Antipsychotic Drugs

(Neuroleptics )Dr. Saad Badai

University of Baghdad / Al-Kindy College of
Medicine
Department of Pharmacology
Neuroleptics
• The neuroleptic drugs (also called
antipsychotic drugs, or major tranquilizers)
• Are used primarily to treat schizophrenia,
but they are also effective in other
psychotic states, such as manic states with
psychotic symptoms
 Schizophrenia
• Schizophrenia is a particular type of psychosis—that
is, a mental disorder caused by some inherent
dysfunction of the brain. It is characterized by
delusions, hallucinations (often in the form of
voices), and thinking or speech disturbances.
Schizophrenia has a strong genetic component and
probably reflects some fundamental biochemical
abnormality, possibly a dysfunction of the
dopaminergic neurons.
 classification

• First generation of these drugs

is called (typical) included many
drugs some of them were
obsoleted
• Second generation included
many other agents called
(atypical)with fewer side effects
Neuroleptics

• These drugs in schizophrenia reduce positive symptoms (i.e.

paranoia, hallucination, delusions) more than negative symptoms (
i.e. emotional blunting, cognitive deficit, poor socialization).
• Atypical antipsychotics are more effective against negative symptoms
and less toxic
• In 2003 FDA declared that atypical antipsychotic has increased risk of
hyperglycemia and diabetes
 Neuroleptics –mechanism of action
Dopamine receptor–blocking activity in the brain:
• Most of the neuroleptic drugs block dopamine receptors
in the brain and the periphery .
• Five types of dopamine receptors have been identified:
- D1 and D5 receptors activate adenylyl cyclase.
- D2, D3 and D4 receptors inhibit adenylyl cyclase, or
mediate membrane K+ channel opening leading to
neuronal hyperpolarization.
• The neuroleptic drugs bind to these receptors to varying
degrees of affinity.
Neuroleptic receptors action

• D2 receptor blockade correlated with antipsychotic effects

• D3 and D4 receptors blocking has also therapeutic effects.
• Blocking of serotonin receptors has beneficial effects against negative
symptoms.
• Blocking of other receptors like:
- Histamine – sedation
- Muscarinic – anticholinergic effects (e.g. dry mouth, urine retention,
constipation ..)
- α adrenergic receptors - hypotension
•
pharmacokinetics

• Well absorbed and rapid action after iv and im injection

• Slow absorption after oral administration
• Metabolized into active metabolites
• Some of them can be prepared in the form of depot (sustained –
release by using fat as vehicle for the drug), there are advantages of
this preparation which is given once in intervals from 1-4 weeks:
- High percentage of schizophrenia are poor compliant for drug intake
or even swallow oral drug.
- Absence of first pass metabolism which occurs in oral route
- Lower dose
Dopaminergic pathways
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.
The dopamine (DA) hypothesis for schizophrenia
is the basis for rational drug therapy.
- suggest that excessive dopaminergic 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 dopaminergic activity, such as
levodopa (a precursor), amphetamines (releasers of DA),
and apomorphine (a direct dopamine agonist), either
aggravate schizophrenia or produce psychosis de novo in
some patients
The key steps in the synthesis and degradation of DA
and the sites of action of various psychoactive substances
at the dopaminergic synapse
.
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.
 (NE) (5-HT)

Schizophrenia
(DA)

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

Pharmacological Actions

(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:
• Reduce irrational behaviour, agitation and
aggressiveness
• They control psychotic symptomatology. Disturbed
thought and behaviour are gradually normalized
• anxiety is relieved. Hyperactivity, hallucinations,
and delusions are suppressed.
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 chemoreceptor trigger zone .

Almost all neuroleptics, except thioridazine, have antiemetic
effect. However, they are ineffective in motion sickness.
Some of them are used as centrally acting antiemetic like :
- Prochlorperazine (stemitil)
(2) ANS.
- Adrenergic effects :
varying degrees of alpha- adrenergic blocking activity.
- Anticholinergic effects (muscarinic)

(3) Endocrine system.

- increase prolactin release by blocking the inhibitory
action of DA on pituitary gland. This may result
in galactorrhea and gynecomastia.
- reduce gonadotrophins, ACTH, GH and ADH secretion.
Nonpsychiatric indications:
1. antiemetic effect: 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). e.g. prochlorperazine
(stemitil)
2. antihistamine effects: some Phenothiazines
have H1-receptor-blocking action and used for
relief of pruritus e.g promethazine which also
used as preoperative sedatives.
3. droperidol is used in combination with an opioid,
fentanyl, in neurolept-anaesthesia (-analgesia).
Adverse reactions –
A. behavioral effects:
The older typical antipsychotics have serious
side effects made Many patients stop taking
these drugs
1. “pseudodepression” that may be due to
drug-induced akinesia usually
responds to treatment with antiparkinsonian
drugs.
2. Toxic-confusional states may occur
with very high doses of drugs that have
prominent antimuscarinic actions.
B. Neurologic effects:
1 - Extrapyramidal reactions occurring early during
treatment with older agents include typical
Parkinsonian symptoms like akathisia (uncontrollable
restlessness), and acute dystonic reactions
(spastic retrocollis or torticollis). These symptoms can
be treated, with:
- antimuscarinic, e.g. procyclidin
- Anti histamine : e.g. diphenhydramine
- Antiparkinson agents : rarely needed like
amantadine.

- 2. tardive dyskinesia: Persistent involuntary

- movements of mouth, tongue or face
c. Autonomic nervous system effects
- Anticholinergic (anti-muscarinic)
(atropine-like) adverse effects:
- urinary retention
- dry mouth
- midriasis.
- Anti-adrenergic (Alpha-blockade):
- Orthostatic hypotension
- Impaired ejaculation (should be managed by
switching to drugs with less marked
adrenoceptor-blocking actions).
D. Ocular complications
- Chlorpromazine therapy :causes corneal and
lens opacity : Deposits in the anterior portions of
the eye (cornea and lens). They are a common
complication of chlorpromazine chronic use.

- Thioridazine is the only antipsychotic

drug that causes retinal deposits,

.
E. Metabolic and endocrine side effects
- Weight gain clozapine and olanzapine
- Hyperglycemia
- Hyperprolactinemia: this increase in prolactin
results in the following side effects:
- In women : amenorrhea – galactorrhea
syndrome and infertility.
- in men: loss of libido, impotence, and infertility
may result.
F. Toxic or allergic reactions
g. Neuroleptic malignant syndrome
This life-threatening drug reaction 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.
Treatment :
- antiparkinsonian drugs
- Central 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.
Specific drugs

Phenothiazines:
Chlorpromazine (largactil):
- Wide range of action (different receptors)
- Also used in treatment of hiccup
Thioridazine :
- Low EP symptoms
- Retinal pigmentation
Butryphenones:
- Haloperidol
- Droperidol
- High incidence of EP symptoms
 Azepines :
- Clozapine
- Olanzepine

Benzhexoles (atypical agents):

- Risperidone
- Used for long term therapy
- Low EP symptoms
- Act on 5-HT receptors
CNS effects of Antipsychotics
CNS effects