative, antiemetic,
antimuscarinic, and spasmolytic
effects. It is effective
in pruritus, and urticaria.
Etifoxine (Stresam®) produces its anxiolytic effects by binding to β2 and
β3 subunits of the GABAA-receptor. It is used in anxiety disorders.
Nonselective beta-blockers
Many symptoms of anxiety (palpitations, rise in blood
pressure, shaking, tremor, GI hurrying)
are due to sympathetic overactivty and these
symptoms reinforce anxiety. Propranolol and other
nonselective beta-blockers cut the vicious cycle and
provide the symptomatic relief. They do not affect
psychologycal symptoms, such as fear, tension and
worry, but are valuable in acutely stessful situations
(examination fear, unaccustomed public appearance).
SSRIs (selective serotonin reuptake inhibitors)
are effective in obsessive compulsive disorder (OCD),
phobias, panic and many types of sever generalized
anxiety disorders.
Treatment of anxiety
Anxiety is a universal phenomenon, but if it is
frequent and persists in a severe form, it may
cause distress and markedly impair performance.
The established drugs for treatment of excessive
anxiety are BDZs, which must be used in the smallest
possible dose. The usual practice is to give ½ to 2/3 of
DD at bed time to ensure good night’s rest; the remain-
ing part is divided in 2 to 3 doses, given at day time.
Though the plasma half-life of many BDZs, used
in anxiety are longer, divided daytime doses are
required to avoid high plasma peaks.
Buspirone is a nonsedating alternative to BDZs for a
less severe form of generalized anxiety.
The SSRI antidepressants
are now being increasingly used in many forms of severe
anxiety disorders. They produce a delayed but often gratifying
response and combined with BDZs. The SSRIs are now
drugs of choice for treatment of social anxiety in which
BDZs though effective, carry abuse potential on long term use.
Patients with arterial hypertension, angina pectoris,
peptic ulcer, ulcerative colitis, irritable bowel,
gastroesophageal reflux, thyrotoxicosis are often given low
doses of BDZs intermittently in addition to specific
therapy, though anxiety may not be a prominent manifestation.